[{"id":1385,"doi":"10.1080/09513590.2026.2757301","pmid":"42960716","nct_ids":"[]","title":"Metabolic, hormonal, and reproductive effects of GLP-1 receptor agonizts in hyperandrogenic insulin-resistant women: a systematic review","authors":"[\"Sherif Mohamed M\", \"Farrag A\", \"Bachkangi P\"]","journal":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","publication_date":"2026-12-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[CONTEXT] Hyperandrogenic insulin-resistant states, most commonly polycystic ovary syndrome (PCOS) and severe phenotypes such as HAIR-AN syndrome, are characterized by metabolic dysfunction, androgen excess, and reproductive disturbance. Insulin resistance is a central pathogenic driver and therapeutic target. [OBJECTIVE] To systematically evaluate the effects of glucagon-like peptide-1 (GLP-1) receptor agonizts on metabolic, hormonal, and reproductive outcomes in adult women with hyperandrogenic insulin-resistant states. Data Sources and Study Selection: A systematic search identified randomized controlled trials, observational studies, and case series evaluating GLP-1 receptor agonizts in PCOS and HAIR-AN syndrome, reflecting the heterogeneity of the current evidence base.Data extraction and synthesis Outcomes were synthesized across metabolic (anthropometric and glycaemic), hormonal, reproductive, dermatologic, and safety domains, accounting for heterogeneity in interventions and study designs. [RESULTS] Metabolic responses appeared more consistent and robust than endocrine outcomes. Reproductive outcomes such as menstrual regularity were variably reported and showed inconsistent improvement across studies, limiting firm conclusions regarding fertility-related benefit. Evidence in severe phenotypes remains limited but suggestive of clinical benefit. [CONCLUSIONS] GLP-1 receptor agonizts are a promising adjunctive therapy in hyperandrogenic insulin-resistant states, with the strongest evidence for metabolic improvement. Reproductive and endocrine outcomes remain less consistent, likely reflecting heterogeneity in study design, populations, and outcome reporting. Further high-quality, phenotype-specific trials are required.","url":"https://pubmed.ncbi.nlm.nih.gov/42960716/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"endocrine\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":"metabolic, hormonal, and reproductive outcomes","endpoints":null,"effect_estimate":"Metabolic responses more consistent and robust than endocrine outcomes; menstrual regularity inconsistently improved; no numeric estimate","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"women only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"hyperandrogenic insulin-resistant states (PCOS, HAIR-AN syndrome)\", \"sample_size\": null, \"inclusion_exclusion\": \"adult women with hyperandrogenic insulin-resistant states (PCOS, HAIR-AN syndrome); randomised trials, observational studies and case series eligible\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review covers adult women with hyperandrogenic insulin-resistant states, most commonly polycystic ovary syndrome and the severe HAIR-AN phenotype, and reports no BMI, diabetes or age data; IN-063 puts polycystic ovary syndrome on the INDIRECT side.","mediation":"possibly","mediation_notes":"possibly, by the no-data default: anthropometric and glycaemic outcomes are among those synthesised, but the review reports no weight change, no HbA1c and no mediation analysis, so improvement in hormonal, reproductive and dermatologic outcomes is not separated from the metabolic change that accompanied it.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no pooled estimate or CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review whose synthesis is qualitative. No pooled estimate, confidence interval or p value is reported, so it adds no new primary outcome data (EVIDENCE-MODEL section 3, IN-062).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A qualitative systematic review with no pooled estimate, drawing on randomised trials, observational studies and case series; the authors note heterogeneity in study design, populations and outcome reporting, inconsistent reporting of reproductive outcomes, and limited evidence in severe phenotypes.","plain_summary":"This systematic review gathered randomised trials, observational studies and case series of GLP-1 receptor agonists in adult women with hyperandrogenic insulin-resistant states, most commonly polycystic ovary syndrome and severe phenotypes such as HAIR-AN syndrome. Metabolic results, meaning weight and blood-sugar measures, were described as more consistent and robust than hormonal ones, while reproductive outcomes such as menstrual regularity improved inconsistently across studies and evidence in the severe phenotypes remained limited. The synthesis is qualitative: no pooled estimate and no numbers are given, so the size of any benefit is unknown.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":851,"doi":"10.1016/j.jhep.2026.08.028","pmid":"42805503","nct_ids":"[]","title":"EASL-EASD-EASO Guidance for the Use of Resmetirom and Semaglutide as MASH-Targeted Therapy","authors":"[\"European Association for the Study of the Liver (EASL). Electronic address: easloffice@easloffice.eu\", \"European Association for the Study of Diabetes (EASD)\", \"European Association for the Study of Obesity (EASO)\"]","journal":"Journal of hepatology","publication_date":"2026-12-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Adults with metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are at risk for cardiometabolic complications and major adverse liver-related outcomes (MALO), including cirrhosis, cancer, and liver transplantation. Non-invasive tests (NIT) for hepatic fibrosis, including vibration-controlled transient elastography (VCTE), magnetic resonance elastography (MRE), or enhanced liver fibrosis (ELF) score, can replace liver biopsy to identify high risk for MALO (e.g. VCTE 10-20 kPa, MRE 3.1-5.0 kPa, or ELF 9.8-11.3), in which pharmacotherapy may be considered. Following approval by regulatory agencies, this joint EASL-EASD-EASO guidance provides updated recommendations for the use of resmetirom (80mg/100mg po) and semaglutide (2.4 mg sc weekly) in MASH, covering treatment candidate selection, treatment initiation, monitoring, and discontinuation. Pharmacotherapy is recommended for adults with non-cirrhotic MASH and fibrosis stages 2-3 (based on NITs or biopsy), alongside structured lifestyle intervention and optimized comorbidity management. Therapy selection should be individualized according to preferences, potential risks, and cardio-renal-metabolic profile, including presence of obesity, type 2 diabetes (T2D), cardiovascular, and chronic kidney disease. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), may be preferred in adults with obesity or T2D as well as with established cardiovascular (CV) disease or high CV risk because of its cardiometabolic benefits, whereas resmetirom may be prioritized in individuals without obesity or those already receiving or intolerant to GLP-1RAs. Additional recommendations include structured safety and efficacy monitoring such as nutritional and sarcopenia assessment during semaglutide or use of fibrosis NITs for longitudinal response criteria. Ongoing studies are evaluating long-term effectiveness of both agents to reduce MALO. In adults with MASH cirrhosis, resmetirom or semaglutide appear safe but should not be used as MASH-targeted treatment, until further data establish liver-related benefits.","url":"https://pubmed.ncbi.nlm.nih.gov/42805503/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of Interest Will be provided by the EASL CPG office","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"guideline","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg sc weekly\", \"route\": \"subcutaneous\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"muscle\", \"liver\", \"cancer\", \"adverse_effects\", \"nutrition\"]","outcome_type":"none","primary_outcome":"recommendations on candidate selection, initiation, monitoring and discontinuation of resmetirom and semaglutide in MASH","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (semaglutide may be preferred in adults with obesity; resmetirom in those without)\", \"diabetes_status\": \"mixed\", \"cvd_status\": \"mixed\", \"ckd_status\": \"mixed\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"non-cirrhotic MASH with fibrosis stages 2-3\", \"sample_size\": null, \"inclusion_exclusion\": \"adults with non-cirrhotic MASH and fibrosis stages 2-3 by non-invasive tests or biopsy\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: guidance for adults with MASH and liver fibrosis stages 2-3; no study population is described, and the condition is one the target population does not have.","mediation":"not_applicable","mediation_notes":"Not applicable: a guidance document with no outcome data.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Guideline / practice guidance\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI reported; guidance document\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a joint society guideline without new primary data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The conflicts statement says only that declarations will be provided by the EASL CPG office; none are listed.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Advises nutritional and sarcopenia assessment during semaglutide; in MASH cirrhosis resmetirom or semaglutide appear safe but should not be used as MASH-targeted treatment.","limitations":"Consensus guidance with no new primary data; the abstract notes that ongoing studies are still evaluating long-term effects on major adverse liver-related outcomes.","plain_summary":"European liver, diabetes and obesity societies issued joint guidance on using semaglutide (2.4 mg weekly by injection) or resmetirom in adults with MASH, an inflammatory fatty-liver disease. Drug treatment is recommended for non-cirrhotic MASH with fibrosis stages 2-3, with semaglutide possibly preferred for people with obesity, type 2 diabetes or cardiovascular disease. In MASH cirrhosis neither drug should be used as MASH-targeted treatment until liver benefits are shown. This is a recommendation document and reports no new study results.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":553,"doi":"10.1016/j.metop.2026.100495","pmid":"42750798","nct_ids":"[]","title":"Therapeutic modulation of the gut-brain axis in alcohol use disorder: A systematic review","authors":"[\"Bhandari P\", \"Sideeg A\", \"Elfeki M\", \"Xie C\", \"Singal AK\"]","journal":"Metabolism open","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Alcohol Use Disorder (AUD) involves gut-brain axis dysfunction. Modulating microbiota offers a promising therapeutic strategy. [METHODS] Clinical trials on fecal microbiota transplant (FMT), prebiotics (inulin), probiotics, and neurohormonal agents like glucagon-like peptide-1 (GLP-1) and ghrelin receptor antagonists) were identified through PubMed, Google Scholar, Scopus, and ClinicalTrials.gov (until 07/31/2026). Of the eleven included studies, five identified gut dysbiosis as a common feature in individuals with AUD. [RESULTS] Gut dysbiosis-directed interventions were associated with benefits on behavioral (alcohol craving, consumption, relapse), psychological (anxiety, sociability), and physiological (MELD score, AST/ALT ratio, systemic inflammation) outcomes. However, the magnitude and consistency of these effects varied among studies. Three studies specifically involved AUD patients with alcohol-associated liver disease (ALD), while the others focused on AUD. In another study, Ghrelin, which was investigated as a neurohormonal target, emerged as a potential anti-inflammatory agent. However, ghrelin receptor antagonism in the presence of alcohol did not alter systemic inflammation. Of five trials using GLP-1 receptor agonists, three showed a reduction in alcohol use, but the other two, although directionally consistent, did not reach statistically significant effects. The current evidence supports the gut-brain axis as a dual therapeutic target, offering potential benefits for both AUD and ALD. Microbial therapies (FMT, probiotics, prebiotics) show some benefits in AUD, albeit studies are small. Hormonal targets such as ghrelin and GLP-1 receptors are mechanistically relevant. Data on ghrelin are limited. Data on GLP-1 receptor agonists are directionally consistent but not statistically robust. Large-scale, controlled trials are needed to validate and optimize the integration of this approach into AUD treatment strategies.","url":"https://pubmed.ncbi.nlm.nih.gov/42750798/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AKS serves as a consultant on the SBIR grant for Pleiogenix pharma; served as DSMB member for phase-2b DUR-928 trial for Durect pharma; serves on advisory board for Orphalan and Disc Medicine; Speaks and writes for Medscape, CLD Foundation, Expert Perspectives, Gastro Endo News, Dynamed, Medical Education Speakers Network, Up-to-Date, Madrigal Pharma, Practice Point. All other authors declare no conflicts of interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"addiction\", \"psychiatric\"]","outcome_type":"mixed","primary_outcome":"alcohol use (craving, consumption, relapse) plus psychological and physiological (liver and inflammatory) measures","endpoints":null,"effect_estimate":"of five GLP-1 receptor agonist trials, three showed reduced alcohol use and two were directionally consistent but not statistically significant; no pooled estimate","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"alcohol use disorder (three studies in people with alcohol-associated liver disease)\", \"sample_size\": null, \"inclusion_exclusion\": \"clinical trials of fecal microbiota transplant, prebiotics, probiotics and neurohormonal agents (GLP-1, ghrelin receptor antagonists) in alcohol use disorder\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: trials enrolled people selected for alcohol use disorder (some with alcohol-associated liver disease) rather than for obesity or diabetes; age, BMI and diabetes status are not reported.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight or metabolic change in the GLP-1 trials, so these are not separated from a drug effect (the evidence model's default).","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"no pooled estimate or CI reported; eleven included studies; five GLP-1 receptor agonist trials described\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a qualitative systematic review without pooled estimates; the GLP-1 portion is five trials the authors call not statistically robust. The alternative is LOW.","funding_source":"NIGMS NIH HHS; NIAAA NIH HHS","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"One author (AKS) reports consulting, DSMB, advisory board and speaking or writing roles with several companies and medical-education outlets; the other authors declare none.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A qualitative review of few, small studies across mixed interventions, with effects that varied in size and consistency; the authors describe the GLP-1 receptor agonist data as directionally consistent but not statistically robust.","plain_summary":"This systematic review of eleven included studies looked at treatments aimed at the gut-brain link in alcohol use disorder, and describes five trials of GLP-1 receptor agonists. Three of the five GLP-1 trials showed less drinking, while the other two pointed the same way without reaching statistical significance. The authors judge the GLP-1 data directionally consistent but not statistically robust and call for large controlled trials.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":645,"doi":"10.1016/j.xnsj.2026.100938","pmid":"42740823","nct_ids":"[]","title":"Do glucagon-like peptide-1 receptor agonists influence cervical fusion outcomes? A systematic review and meta-analysis","authors":"[\"Alves MLM\", \"da Silva Moura Costa AO\", \"do Vale Moura Costa J\", \"Garrido GA\", \"Gonzalez JVP\", \"Ferreira JSN\", \"de Andrada Pereira B\"]","journal":"North American Spine Society journal","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in patients with obesity and type 2 diabetes, but their procedure-specific effects in cervical fusion remain unclear. [METHODS] A systematic review and meta-analysis following PRISMA 2020 and MOOSE, prospectively registered in PROSPERO, searched PubMed, Embase, and Web of Science through April 28, 2026. Comparative studies evaluating perioperative GLP-1RA use in adults undergoing cervical fusion were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Random-effects meta-analyses were performed in Review Manager Web (RevMan Web). Certainty of evidence was assessed using the GRADE approach for clinically important outcomes. [RESULTS] Six propensity score-matched retrospective cohort studies involving 17,310 patients were included. In the primary analyses, GLP-1RA use was not associated with significant differences in pseudarthrosis (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.33-2.89; p = .96), dysphagia (OR 0.89, 95% CI 0.38-2.05; p = .68), hospital readmission (OR 0.67, 95% CI 0.39-1.17; p = .12), or device failure (OR 0.83, 95% CI 0.44-1.56; p = .41). Secondary outcomes were also not significantly different between groups. [CONCLUSIONS] Perioperative GLP-1RA use was not associated with a consistent pattern of worse postoperative outcomes after cervical fusion. Prospective, procedure-specific studies with standardized exposure and outcome definitions are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42740823/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"perioperative\"]","outcome_type":"mixed","primary_outcome":"pseudarthrosis, dysphagia, hospital readmission and device failure after cervical fusion","endpoints":null,"effect_estimate":"no significant differences: pseudarthrosis OR 0.98, dysphagia OR 0.89, hospital readmission OR 0.67, device failure OR 0.83; secondary outcomes also not significantly different","confidence_interval":"95% confidence interval [CI] 0.33-2.89 (pseudarthrosis)","p_value":"p = .96 (pseudarthrosis)","sample_size":17310,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"cervical fusion surgery\", \"sample_size\": 17310, \"inclusion_exclusion\": \"comparative studies of perioperative GLP-1RA use in adults undergoing cervical fusion\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: adults having cervical fusion; the age, BMI and diabetes status of pooled patients are not reported in the abstract.","mediation":"unlikely","mediation_notes":"Unlikely: no significant differences were found, so there is no effect to attribute to weight change.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 17310, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI] 0.33-2.89 (pseudarthrosis)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: pooled observational (retrospective propensity-matched) studies only, with wide CIs; the authors applied GRADE but its ratings are not given in the abstract.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no known competing financial interests or personal relationships.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No significant differences in pseudarthrosis, dysphagia, readmission or device failure; no consistent pattern of worse postoperative outcomes.","limitations":"All six pooled studies are retrospective cohorts, so results are associations open to confounding; the authors call for prospective, procedure-specific studies with standardized exposure and outcome definitions.","plain_summary":"This meta-analysis pooled six retrospective propensity-matched studies covering 17,310 adults having neck (cervical) fusion surgery. Using a GLP-1 drug around the time of surgery was not linked to significant differences in failed fusion (OR 0.98), swallowing problems (OR 0.89), readmission (OR 0.67) or device failure (OR 0.83), nor in secondary outcomes. Because all the studies were observational, this shows no clear association rather than proof of safety.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":867,"doi":"10.1016/j.obpill.2026.100335","pmid":"42820241","nct_ids":"[]","title":"Fat and lean mass changes during incretin-based therapy with structured exercise and nutritional support: A retrospective real-world pilot study","authors":"[\"Kucuk Yetgin M\", \"Gletsu-Miller N\", \"Chapman RR\", \"Gelber E\", \"Snyder J\", \"Gregg D\", \"Nabhan D\"]","journal":"Obesity pillars","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Incretin-based therapies are highly effective for weight reduction, but changes in lean mass during treatment remain a clinical concern. This study evaluated changes in fat mass and lean mass in individuals receiving structured exercise and nutritional support during incretin-based therapies. [METHODS] In this single-center retrospective observational chart-review study, 11 adults who underwent 9-12 months of incretin-based therapy and were offered a program providing supervised exercise and individualized nutritional support were analyzed. No control group was included. Treatments included glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonists. Body composition was assessed using dual-energy X-ray absorptiometry (DXA). Data were assessed for parametric assumptions, and pre- and post-intervention comparisons were performed using paired-samples t tests. [RESULTS] Significant reductions were observed in body weight (mean change: -4.99 kg [95% CI: -7.65 to -2.34]; p = 0.002) and fat mass (-4.37 kg [95% CI: 6.36 to -2.39]; p < 0.001), corresponding to a mean total weight reduction of 4.71% and a mean fat mass reduction of 11.06%, respectively. Lean mass did not change significantly (-0.62 kg [95% CI: 2.20 - 0.95]; p = 0.397). At the aggregate cohort-level, weight reduction composition analysis indicated that 87.58% of total weight reduction was attributable to fat mass, and 12.42% to lean mass. [CONCLUSION] Incretin-based therapy delivered within a structured exercise and nutritional support program was associated with fat-dominant weight reduction without a statistically significant change in lean mass. These findings are hypothesis-generating and warrant confirmation in adequately powered prospective controlled studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42820241/","source_name":"pubmed","source_tier":1,"coi_statement":"Eitan Gelber (Director of Assessment & Training), John Snyder (Senior Physical Performance Specialist & Sports Scientist), Donny Gregg (Senior Exercise Physiologist), and Dustin Nabhan (Chief Scientific Advisor and Consultant Sports Scientist) are affiliated with Apeiron Life, California where the study was conducted. This affiliation is declared as a potential conflict of interest.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"case_series","drugs":"[\"glp-1 receptor agonists\", \"gip/glp-1 receptor co-agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"none (no control group; pre-post comparison)\", \"treatment_duration\": \"9-12 months\"}","domains":"[\"lean_mass\", \"body_composition\", \"nutrition\"]","outcome_type":"intermediate","primary_outcome":"change in fat mass and lean mass by DXA","endpoints":null,"effect_estimate":"body weight -4.99 kg and fat mass -4.37 kg (both significant); lean mass -0.62 kg, not significant (p = 0.397); 87.58% of weight reduction attributed to fat mass","confidence_interval":"95% CI: -7.65 to -2.34 (body weight)","p_value":"p = 0.002 (body weight); p < 0.001 (fat mass); p = 0.397 (lean mass)","sample_size":11,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"adults on incretin-based therapy offered a supervised exercise and nutrition program\", \"sample_size\": 11, \"inclusion_exclusion\": \"adults with 9-12 months of incretin-based therapy offered supervised exercise and nutritional support at one centre\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: 11 adults on incretin therapy at one centre; age, BMI and diabetes status are not reported in the abstract.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is body-composition change during weight loss itself; the unseparated confounder is the co-delivered exercise and nutrition program, not weight change.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Case series\", \"sample_size\": 11, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"none (no control group; pre-post comparison)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI: -7.65 to -2.34 (body weight)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: single-centre retrospective chart review of 11 participants without a control group; the authors call it hypothesis-generating.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Four authors are affiliated with Apeiron Life, California, where the study was conducted, and declare this as a potential conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Single-centre retrospective chart review of 11 adults with no control group; the drugs cannot be separated from the exercise and nutrition program, and the authors call the findings hypothesis-generating.","plain_summary":"This chart review followed 11 adults at one centre who took GLP-1 or GIP/GLP-1 drugs for 9-12 months alongside supervised exercise and nutrition support. Body weight fell by 4.99 kg and fat mass by 4.37 kg on average, while lean mass did not change significantly (-0.62 kg). With no comparison group and so few people, the drugs cannot be separated from the exercise and nutrition program, and the authors call the findings hypothesis-generating.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":895,"doi":"10.1007/s40200-026-02089-x","pmid":"42802751","nct_ids":"[]","title":"Incretin-based injectable strategies versus intensified insulin for treatment intensification and simplification in type 2 diabetes: a systematic review and meta-analysis","authors":"[\"Mahmood T\", \"Myrtziou I\", \"Kanakis I\"]","journal":"Journal of diabetes and metabolic disorders","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Prandial insulin intensification in Type 2 Diabetes (T2D) improves glycaemia but increases regimen complexity, weight gain, and hypoglycaemia risk. Our aim was to evaluate if Incretin-based injectable strategies offer a lower-burden alternative across intensification and simplification pathways. [METHODS] PubMed/MEDLINE, CENTRAL, Scopus, and ClinicalTrials.gov were searched to November 2025 for Randomised Controlled Trials (RCT) comparing incretin-based injectable regimens with intensified insulin strategies in adults with T2D. Primary outcomes were HbA1c change and trial-defined hypoglycaemia. Secondary outcomes included body weight, HbA1c target achievement, severe hypoglycaemia, insulin dose, gastrointestinal adverse events, and adverse-event withdrawals. Random or fixed-effects models were applied where appropriate, with subgroup analyses by regimen and by intensification versus simplification design. [RESULTS] Eighteen RCTs were included. Incretin-based regimens significantly reduced HbA1c as compared to intensified insulin (MD -0.19%, 95% CI: -0.34 to -0.05, P = 0.01) and also increased HbA1c target achievement (RR 1.27, 95% CI: 1.05 to 1.54, P = 0.01). Effects differed by regimen and design: tirzepatide produced the largest HbA1c reduction, fixed-ratio or once-weekly combination regimens showed similar HbA1c efficacy, and simplification trials generally preserved glycaemic control. Incretin-based regimens decreased trial-defined hypoglycaemia (RR 0.48, 95% CI: 0.35 to 0.66, P = 0.00001), severe hypoglycaemia (RR 0.32, 95% CI: 0.19 to 0.51, P = 0.00001), and body weight (MD -4.65 kg, 95% CI: -5.85 to -3.44, P = 0.00001). Gastrointestinal adverse events were more frequent with incretin-based regimens. [CONCLUSION] Incretin-based injectable strategies are a favourable alternative to intensified insulin when hypoglycaemia, weight gain, and treatment burden are priorities, but benefits differ between intensification and simplification settings. [SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02089-x.","url":"https://pubmed.ncbi.nlm.nih.gov/42802751/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interestsThe authors declare no competing interests.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"intensified insulin strategies\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":"HbA1c change and trial-defined hypoglycaemia","endpoints":null,"effect_estimate":"HbA1c MD -0.19%; HbA1c target achievement RR 1.27; trial-defined hypoglycaemia RR 0.48; severe hypoglycaemia RR 0.32; body weight MD -4.65 kg; gastrointestinal adverse events more frequent with incretin regimens","confidence_interval":"95% CI: -0.34 to -0.05 (HbA1c)","p_value":"P = 0.01 (HbA1c)","sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes needing treatment intensification or simplification\", \"sample_size\": null, \"inclusion_exclusion\": \"RCTs in adults with T2D comparing incretin-based injectable regimens with intensified insulin strategies\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all included trials enrolled adults with type 2 diabetes needing insulin intensification or simplification.","mediation":"not_applicable","mediation_notes":"Not applicable: the reported outcomes (HbA1c, hypoglycaemia, body weight) are metabolic measures themselves.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"intensified insulin strategies\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -0.34 to -0.05 (HbA1c)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis of randomised trials, but the primary outcome is a biomarker, effects varied by regimen and design, and the abstract does not report trial quality.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Less trial-defined hypoglycaemia (RR 0.48) and severe hypoglycaemia (RR 0.32) with incretin regimens; gastrointestinal adverse events more frequent.","limitations":"Effects differed by regimen and between intensification and simplification designs, the pooled HbA1c difference is small, and the abstract gives no trial-quality or heterogeneity results or participant total; the population is limited to type 2 diabetes.","plain_summary":"This meta-analysis of eighteen randomised trials in adults with type 2 diabetes compared incretin-based injections, including tirzepatide, with intensified insulin. Incretin regimens lowered HbA1c slightly more (mean difference -0.19%), cut trial-defined hypoglycaemia (RR 0.48) and lowered body weight (mean difference -4.65 kg), but gastrointestinal side effects were more frequent. Effects differed by regimen and between trials that intensified and trials that simplified treatment.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":984,"doi":"10.1016/j.obpill.2026.100333","pmid":"42831032","nct_ids":"[\"NCT04184622\"]","title":"Evaluation of clinical relevance of weight nadirs and weight regain during 3 years of treatment with tirzepatide in participants with obesity or overweight and prediabetes","authors":"[\"Aronne LJ\", \"Vincent RP\", \"Klein KR\", \"Brumm JF\", \"Jouravskaya I\", \"Cao D\", \"Dimitriadis GK\", \"Dunn JP\"]","journal":"Obesity pillars","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] For adults with obesity, fluctuations in body weight are expected to occur during weight management. Weight nadirs, which can become a point of focus for people living with obesity, are often hard to maintain. This study aimed to investigate the not well-defined clinical relevance of weight nadir, especially during long-term treatment with an obesity medication. [METHODS] This was a post hoc analysis of the phase 3, double-blind, randomized, placebo-controlled SURMOUNT-1 3-year clinical trial in participants with obesity or overweight and at least one weight-related complication. The analysis included participants who were tirzepatide-adherent (≥75% of doses received) with obesity, or overweight, and prediabetes at randomization and had ≥5% weight reduction from baseline at time of weight nadir. Weight regain analyses from weight nadir to Week 176 included mean percent change, and participants were grouped as having <5%, 5% to <10%, and ≥10% weight regain. [RESULTS] In this post hoc analysis, the mean weight regain from nadir weight to Week 176 was 3.8 kg, 4.4 kg, and 3.7 kg for those treated with tirzepatide 5 mg, 10 mg, and 15 mg, respectively. For the pooled tirzepatide doses, 70% of participants had <5% weight regain, 22% of participants had 5 to <10% weight regain, and 8% of participants had ≥10% weight regain. The median percent of weight reduction maintenance from time of weight nadir to Week 176 was 94.8%, 69.9%, and 44.3%, for <5%, 5-<10%, and ≥10%, respectively. While at baseline 94% of tirzepatide-treated participants had high waist-to-height ratio (WHtR) (>0.59), at week 176 this had reduced to 45%, 59%, and 68% in the <5%, 5% to <10%, and ≥10% weight regain groups, respectively. At Week 176, conversion from prediabetes to normoglycemia occurred in over 90% of tirzepatide-treated participants regardless of weight regain. [CONCLUSION] These findings suggest that most tirzepatide-treated participants with baseline prediabetes in the SURMOUNT-1 3-year study had limited weight regain after reaching weight nadir and sustained improvements in glycemia (SURMOUNT-1 ClinicalTrials.gov identifier: NCT04184622.). [CLINICAL RELEVANCE] In the current study, 92% of prediabetes participants treated with tirzepatide in the SURMOUNT-1 3-year study had a stable weight journey. Their limited weight regain from weight nadir appears not to be clinically meaningful, as improvements in cardiometabolic risk parameters were largely maintained.","url":"https://pubmed.ncbi.nlm.nih.gov/42831032/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"5 mg, 10 mg, and 15 mg\", \"comparator\": \"none in this analysis (tirzepatide-treated participants only; the parent trial was placebo-controlled)\", \"route\": null, \"treatment_duration\": \"3 years\"}","domains":"[\"metabolic\", \"discontinuation\"]","outcome_type":"surrogate","primary_outcome":"weight regain from weight nadir to Week 176","endpoints":null,"effect_estimate":"mean regain from nadir 3.8 kg, 4.4 kg and 3.7 kg (5, 10, 15 mg); pooled doses: 70% <5% regain, 22% 5 to <10%, 8% ≥10%; over 90% converted from prediabetes to normoglycemia regardless of regain","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":"to Week 176","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (obesity or overweight, with at least one weight-related complication)\", \"diabetes_status\": \"not reported in abstract (prediabetes required for this analysis)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity or overweight with prediabetes\", \"sample_size\": null, \"inclusion_exclusion\": \"tirzepatide-adherent (≥75% of doses received), obesity or overweight with prediabetes at randomization, ≥5% weight reduction from baseline at nadir\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity or overweight with a weight-related complication, and prediabetes; the analysis is restricted to adherent participants with ≥5% weight reduction.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcomes are weight nadir and weight regain themselves, so whether weight loss explains them is not a separate question; no mediation analysis was reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"none in this analysis (tirzepatide-treated participants only; the parent trial was placebo-controlled)\", \"follow_up_duration\": \"to Week 176\", \"outcome_type\": \"surrogate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; analysed number not stated\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a post hoc, descriptive subset of one RCT, selected on adherence and response, with no comparator, no CIs and no analysed number in the abstract.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A post hoc, descriptive analysis restricted to adherent tirzepatide participants with at least 5% weight reduction, so randomisation does not protect it and there is no placebo comparison; the analysed number is not given.","plain_summary":"This post hoc analysis of the SURMOUNT-1 trial looked only at people with obesity or overweight and prediabetes who stayed on tirzepatide and lost at least 5% of their weight. After their lowest weight, 70% had regained less than 5% by Week 176, 22% had regained 5 to <10% and 8% had regained 10% or more; over 90% moved from prediabetes to normal blood sugar regardless of regain. There is no placebo comparison in this analysis, so it describes treated responders rather than a drug effect.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1067,"doi":"10.1016/j.xnsj.2026.100942","pmid":"42871273","nct_ids":"[]","title":"GLP-1 receptor agonists in elective spine surgery: a systematic review of fusion outcomes, perioperative safety, and procedure-specific risk","authors":"[\"Ferraz VR\", \"Dawoud B\", \"Mercier PA\", \"Mattei TA\"]","journal":"North American Spine Society journal","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used in patients with obesity and type 2 diabetes mellitus undergoing elective spine surgery. Although these agents may improve metabolic risk profiles, their associations with spinal fusion, perioperative complications, and procedure-specific outcomes remain incompletely defined. [METHODS] We conducted a systematic review and qualitative synthesis of comparative clinical studies evaluating adults undergoing spine surgery with documented preoperative or perioperative GLP-1 RA exposure. Eligible studies assessed fusion-related outcomes, perioperative medical complications, surgical site infection, readmission, length of stay, healthcare utilization or costs, and musculoskeletal outcomes. The review was conducted in accordance with PRISMA 2020 principles, with eligibility criteria defined using a PICOS framework. [RESULTS] Twenty-three studies were included, consisting predominantly of retrospective cohort studies and propensity-matched database analyses. Lumbar fusion studies generally reported favorable or neutral associations between GLP-1 RA exposure and pseudarthrosis, infection, readmission, and healthcare utilization, although some transforaminal lumbar interbody fusion cohorts reported adverse associations. Cervical fusion outcomes were more heterogeneous and appeared to vary by surgical approach. Anterior cervical fusion studies generally reported neutral or favorable outcomes, whereas posterior cervical fusion studies yielded conflicting findings. Gastrointestinal safety data were sparse, no included study reported postoperative pancreatitis, and preoperative treatment duration and longitudinal BMI or weight change were incompletely characterized. [CONCLUSIONS] Current evidence suggests that GLP-1 RA exposure is associated with procedure-specific differences in outcomes after elective spine surgery. Because the available evidence is predominantly observational, these findings should be interpreted as associations rather than evidence of direct causal benefit or harm. Perioperative GLP-1 RA management should be individualized according to surgical procedure, metabolic status, gastrointestinal symptoms, renal and hydration risk, and nutritional or sarcopenia-related vulnerability.","url":"https://pubmed.ncbi.nlm.nih.gov/42871273/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"kidney\", \"muscle\", \"immune\", \"adverse_effects\", \"nutrition\", \"gastrointestinal\", \"perioperative\"]","outcome_type":"mixed","primary_outcome":"fusion outcomes, perioperative complications, surgical site infection, readmission, length of stay and costs after elective spine surgery","endpoints":null,"effect_estimate":"no pooled estimate; lumbar fusion studies mostly favourable or neutral, some transforaminal lumbar interbody fusion cohorts adverse; cervical results heterogeneous, with posterior cervical fusion conflicting; no included study reported postoperative pancreatitis","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"elective spine surgery\", \"sample_size\": null, \"inclusion_exclusion\": \"comparative studies of adults having spine surgery with documented preoperative or perioperative GLP-1 RA exposure\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: adults having elective spine surgery; the age, BMI and diabetes status of included patients are not reported in the abstract.","mediation":"possibly","mediation_notes":"Possibly: the authors note that longitudinal BMI or weight change was incompletely characterized across the included studies, so weight change is not separated from a drug effect.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no pooled estimate or CI reported; qualitative synthesis of twenty-three studies\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a qualitative systematic review with no pooled estimate or new primary data, built mostly on retrospective cohorts; the alternative is LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors certify no conflict of interest with any financial organization regarding the material discussed.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Some transforaminal lumbar interbody fusion and posterior cervical fusion cohorts reported adverse or conflicting associations; gastrointestinal safety data were sparse and no included study reported postoperative pancreatitis.","limitations":"The evidence is predominantly observational and should be read as association; preoperative treatment duration and BMI or weight change were incompletely characterized, and the synthesis is qualitative without pooled estimates.","plain_summary":"This systematic review gathered twenty-three studies, mostly retrospective database analyses, of adults exposed to GLP-1 drugs around elective spine surgery. Results depended on the operation: lower-back (lumbar) fusion studies were generally linked to neutral or favourable outcomes, though some transforaminal lumbar interbody fusion cohorts showed adverse associations, and neck (cervical) fusion results were mixed. The findings are associations from observational studies, not proof that the drugs help or harm.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1079,"doi":"10.1016/j.jsea.2026.100088","pmid":"42892915","nct_ids":"[]","title":"Evaluating the safety of glucagon-like peptide-1 agonist use in non-diabetic overweight patients undergoing shoulder arthroplasty","authors":"[\"Hummel A\", \"Acuña AJ\", \"Hornung A\", \"Lew R\", \"Harkin W\", \"Garrigues GE\", \"Nicholson G\"]","journal":"Journal of shoulder and elbow arthroplasty","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Initially indicated for diabetes mellitus (DM), glucagon-like peptide 1 (GLP-1) agonists are now indicated for obesity management in isolation of DM. While prior studies have examined post-operative outcomes after total shoulder arthroplasty (TSA) in GLP-1 users with DM, there is a paucity of literature evaluating its use in non-diabetic patients for weight loss rather than glucose control. Therefore, our analysis compared 90-day and 2-year outcomes following TSA between non-diabetic obese GLP-1 users and a matched cohort of obese GLP-1 non-users. [METHODS] The PearlDiver Mariner database was queried to identify patients who underwent anatomic TSA and reverse TSA between 2010 and 2023. Patients with a history of DM or who underwent TSA for cancer, infection, or pathologic fractures were excluded. Patients with a body mass index ≥ 30 kg/m2 within 6 months of surgery were included. GLP-1 users (within 3 months of surgery) were matched in a 1:10 ratio to GLP-1 non-users by age, sex, Elixhauser Comorbidity Index, smoking status, and various comorbidities. Multivariate logistic regression models were utilized to compare outcomes at 90 days and 2 years. [RESULTS] After matching, 462 GLP-1 users and 4,377 GLP-1 non-users were included in our analysis. GLP-1 users had higher readmission rates (odds ratio: 2.034; 95% confidence interval: 1.594-2.578; P < .001) and subsequently overall complication rates (odds ratio: 1.474; 95% confidence interval: 1.295-1.799; P < .001) compared to GLP-1 non-users at 90 days. However, no differences were seen between cohorts for the remaining 90-day outcomes nor for all evaluated 2-year outcomes including prosthetic joint infection, fracture, and all-cause revision. [DISCUSSION] Our analysis found a higher incidence of overall complications at 90 days among obese, non-diabetic GLP-1 users, driven largely by an increased incidence of readmissions. However, there were largely comparable outcomes at 2 years. These findings suggest that while GLP-1 agonists may be reasonable to use in the perioperative period, interventions to reduce readmissions among these patients may be warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42892915/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"matched obese GLP-1 non-users\", \"treatment_duration\": null}","domains":"[\"bone\", \"immune\", \"cancer\", \"addiction\", \"adverse_effects\", \"perioperative\"]","outcome_type":"hard","primary_outcome":"90-day and 2-year outcomes after shoulder arthroplasty (readmission, overall complications, prosthetic joint infection, fracture, all-cause revision)","endpoints":null,"effect_estimate":"90-day readmission OR 2.034 and overall complications OR 1.474, both higher in GLP-1 users; no differences in the remaining 90-day outcomes or in any 2-year outcome (prosthetic joint infection, fracture, all-cause revision)","confidence_interval":"95% confidence interval: 1.594-2.578 (readmission)","p_value":"P < .001","sample_size":4839,"follow_up":"90 days and 2 years","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"obesity required (BMI ≥ 30 kg/m2)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"anatomic or reverse total shoulder arthroplasty\", \"sample_size\": 4839, \"inclusion_exclusion\": \"TSA patients with BMI ≥ 30 kg/m2 and GLP-1 use within 3 months of surgery (users); history of diabetes and TSA for cancer, infection or pathologic fracture excluded\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all patients had obesity (BMI ≥ 30 kg/m2) and were undergoing shoulder arthroplasty; people with diabetes were excluded.","mediation":"possibly","mediation_notes":"Possibly: no weight change, HbA1c or mediation analysis is reported, so weight and metabolic change are not separated from a drug effect (the evidence model's default); matching on age, sex, Elixhauser Comorbidity Index, smoking status and comorbidities addresses confounding, not mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 4839, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"matched obese GLP-1 non-users\", \"follow_up_duration\": \"90 days and 2 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval: 1.594-2.578 (readmission)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational database cohort with matching; confounding by indication is possible and the drugs and doses are not specified.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Higher 90-day readmission (OR 2.034) and overall complications (OR 1.474) among GLP-1 users; no difference in 2-year prosthetic joint infection, fracture or all-cause revision.","limitations":"Retrospective database study with matching rather than randomisation, so residual confounding is possible; the specific drugs, doses and duration of use are not given in the abstract.","plain_summary":"In a database of people with obesity but no diabetes having shoulder replacement between 2010 and 2023, 462 GLP-1 users were compared with 4,377 matched non-users. GLP-1 use was linked to more readmissions (odds ratio 2.034) and more overall complications (odds ratio 1.474) within 90 days, but not to differences in the other 90-day outcomes or in 2-year infection, fracture or revision. As an observational study, it shows associations, not cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1382,"doi":"10.1016/j.obpill.2026.100346","pmid":"42936354","nct_ids":"[\"NCT05869903\"]","title":"Efficacy and safety of orforglipron in adults with body mass index of 27 to less than 30 kg/m2 and adiposity-related complications: A post hoc analysis of the ATTAIN-1 trial","authors":"[\"Almandoz JP\", \"Miras AD\", \"Blüher M\", \"Orozco Del Pino P\", \"Mojdami D\", \"Batterham RL\", \"Trice K\", \"Goebel B\", \"Tangi F\"]","journal":"Obesity pillars","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Orforglipron, an oral small-molecule glucagon-like peptide-1 receptor agonist, improved body weight and cardiometabolic parameters in the phase 3 ATTAIN-1 trial, but its efficacy and safety in adults with body mass index (BMI) of ≥27 to <30 kg/m2 and adiposity-related complications have not been characterized. Adults with overweight and an adiposity-related complication are at substantial cardiometabolic risk, and obesity medications are recommended for this group. [METHODS] This was a post-hoc analysis of the ATTAIN-1 trial (NCT05869903), a phase 3, randomized, double-blind, placebo-controlled trial in which adults without diabetes and with obesity or overweight were randomized 3:3:3:4 to once-daily oral orforglipron 5.5, 9, or 17.2 mg or placebo for 72 weeks. The present analysis included the subset of randomized participants with BMI ≥27 to <30 kg/m2 and ≥1 adiposity-related complication. Endpoints included change from baseline to Week 72 the percent change in body weight, BMI, categorical weight-loss, waist circumference, lipids, patient-reported outcomes, and safety. Effect estimates are reported using efficacy and treatment-regimen estimands. Efficacy endpoints were also reported per sex subgroup. [RESULTS] This analysis included 260 participants (orforglipron 5.5 mg: 56; 9 mg: 64; 17.2 mg: 62; placebo: 78). At Week 72, orforglipron was associated with greater mean percent body weight reduction (17.2 mg: -13.5%) versus placebo (-0.3%) (nominal p < 0.001). Females experienced up to -18.8% mean body weight reduction and males up to -10.0%. Orforglipron was associated with improvements in waist circumference, triglycerides, and low-density lipoprotein cholesterol, as well as improvements in patient-reported outcomes. Safety profile was consistent with previous trials with predominantly mild-to-moderate gastrointestinal events. [CONCLUSION] In this post hoc analysis of ATTAIN-1, participants with BMI ≥27 to <30 kg/m2 and ≥1 adiposity-related complication, orforglipron was associated with improvements in anthropometric and cardiometabolic parameters, with a safety profile broadly consistent with the overall ATTAIN-1 trial (ClinicalTrials.gov identifier: NCT05869903).","url":"https://pubmed.ncbi.nlm.nih.gov/42936354/","source_name":"pubmed","source_tier":1,"coi_statement":"Jaime P Almandoz reported receiving personal fees for consulting and advisory activities from AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly and Company, Haleon, Kailera, Metsera/Pfizer, Novo Nordisk, Rivus Pharmaceuticals, Rhythm Pharmaceuticals, and Wave Life Sciences. Alexander Dimitri Miras has received research funding from Anabio, Boehringer Ingelheim, the European Union, Fractyl, Gila, Jon Moulton Charitable Foundation, Medical Research Council, National Institute for Health and Care Research, Eli Lilly, Novo Nordisk, Herbalife and Randox. He has received honoraria for lectures and presentations from Algorithm, AstraZeneca, Boehringer Ingelheim, Currax Pharmaceuticals, Eli Lilly, Ethicon, GI Dynamics, Medtronic, Novo Nordisk, and Screen Health. He is a shareholder in Kiso and the Beyond BMI clinic, which provides clinical obesity care. Matthias Blüher received honoraria as a consultant and speaker from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Novo Nordisk, Pfizer, and Sanofi, and received payment from Boehringer Ingelheim for his participation on a Data Safety Monitoring Board. Pedro Orozco Del Pino, Donna Mojdami, Rachel L Batterham, Kevin Trice, Benjamin Goebel, and Fatih Tangi are employees and shareholders of Eli Lilly and Company.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"rct","drugs":"[\"orforglipron\"]","drug_details":"{\"dose\": \"5.5, 9, or 17.2 mg once daily\", \"treatment_duration\": \"72 weeks\", \"comparator\": \"placebo\", \"route\": \"oral\"}","domains":"[\"body_composition\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percent change in body weight from baseline to Week 72","endpoints":null,"effect_estimate":"At Week 72 mean percent body weight reduction was -13.5% with orforglipron 17.2 mg versus -0.3% with placebo (nominal p < 0.001); females reduced body weight by up to -18.8% and males by up to -10.0%; waist circumference, triglycerides, low-density lipoprotein cholesterol and patient-reported outcomes also improved.","confidence_interval":"not reported in abstract","p_value":"nominal p < 0.001","sample_size":260,"follow_up":"72 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"excluded (the subset is restricted to BMI ≥27 to <30 kg/m2, described as overweight)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"overweight (BMI ≥27 to <30 kg/m2) with at least one adiposity-related complication, without diabetes\", \"sample_size\": 260, \"inclusion_exclusion\": \"adults without diabetes with obesity or overweight in the parent trial; this analysis restricted to BMI ≥27 to <30 kg/m2 with at least one adiposity-related complication\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 260 participants had BMI ≥27 to <30 kg/m2 with at least one adiposity-related complication, and the parent trial enrolled adults without diabetes; no age data are reported.","mediation":"not_applicable","mediation_notes":"not_applicable: the headline outcome is percent change in body weight, with BMI, categorical weight loss and waist circumference alongside it, so whether weight loss explains the result is not a question (IN-062). The lipid and patient-reported improvements were reported next to a -13.5% weight reduction and were not separated from it, so no independent mediation claim is made for them.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 260, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"72 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; nominal p < 0.001 for the weight endpoint; 260 participants across four groups (56, 64, 62 and 78)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a post hoc subgroup analysis of 260 of the randomised participants in one double-blind, placebo-controlled phase 3 trial. Randomisation and blinding are strong, but the subset was not prespecified, the p value is described as nominal, no confidence intervals are given, and the endpoints are weight, anthropometry, lipids and patient-reported outcomes rather than clinical events.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Three academic authors report consulting fees, research funding, honoraria or shareholdings from many pharmaceutical companies including Eli Lilly and Novo Nordisk, and six authors are employees and shareholders of Eli Lilly and Company.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly and Company; six authors are its employees and shareholders and others report its consulting fees, honoraria or research funding.","adverse_events":"safety profile consistent with previous trials, with predominantly mild-to-moderate gastrointestinal events","limitations":"A post hoc, not prespecified, subgroup analysis of one phase 3 trial: 260 participants across four groups, p values described as nominal, no confidence intervals, and endpoints limited to weight, anthropometry, lipids and patient-reported outcomes over 72 weeks.","plain_summary":"This is a post hoc analysis of 260 participants from the randomised, double-blind, placebo-controlled ATTAIN-1 trial who had a BMI ≥27 to <30 kg/m2 with at least one adiposity-related complication and who did not have diabetes. At Week 72, once-daily oral orforglipron 17.2 mg was associated with a mean body weight reduction of -13.5% against -0.3% on placebo (nominal p < 0.001), with improvements in waist circumference, triglycerides, low-density lipoprotein cholesterol and patient-reported outcomes; females reduced body weight by up to -18.8% and males by up to -10.0%. Safety was described as consistent with previous trials, predominantly mild-to-moderate gastrointestinal events. The subgroup was not prespecified and no confidence intervals are reported.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1410,"doi":"10.1016/j.mtbio.2026.103778","pmid":"42985244","nct_ids":"[]","title":"Triaptosis-based biomimetic nanoparticle for the treatment of oral squamous cell carcinoma lymph node metastasis","authors":"[\"Li ZZ\", \"Wu J\", \"Zhou K\", \"Yuan Z\", \"Luo HY\", \"Liu Y\", \"Cao LM\", \"Wang GR\", \"Liu B\", \"Wu Q\", \"Xu C\", \"Song Z\", \"Bu LL\"]","journal":"Materials today. Bio","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Lymph node metastasis (LNM) is a major determinant of poor prognosis in oral squamous cell carcinoma (OSCC) and remains difficult to treat due to the immunosuppressive tumor microenvironment and limited response to immune checkpoint blockade. Here, we report a biomimetic nanotherapeutic platform designed to induce triaptosis and enhance antitumor immunity for the treatment of metastatic OSCC. Semaglutide-loaded cerium oxide nanoparticles were engineered and further coated with macrophage membranes to construct Semg@Ce@MM, enabling improved tumor targeting and immune compatibility. The nanoplatform exerts dual therapeutic actions: cerium-mediated pro-oxidative activity triggers VPS34-associated triaptosis characterized by cytoplasmic vacuolization, while semaglutide activates MAPK signaling to enhance tumor cell susceptibility to death. In vitro studies demonstrate potent antitumor activity, including inhibition of tumor cell proliferation and invasion. In a lymph node metastasis model, Semg@Ce@MM significantly suppresses metastatic tumor growth, promotes dendritic cell maturation, increases CD4+ and CD8+ T cell infiltration, and reprograms tumor-associated macrophages toward a pro-inflammatory phenotype. Importantly, Semg@Ce@MM synergizes with anti-PD-L1 therapy to overcome resistance to immune checkpoint blockade while maintaining favorable biosafety. This work establishes a triaptosis-based nanomedicine strategy for the treatment of metastatic OSCC and highlights a promising combinatorial approach that integrates oxidative stress mediated cell death with cancer immunotherapy.","url":"https://pubmed.ncbi.nlm.nih.gov/42985244/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"cellular_in_vitro","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"cancer\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1461,"doi":"10.1007/s40200-026-02108-x","pmid":"42968774","nct_ids":"[]","title":"Efficacy and safety of semaglutide versus placebo in adults with overweight or obesity without diabetes: updated meta-analysis of randomized trials","authors":"[\"Wajid R\", \"Kumar R\", \"Muneer M\", \"Nauroz Ali M\", \"Ul Mustafa J\", \"Qamar J\", \"Asif D\", \"Ziaulhaque S\", \"Sohail I\", \"Khamisani FA\", \"Noureen M\", \"Fatima S\", \"Saqlain A\", \"Kumar L\", \"Raja A\"]","journal":"Journal of diabetes and metabolic disorders","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity poses significant challenges for those seeking long-term weight loss through diet and exercise alone. Semaglutide is a GLP-1 receptor agonist approved for chronic weight management in eligible adults. [METHODS] In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of semaglutide for treating obesity in adults without diabetes. The protocol was registered in PROSPERO (CRD420261338170). PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched through February 28, 2026. We included randomized controlled trials (RCTs) comparing semaglutide with placebo in adults without diabetes with BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 and at least one obesity-related comorbidity. The Cochrane Risk of Bias 2 Tool, GRADE methodology, RevMan v5.4, and CMA v3 were used for risk-of-bias assessment, certainty-of-evidence assessment, data analyses, and meta-regression analyses respectively. [RESULTS] We included 10 RCTs with a total of 7,131 participants. Risk-of-bias was judged at the level of each outcome: all included trials were at low risk-of-bias for the efficacy outcomes and the prespecified safety outcomes, while cardiovascular and psychiatric disorders raised some concerns. Compared to placebo, semaglutide produced significantly greater reductions in percentage change in body weight (WMD -12.29%, 95% CI -13.38 to -11.20, I2 88%, 95% PI -16.06 to -8.52; 10 studies, n = 6975), absolute change in body weight from baseline (WMD -12.67 kg, 95% CI -13.53 to -11.81, I2 77%, 95% PI -15.36 to -9.98; 10 studies, n = 6975), BMI (WMD -4.55 kg/m2, 95% CI -5.08 to -4.03, I2 86%, 95% PI -6.33 to -2.78; 8 studies, n = 6573), and waist circumference (WMD -9.42 cm, 95% CI -10.27 to -8.56, I2 79%, 95% PI -12.12 to -6.71; 10 studies, n = 6970). Participants assigned to semaglutide also had a higher probability of reaching a ≥ 5%, 10%, 15%, or 20% loss of body weight (9 studies, n = 6103). However, substantial between-study heterogeneity was observed for efficacy outcomes, indicating that the magnitude of benefit varied across trials. With semaglutide, individuals experienced a greater number of total adverse events (aggregate proportions 90.0% vs. 85.0%; RR 1.06, 95% CI 1.03 to 1.10, I2 72%; 9 studies, n = 6922) and discontinuation due to adverse events (aggregate proportions 6.0% vs. 3.0%; RR 1.86, 95% CI 1.41 to 2.45, I2 0%; 10 studies, n = 7129) than did individuals taking the placebo; while for serious adverse events (RR 1.16, 95% CI 0.90 to 1.51, I2 40%; 10 studies, n = 7129) the estimate was imprecise, did not establish a clear difference and the interval remains compatible with a potentially important increase in risk. These pooled figures represent average effects and may not apply equally across different semaglutide doses, formulations, treatment duration, or patient populations. Certainty-of-evidence was low for the primary outcome of percentage change in body weight and for absolute change in body weight and change in BMI, and very low for change in waist circumference. [CONCLUSION] Semaglutide was associated with clinically meaningful weight loss during trial treatment periods in adults with overweight or obesity without diabetes; however, low-certainty evidence and substantial between-study heterogeneity warrant cautious interpretation of the magnitude of benefit. [SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02108-x.","url":"https://pubmed.ncbi.nlm.nih.gov/42968774/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interestsThe authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1490,"doi":"10.1002/osp4.70204","pmid":"42991391","nct_ids":"[]","title":"Vibration-Controlled Transient Elastography (VCTE)-Based Prevalence and Assessment of Hepatic Steatosis and Fibrosis in a UK Tertiary Hospital-Based Specialist Weight Management Service: A Real-World Evaluation","authors":"[\"Willis SA\", \"Ahsan M\", \"Rathi K\", \"Lawrence I\", \"Davies MJ\", \"Webb DR\", \"King JA\", \"Ahmad E\"]","journal":"Obesity science & practice","publication_date":"2026-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic dysfunction-associated steatotic liver disease is common in severe obesity; however, liver health assessment is inconsistently implemented in specialist weight management services and real-world data are scarce. This study evaluated the prevalence and severity of vibration-controlled transient elastography (VCTE)-defined hepatic steatosis and fibrosis risk in adults attending a UK-based Tier 3 specialist weight management service, and explored associations with clinical and metabolic characteristics. [METHODS] This retrospective cross-sectional study included 96 adults referred to a specialist weight management service who underwent baseline VCTE (FibroScan) between June 2024 and November 2025. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) estimated hepatic steatosis and fibrosis risk, respectively. Demographic, anthropometric, clinical, and biochemical variables were extracted from electronic records. Generalized linear models identified factors associated with CAP and LSM, with sensitivity analyses adjusting for incretin-based therapy use. [RESULTS] Participants were predominantly female (83.3%) and White European (81.3%), with mean age 48.7 ± 12.5 years and BMI 42.0 ± 9.4 kg/m2. VCTE-defined steatosis was present in 82.3% (CAP ≥ 248 dB·m-1), with 57.3% classified as severe (CAP ≥ 280 dB·m-1). Overall, 26.1% had elevated fibrosis risk (LSM ≥ 8 kPa), including 6.3% classified as high risk (LSM > 12 kPa). In multivariable analyses, higher BMI, HbA1c and ALT were independently associated with greater CAP, whereas BMI and HbA1c were independently associated with higher LSM. Further adjustment for incretin-based pharmacotherapy use did not alter these relationships. [CONCLUSIONS] Hepatic steatosis and elevated fibrosis risk are highly prevalent in adults attending specialist weight management services. Adiposity and glycemic burden appear to be key determinants, supporting the integration of non-invasive liver assessment into specialist obesity care pathways.","url":"https://pubmed.ncbi.nlm.nih.gov/42991391/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:20+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"body_composition\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1519,"doi":"10.1038/s41591-026-04752-5","pmid":"43003902","nct_ids":"[]","title":"Resistance exercise to attenuate lean mass loss during tirzepatide therapy for obesity: a randomized controlled trial","authors":"[\"Green DJ\", \"Haynes A\", \"Underwood DR\", \"Winterton ER\", \"Green AA\", \"Daly RM\", \"George ES\", \"Lester L\", \"Naylor LH\", \"Hillis GS\", \"Fegan PG\", \"Yeap BB\"]","journal":"Nature medicine","publication_date":"2026-11-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Incretin mimetics as obesity therapy induce substantial weight and fat loss but also decrease lean soft tissue mass, possibly impairing skeletal muscle function. Here, in this two-arm randomized controlled trial of adding resistance exercise (REx) to tirzepatide (T), 120 adults with overweight or obesity were treated with tirzepatide and randomized to thrice-weekly resistance exercise training or usual activities for 40 weeks. Tirzepatide was safe, and most participants tolerated up-titration to 15 mg weekly. Adherence to resistance exercise was 91%. Weight loss achieved was similar (T = -22.61 kg, T+REx = -22.28 kg, P = 0.694). For primary outcomes, loss of total fat mass was similar (T = -17.19 kg, T+REx = -17.98 kg, P = 0.700; between-group difference = -0.77 kg, 95% confidence interval (CI): -2.14 kg to 0.60 kg), but resistance exercise reduced loss of total lean soft tissue mass (T = -4.67 kg, T+REx = -3.57 kg, P < 0.001; between-group difference = 1.09 kg, 95% CI: 0.43-1.75 kg). For related endpoints, resistance exercise reduced loss of appendicular lean soft tissue mass (T = -3.55 kg, T+REx = -2.92 kg, P < 0.001). Upper and lower body muscle strength decreased with tirzepatide (bench press -4.09 kg, lat pulldown -4.42 kg, knee extension -4.42 kg) but increased with T+REx (+4.68 kg, +8.58 kg, +5.88 kg, respectively, all P < 0.001 versus tirzepatide). In conclusion, resistance exercise training attenuated loss of total lean soft tissue mass, representing an effective adjunct to tirzepatide anti-obesity therapy. Australian New Zealand Clinical Trials Registry identifier: ACTRN12623001236684 .","url":"https://pubmed.ncbi.nlm.nih.gov/43003902/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: D.J.G. has received speaker honoraria from Eli Lilly. P.G.F. has received speaker honoraria from Novo Nordisk, Eli Lilly and Boehringer Ingelheim. B.B.Y. has received speaker honoraria from Eli Lilly and Boehringer Ingelheim and participated in an advisory role for Eli Lilly (all honoraria were paid to the University of Western Australia) and is a shareholder and clinical advisor to ProGenis Pharmaceuticals. R.M.D. has received speaker honoraria from Abbott, Fresenius Kabi and Nutricia Australia and educational grants from Abbott. The other authors declare no competing interests.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-11-11T18:58:01+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"treatment_duration\": \"40 weeks\", \"dose\": \"initiated at 2.5 mg and increased by 2.5 mg every 4 weeks, aiming for a 15 mg weekly maintenance dose at week 20; 78 participants finished on 15 mg\", \"route\": \"subcutaneous\", \"comparator\": \"tirzepatide with usual activities (no resistance exercise); every participant received tirzepatide, with no arm without it\"}","domains":"[\"muscle\", \"lean_mass\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"co-primary: changes in DXA total fat mass and total lean soft tissue mass","endpoints":null,"effect_estimate":"Tirzepatide plus resistance exercise vs tirzepatide with usual activities: total lean soft tissue mass loss smaller (T = -4.67 kg, T+REx = -3.57 kg; between-group difference 1.09 kg, P < 0.001); total fat mass loss similar (T = -17.19 kg, T+REx = -17.98 kg; between-group difference -0.77 kg, P = 0.700); weight loss similar (T = -22.61 kg, T+REx = -22.28 kg, P = 0.694); bench press, lat pulldown and knee extension strength fell with tirzepatide alone and rose with T+REx (all P < 0.001 versus tirzepatide); no between-group difference in blood pressure, glycaemia or lipids (all P > 0.05)","confidence_interval":"0.43 to 1.75 kg for the lean soft tissue mass difference; −2.14 to 0.60 kg for the fat mass difference; Bonferroni-adjusted co-primary outcomes, labelled 95% CI in the abstract (97.5%)","p_value":"P < 0.001 (lean soft tissue mass); P = 0.700 (fat mass)","sample_size":120,"follow_up":"40 weeks","direction":"mixed","population":"{\"mean_age\": 57.7, \"age_range\": \"50.1−70.3\", \"age_min\": 50, \"sex_distribution\": \"50% female\", \"bmi_mean\": \"33.08 (T) and 34.62 (T+REx), baseline marginal means; no whole-cohort mean stated\", \"bmi_min\": 27, \"obesity_status\": \"required (BMI ≥30 kg m−2, or ≥27 kg m−2 with at least one weight-related comorbidity); 86.7% obese, 13.3% overweight\", \"diabetes_status\": \"excluded (history of diabetes mellitus)\", \"cvd_status\": \"excluded (history of cardiovascular disease)\", \"ckd_status\": \"eGFR <45 ml min−1 excluded; otherwise not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"overweight or obesity (sedentary, community-dwelling men and postmenopausal women aged 50−70)\", \"sample_size\": 120, \"inclusion_exclusion\": \"men and postmenopausal women aged 50−70, BMI ≥30 or ≥27 with a weight-related comorbidity, under 60 minutes of moderate or higher intensity exercise a week; excluded diabetes, cardiovascular disease, pancreatitis, prior incretin therapy, bariatric surgery, statins or antihypertensives within 3 months, eGFR <45 and HbA1c >7.0%\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had overweight or obesity (entry BMI ≥30, or ≥27 with a weight-related comorbidity; 86.7% obese), although they were aged 50−70 (mean 57.7) without diabetes or cardiovascular disease.","mediation":"not_applicable","mediation_notes":"The co-primary outcomes are body composition (fat and lean soft tissue mass), so weight-loss mediation is not applicable. Weight loss was similar in both arms, so the smaller lean mass loss with exercise is not explained by a difference in weight loss; tirzepatide's own changes were not separated from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 120, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"tirzepatide with usual activities (no resistance exercise); every participant received tirzepatide, with no arm without it\", \"follow_up_duration\": \"40 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"97.5% CIs reported for the co-primary outcomes; 120 randomised, 111 (93%) completed\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: single-centre, open-label randomized trial of 120 people, 111 completing, with intermediate outcomes (DXA body composition, strength); the randomization tests resistance exercise added to tirzepatide, and there is no arm without tirzepatide, so the drug's own effects are uncontrolled.","funding_source":"Western Australian State Government Research Excellence Award (REA2022) and Australian Postgraduate Awards; Eli Lilly supplied tirzepatide only","industry_funded":"partial","manufacturer":"Eli Lilly (supplied tirzepatide)","author_conflicts":"Three authors report speaker honoraria from Eli Lilly (with Novo Nordisk and Boehringer Ingelheim for some), one of them also an advisory role for Eli Lilly and shares in and an advisory role with ProGenis Pharmaceuticals, a fourth reports honoraria and grants from Abbott, Fresenius Kabi and Nutricia Australia, and the others declare no competing interests.","sponsor_role":"Eli Lilly reviewed the protocol, supplied tirzepatide through an investigator-initiated trial program and reviewed a manuscript draft for intellectual property or new safety issues, with no changes made; no other funding and no role in trial conduct","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"Gastrointestinal events common and at similar frequencies in both arms (nausea in about half; vomiting, constipation, diarrhea and indigestion each about one-third); six serious adverse events (five in T, one in T+REx), all judged unrelated to treatment; six withdrawals for adverse events","limitations":"Single-centre, open-label 40-week trial of 120 people with no arm without tirzepatide, so tirzepatide's own effects are uncontrolled changes over time; DXA lean soft tissue mass is not the same as muscle mass, strength testers were not blinded, participants were sedentary adults without diabetes or cardiovascular disease, and the long-term effect of the lean mass difference is unknown.","plain_summary":"In this 40-week randomized trial, 120 adults aged 50−70 with overweight or obesity and no diabetes all took tirzepatide and were assigned either to supervised resistance exercise three times a week or to their usual activities. Weight loss was similar in both groups (-22.61 kg and -22.28 kg) and fat mass loss did not differ, but the exercise group lost less lean soft tissue mass (-3.57 kg against -4.67 kg). Bench press, lat pulldown and knee extension strength fell in people on tirzepatide alone and rose with added exercise. Every participant took tirzepatide, so the trial tests the added exercise; the drug's own effects are changes over time with no untreated group for comparison.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1520,"doi":"10.1016/j.lanepe.2026.101881","pmid":null,"nct_ids":"[]","title":"GLP-1 receptor agonist discontinuation and cardiovascular events and all-cause mortality in people with type 2 diabetes: a retrospective cohort study","authors":"[\"Ceriello A\", \"Prattichizzo F\", \"Lucisano G\", \"La Grotta R\", \"Berra CC\", \"De Cosmo S\", \"Candido R\", \"Cosentino F\", \"Caballero AE\", \"McGowan B\", \"Nauck MA\", \"Russo GT\", \"Nicolucci A\"]","journal":"The Lancet regional health. Europe","publication_date":"2026-11-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"BACKGROUND: Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) has been associated with the deterioration of cardiovascular risk factors, especially body weight. However, whether the interruption of such medication, compared with their continued use, is associated with an increased risk of cardiovascular events or mortality is unclear.\nMETHODS: Leveraging data collected between 2004 and 2024 from 301 diabetes clinics in Italy, we conducted a retrospective cohort study in which people with type 2 diabetes (T2D), without cardiovascular diseases, and initiating a GLP-1RA were categorized as persistent users or as discontinuation group. The primary endpoint was a composite of myocardial infarction, stroke, or death from any cause, accounting for immortal time bias through the treatment-exposed person-time approach and using propensity score matching (PSM) to obtain balanced groups. Poisson and Cox regression models were used. We also examined the associated trends of risk factors levels.\nFINDINGS: Of the 80,302 subjects initiating a therapy with a GLP-1RA, 31,687 (39.5%) were still on therapy at the last visit, while 48,615 (60.5%) had discontinued treatment. Mean exposure was 2.97 ± 2.93 years among persistent users and 1.21 ± 2.13 years in the discontinuation group. Follow-up was 3.65 ± 3.03 and 4.25 ± 3.41 years, respectively. In the two groups obtained after PSM, each composed of 28,713 subjects, the IRR for the primary endpoint was 2.01 (95% confidence interval [CI] 1.77–2.28) while the relative HR was 2.03 (95% CI 1.92–2.14). The IRR for death from any cause was 4.67 (95% CI 4.11–5.30) and the corresponding HR 4.81 (95% CI 4.39–5.26). Risk factors were not meaningfully different after discontinuation in people with or without a primary endpoint.\nINTERPRETATION: In people with T2D and without previous cardiovascular disease, interrupting a therapy with GLP-1RA was associated with a higher risk of a composite of myocardial infarction, stroke, or death from any cause compared to those continuing the treatment.\nFUNDING: This work was supported, in part, by the Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica.","url":"https://doi.org/10.1016/j.lanepe.2026.101881","source_name":"crossref","source_tier":1,"coi_statement":"AC reports on being on Advisory Board, Consultancy, Lectures: Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Hikamr Pharma, Guidotti, Eli Lilly, MSD, Merck, Novo, Roche Diagnostics, Sanofi, Servier, SUN Pharma. MN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gasherbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers’ bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. He is on a data monitoring and safety board for Inventiva. BG has received speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Astra Zeneca, Janssen, Pfizer, MSD and a research grant from Novo Nordisk; and is a shareholder of Reset Health. FC receives consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Mundipharma, Novo Nordisk, and Pfizer. AN received research grants from Novo Nordisk, Sanofi, AlfaSigma, and Theras. GTR is on the advisory board and does consultancy and lectures for Novo Nordisk, AstraZeneca, Sanofi, Boehringer, Lilly, Mundipharma, and Sankyo. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T19:38:00+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"people who discontinued the GLP-1RA (compared with persistent users who continued it)\", \"dose\": \"various\", \"route\": \"various\", \"treatment_duration\": \"mean exposure 2.97 ± 2.93 years in persistent users and 1.21 ± 2.13 years in the discontinuation group\"}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\", \"discontinuation\"]","outcome_type":"hard","primary_outcome":"composite of nonfatal myocardial infarction, nonfatal stroke, or death from any cause","endpoints":null,"effect_estimate":"Discontinuation vs persistent use (matched groups): primary composite IRR 2.01, HR 2.03; death from any cause IRR 4.67, HR 4.81; primary-endpoint HR 1.61 with BMI <30 and 2.27 with BMI ≥30; risk factors not meaningfully different after discontinuation between people with and without a primary endpoint","confidence_interval":"95% CI 1.77–2.28 (IRR) and 95% CI 1.92–2.14 (HR) for the primary endpoint; 95% CI 4.11–5.30 (IRR) and 95% CI 4.39–5.26 (HR) for death from any cause","p_value":null,"sample_size":57426,"follow_up":"mean 3.65 ± 3.03 years (persistent users) and 4.25 ± 3.41 years (discontinuation group)","direction":"benefit","population":"{\"mean_age\": \"64.62 (SD 10.73) in persistent users and 64.68 (SD 11.06) in the discontinuation group, after matching\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"39.97% women in each matched group\", \"bmi_mean\": \"32.78 (persistent users) and 32.77 (discontinuation group), after matching\", \"bmi_min\": null, \"obesity_status\": \"mixed (not required; analysis stratified BMI ≥30 vs <30; mean BMI 32.78 after matching)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"excluded (prior major cardiovascular event)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes without cardiovascular disease, starting a GLP-1RA\", \"sample_size\": 57426, \"inclusion_exclusion\": \"type 2 diabetes clinic patients starting a GLP-1RA; prior major cardiovascular event excluded; a single prescription followed by less than 12 months without renewal excluded\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and mean BMI 32.78 after matching; prior cardiovascular disease was excluded, and mean age 64.62 falls in the target range.","mediation":"possibly","mediation_notes":"The study tracked HbA1c, weight, blood pressure, lipids and eGFR; after stopping there was only a small weight regain and no worsening of glycaemic control, and within the discontinuation group risk factors differed little between people with and without an event. That is an exploratory comparison of risk-factor trends, not a participant-level mediation analysis, and propensity matching on baseline BMI and HbA1c addresses confounding, not mediation, so mediation stays possibly.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 57426, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"people who discontinued the GLP-1RA (compared with persistent users who continued it)\", \"follow_up_duration\": \"mean 3.65 ± 3.03 years (persistent users) and 4.25 ± 3.41 years (discontinuation group)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 1.77–2.28 (IRR) and 95% CI 1.92–2.14 (HR) for the primary endpoint; 95% CI 4.11–5.30 (IRR) and 95% CI 4.39–5.26 (HR) for death from any cause\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single large retrospective cohort with propensity-matched groups and hard outcomes, capped at LOW for an individual observational study (rule 2); the authors themselves flag residual confounding and reverse causation and call the findings hypothesis generating.","funding_source":"Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica, in part","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Six authors report advisory, consulting, lecture, speaker or grant relationships with drug companies, including Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi and Boehringer Ingelheim; the other authors declare no competing interests.","sponsor_role":"The funder had no role in study design, data collection, data analysis, interpretation or writing of the report.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk (semaglutide, which a minor portion of the cohort used). The statement also names Eli Lilly, AstraZeneca and Sanofi; which other GLP-1RAs were used is in Supplementary Table S1, not cached.","adverse_events":"not reported","limitations":"Observational registry study open to residual confounding and reverse causation: there were no data on why people stopped, no socioeconomic data, no cause-specific mortality and no reliable heart failure hospitalisation data, about one-third of initiators were excluded, and the authors judge the mortality association too large to be explained by stopping the drug alone. Italian diabetes clinics only, so the findings may not extend to obesity treatment without diabetes or to tirzepatide, and there is no comparison with never-users.","plain_summary":"This study used records from 301 Italian diabetes clinics on people with type 2 diabetes and no prior cardiovascular disease who started a GLP-1 receptor agonist, comparing those who kept taking it with matched people who stopped (28,713 in each group). Stopping was linked to a higher rate of heart attack, stroke or death from any cause (HR 2.03; 95% CI 1.92–2.14) and of death from any cause alone (HR 4.81; 95% CI 4.39–5.26); seen the other way, continuing the drug was associated with lower risk. Weight and other risk factors did not differ meaningfully between people who stopped and did or did not have an event. This is an association from observational data, not proof that stopping caused the harm: the authors say stopping may mark people already at higher risk, and the study cannot compare continuing with never taking the drug.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1521,"doi":"10.1056/nejmoa2610676","pmid":"43001755","nct_ids":"[\"NCT05931367\", \"NCT05929066\"]","title":"Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity","authors":"[\"Schnitzer TJ\", \"Hunter DJ\", \"Conaghan PG\", \"Sharma AM\", \"Pedersen SD\", \"Chen K\", \"Park SY\", \"Makarova N\", \"Giblin K\", \"Forrester T\", \"TRIUMPH-4 and TRIUMPH-1-OA Investigators\"]","journal":"The New England journal of medicine","publication_date":"2026-11-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide, an investigational triple agonist of GIP, GLP-1, and glucagon receptors, may be useful for the treatment of painful knee osteoarthritis in persons with obesity. [METHODS] In two phase 3 trials, adults without diabetes who had painful knee osteoarthritis and a body-mass index of at least 27 were randomly assigned to receive once-weekly subcutaneous retatrutide (9 or 12 mg in TRIUMPH-4 and 4, 9, or 12 mg in TRIUMPH-1-OA) or placebo. In TRIUMPH-4, the primary end points were the change in the WOMAC pain score (range, 0 to 10, with higher scores indicating worse pain) and the percent change in body weight at week 68. In TRIUMPH-1-OA, the primary end point was the change in the WOMAC pain score at week 80. For non-pain-related end points, intercurrent events were handled with a treatment-policy strategy. For pain-related end points, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events that suggested treatment failure and a treatment-policy strategy elsewhere. We also report results for an intention-to-treat (ITT) estimand. [RESULTS] A total of 445 participants underwent randomization in TRIUMPH-4 and 574 in TRIUMPH-1-OA. At 68 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-4 were -3.96 (9 mg) and -3.74 (12 mg), versus -2.12 with placebo (difference vs. placebo, -1.83 [95% confidence interval {CI}, -2.37 to -1.30] and -1.61 [95% CI, -2.16 to -1.07], respectively). For the ITT estimand, the corresponding differences from placebo were -1.70 (95% CI, -2.19 to -1.22) and -1.38 (95% CI, -1.91 to -0.85) (P<0.001 for all comparisons). The mean percent changes in body weight with retatrutide were -20.0% (9 mg) and -23.7% (12 mg), versus -4.6% with placebo (difference vs. placebo, -15.4 percentage points [95% CI, -18.7 to -12.1] and -19.2 percentage points [95% CI, -22.4 to -15.9]; P<0.001 for both comparisons). At 80 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-1-OA were -3.22 (4 mg), -3.48 (9 mg), and -3.64 (12 mg), versus -1.87 with placebo (difference vs. placebo, -1.35 [95% CI, -1.92 to -0.78], -1.61 [95% CI, -2.20 to -1.02], and -1.77 [95% CI, -2.34 to -1.20], respectively). For the ITT estimand, the corresponding differences from placebo were -0.96 (95% CI, -1.61 to -0.30), -1.41 (95% CI, -2.07 to -0.75), and -1.64 (95% CI, -2.26 to -1.02) (P≤0.005 for all comparisons). In both trials, serious adverse events were more common with retatrutide than with placebo, and the most common adverse events were gastrointestinal. [CONCLUSIONS] In participants with painful knee osteoarthritis and obesity, treatment with retatrutide resulted in significantly greater reductions in both the WOMAC pain score and body weight than placebo. (Funded by Eli Lilly; TRIUMPH-4 and -1 ClinicalTrials.gov numbers, NCT05931367 and NCT05929066.).","url":"https://pubmed.ncbi.nlm.nih.gov/43001755/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-11-11T20:27:41+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"9 or 12 mg once weekly (TRIUMPH-4); 4, 9, or 12 mg once weekly (TRIUMPH-1-OA); started at 2 mg and escalated every 4 weeks\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\", \"treatment_duration\": \"68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)\"}","domains":"[\"osteoarthritis\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"change in WOMAC knee pain score (0 to 10) in both trials, with percent change in body weight as a co-primary end point in TRIUMPH-4; at week 68 (TRIUMPH-4) and week 80 (TRIUMPH-1-OA)","endpoints":null,"effect_estimate":"WOMAC pain difference vs placebo (hybrid estimand): TRIUMPH-4 -1.83 (9 mg) and -1.61 (12 mg) at 68 weeks; TRIUMPH-1-OA -1.35 (4 mg), -1.61 (9 mg), -1.77 (12 mg) at 80 weeks; ITT differences -1.70 and -1.38 (TRIUMPH-4) and -0.96, -1.41, -1.64 (TRIUMPH-1-OA). Body weight -20.0% (9 mg) and -23.7% (12 mg) vs -4.6% with placebo in TRIUMPH-4 (differences -15.4 and -19.2 percentage points). Serious adverse events more common with retatrutide in both trials.","confidence_interval":"TRIUMPH-4 pain: 95% CI -2.37 to -1.30 (9 mg) and -2.16 to -1.07 (12 mg); TRIUMPH-1-OA pain: 95% CI -1.92 to -0.78, -2.20 to -1.02, -2.34 to -1.20; TRIUMPH-4 weight: 95% CI -18.7 to -12.1 and -22.4 to -15.9","p_value":"P<0.001 for all TRIUMPH-4 comparisons (pain and weight); P≤0.005 for all TRIUMPH-1-OA comparisons (ITT pain)","sample_size":1019,"follow_up":"68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)","direction":"mixed","population":"{\"mean_age\": \"55.2 (SD 9.7) in TRIUMPH-4 and 56.1 (SD 9.1) in TRIUMPH-1-OA (Table 1 totals)\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"63.4% women (TRIUMPH-4); 75.8% women (TRIUMPH-1-OA)\", \"bmi_mean\": \"40.3 to 41.0 across arms and trial totals (Table 1)\", \"bmi_min\": 27, \"obesity_status\": \"required (BMI ≥27 kg/m2 with at least one obesity-related complication; about 80% had BMI >35)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"painful knee osteoarthritis with obesity\", \"sample_size\": 1019, \"inclusion_exclusion\": \"adults ≥18 with radiographic knee OA and WOMAC pain 4 to 9 in the index knee, BMI ≥27 with an obesity-related complication, at least one failed diet attempt; excluded diabetes and weight change >5 kg in the prior 90 days\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (BMI ≥27 with an obesity-related complication; arm mean BMI 40.3 to 41.0, about 80% above 35) and painful knee osteoarthritis. Diabetes was excluded and mean age (55.2 and 56.1) sits at the lower edge of the target range, but no normal-weight people were enrolled.","mediation":"likely","mediation_notes":"Weight fell by 20.0% and 23.7% on retatrutide against 4.6% on placebo at 68 weeks, and knee pain is an outcome weight loss is known to improve; the authors name reduced knee loading as a leading candidate mechanism and call the mechanisms incompletely understood. No mediation analysis, weight-matched comparison or pre-weight-loss measurement was reported (pain was first assessed at week 16), so the pain benefit cannot be separated from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1019, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: TRIUMPH-4 pain: 95% CI -2.37 to -1.30 (9 mg) and -2.16 to -1.07 (12 mg); TRIUMPH-1-OA pain: 95% CI -1.92 to -0.78, -2.20 to -1.02, -2.34 to -1.20; TRIUMPH-4 weight: 95% CI -18.7 to -12.1 and -22.4 to -15.9\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: two randomized, double-blind, placebo-controlled phase 3 trials of moderate size (445 and 574 randomized) that replicate each other, with an intermediate primary outcome (a validated symptom scale); the risk of unblinding from gastrointestinal effects on a self-reported pain score and sponsor involvement in the analysis keep it below HIGH.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly and Company","author_conflicts":"not reported","sponsor_role":"Lilly was involved in study design and conduct, data collection, management, analysis and interpretation, manuscript preparation, review or approval, and the decision to submit; it had no right to veto publication; final decisions rested with the authors, who included Lilly employees.","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Serious adverse events were more common with retatrutide (TRIUMPH-4: 9.5% and 10.8% vs 2.0% with placebo; TRIUMPH-1-OA: 4.2% (4 mg), 9.8% (9 mg) and 14.6% (12 mg) vs 6.9%); gastrointestinal events (nausea, diarrhoea, constipation) were the most common, mostly mild to moderate and during dose escalation; discontinuation for adverse events 2.8%–18.2% with retatrutide vs 4.0%–6.2% with placebo; dysesthesia 6.3%–20.9% vs 0.7%; one death in each TRIUMPH-4 retatrutide group, judged unrelated, and none in TRIUMPH-1-OA.","limitations":"The authors note pain was first assessed at week 16, hsCRP only at start and end, enrolment was limited to people with overweight or obesity and knee OA, and the trials did not assess OA progression or joint replacement. A self-reported pain outcome alongside frequent gastrointestinal effects risks unblinding, and the sponsor took part in design, analysis and writing, with sponsor employees among the authors.","plain_summary":"Two phase 3 trials randomly assigned adults with painful knee osteoarthritis, a BMI of at least 27 and no diabetes (445 in TRIUMPH-4, 574 in TRIUMPH-1-OA) to weekly injections of retatrutide, an investigational drug acting on GLP-1, GIP and glucagon receptors, or placebo for 68 or 80 weeks. Knee pain on a 0 to 10 scale improved more with retatrutide at every dose (for example a difference of -1.83 points with 9 mg at 68 weeks), and body weight fell 20.0% and 23.7% against 4.6% with placebo. Serious adverse events were more common with retatrutide in both trials, and stomach and bowel side effects were the most frequent. Everyone enrolled had obesity, so the trials do not show what the drug would do in people of normal weight, much of the pain relief may come from the weight loss itself, and the trials were funded by Eli Lilly, the drug's maker.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1423,"doi":"10.1161/jaha.126.053850","pmid":"42998247","nct_ids":"[]","title":"Initial Diabetes Therapy After Coronary Artery Bypass Grafting and Long-Term Outcomes","authors":"[\"Tam V\", \"Schaff HV\", \"Thao V\", \"Van Houten H\", \"Frye RL\", \"Greason KL\", \"AlJamal YN\", \"Spencer PJ\", \"Rowse PG\", \"Crestanello JA\"]","journal":"Journal of the American Heart Association","publication_date":"2026-11-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Type 2 diabetes (T2D) is common among patients undergoing coronary artery bypass grafting (CABG), but optimal post-CABG glucose-lowering therapy remains uncertain. [METHODS] We conducted a retrospective cohort study using the OptumLabs Data Warehouse of adults with T2D undergoing isolated CABG from 2012-2024. Follow-up began 30 days after discharge. Glucose-lowering therapy was modeled as a time-varying exposure with patients contributing no-observed-therapy person-time until the first qualifying post-discharge fill. Pairwise comparisons used stabilized inverse probability of treatment weighting. The primary outcome was all-cause mortality; secondary outcomes were heart failure hospitalization, stroke, and repeat coronary revascularization. [RESULTS] Among 19,237 patients, 24.9% had no observed post-discharge therapy, 42.8% received metformin, 22.9% received insulin, and 9.4% received GLP-1RA/SGLT2i therapy. All active therapies were associated with lower mortality compared with no observed therapy, including GLP-1RA/SGLT2i (HR 0.71, 95% CI 0.58-0.87), metformin (HR 0.60, 95% CI 0.55-0.66), and insulin (HR 0.75, 95% CI 0.67-0.84). Among active therapies, metformin was associated with lower mortality than insulin (HR, 0.61 [0.54-0.70]); GLP-1RA/SGLT2i comparisons with metformin and insulin were less precise. Metformin was also associated with lower cumulative incidence of heart failure hospitalization than no observed therapy and insulin, and lower stroke incidence than insulin. [CONCLUSIONS] Observed glucose-lowering therapy initiation after CABG was associated with lower mortality compared with no observed therapy across all active treatment groups. These findings highlight a potential care gap and suggest that proper initiation of diabetes therapy after CABG represents an important opportunity to improve long-term outcomes following surgical revascularization.","url":"https://pubmed.ncbi.nlm.nih.gov/42998247/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1424,"doi":"10.1007/s00415-026-14251-9","pmid":"42998120","nct_ids":"[]","title":"GLP-1 receptor agonist use in patients with minor stroke is associated with lower risk of post-stroke dementia","authors":"[\"Kakadiya J\", \"Chen H\", \"Rai P\", \"Dhaduk V\", \"Bathla G\", \"Essibayi MA\", \"Azzam AY\", \"Salim HA\", \"Ahmed S\", \"Soni N\", \"Yedavalli VS\", \"Dmytriw AA\", \"Latifi S\", \"Mcintyre MK\", \"Mandel D\", \"Altschul DJ\", \"Colasurdo M\", \"Malhotra A\", \"Gandhi D\", \"Lakhani DA\"]","journal":"Journal of neurology","publication_date":"2026-11-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Minor ischemic stroke is associated with increased risks of post-stroke dementia independent of stroke recurrence, yet there are no guideline-recommended therapies targeted at cognitive outcomes. Glucagon-like peptide - 1 receptor agonists (GLP-1RAs) have been shown to be associated with lower risk of dementia among diabetes patients; however, their effect on cognitive outcomes among minor stroke patients is largely unknown. [METHODS] This retrospective cohort study used de-identified electronic health record data from the TriNetX US Collaborative Network (2016-2025). Adult patients with minor ischemic stroke (NIHSS ≤ 5 and non-disabling) were included. Patients with prior intracranial hemorrhage, mood disorders, anxiety disorders, cognitive impairment, or dementia were excluded. GLP-1RA use was defined as a prescription prior to or within 3 months of stroke diagnosis. After 1:1 propensity score matching on 75 baseline characteristics, outcomes were assessed over a 5 year follow-up using Kaplan-Meier analysis and Cox proportional hazards models. [RESULTS] After propensity score matching, 1,425 patients per group were analyzed. Mean age was 60.7 years, with diabetes present in 92.7% and mean HbA1c of 8.7%. GLP-1RA use was associated with a 48% lower hazard of post-stroke dementia (3.4% vs. 7.0%, HR 0.52 [95% CI 0.37-0.74]) and a 31% lower hazard of other neurocognitive complaints (17.2% vs 25.6%, HR 0.69 [95% CI 0.59-0.81]) over 5 years. GLP-1RA use was also associated with reduced mortality (4.4% vs. 8.8%; HR 0.57 [95% CI 0.42-0.77]) and major ischemic stroke (1.5% vs. 2.7%; HR 0.59 [95% CI 0.35-1.01]). No significant difference in intracranial hemorrhage rates was observed. [CONCLUSIONS] Among this cohort of minor ischemic stroke patients mostly with concomitant diabetes, GLP-1RA use was associated with significantly reduced risks of post-stroke dementia and other neurocognitive complaints. These findings support prioritizing GLP-1RA use for diabetic patients who suffered minor ischemic stroke. Prospective trials are warranted to confirm causality and determine optimal implementation.","url":"https://pubmed.ncbi.nlm.nih.gov/42998120/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflicts of interest: DAL is consultant for iSchemaView RapidAI and DocPanel Technologies, and is Scientific advisory board member for Upstream Vision. VSY is consultant for iSchemaView, RapidAI. DJA reports securities holdings in Von Vascular, Inc, and compensation from Johnson and Johnson International, Stryker Corporation, Medtronic USA, Inc, and MicroVention, Inc, for consultant services. DG receives research grants from the Focused Ultrasound Foundation, NIH, University of Maryland Medical Center, and Microvention, and is a consultant for Navigantis. Other authors have no relevant disclosures to report. Ethical approval: The study protocol was reviewed by the Institutional Review Board of West Virginia University (Reference: #STUDY00000320), which also granted a waiver of informed consent owing to the retrospective design and exclusive use of anonymized patient data. The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki for research involving human participants. Guarantor: Dhairya A Lakhani, MD.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cerebrovascular\", \"cognition\", \"dementia\", \"mortality\", \"metabolic\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1426,"doi":"10.1016/j.diabres.2026.113638","pmid":"42994759","nct_ids":"[]","title":"Exploring time-varying cardiovascular effects of GLP-1 receptor agonists: A multi-state network meta-analysis of cardiovascular outcome trials","authors":"[\"Wang Z\", \"Zhang P\", \"Zhang Y\", \"Bai J\"]","journal":"Diabetes research and clinical practice","publication_date":"2026-11-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To explore time-varying cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and transition-specific estimates obtainable from published outcome curves. [METHODS] Ten placebo-controlled cardiovascular outcome trials included 87,334 participants and eight GLP-1 RA regimens. Reconstructed major adverse cardiovascular event (MACE) data and all-cause mortality data, directly reconstructed for four trials and synthesised for four, informed a three-state model. Two trials contributed MACE data only. The model assumed no treatment effect on death before a first non-fatal MACE. Conventional random-effects meta-analysis provided a comparator. [RESULTS] Conventional meta-analysis yielded a MACE hazard ratio (HR) of 0.856 (95% confidence interval 0.810-0.905). Modelled transition HRs for first non-fatal MACE at 24 months ranged from 0.51 to 1.38; all 95% credible intervals included 1. Semaglutide posterior median curves suggested larger early reductions that attenuated over time. Mortality attribution depended on structural assumptions, and several sensitivity analyses showed incomplete convergence. [CONCLUSIONS] Conventional synthesis supported a class-level MACE reduction. Multi-state estimates suggested possible time-varying patterns but remained imprecise and assumption-dependent. These data did not establish a reliable efficacy hierarchy or empirically distinguish event prevention from post-event survival effects.","url":"https://pubmed.ncbi.nlm.nih.gov/42994759/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1428,"doi":"10.1007/s00210-026-06025-x","pmid":"42993217","nct_ids":"[]","title":"Disproportionality analysis of ventricular extrasystoles reported with semaglutide in VigiBase and the FDA Adverse Event Monitoring System","authors":"[\"Wu D\", \"Yang R\", \"Zeng J\", \"Bai Z\", \"Zhang C\", \"Fan X\", \"Zhou X\", \"Wu L\", \"Zhu S\", \"Akin I\", \"Zhou X\", \"Chang L\", \"Hashimoto K\", \"Wei Y\"]","journal":"Naunyn-Schmiedeberg's archives of pharmacology","publication_date":"2026-11-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide is widely used to treat type 2 diabetes and obesity and to reduce cardiovascular risk. However, its association with cardiac rhythm-related adverse-event reporting in routine clinical practice remains incompletely characterized. To investigate cardiovascular and rhythm-related adverse-event reporting associated with semaglutide, with a focus on ventricular extrasystoles, we conducted a disproportionality analysis of individual case safety reports from VigiBase and the FDA Adverse Event Monitoring System (AEMS; formerly the FDA Adverse Event Reporting System [FAERS]). Reports were included when semaglutide was recorded as a suspected drug, according to database-specific criteria. Cardiovascular outcomes were identified using Medical Dictionary for Regulatory Activities Preferred Terms. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) were calculated. A cross-database reporting signal was defined as at least three semaglutide-associated reports and a lower 95% CI bound exceeding 1 in each database. After deduplication and application of the predefined inclusion criteria, 1980 semaglutide-associated cardiovascular reports from VigiBase and 1754 from AEMS were included. Among the screened cardiovascular and rhythm-related preferred terms, ventricular extrasystoles was the only term that met the prespecified signal criterion in both databases. Ventricular extrasystoles, clinically corresponding to premature ventricular contractions, showed disproportionate reporting in VigiBase (ROR 1.77, 95% CI 1.31-2.40) and AEMS (ROR 1.37, 95% CI 1.00-1.88; unrounded lower CI bound > 1). Ventricular extrasystoles showed a consistent disproportionality signal across VigiBase and AEMS. Although spontaneous reporting data cannot establish incidence, causality, or prognostic significance, this finding warrants prospective investigation using systematic electrocardiographic assessment and ambulatory rhythm monitoring.","url":"https://pubmed.ncbi.nlm.nih.gov/42993217/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Competing interests: Dr. Hashimoto reports receiving research funding from Otsuka (Japan) outside the submitted work. All other authors declare no conflicts of interest. Disclaimer: The information presented in this article is based on data obtained from the WHO global individual case safety reports database (VigiBase®) maintained by the Uppsala Monitoring Centre (UMC). The authors alone are responsible for the interpretation and conclusions drawn from these data. The views expressed in this publication do not necessarily reflect the views of the UMC, the World Health Organization, or its member states. Role of the funder/sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1494,"doi":"10.1210/endrev/bnag044","pmid":"42989433","nct_ids":"[]","title":"Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Review of Preclinical and Human Data","authors":"[\"Braunstein EW\", \"Braunstein GD\"]","journal":"Endocrine reviews","publication_date":"2026-11-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Preclinical rodent studies showing a dose-dependent increase in thyroid C-cell hyperplasia and neoplasia with Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs), led the United States Federal Drug Administration to require a boxed warning contraindicating GLP-1RAs for patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome. However, neither primate oncogenicity studies nor patient clinical trials showed C-cell stimulation, calling into question the relevance of rodent models to humans. Indeed, rodents have a high rate of spontaneous thyroid C-cell tumors, a higher number of thyroid C-cells and GLP-1 receptors and use a different pathway from humans in MTC oncogenesis. Although, the majority of meta-analyses of randomized clinical trials and cohort studies using administrative, electronic medical record and/or registry databases report no clear association between GLP-1RA use and thyroid cancer development, pharmacovigilance database studies do demonstrate a positive relationship; however, this association can only be inferred as a possible signal rather than causation and is likely due to notoriety or reporting bias. Additionally, analysis of the overall trends of thyroid cancer incidence in the U.S. since the release of GLP-1RAs for patient use in 2005 show an early increase, probably due to overdiagnosis of papillary carcinoma (PTC); however, the relative proportion of MTC has actually decreased. Because the preponderance of data does not support a causative relationship between GLP-1RA use and MTC (or PTC), we conclude that the need for the boxed warning about the risk of C-cell neoplasia is no longer necessary.","url":"https://pubmed.ncbi.nlm.nih.gov/42989433/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:21+00:00","study_design":"pharmacovigilance","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cancer\", \"adverse_effects\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1504,"doi":"10.1080/19390211.2026.2752609","pmid":"42989960","nct_ids":"[]","title":"A Nature-Derived Peptide Promotes Satiety Hormone Response and Weight Loss In Vivo","authors":"[\"Abramov M\", \"Goldfarb E\", \"Haham D\", \"Akiva E\", \"van Klinken JW\", \"Barbash Z\"]","journal":"Journal of dietary supplements","publication_date":"2026-11-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The global rise of obesity highlights the critical need for effective weight-management strategies. GLP-1 receptor agonists have transformed obesity care, yet gastrointestinal intolerance, high cost, and weight regain after discontinuation highlight the need for complementary, orally available options. An alternative is to stimulate the body's own GLP-1 release through the nutrient-sensing GPCRs on enteroendocrine L cells that a meal engages. Using an AI-guided screen of common food proteins, we identified nature-derived peptides (NDPs): sequences native to edible proteins that were reproduced synthetically and engage these receptors. Unlike peptide drugs engineered for systemic exposure, NDPs are intended to act locally at the gut epithelium. Our lead, NDP-35 (from Coffea arabica), is a potent, selective GPR40 agonist (EC50 = 32.7 nM); in mice, it raised plasma GLP-1, GIP, and PYY while lowering hunger hormones, reproducing the coordinated satiety hormone response of a meal at minimal caloric cost. Over 28 days of oral dosing in diet-induced obese rats, NDP-35 reduced food intake and lowered body weight by ∼5%, versus a 3% gain in vehicle-treated animals; a subcutaneous semaglutide arm was included as a reference comparator and endpoint values were of similar magnitude to NDP-35. Terminal clinical chemistry and organ-weight markers showed no treatment-related changes over the dosing period. A structurally distinct peptide, NDP-45 (from banana), reproduced these effects. NDP-35 and NDP-45 are promising preclinical food-protein-derived peptide candidates that stimulate enteroendocrine hormone responses and reduce food intake and body weight in rodent models, warranting further evaluation as an oral approach to appetite and body-weight control.","url":"https://pubmed.ncbi.nlm.nih.gov/42989960/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:29+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1406,"doi":"10.1016/j.clnesp.2026.105216","pmid":"42988221","nct_ids":"[\"NCT06423599\"]","title":"Semaglutide versus diet-based weight loss in obesity and heart failure with reduced ejection fraction (FIT-HF): Protocol for a randomized controlled trial","authors":"[\"El-Sheikh M\", \"Bandholm T\", \"Jørgensen NB\", \"Ulrik CS\", \"Barløse M\", \"Møller S\", \"Siebner HR\", \"Grand J\", \"Barasa A\", \"Petersen M\", \"Madsbad S\", \"Yang Lee MM\", \"Dirksen C\", \"Hove JD\"]","journal":"Clinical nutrition ESPEN","publication_date":"2026-11-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND & AIMS] Obesity is common in heart failure with reduced ejection fraction (HFrEF), but the functional, mechanistic, and safety consequences of intentional weight loss remain uncertain. Incretin-based therapies improve symptoms and functional capacity in obesity-related heart failure with preserved ejection fraction, whereas evidence in HFrEF is limited, and prior glucagon-like peptide-1 receptor agonist trials have raised safety concerns. The FIT-HF trial tests whether semaglutide-based weight loss is superior to intensive diet-based weight loss for improving exercise capacity in adults with obesity and stable HFrEF. [METHODS] FIT-HF is an investigator-initiated, randomized, parallel-group, open-label, assessor-blinded, active-comparator superiority trial enrolling 100 adults with body mass index ≥30 kg/m2, left ventricular ejection fraction ≤40%, New York Heart Association class I-III symptoms, and stable guideline-directed heart failure therapy. Participants are randomized 1:1 to once-weekly subcutaneous semaglutide, titrated to a target dose of 2.4 mg, or low-calorie total dietary replacement of approximately 800 kcal/day for 8 weeks followed by a dietitian-led weight-maintenance program. Both groups receive lifestyle counseling, heart failure care, and structured physical training from week 16. Follow-up is 52 weeks. The primary endpoint is the adjusted between-group difference in change in weight-indexed peak oxygen uptake (VO2peak) from baseline to week 52, assessed by cardiopulmonary exercise testing. Supportive secondary endpoints include Kansas City Cardiomyopathy Questionnaire score, 6-min walk distance, left ventricular end-systolic volume assessed by cardiovascular magnetic resonance, high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide. Exploratory work packages assess safety, cardiac/pulmonary physiology, body composition, physical activity, and metabolic/biomarker responses. [DISCUSSION] FIT-HF is the first direct comparison of these weight-loss strategies in obesity and HFrEF, integrating VO2peak with multimodal phenotyping to interpret physiological profiles alongside achieved weight loss and body composition. [CLINICAL TRIAL REGISTRATION] European Clinical Trials Information System: European Union trial number: CT-2023-503753-35-01; ClinicalTrials.gov identifier: NCT06423599.","url":"https://pubmed.ncbi.nlm.nih.gov/42988221/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1408,"doi":"10.1007/s00535-026-02525-y","pmid":"42986409","nct_ids":"[]","title":"Annualized fibrosis dynamics in metabolic dysfunction-associated steatotic liver disease: a paired-biopsy cohort","authors":"[\"Kawanaka M\", \"Miyamoto K\", \"Murakami S\", \"Li J\", \"Liu Y\", \"Tanaka E\", \"Miyake N\", \"Adachi T\", \"Takeuchi Y\", \"Onishi H\", \"Nishino K\", \"Fushimi T\", \"Urata N\", \"Kawamoto H\", \"Otsuka M\"]","journal":"Journal of gastroenterology","publication_date":"2026-11-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Fibrosis stage is the strongest histologic determinant of outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), but annualized fibrosis dynamics under routine care remain insufficiently quantified. We characterized fibrosis progression rate (FPR) in a long-term, pre-incretin paired-biopsy cohort to provide reference data for emerging metabolic therapies. [METHODS] We analyzed 153 patients with MASLD who underwent repeat liver biopsy at a single center over a median interval of 5.9 years (range, 0.5-24). No patient received a GLP-1 receptor agonist or a dual GLP-1/GIP receptor agonist during follow-up. FPR was defined as the annualized change in fibrosis stage (stage/year). Factors associated with fibrosis improvement were examined using multivariable logistic regression. [RESULTS] Fibrosis improved in 38 patients (25%), remained stable in 66 (43%), and progressed in 49 (32%). FPR varied substantially among patients with improvement or progression, revealing bidirectional and heterogeneous fibrosis dynamics not captured by categorical staging alone. FPR shifted in parallel with MASLD activity score change and was more closely related to changes in hepatocellular ballooning and lobular inflammation than to steatosis. Male sex, advanced baseline fibrosis, and ≥5% body weight reduction were associated with fibrosis improvement, with the likelihood increasing as these factors accumulated. [CONCLUSION] In this real-world pre-incretin paired-biopsy cohort, fibrosis change under routine care was bidirectional and heterogeneous, with wide variation in annualized rate. These data provide a reference for evaluating how emerging metabolic therapies modify the longitudinal course of MASLD.","url":"https://pubmed.ncbi.nlm.nih.gov/42986409/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: Miwa Kawanaka has received consulting fees from Fujirebio, AbbVie Inc., and Souwakai. All other authors declare no conflicts of interest. Ethical approval: The Ethics Committee of Kawasaki Medical School approved the study (No. 3864–02), which was conducted in accordance with the Declaration of Helsinki. Consent to participate: The requirement for written informed consent was waived because existing clinical and histologic data were used. An opt-out procedure approved by the ethics committee was implemented.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"liver\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1409,"doi":"10.1093/ajhp/zxag376","pmid":"42985835","nct_ids":"[]","title":"NSAID initiation and risk for gastrointestinal bleeding in patients receiving GLP-1 receptor agonists: A retrospective cohort study","authors":"[\"Miller E\", \"Cantrell M\", \"Lund BC\"]","journal":"American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists","publication_date":"2026-11-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been purported to increase risk for gastrointestinal (GI) bleeding. Our objective was to determine whether GLP-1 RAs are associated with increased risk for GI adverse events following the initiation of a nonsteroidal anti-inflammatory drug (NSAID). [METHODS] This retrospective cohort study used national administrative data from the Veterans Health Administration to identify patients with type 2 diabetes who initiated an NSAID while concurrently receiving a GLP-1 RA or a comparator agent: a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) or a dipeptidyl peptidase-4 inhibitor (DPP-4i). The primary outcome measure was the incidence of a GI bleed or ulcer within 12 months of NSAID initiation. Cox proportional hazards regression was used to compare risk for GI bleeding or ulcer between GLP-1 RA recipients and the comparator groups while adjusting for confounders. A sensitivity analysis was conducted using GI bleed as a secondary outcome. [RESULTS] A total of 13,433 patients received a GLP-1 RA, 24,480 received an SGLT-2i, and 30,968 received a DPP-4i. The primary outcome occurred in 0.9% (n = 117) of patients receiving a concurrent GLP-1 RA, 1.0% (n = 243) of those receiving an SGLT-2i, and 1.0% (n = 308) of those receiving a DPP-4i. In adjusted regression analyses, no difference in risk for GI bleeding or ulcer was observed between GLP-1 RAs and either comparator (SGLT-2i: hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.68-1.07; DPP-4i: HR, 0.82; 95% CI, 0.66- 1.01). Similar nonsignificant results were observed for the secondary outcome. [CONCLUSION] We did not observe an increased risk for developing a GI bleed or ulcer within the year following NSAID initiation with concurrent GLP-1 RA therapy, relative to comparator agents.","url":"https://pubmed.ncbi.nlm.nih.gov/42985835/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1432,"doi":"10.1016/j.ejvs.2026.11.015","pmid":"42988105","nct_ids":"[]","title":"Associations between Antidiabetic Drug Classes and Aortic Aneurysm Risk in Patients with Type 2 Diabetes: A Nationwide Cohort Study","authors":"[\"Lu YW\", \"Joni Shao YH\", \"Hsu CY\", \"Hsiao CY\", \"Chen WT\", \"Shih CC\", \"Lip GYH\", \"Huang PH\"]","journal":"European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery","publication_date":"2026-11-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Aortic aneurysm (AA) is a potentially life threatening condition that often remains asymptomatic for prolonged periods. Although type 2 diabetes mellitus (T2DM) increases cardiovascular risk, epidemiological studies have paradoxically reported a lower incidence of AA in patients with T2DM. Antidiabetic therapies may contribute to this inverse association, but class specific effects remain unclear. This study evaluated associations between antidiabetic drug classes and incident AA. [METHODS] This was a nationwide, population based, retrospective cohort study of adults with T2DM in Taiwan's National Health Insurance Research Database between 2009 and 2022. Associations between antidiabetic drug classes and incident AA were evaluated using Cox proportional hazards models with time varying medication exposure, adjusted for demographic characteristics, diabetes severity, comorbidities, tobacco related diagnoses, and concomitant medications. Subgroup and sensitivity analyses were considered exploratory. [RESULTS] Among 3 295 564 adults with T2DM (mean age 60.0 years; 52.8% men) followed for 8.5 ± 4.7 years, 45.5% received at least three antidiabetic drug classes. In multivariable time varying Cox models, metformin (adjusted hazard ratio [aHR] 0.78, 95% confidence interval [CI] 0.75 - 0.82), thiazolidinediones (aHR 0.71, 95% CI 0.65 - 0.77), sulfonylureas/meglitinides (aHR 0.82, 95% CI 0.78 - 0.85), and α-glucosidase inhibitors (aHR 0.83, 95% CI 0.77 - 0.89) were associated with lower AA risk. DPP-4 inhibitors (aHR 0.95, 95% CI 0.90 - 1.00), sodium-glucose cotransporter 2 (SGLT2) inhibitors (aHR 0.90, 95% CI 0.81 - 1.00), and glucagon like peptide 1 receptor agonists (GLP-1RAs) (aHR 0.69, 95% CI 0.50 - 0.95) also showed inverse associations, whereas insulin use was associated with higher AA risk (aHR 1.14, 95% CI 1.08 - 1.20). The inverse associations of conventional oral antidiabetic agents remained robust across sensitivity analyses. In contrast, the inverse associations for DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1RAs were attenuated and no longer statistically significant in patients with an index date from 2011 onward. [CONCLUSION] In this nationwide T2DM cohort, conventional oral antidiabetic agents were consistently associated with a lower observed AA risk. Although newer glucose lowering therapies showed similar inverse associations, these findings were less robust and warrant cautious interpretation and prospective confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42988105/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1433,"doi":"10.1016/j.diabres.2026.113646","pmid":"42987980","nct_ids":"[]","title":"The effect of subcutaneous semaglutide injection on blood pressure: a systematic review and meta-analysis of randomized controlled trials","authors":"[\"Ahmadi N\", \"Zandi R\", \"Norouzi M\", \"Prabahar K\", \"Kashi A\", \"Basiri A\", \"Varkaneh HK\"]","journal":"Diabetes research and clinical practice","publication_date":"2026-11-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Hypertension remains a leading contributor to cardiovascular disease globally. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), reduces blood pressure in clinical trials, but the consistency and magnitude of this effect across populations is unclear. We conducted a systematic review and meta-analysis of placebo-controlled randomized trials reporting blood pressure changes in patients receiving subcutaneous semaglutide. MEDLINE, Web of Science, and Embase were searched through December 2025. Pooled weighted mean differences with 95% confidence intervals were calculated using random-effects inverse-variance models. Cochrane's RoB 2.0 assessed risk of bias, and the Grading of recommendations Assessment Development and Evaluation (GRADE) approach was used to evaluate the certainty of the evidence. Our meta-analysis included seven trials with approximately 20,000 patients. Semaglutide reduced systolic blood pressure (SBP) significantly compared with placebo across 11 arms (20,011 participants): weighted mean difference -3.46 mmHg (95% CI: -4.44 to -2.49; I2 = 29.5%; high certainty of evidence). A modest reduction in diastolic blood pressure (DBP) was also observed (-0.56 mmHg, 95% CI: -0.82 to -0.29; I2 = 0.0%; moderate certainty of evidence). However, sensitivity analysis revealed that the DBP effect was dependent on a single large study, with loss of significance upon its exclusion. Subcutaneous semaglutide produces meaningful SBP reduction across diverse patient populations, with minimal DBP changes. Blood pressure improvement represents one component of semaglutide's cardiometabolic benefits.","url":"https://pubmed.ncbi.nlm.nih.gov/42987980/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1417,"doi":"10.5826/mrm.2026.1137","pmid":"42979856","nct_ids":"[]","title":"Tirzepatide for the treatment of obstructive sleep apnea: from apnea-hypopnea index reduction to cardiometabolic risk mitigation-a narrative review","authors":"[\"Mesfin-Bireda S\", \"Hillman Urek K\"]","journal":"Multidisciplinary respiratory medicine","publication_date":"2026-11-04","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obstructive sleep apnea (OSA) is a chronic respiratory disorder with nocturnal oxygen desaturation that is often associated with multisystemic sequelae such as hypertension, cardiovascular diseases, and increased morbidity and mortality. Obesity has been proposed as a modifiable risk factor; hence, the recent shift in focus to investigating anti-obesity medications for the management of OSA. Tirzepatide is the first U.S. FDA-approved pharmacotherapy for the treatment of moderate-to-severe OSA in adults with obesity to be utilized in combination with low caloric intake and physical activity, given its prior success in managing type 2 diabetes (T2D) and obesity. [METHODS] This narrative review evaluates tirzepatide and the SURMOUNT-OSA trial program as the key contemporary anchors for the pharmacological treatment of OSA in adults with concurrent obesity. Because the randomized evidence base currently comprises a single pivotal trial program, the review centers on SURMOUNT-OSA and its prespecified endpoints along with post hoc analyses, supplemented by observational, modeling, and mechanistic studies. [RESULTS] In the SURMOUNT-OSA program, tirzepatide produced randomized, placebo-controlled reductions in the apnea-hypopnea index, sleep apnea-specific hypoxic burden, body weight, and systemic inflammation. The program was designed around respiratory and metabolic endpoints rather than clinical events, so it cannot support conclusions about mortality, cardiovascular, or renal outcomes. Favorable signals for those events, including all-cause mortality, major adverse kidney events, and major adverse cardiovascular events, come only from nonrandomized observational cohorts and are best regarded as directional and exploratory rather than definitive. [CONCLUSIONS] Tirzepatide may help frame OSA as a multifactorial and partially metabolically treatable disease and may represent a clinically meaningful expansion of treatment options alongside, rather than as a replacement for, established mechanical and procedural therapies. The available evidence is anchored in a single phase 3 trial program and limited by short follow-up and the absence of definitive comparative and long-term outcome data. Long-term durability of effect after discontinuation, generalizability beyond the SURMOUNT-OSA-eligible population, OSA-specific economic analysis, and head-to-head comparisons against CPAP remain the principal unsettled questions requiring dedicated long-term studies before firm clinical recommendations can be made.","url":"https://pubmed.ncbi.nlm.nih.gov/42979856/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"sleep\", \"mortality\", \"adverse_effects\", \"nutrition\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1442,"doi":"10.1111/dom.71511","pmid":"42978220","nct_ids":"[]","title":"Association Between Weight Loss on Incretin-Based Therapy and Cardiovascular Outcomes and Mortality: A Systematic Review and Meta-Regression","authors":"[\"Skelin M\", \"Perkov-Stipičin B\", \"Bračić V\", \"Škugor ZM\", \"Krečak I\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-11-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The primary aim was to evaluate, using aggregate-data meta-regression, whether body weight loss induced by incretin mimetic therapy is associated with reductions in three-point major adverse cardiovascular events (3P-MACE), individual cardiovascular outcomes and mortality. A secondary aim was to estimate the overall cardiovascular effects of incretin mimetics compared with placebo. [METHODS] A systematic review of placebo-controlled randomized trials was conducted using MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. Eligible trials reported cardiovascular hazard ratios (HRs) and weight changes. The primary analysis was an aggregate-data meta-regression, with the prespecified moderator defined as the placebo-adjusted percentage weight difference at the latest reported follow-up time point. Standard meta-analysis was performed to estimate overall treatment effects. [RESULTS] Sixteen randomized trials including 97 199 participants with and without diabetes were analysed. Meta-regression showed no statistically significant association between greater body weight loss and treatment HRs for 3P-MACE, cardiovascular or all-cause mortality, myocardial infarction, stroke and hospitalization for heart failure (HHF). These findings do not establish an individual-level or causal relationship. Meta-analysis showed significant reductions in 3P-MACE (15%), cardiovascular mortality (13%), all-cause mortality (12%), myocardial infarction (14%), stroke (13%) and HHF (10%). [CONCLUSION] Greater trial-level placebo-adjusted body weight loss was not significantly associated with lower treatment HRs for the cardiovascular and mortality outcomes examined, including 3P-MACE and HHF. These findings do not exclude an individual-level contribution of weight loss to cardiovascular benefit or establish causality. Individual-participant-level analyses are needed to clarify the relationship between weight loss and cardiovascular outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42978220/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1446,"doi":"10.1007/s40265-026-02420-z","pmid":"42977842","nct_ids":"[]","title":"Safety and Tolerability of Sodium-Glucose Cotransporter-2 Inhibitors: A State-of-the-Art Narrative Review","authors":"[\"Kunutsor SK\", \"Seidu S\"]","journal":"Drugs","publication_date":"2026-11-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have evolved from glucose-lowering agents to foundational therapies for the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease, with substantial benefits for cardiovascular, kidney, and survival outcomes. As their indications continue to expand, a comprehensive understanding of their safety and tolerability has become increasingly important for optimizing patient care. Building on our recent state-of-the-art review of glucagon-like peptide-1 receptor agonists, this review provides a contemporary synthesis of the evidence on the safety and tolerability of SGLT-2is. We critically appraise data from randomized controlled trials, cardiovascular and kidney outcome trials, pharmacovigilance databases, large observational studies, and systematic reviews and meta-analyses. The available evidence demonstrates that SGLT-2is have a favorable overall safety profile, with genital mycotic infections representing the most consistently observed adverse event. Volume depletion and euglycemic diabetic ketoacidosis remain clinically important but are uncommon and are largely preventable through appropriate patient selection, patient education, and temporary treatment interruption during high-risk clinical situations. Fournier's gangrene should be regarded as a very rare but serious complication requiring prompt recognition and treatment. In contrast, randomized trials and meta-analyses generally indicate a reduced risk of acute kidney injury, while evidence concerning fracture, lower-limb amputation, hepatotoxicity, pancreatitis, and cancer is less definitive. Although consistent class-wide increases in these latter outcomes have not been established, uncommon or agent-specific risks cannot be excluded, particularly where event numbers are small or follow-up is limited. Overall, treatment discontinuation because of adverse events is low across major cardiovascular, heart failure, and kidney outcome trials, supporting the excellent tolerability of this therapeutic class. Comparative evidence suggests only modest differences among individual SGLT-2is, although definitive conclusions remain limited by the absence of direct, large, randomized head-to-head trials. We also summarize practical strategies for adverse-event mitigation, monitoring, temporary treatment interruption, and individualized patient selection. As the clinical applications of SGLT-2is continue to broaden, ongoing pharmacovigilance, inclusive clinical trials, and comparative safety studies will be essential to further refine their benefit-risk profile and optimize their safe use across diverse patient populations.","url":"https://pubmed.ncbi.nlm.nih.gov/42977842/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of Interest: Setor K. Kunutsor and Samuel Seidu have no conflicts of interest that are directly relevant to the content of this article. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Declaration of Generative AI and AI-Assisted Technologies: During the preparation of this work, the author used the 4o version of ChatGPT, developed by OpenAI, as a language tool to refine the writing and enhance the clarity of the work. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article. Availability of Data and Material: This is a narrative review; no new scientific data were generated, and all data are within the paper. Code Availability: Not applicable. Author Contributions: SKK: conceptualization, methodology, data curation, formal analysis, investigation, original draft, writing (review and editing). SS: methodology, data curation, formal investigation, writing (review and editing).","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"pharmacovigilance","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cognition\", \"bone\", \"immune\", \"cancer\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1448,"doi":"10.1111/dom.71481","pmid":"42977570","nct_ids":"[]","title":"Bleeding and Thromboembolic Outcomes Following GLP-1 Receptor Agonist Initiation in Patients With Type 2 Diabetes and Atrial Fibrillation Receiving Direct Oral Anticoagulants: A Target Trial Emulation","authors":"[\"Du F\", \"Cicali B\", \"Singh Ospina NM\", \"Ruzieh M\", \"Schmidt S\", \"Jiao T\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-11-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Patients with atrial fibrillation (AF) and Type 2 diabetes (T2D) require coordinated stroke prevention and metabolic risk management. Direct oral anticoagulants (DOACs) are standard for stroke prevention, while glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in T2D. In DOAC users, GLP-1RA initiation may alter body weight and gastrointestinal physiology, potentially increasing DOAC exposure and thereby elevating bleeding risk. We aim to investigate the impact of GLP-1RA initiation on risks of thromboembolic disease and bleeding in patients with T2D and AF receiving DOACs. [MATERIALS AND METHODS] We emulated a target trial comparing GLP-1RA versus dipeptidyl peptidase-4 (DPP-4) inhibitor initiation. We identified Medicare beneficiaries aged ≥ 65 years with T2D and AF receiving DOACs. Randomization was emulated using 1:1 propensity score matching. Primary outcomes include thromboembolic disease and bleeding. Per-protocol effects were estimated using inverse-probability-censoring-weighted Cox proportional hazards models. [RESULTS] After matching, 930 patients were included in each group, with mean follow-up of 1 year. Mean age was 74.7 vs. 74.2 years, and 47.1% vs. 44.2% were women in the GLP-1RA vs. DPP-4 inhibitor groups. GLP-1RA initiation was associated with higher bleeding risk (HR 1.18, 95% CI: 1.03-1.36), lower all-cause mortality (HR 0.58, 95% CI: 0.36-0.95), and similar thromboembolic risk (HR 1.50, 95% CI: 0.22-10.43). [CONCLUSIONS] Among DOAC-treated patients with T2D and AF, GLP-1RA initiation was associated with a less favourable bleeding profile but no evident increase in thromboembolic risk. These findings support careful clinical monitoring and further studies incorporating body weight and renal function to inform individualized treatment.","url":"https://pubmed.ncbi.nlm.nih.gov/42977570/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"mortality\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1499,"doi":"10.1111/dom.71470","pmid":"42977546","nct_ids":"[]","title":"Semaglutide, Tirzepatide and Clinically Recorded Alcohol-Related Outcomes in Type 2 Diabetes: A Target Trial Emulation","authors":"[\"Tang H\", \"Zhang B\", \"Lu Y\", \"Lu Y\", \"Wang H\", \"Davis CN\", \"Kranzler HR\", \"Chen Y\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-11-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To compare the risk of incident alcohol use disorder (AUD) among adults with Type 2 diabetes (T2D) initiating semaglutide, tirzepatide or sodium-glucose cotransporter-2 inhibitors (SGLT2i). [MATERIALS AND METHODS] We conducted a target trial emulation using de-identified electronic health record data from the TriNetX research network (June 2022-January 2025). Adults with T2D newly initiating semaglutide, tirzepatide or an SGLT2i were included. The primary outcome was clinically recorded hospitalization or emergency department (ED) visits for AUD. Cox proportional hazards models with 1:1 propensity score matching (PSM) estimated hazard ratios (HRs) and 95% CIs. Sensitivity and subgroup analyses as well as secondary outcomes assessed the robustness of the findings. [RESULTS] During a mean follow-up of 0.81-1.02 years, the incidence rates (IRs) of clinically recorded hospitalization or ED visits for AUD were 2.42 versus 4.53 per 1000 person-years for semaglutide versus SGLT2i, with an HR of 0.54 (95% CI, 0.45-0.64). Similarly, the IRs were 2.34 versus 3.98 per 1000 person-years for tirzepatide versus SGLT2i, with an HR of 0.61 (95% CI, 0.46-0.83). In the direct comparison of semaglutide versus tirzepatide, IRs were 2.43 and 2.36 per 1000 person-years, respectively, with no difference in risk (HR, 0.98; 95% CI, 0.73-1.31). Results were consistent across sensitivity and subgroup analyses and secondary outcomes. [CONCLUSIONS] In adults with T2D, semaglutide and tirzepatide were associated with lower rates of clinically recorded AUD-related outcomes than SGLT2i, with no difference between the two GLP-1RA medications.","url":"https://pubmed.ncbi.nlm.nih.gov/42977546/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:23+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"addiction\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1419,"doi":"10.1016/j.bone.2026.118160","pmid":"42971377","nct_ids":"[]","title":"The effect of glucagon-like peptide-1 receptor agonists on bone metabolism: A systematic review and meta-analysis of randomized placebo-controlled trials of predominantly first-generation agents","authors":"[\"Safargar M\", \"Ahmadi N\", \"Prabahar K\", \"Zandi R\", \"Kord-Varkaneh H\"]","journal":"Bone","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiometabolic outcomes, but their isolated effects on human bone remodeling remain uncertain because prior syntheses pooled heterogeneous study designs and active antidiabetic comparators. This systematic review and meta-analysis quantified the effects of GLP-1RAs versus placebo on densitometric, biochemical, and inflammatory markers of bone metabolism in randomized controlled trials (RCTs). [METHODS] Scopus, Web of Science, Embase, and PubMed/MEDLINE were searched from inception through May 12, 2026 for randomized placebo-controlled trials of GLP-1RAs or dual incretin agonists administered for 12 to 52 weeks. Eleven trials provided compatible data for random-effects meta-analysis and one additional trial was synthesized narratively, comprising 11 trials of first-generation agents (exenatide, dulaglutide, liraglutide) and one trial of second-generation semaglutide (1.0 mg/week), with zero eligible placebo-controlled trials identified for semaglutide 2.4 mg/week or tirzepatide. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated for dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD), bone turnover markers, and high-sensitivity C-reactive protein (hs-CRP), and evidence certainty was rated using GRADE. [RESULTS] Compared with placebo, GLP-1RA treatment reduced lumbar spine BMD (WMD: -0.02 g/cm2, 95% CI: -0.03 to -0.00, I2 = 0.0%; 3 trials, N = 222; Moderate certainty) and increased the bone resorption marker C-terminal telopeptide (CTX) (WMD: 0.05 μg/L, 95% CI: 0.01 to 0.08, I2 = 72.5%; 6 trials, N = 439; Low certainty), while reducing serum hs-CRP (WMD: -0.49 mg/L, 95% CI: -0.97 to -0.00, I2 = 0.0%; 4 trials [5 arms], N = 340; Low certainty). No significant differences were observed for femoral neck BMD (WMD: 0.01 g/cm2, 95% CI: -0.02 to 0.04, I2 = 68.9%; 5 trials [6 arms], N = 323; Very Low certainty), total hip BMD (WMD: 0.00 g/cm2, 95% CI: -0.02 to 0.03, I2 = 70.8%; 5 trials [6 arms], N = 382; Low certainty), or procollagen type 1 N-terminal propeptide (P1NP) (WMD: -1.24 μg/L, 95% CI: -3.61 to 1.13, I2 = 0.0%; 5 trials, N = 399; Moderate certainty), and leave-one-out exclusion of the single semaglutide trial did not alter the direction or significance of any pooled estimate. [CONCLUSIONS] Treatment with predominantly first-generation GLP-1RAs over 12 to 52 weeks increases osteoclastic bone resorption and induces a small, borderline reduction in lumbar spine BMD while preserving hip BMD and lowering systemic inflammation. Because existing placebo-controlled RCTs largely reflect earlier-generation agents with moderate weight loss, these findings cannot be extrapolated to higher-potency anti-obesity therapies such as semaglutide 2.4 mg/week or tirzepatide, which require dedicated long-term skeletal safety trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42971377/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"lean_mass\", \"bone\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1456,"doi":"10.1111/dom.71506","pmid":"42972883","nct_ids":"[]","title":"Real-World Comparison of Cardiorenal Outcomes With SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists in Type 2 Diabetes","authors":"[\"Huang CH\", \"Wu JL\", \"Ling TC\", \"Yang AS\", \"Wu SH\", \"Huang CC\", \"Lai EC\", \"Chang YT\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To compare cardiorenal outcomes, mortality and safety between sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in adults with Type 2 diabetes (T2D). [MATERIALS AND METHODS] We conducted a retrospective, new-user cohort study using the TriNetX global federated health research network. We identified 249 237 propensity score-matched pairs (498 474 total patients) who initiated SGLT-2i or GLP-1 RA between 2018 and 2023. The primary outcome was a kidney failure/death composite, defined as kidney failure, dialysis, kidney transplantation or all-cause mortality. Secondary outcomes included composite cardiovascular events, mortality and safety profiles. [RESULTS] SGLT-2i initiation was associated with a lower risk of the kidney failure/death composite compared with GLP-1 RA (HR: 0.87, 95% CI: 0.85-0.89). For the kidney-specific component, SGLT-2i initiation was associated with a lower risk of kidney failure, dialysis or kidney transplantation (HR: 0.74, 95% CI: 0.71-0.78), while all-cause mortality was also lower (HR: 0.90, 95% CI: 0.88-0.93). The composite cardiovascular outcome (myocardial infarction, stroke, acute heart failure, cardiogenic shock, cardiac arrest or death) was broadly comparable between groups (HR: 0.98, 95% CI: 0.97-1.00). [CONCLUSIONS] SGLT-2i initiation was associated with lower risks of kidney failure-related outcomes and all-cause mortality compared with GLP-1 RA initiation, while cardiovascular outcomes were broadly comparable. These findings may inform individualized treatment selection in adults with T2D.","url":"https://pubmed.ncbi.nlm.nih.gov/42972883/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1458,"doi":"10.4274/balkanmedj.galenos.2026.2026-7-49","pmid":"42969666","nct_ids":"[]","title":"GLP-1 Receptor Agonists Versus Empagliflozin or Dapagliflozin in the MASLD-Heart Failure Phenotype: An Exploratory Propensity-Matched Cohort Study","authors":"[\"Gautam N\", \"Huynh TM\", \"Truong HH\", \"Duong N\"]","journal":"Balkan medical journal","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Treatment selection may confound observational comparisons of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with metabolic dysfunction-associated steatotic liver disease and heart failure (HF). [AIMS] To compare recorded outcomes between treatment groups and examine whether the associations persisted after restricting the analysis by agent and diabetes status and separating early and later outcome windows. [STUDY DESIGN] Retrospective, initiation-based, active-comparator cohort study (new-user design not verified). [METHODS] We used the TriNetX US Collaborative Network and a common index eligibility period from January 1, 2018, through June 2, 2026. The revised analyses were performed on September 12, 2026. An additional sensitivity analysis of acute HF excluded patients with this outcome before the start of the day 1-1825 window. The primary analysis compared semaglutide, liraglutide, or dulaglutide with empagliflozin or dapagliflozin using 1:1 propensity score matching and assessed outcomes during days 1-1825. Separate analyses of the broader GLP-1 RA group examined outcomes during days 1-90 and 91-1825 and among patients with type 2 diabetes and no recorded type 1 diabetes. We report endpoint-specific event proportions, risk differences, hazard ratios (HRs), 95% confidence intervals (CIs), and proportionality test results. [RESULTS] The primary analysis included 8,550 patients per group after matching. Mortality occurred in 599/8,514 (7.0%) versus 861/8,509 (10.1%); the HR was 0.607 (95% CI, 0.546-0.673). Coded acute HF diagnoses occurred in 1,217/8,550 (14.2%) versus 2,525/8,550 (29.5%); the HR was 0.398 (95% CI, 0.372-0.427), with evidence of non-proportional hazards. In separately matched descriptive interval analyses (8,489 patients per group), the HR for coded acute HF was 0.262 (95% CI, 0.236-0.291) during days 1-90 and 0.507 (95% CI, 0.469-0.548) during days 91-1825. The HR for acute kidney injury during the later interval was 0.740 (95% CI, 0.650-0.842). Among 5,709 matched pairs with type 2 diabetes and no recorded type 1 diabetes, the HR for coded acute HF was 0.431 (95% CI, 0.397-0.468), whereas the HR for ketoacidosis was 0.683 (95% CI, 0.455-1.025). No advantage was observed for acute pancreatitis in any analysis. In a separate analysis excluding patients with prior acute HF, the HR was 0.421 (95% CI, 0.362-0.489), with evidence of non-proportional hazards. Albumin and bilirubin remained imbalanced in a direction favoring the GLP-1 RA group; body mass index also remained imbalanced. [CONCLUSION] GLP-1 RA exposure was associated with lower observed hazards for several outcomes, and the association with coded acute HF was weaker after day 90. The early concentration and magnitude of this association make treatment channeling a plausible explanation, although this analysis cannot establish that explanation. These exploratory findings do not support causal inferences or treatment-preference conclusions and do not challenge randomized evidence supporting SGLT2i use in HF.","url":"https://pubmed.ncbi.nlm.nih.gov/42969666/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"mortality\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1459,"doi":"10.1097/hpc.0000000000000445","pmid":"42969445","nct_ids":"[]","title":"Semaglutide and Cardiovascular Death: a Systematic Review and Meta-Analysis Cardioprotective Efficacy of Semaglutide","authors":"[\"Marino G\", \"Aquilani S\", \"Di Fusco SA\", \"Concistrè A\", \"Nardi F\", \"Gabrielli D\", \"Imperoli G\", \"Colivicchi F\"]","journal":"Critical pathways in cardiology","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Cardiovascular death (CVD) remains a leading cause of global mortality. Although semaglutide reduces major adverse cardiovascular events (MACE), the consistency and exact magnitude of its standalone effect on CVD across various patient phenotypes require comprehensive evaluation. This meta-analysis systematically evaluated the clinical efficacy of semaglutide on CVD risk across randomized controlled trials (RCTs). [METHODS] PubMed, Embase, and ClinicalTrials.gov were searched up to July 2026 to identify RCTs comparing semaglutide with placebo in adults with type 2 diabetes mellitus (T2DM), overweight or obesity, heart failure with preserved ejection fraction (HFpEF) or chronic kidney disease, reporting CVD as a primary, secondary or exploratory outcome. Pooled hazard ratio (HR) and 95% confidence intervals (CI) were calculated using a random-effects restricted maximum likelihood (REML) model. Publication bias and study robustness were assessed via Egger's test, Begg's test, and trim-and-fill analysis. [RESULTS] Seven high-quality RCTs comprising 38412 patients were included. Semaglutide significantly reduced the risk of CVD by 17% compared with placebo (pooled HR = 0.83, 95% CI: 0.72-0.95; P = 0.01). Inter-study heterogeneity was low-to-moderate (I 2= 27.44%, P = 0.18). Subgroup analyses confirmed uniform benefits across different clinical phenotypes (T2DM; overweight or obesity without diabetes; and obesity-related HFpEF, with or without T2DM; P = 0.63) and administration routes (oral versus subcutaneous; P = 0.74). Meta-regression identified trial duration as a key moderator (R 2 = 85.27%, P = 0.089), whereas sex, age, BMI, HbA1c and concomitant SGLT2i therapy did not modify the treatment effect. Publication bias tests were non-significant, and trim-and-fill simulations confirmed the stability of the primary pooled estimate. [CONCLUSION] Semaglutide delivers a robust and consistent 17% reduction in CVD across diverse cardiometabolic populations, including patients with T2DM, overweight or obesity without diabetes, and obesity-related HFpEF. These findings strongly support its role as a foundational cardioprotective intervention, independent of baseline glycemic status or the administration route.","url":"https://pubmed.ncbi.nlm.nih.gov/42969445/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1463,"doi":"10.23876/j.krcp.26.241","pmid":"42968232","nct_ids":"[]","title":"Effect of combined sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonist therapy in patients with chronic kidney disease: a real-world analysis","authors":"[\"Ho CW\", \"Chuang MH\", \"Wu VC\", \"Tu YK\", \"Wu YC\", \"Chen JY\"]","journal":"Kidney research and clinical practice","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] This study aimed to evaluate the kidney, cardiovascular, and mortality outcomes of combined sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) therapy compared with SGLT2i monotherapy in patients with chronic kidney disease (CKD). [METHODS] Using TriNetX electronic health records, we compared patients initiating combined therapy with those initiating SGLT2i alone. Propensity score matching (1:1) was applied. The index date was defined as treatment initiation, with patients required to maintain the assigned treatment strategy during the first 6 months. Outcome follow-up began 6 months after the index date and continued to 2 years after the index date. Primary outcomes were major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE), and the secondary outcome was all-cause mortality. [RESULTS] Among 178,930 patients, 1,154 (0.65%) initiated combined therapy of SGLT2i and GLP-1RA, and 24,134 (13.49%) initiated monotherapy of SGLT2i. After matching, each group included 1,150 patients. Combined therapy was associated with a lower risk of MAKE (adjusted hazard ratio [aHR], 0.62; 95% confidence interval [CI], 0.48-0.80; p < 0.01) and all-cause mortality (aHR, 0.58; 95% CI, 0.40-0.83; p < 0.01) compared with SGLT2i alone. There was no significant reduction in risk of MACE (aHR, 0.88; 95% CI, 0.70-1.11; p = 0.29). [CONCLUSION] Among patients with CKD, initiation of combined SGLT2i and GLP-1RA therapy was associated with lower risks of MAKE and all-cause mortality compared with SGLT2i monotherapy. Further studies are needed to clarify effects on kidney and mortality outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42968232/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1470,"doi":"10.1021/acs.molpharmaceut.6c00761","pmid":"42969740","nct_ids":"[]","title":"PET Imaging of Dual GLP-1R and GIPR Targeting with [18F]AlF-NOTA-Asp2-Tirzepatide","authors":"[\"Tudi K\", \"Jie Z\", \"Chen Z\", \"Liao W\", \"Liu Y\", \"Tang G\"]","journal":"Molecular pharmaceutics","publication_date":"2026-11-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Tirzepatide is a clinical dual GLP-1R and GIPR agonist for type 2 diabetes and obesity, and non-invasive approaches to assess its in vivo biodistribution and systemic toxicity in living animals remain limited. Both receptors also serve as potential targets for neuroendocrine tumor imaging, and dual-target PET probes for simultaneous GLP-1R and GIPR detection are still lacking. Herein, we developed a novel PET probe [18F]AlF-NOTA-Asp2-tirzepatide via structural modification of tirzepatide. This probe successfully visualized the in vivo distribution of tirzepatide, which was primarily eliminated through the renal system. The C20 fatty diacid moiety caused elevated uptake in the heart, liver and blood due to enhanced albumin binding. In vitro assays verified its reliable GLP-1R and moderate GIPR binding affinity. Persistent tumor accumulation was observed in INS-1 and A549-GIPR xenografts, allowing effective tumor visualization. In summary, [18F]AlF-NOTA-Asp2-tirzepatide features facile radiolabeling and enables the clear visualization of tirzepatide in vivo, along with favorable dual-targeting performance, while excessive non-target uptake still needs to be optimized for further clinical translation.","url":"https://pubmed.ncbi.nlm.nih.gov/42969740/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:12+00:00","study_design":"cellular_in_vitro","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"cancer\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1336,"doi":"10.2500/aap.2026.47.260068","pmid":"42952036","nct_ids":"[]","title":"Association of type 2 diabetes, obesity, and metabolic syndrome with patient-reported response to aeroallergen subcutaneous immunotherapy: A real-world cross-sectional study","authors":"[\"Capellan Durante E\", \"Ilan I\", \"Choi J\", \"Cohen J\", \"Upad A\", \"Sullivan L\", \"Hudes G\", \"Ramesh M\", \"Ferastraoaru D\"]","journal":"Allergy and asthma proceedings","publication_date":"2026-11-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Although recent studies have examined the impact of metabolic diseases on the immune system, limited data exist on how these conditions and their treatments affect therapeutic approaches for atopic diseases, including subcutaneous immunotherapy (SCIT). Objective: The objective was to evaluate the association of type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome, and patient-reported clinical response to SCIT in a real-world setting. Methods: We conducted an observational cross-sectional study of adults receiving SCIT at Montefiore Medical Center, Bronx, New York, between July and September 2024. The SCIT response was assessed by using visual analog scale scores for overall allergic rhinitis (AR) symptoms, nasal congestion, rhinorrhea, and ocular symptoms, stratified by T2DM, obesity (body mass index ≥ 30 kg/m²), and metabolic syndrome. Results: Overall, 95 patients were included, with a mean ± standard deviation age of 51 ± 16 years, the majority being women (71%). Twenty-five patients (26%) had T2DM, 53 (56%) were obese, and 27 (28%) had metabolic syndrome. In the entire cohort, 67% had improvement in overall AR symptoms with SCIT, 72% in nasal congestion, 67% in rhinorrhea, and 63% in ocular symptoms. T2DM was associated with significantly reduced odds of overall symptom improvement (odds ratio [OR] 0.23 [95% confidence interval {CI}, 0.06-0.89]; p = 0.037). The patients with metabolic syndrome had significantly lower odds of improvement in overall AR symptoms (OR 0.21 [95% CI, 0.03-0.61]; p = 0.010), nasal congestion (OR 0.24 [95% CI, 0.06-0.88]; p = 0.036), and rhinorrhea (OR 0.22 [95% CI, 0.06- 0.75]; p = 0.019) while on SCIT. Use of metformin, insulin, sulfonylureas, or glucagon-like peptide-1 receptor agonists did not significantly influence the SCIT response. Conclusion: T2DM and metabolic syndrome may identify a subgroup of patients with lower improvement after SCIT. Prospective studies are needed to determine whether metabolic disorders predict SCIT-associated responsiveness.","url":"https://pubmed.ncbi.nlm.nih.gov/42952036/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"unknown","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"route\": null, \"dose\": \"various\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"immune\", \"metabolic\", \"ophthalmologic\"]","outcome_type":"intermediate","primary_outcome":"patient-reported response to subcutaneous immunotherapy on visual analog scale scores for overall allergic rhinitis symptoms, nasal congestion, rhinorrhea and ocular symptoms","endpoints":null,"effect_estimate":"For GLP-1 receptor agonists: no significant influence on the response to subcutaneous immunotherapy, with no estimate given. The reported estimates belong to the metabolic conditions, not to drug use: type 2 diabetes OR 0.23 [95% CI, 0.06-0.89]; p = 0.037 and metabolic syndrome OR 0.21 [95% CI, 0.03-0.61]; p = 0.010 for overall symptom improvement.","confidence_interval":"not reported in abstract","p_value":null,"sample_size":95,"follow_up":null,"direction":"null","population":"{\"mean_age\": 51, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"71% women\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed: 53 (56%) were obese, obesity defined as body mass index ≥ 30 kg/m²\", \"diabetes_status\": \"mixed: twenty-five patients (26%) had type 2 diabetes\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": \"allergic rhinitis treated with aeroallergen subcutaneous immunotherapy\", \"sample_size\": 95, \"inclusion_exclusion\": \"adults receiving subcutaneous immunotherapy at one medical centre in the Bronx, New York, between July and September 2024\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: adults receiving allergen immunotherapy, mean age 51 ± 16 years, of whom 53 of 95 (56%) were obese and twenty-five (26%) had type 2 diabetes; the population was selected for its allergic disease rather than for obesity or diabetes, and no result is reported separately for the patients who had neither.","mediation":"unlikely","mediation_notes":"unlikely: the reported GLP-1 receptor agonist result is null, so there is no effect whose mediation by weight loss or metabolic improvement could be judged (IN-062). No weight change or HbA1c data are reported for the drug users.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": 95, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"odds ratios with 95% confidence intervals and p values reported for the metabolic conditions, none for the GLP-1 receptor agonist result; 95 patients in total\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a cross-sectional study of treated users at one medical centre over three months, 95 patients, with patient-reported visual analog scale outcomes and no untreated comparator group, which IN-063 rates VERY_LOW as it does a case series. The GLP-1 receptor agonist comparison is reported only as not significant, with no estimate, confidence interval, p value or user count.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A single-centre cross-sectional study of 95 patients assessed over three months, with patient-reported visual analog scale outcomes; the GLP-1 receptor agonist finding is a secondary medication-use analysis reported without any estimate, and the authors say prospective studies are needed.","plain_summary":"This cross-sectional study at one New York medical centre asked 95 adults receiving allergen immunotherapy how well the treatment was working and compared the answers by metabolic condition and by medication. Mean age was 51 ± 16 years and 71% were women; 53 (56%) were obese and twenty-five (26%) had type 2 diabetes. Type 2 diabetes was associated with lower odds of overall symptom improvement (OR 0.23 [95% CI, 0.06-0.89]; p = 0.037) and so was metabolic syndrome (OR 0.21 [95% CI, 0.03-0.61]; p = 0.010), while use of GLP-1 receptor agonists, metformin, insulin or sulfonylureas was not linked to the response, with no estimate given for it. Being observational and cross-sectional, the study shows associations, not cause.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1464,"doi":"10.1016/j.cpcardiol.2026.103492","pmid":"42967552","nct_ids":"[]","title":"Association of GLP-1 receptor agonist and SGLT2 inhibitor use with outcomes in patients with type 2 diabetes undergoing pacemaker implantation","authors":"[\"Avidan Y\", \"Jonas M\", \"Hadar D\", \"Arena R\", \"Popovic D\", \"Kassem S\"]","journal":"Current problems in cardiology","publication_date":"2026-11-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Heart failure (HF) remains prevalent following pacemaker implantation, with patients with type 2 diabetes mellitus (T2DM) representing a particularly vulnerable population. Whether use of contemporary glucose-lowering therapies is associated with subsequent clinical outcomes has not been well characterized. We investigated the associations of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, individually and in combination, with post-implantation clinical outcomes. [METHODS] Electronic health records identified 3,609 patients with T2DM who underwent pacemaker implantation from 2016-2023. Based on peri-implantation medication dispensing, patients were classified as SGLT2i (n = 438), GLP-1RA (n = 193), combined therapy (n = 231), or neither (n = 2,747). Following a 90-day landmark period, three-year risks of all-cause mortality and HF hospitalization were evaluated using multinomial propensity score-based inverse probability of treatment weighting and Cox proportional hazards models. [RESULTS] Overall, 463 patients (12.8%) died. All treatment groups showed lower all-cause mortality than controls, with the greatest reduction observed in the combination therapy group (HR 0.41; 95% CI, 0.22-0.77; P = 0.006). HF hospitalization occurred in 295 patients (8.2%), significantly reduced in combination therapy (HR 0.35; 95% CI, 0.17-0.74; P = 0.006), with trends toward benefit in monotherapy groups. [CONCLUSIONS] Among patients with T2DM undergoing permanent pacemaker implantation, SGLT2i and GLP-1RA therapy were associated with lower all-cause mortality, while combined therapy was additionally associated with fewer HF hospitalizations. These findings support further evaluation of cardiometabolic therapies after pacemaker implantation in randomized trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42967552/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":650,"doi":"10.1016/j.lanepe.2026.101840","pmid":"42733510","nct_ids":"[]","title":"Integrating incretin-based therapies into comprehensive obesity care: an EASO position statement","authors":"[\"Correia JC\", \"Baker JL\", \"Boyland E\", \"Busetto L\", \"Fábryová L\", \"Helgason T\", \"Sbraccia P\", \"Woodward E\", \"Yumuk V\", \"Pataky Z\", \"European Association for the Study of Obesity (EASO)\"]","journal":"The Lancet regional health. Europe","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Incretin-based therapies have transformed obesity treatment, producing substantial weight loss and benefits across cardiometabolic outcomes. However, translating therapeutic efficacy into sustainable population-level benefit remains challenging across European healthcare systems that vary in workforce capability, multidisciplinary care, reimbursement, access, and monitoring infrastructure. We describe this mismatch as the EASO Integration Paradox: therapeutic innovation has advanced more rapidly than the health-system structures required for its optimal, equitable, and sustainable implementation. In this EASO Position Statement, we propose the EASO Integration Framework, a model for integrating incretin-based therapies into comprehensive obesity care. The framework is organized around five interdependent pillars: Right Patient, Right Care, Right Workforce, Right Data, and Right Access. We also outline a European research and implementation agenda focused on real-world evidence, harmonised monitoring, workforce development, pharmacovigilance, and equitable access. The challenge is no longer whether incretin-based therapies should be used, but how they should be implemented responsibly within comprehensive obesity care pathways.","url":"https://pubmed.ncbi.nlm.nih.gov/42733510/","source_name":"pubmed","source_tier":1,"coi_statement":"JCC reports honoraria from Novo Nordisk and Eli Lilly, with payments made to his institution, and support from Novo Nordisk for travel and congress registration. JLB reports consulting fees and honoraria from Novo Nordisk, with payments made to her institution, and serves as President-Elect and Trustee of the European Association for the Study of Obesity (EASO), without remuneration. EB declares no financial competing interests and serves as an EASO Trustee and Chair of a WHO Technical Advisory Group. LB reports consulting relationships with Novo Nordisk, Eli Lilly, Amgen, Boehringer Ingelheim, Recordati, Pfizer, and Roche, and honoraria from Rhythm. LF reports honoraria from Eli Lilly, Novo Nordisk, Zentiva, and Boehringer Ingelheim; participation on advisory boards for Eli Lilly, Novo Nordisk, and Boehringer Ingelheim; and unpaid leadership roles as President of the Slovak Obesity Association, EASO Vice President, Chair of the Obesitology Section of the Slovak Diabetes Society, and member of the Slovak Atherosclerosis Society. TH reports travel support from EASO to attend professional and scientific meetings in connection with his role as an EASO Trustee and serves as an EASO Trustee. PS reports consulting fees from Boehringer Ingelheim, Chiesi, Eli Lilly, Novo Nordisk, Roche, and Theras, and honoraria from Chiesi, Eli Lilly, Novo Nordisk, and Theras; all payments were made directly to him. EW declares no competing interests. VY serves as President and Trustee of EASO. ZP declares no competing interests.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"guideline","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"adverse_effects\"]","outcome_type":"none","primary_outcome":"a framework (the EASO Integration Framework) for integrating incretin-based therapies into comprehensive obesity care","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (obesity care scope; no BMI criterion stated)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: a position statement on obesity care, a condition the target population does not have; there is no study population.","mediation":"not_applicable","mediation_notes":"Not applicable: no outcome data.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Guideline / practice guidance\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: position statement with no new primary data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Several authors report honoraria, consulting fees, advisory-board roles or travel support from companies including Novo Nordisk, Eli Lilly and Boehringer Ingelheim; several hold EASO leadership roles; others declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Expert position statement proposing a framework, with no new outcome data in the abstract; its recommendations rest on expert consensus rather than a stated evidence review.","plain_summary":"This European Association for the Study of Obesity (EASO) position statement proposes a framework for building incretin-based drugs into comprehensive obesity care, organised around five pillars covering patients, care, workforce, data and access. It presents no new study data and sets out a European research and implementation agenda. Several authors report payments from companies including Novo Nordisk and Eli Lilly.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":860,"doi":"10.1002/hup.70066","pmid":"42803597","nct_ids":"[]","title":"Tirzepatide Initiation in Lithium-Treated Bipolar Disorder: Renal Biomarker Trajectories and Lithium Safety Signals Over 12 Months in a Real-World Cohort","authors":"[\"Rescalli MB\", \"Fagiolini A\", \"Carmellini P\", \"Pinzi M\", \"Castaldo F\", \"Cuomo A\"]","journal":"Human psychopharmacology","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To assess early renal and lithium-related safety and 12-month renal biomarker trajectories after tirzepatide initiation in lithium-treated adults with bipolar disorder. [METHODS] We retrospectively studied 23 adults at one centre. The principal 12-week renal safety measures were serum creatinine and derived CKD-EPI 2021 creatinine-based eGFR. Secondary outcomes included lithium, electrolytes, gastrointestinal symptoms, acute kidney injury meeting KDIGO creatinine criteria and discontinuation. Twelve-month trajectories and body-surface-area-unindexed eGFR were exploratory. [RESULTS] At 12 weeks, creatinine changed by -3 ± 12 μmol/L (p = 0.196), indexed eGFR by +2.6 ± 15.1 mL/min/1.73 m2 (p = 0.259) and lithium by +0.08 ± 0.17 mmol/L (p = 0.030). Among 20 on-treatment completers at 12 months, weight decreased by 17.7 ± 6.0%, creatinine by 12 ± 9 μmol/L, indexed eGFR increased by 13.0 ± 12.1 mL/min/1.73 m2 and unindexed eGFR by 4.5 ± 14.3 mL/min. Two patients had lithium > 1.2 mmol/L; one developed clinician-attributed symptomatic toxicity and discontinued tirzepatide. No acute kidney injury meeting KDIGO creatinine criteria could be confirmed from available records. [CONCLUSIONS] Co-prescription warrants structured monitoring and sick-day education. Creatinine-based eGFR changes during major weight loss do not establish renal benefit or exclude kidney injury.","url":"https://pubmed.ncbi.nlm.nih.gov/42803597/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"kidney\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"12-week change in serum creatinine and CKD-EPI 2021 creatinine-based eGFR (renal safety)","endpoints":null,"effect_estimate":"At 12 weeks creatinine changed by -3 ± 12 μmol/L (p = 0.196) and indexed eGFR by +2.6 ± 15.1 mL/min/1.73 m2 (p = 0.259), neither significant; lithium rose by +0.08 ± 0.17 mmol/L (p = 0.030). Among 20 completers at 12 months weight decreased by 17.7 ± 6.0% and indexed eGFR increased by 13.0 ± 12.1 mL/min/1.73 m2.","confidence_interval":null,"p_value":"creatinine p = 0.196; indexed eGFR p = 0.259; lithium p = 0.030","sample_size":23,"follow_up":"12 months","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"bipolar disorder treated with lithium\", \"sample_size\": 23, \"inclusion_exclusion\": \"lithium-treated adults with bipolar disorder starting tirzepatide, single centre\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: the population was selected for lithium-treated bipolar disorder rather than for obesity or diabetes; age, BMI, obesity and diabetes status are not reported in the abstract.","mediation":"possibly","mediation_notes":"Weight decreased by 17.7 ± 6.0% among 12-month completers, and the authors warn that creatinine-based eGFR changes during major weight loss neither show kidney benefit nor rule out injury; the analysis does not separate weight loss from other effects.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 23, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"12 months\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"no CI reported; mean ± SD with p values; 23 adults, 20 completers at 12 months\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: single-centre retrospective study of 23 adults with no comparison group.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Lithium rose at 12 weeks (p = 0.030); two patients had lithium > 1.2 mmol/L, one with clinician-attributed symptomatic toxicity who discontinued tirzepatide; no acute kidney injury meeting KDIGO creatinine criteria could be confirmed from available records.","limitations":"Small (23 adults), single-centre, retrospective study with no comparison group; the authors note that creatinine-based eGFR changes during major weight loss neither establish renal benefit nor exclude kidney injury.","plain_summary":"This retrospective study followed 23 adults at one centre who were taking lithium for bipolar disorder when they started tirzepatide. At 12 weeks creatinine and eGFR did not change significantly, but lithium levels rose (p = 0.030); two patients had lithium above 1.2 mmol/L and one stopped tirzepatide after symptomatic toxicity. Among 20 completers at 12 months weight decreased by 17.7 ± 6.0% and eGFR rose, which the authors say does not show kidney benefit. With no comparison group and a small sample, these are observations, not proof of cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":955,"doi":"10.1210/jendso/bvag224","pmid":"42857401","nct_ids":"[]","title":"Current review of glucagon-like peptide 1 receptor agonists and risk of nonarteritic anterior ischemic optic neuropathy","authors":"[\"Ruan F\", \"Gnana B\", \"Mei C\", \"Gong W\", \"Limaye S\", \"Kim D\", \"Person EA\"]","journal":"Journal of the Endocrine Society","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Emerging data has identified a potential association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and nonarteritic anterior ischemic optic neuropathy (NAION), a typically sudden, painless, and irreversible cause of optic nerve-mediated vision loss. This review synthesizes the current clinical, epidemiologic, and potential mechanism linking GLP-1RA-based therapies to NAION risk, informing balanced risk assessment and interdisciplinary clinical decision-making. A structured PubMed search was performed using terms including \"GLP-1 receptor agonist,\" \"semaglutide,\" \"liraglutide,\" \"tirzepatide,\" and \"nonarteritic anterior ischemic optic neuropathy,\" in addition to NAION risk factors, including disc-at-risk anatomy, type 2 diabetes, obstructive sleep apnea, hypertension, hyperlipidemia, renal disease, and ischemic heart disease. A small cup-to-disc ratio (\"disc-at-risk\") was found to be the most robust anatomical predictor of NAION. Systemic microvascular disease (diabetes, hypertension, hyperlipidemia) and conditions such as obstructive sleep apnea and end-stage renal disease were also linked to increased susceptibility to optic nerve head ischemia. Although data across electronic health records, national registries, and pharmacovigilance analyses suggest a very low absolute incidence of NAION, the use of GLP-1RAs demonstrates a statistically significant association with NAION development, yielding relative risk estimates between 1.2 and 4.3. At this time, the potential association between GLP-1RA therapy and NAION should be interpreted as a safety signal rather than a contraindication. Screening for disc-at-risk anatomy, consideration of prior NAION history, and patient counseling regarding acute visual symptoms may be warranted prior to initiation of therapy. As evidence evolves, collaboration between endocrinologists and ophthalmologists will be essential to support safe and effective patient care.","url":"https://pubmed.ncbi.nlm.nih.gov/42857401/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"narrative_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"sleep\", \"metabolic\", \"adverse_effects\", \"ophthalmologic\"]","outcome_type":"hard","primary_outcome":"risk of nonarteritic anterior ischemic optic neuropathy (NAION) with GLP-1RA use","endpoints":null,"effect_estimate":"Statistically significant association between GLP-1RA use and NAION, with relative risk estimates between 1.2 and 4.3 across health records, registries and pharmacovigilance analyses; very low absolute incidence","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a review whose underlying study populations are not described in the abstract.","mediation":"possibly","mediation_notes":"The abstract reports a harm association but no weight, glycaemic or mediation analysis; diabetes, hypertension, sleep apnoea and kidney disease are discussed as NAION risk factors, and the abstract does not say how they were separated from drug use.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI reported; range of relative risk estimates only\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: review of published clinical, epidemiologic and pharmacovigilance data with no new primary data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"GLP-1RA use is associated with NAION (relative risk estimates between 1.2 and 4.3) with very low absolute incidence; the authors treat it as a safety signal, not a contraindication.","limitations":"Review of a structured PubMed search, not described as systematic and with no pooled analysis; the underlying data are observational, registry and pharmacovigilance sources, and NAION risk factors such as diabetes and sleep apnoea overlap with reasons for GLP-1RA use.","plain_summary":"This review of published studies looked at whether GLP-1 receptor agonists are linked to NAION, a sudden, painless and irreversible form of vision loss. Across health records, national registries and pharmacovigilance data, GLP-1RA use was associated with NAION, with relative risk estimates between 1.2 and 4.3, while the absolute incidence was very low. The authors treat this as a safety signal rather than a reason not to prescribe; the underlying data are observational, so this is an association, not proof that the drugs cause NAION.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1034,"doi":"10.1016/j.xkme.2026.101516","pmid":"42890508","nct_ids":"[]","title":"Four Pillars in Type 2 Diabetes and Chronic Kidney Disease G4-G5: Mission Impossible-or Not Too Late to Start?","authors":"[\"Yamanouchi M\", \"Sawa N\", \"Furuichi K\", \"Wada T\"]","journal":"Kidney medicine","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The 4-pillar therapy-renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, the nonsteroidal mineralocorticoid receptor antagonist finerenone, and glucagon-like peptide 1 receptor agonists-is increasingly applied to improve kidney and cardiovascular outcomes in adults with type 2 diabetes and chronic kidney disease (CKD). However, landmark trials underpinning current recommendations largely enrolled participants down to estimated glomerular filtration rate thresholds of ∼20-30 mL/min/1.73 m2, leaving uncertainty in CKD G4-G5. This uncertainty contributes to an implementation gap in advanced CKD, which is as follows: missing pillars are often not initiated, therapies are interrupted during clinical complications, and they are not reinitiated once acute triggers resolve despite high absolute kidney and cardiovascular risk. This narrative review summarizes what current evidence does-and does not-support for initiating, continuing, temporarily withholding, discontinuing, and reinitiating each pillar in type 2 diabetes and CKD G4-G5. We integrate posthoc and subgroup analyses of landmark trials, meta-analyses, and pooled analyses, including low-estimated glomerular filtration rate strata and observational real-world data. The main practical message is that current evidence generally supports a monitoring-based approach to 4-pillar therapy in CKD G4, whereas decisions in CKD G5 remain more individualized and explicitly extrapolative. For clinicians, the key priority is to identify missing pillars, avoid unnecessary permanent discontinuation, and use structured reinitiation when clinically appropriate.","url":"https://pubmed.ncbi.nlm.nih.gov/42890508/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"narrative_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\"]","outcome_type":"none","primary_outcome":"what the evidence supports for initiating, continuing, withholding, discontinuing and reinitiating each of the four pillars, including GLP-1 receptor agonists, in type 2 diabetes with CKD G4-G5","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required (review scope)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD G4-G5 required (review scope)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with CKD G4-G5\", \"sample_size\": null, \"inclusion_exclusion\": \"adults with type 2 diabetes and CKD G4-G5 (review scope)\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review is about adults with type 2 diabetes and CKD G4-G5, conditions the target population does not have; no age or BMI data are given.","mediation":"not_applicable","mediation_notes":"Not applicable: a narrative review with no GLP-1 outcome result to assess.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: narrative review of post hoc and subgroup analyses, meta-analyses, pooled analyses and observational data, with no new primary data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Narrative rather than systematic review; the landmark trials largely enrolled people down to eGFR ∼20-30 mL/min/1.73 m2, so advice for CKD G4-G5 rests on post hoc, subgroup, pooled and observational data, and the authors call decisions in G5 explicitly extrapolative.","plain_summary":"This narrative review looks at four drug groups, including GLP-1 receptor agonists, for adults with type 2 diabetes and advanced chronic kidney disease (stages G4-G5). Drawing on post hoc and subgroup analyses of earlier trials, meta-analyses and observational data, it concludes that a monitoring-based approach is generally supported in G4, while decisions in G5 are more individual and extrapolated. It reports no new data and gives no effect estimate for GLP-1 drugs.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1123,"doi":"10.1002/edm2.70332","pmid":"42872607","nct_ids":"[]","title":"Real-World Metabolic Improvements in Women With and Without Polyendocrine Metabolic Syndrome via a Multidisciplinary Telehealth Care Platform","authors":"[\"Huddleston HG\", \"Blank R\", \"Sommers N\", \"Hellman N\", \"Ramallo F\", \"Pham T\", \"Lindquist K\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To evaluate metabolic outcomes in women with and without Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly Polycystic Ovary Syndrome (PCOS))) receiving multidisciplinary care through a women's health telehealth platform that combines physician and registered dietitian support. [METHODS] Retrospective cohort analysis of 919 women with BMI ≥ 25 initiating care in 2024, with ≥ 6 months follow-up (mean 9.6 months). Participants included 557 with PMOS and 362 without. Outcomes extracted from the electronic health record (EHR) included change in weight, HbA1c, HOMA-IR, fasting insulin, fasting glucose, ALT, AST and total cholesterol between baseline and last measured value. Linear regression models adjusted for baseline values of each outcome, age, BMI, race/ethnicity and follow-up time. [RESULTS] Significant improvements were observed across all metabolic markers for the group overall: HOMA-IR (-14.0%), fasting insulin (-15.6%), fasting glucose (-13.0%), HbA1c (-6.2%), ALT (-21.2%), AST (-25.5%), total cholesterol (-8.0%) and weight (-4.9%). PCOS status was not associated with differential improvement in any outcome after adjustment. GLP-1 receptor agonist use was associated with greater weight loss; however, improvements were also observed in the no-medication group. [CONCLUSIONS] Women with PCOS achieved metabolic improvements equivalent to those without PMOS through a multidisciplinary telehealth model despite presenting with a more adverse metabolic profile at baseline.","url":"https://pubmed.ncbi.nlm.nih.gov/42872607/","source_name":"pubmed","source_tier":1,"coi_statement":"H.G.H. is Chief Medical Advisor at Allara Health, receives research funding, and holds stock options in the company, in addition to her faculty appointment at UCSF. R.B., N.S., N.H., F.R. and T.P. are employees of Allara Health. K.L. received a consulting fee from Allara Health for statistical analysis. The authors' competing interests are noted in the Disclosure section above.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"no-medication group\", \"treatment_duration\": null}","domains":"[\"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":"change in weight, HbA1c, HOMA-IR, fasting insulin, fasting glucose, ALT, AST and total cholesterol from baseline to last measured value","endpoints":null,"effect_estimate":"whole cohort: HOMA-IR -14.0%, fasting insulin -15.6%, fasting glucose -13.0%, HbA1c -6.2%, ALT -21.2%, AST -25.5%, total cholesterol -8.0%, weight -4.9%; GLP-1 RA use associated with greater weight loss (no figure given); PCOS status not associated with differential improvement","confidence_interval":"not reported in abstract","p_value":null,"sample_size":919,"follow_up":"≥ 6 months (mean 9.6 months)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"women only (919 women)\", \"bmi_mean\": null, \"bmi_min\": 25, \"obesity_status\": \"required (overweight or obesity, BMI ≥ 25)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": \"women with BMI ≥ 25 starting multidisciplinary telehealth care, 557 with PMOS (formerly PCOS)\", \"sample_size\": 919, \"inclusion_exclusion\": \"women with BMI ≥ 25 starting care in 2024 with ≥ 6 months follow-up\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were women with BMI ≥ 25 (overweight or obesity), 557 of 919 with PMOS.","mediation":"not_applicable","mediation_notes":"Not applicable for the GLP-1 result, which is weight loss itself; models adjusted for baseline values, age, BMI, race/ethnicity and follow-up time, not for weight change.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 919, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"no-medication group\", \"follow_up_duration\": \"≥ 6 months (mean 9.6 months)\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; no effect size given for the GLP-1 comparison\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single retrospective EHR cohort; GLP-1 use was not randomised, its effect size is not reported, and several authors are tied to Allara Health.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"One author (H.G.H.) is Chief Medical Advisor at Allara Health, receives research funding and holds stock options; five authors are Allara Health employees and one received a consulting fee from Allara Health.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective electronic-record study without randomisation, using the last measured value; the GLP-1 comparison is secondary and unquantified in the abstract, and several authors are employed or paid by Allara Health.","plain_summary":"This records study followed 919 women with a BMI of 25 or more who started care on a women's health telehealth platform, 557 of them with PMOS (formerly called PCOS). Over a mean of 9.6 months, weight fell by 4.9% and blood-sugar, liver and cholesterol markers improved across the group, with no difference by PCOS status after adjustment. GLP-1 receptor agonist use was associated with greater weight loss, though women on no medication also improved; the GLP-1 difference is not quantified, and this is an association, not proof of cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1154,"doi":"10.1111/liv.70926","pmid":"42922180","nct_ids":"[]","title":"Taiwan GEST-TASL-TMASO Joint Position Statement in Managing Metabolic Dysfunction-Associated Steatotic Liver Disease and Obesity","authors":"[\"Cheng PN\", \"Lu CW\", \"Lin CL\", \"Chiang CH\", \"Yang HI\", \"Kao HH\", \"Wang CC\", \"Chou TJ\", \"Chang ML\", \"Hsiao TJ\", \"Peng CY\", \"Huang JF\", \"Chen TP\", \"Dai CY\", \"Yu ML\", \"Huang KC\", \"Kao JH\", \"Lin WY\", \"Liu CJ\"]","journal":"Liver international : official journal of the International Association for the Study of the Liver","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity share common pathogenesis and are increasingly relevant in clinical care. This joint statement addresses the need for comprehensive guidance in Taiwan for MASLD patients with obesity. The Gastroenterological Society of Taiwan, the Taiwan Association for the Study of the Liver, and the Taiwan Medical Association for the Study of Obesity conducted an evidence-based review, integrating epidemiological data, clinical trial outcomes, and expert consensus to develop position statements covering diagnosis, disease burden, pathogenesis, surveillance, and therapeutic strategies. MASLD prevalence in Taiwanese adults is 30%-45%, reaching 60%-70% in individuals with obesity, with similar high prevalence in children and adolescents. Obesity accelerates hepatic and extrahepatic disease progression, including cirrhosis, hepatocellular carcinoma, and cardiovascular complications. Lifestyle interventions, glucagon-like peptide-1 receptor agonists, resmetirom, and bariatric surgery demonstrate efficacy in improving hepatic and metabolic outcomes. Risk stratification using noninvasive tools such as Fibrosis-4 and vibration-controlled transient elastography effectively guides referral and management. A multidisciplinary, precision-based approach, integrating lifestyle modification, pharmacotherapy, surgical options, and risk stratification, is essential for effective MASLD management in patients with obesity, while research into artificial intelligence-driven biomarkers, gut microbiota modulation, and genetic factors represents future directions.","url":"https://pubmed.ncbi.nlm.nih.gov/42922180/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"guideline","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"liver\", \"cancer\", \"addiction\"]","outcome_type":"none","primary_outcome":"hepatic and metabolic outcomes (position statement, no primary outcome)","endpoints":null,"effect_estimate":"No numeric estimate; states that GLP-1 receptor agonists, among other options, demonstrate efficacy in improving hepatic and metabolic outcomes","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (statement scope: MASLD patients with obesity)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity\", \"sample_size\": null, \"inclusion_exclusion\": \"statement scope: MASLD patients with obesity in Taiwan\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the statement is scoped to patients in Taiwan who have metabolic dysfunction-associated steatotic liver disease together with obesity, which the target group does not have; no age, BMI or diabetes data are given. IN-062 makes a position statement scoped to such a population INDIRECT rather than UNKNOWN.","mediation":"not_applicable","mediation_notes":"not_applicable: the statement reports no outcome of its own, so there is no result whose mediation by weight loss could be judged (IN-063). It names GLP-1 receptor agonists among weight-directed therapies for a weight-related liver disease but gives no weight or glycaemic result.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Guideline / practice guidance\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no data reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a joint position statement from three Taiwanese societies, assembled from an evidence-based review of existing data and expert consensus. It contains no new primary outcome data, which section 3 rates NOT_RATED.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A joint position statement with no new primary data: its therapeutic claims rest on an evidence-based review and expert consensus, no estimates are given, and its scope is Taiwan and patients who have both MASLD and obesity.","plain_summary":"Three Taiwanese medical societies issued a joint position statement on managing metabolic dysfunction-associated steatotic liver disease in people who also have obesity, covering diagnosis, disease burden, pathogenesis, surveillance and treatment. It reports that the condition affects 30%-45% of Taiwanese adults and 60%-70% of people with obesity, and lists lifestyle interventions, GLP-1 receptor agonists, resmetirom and bariatric surgery as effective for liver and metabolic outcomes. The statement contains no new data and gives no estimate for any treatment, so it shows nothing about the size of any benefit.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1303,"doi":"10.1016/j.xkme.2026.101518","pmid":"42935909","nct_ids":"[]","title":"Diabetic Retinopathy Risk in SGLT2i vs GLP1RA Initiators With CKD Stages 3-4 and Type 2 Diabetes","authors":"[\"Hansrivijit P\", \"Patorno E\", \"Tesfaye H\", \"Wexler DJ\", \"Roh M\", \"Paik JM\"]","journal":"Kidney medicine","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[RATIONALE & OBJECTIVE] Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) have demonstrated renal and cardiovascular benefits among patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). However, their comparative effects on diabetic retinopathy (DR) outcomes in patients with CKD stages 3-4 and T2D remain unclear. This study aimed to demonstrate the effect of SGLT2i vs GLP1RA in this population. [STUDY DESIGN] Population-based, new-user, active comparator cohort study comparing SGLT2i versus GLP1RA initiators. Subjects were divided into 2 cohorts: (1) incident nonproliferative diabetic retinopathy (NPDR) and (2) DR progression cohort. [SETTING & STUDY POPULATION] Patients with CKD stages 3-4 and T2D across 3 US health care databases: Optum's de-identified Clinformatics Data Mart Database (2014-2024), Merative MarketScan (2014-2022), and Medicare Fee-for-Service (2014-2020). [SELECTION CRITERIA FOR STUDIES] Adults with a new prescription for either SGLT2i or GLP1RA without prior use in the preceding 365 days. The primary outcomes were incident NPDR and DR progression, identified through ICD-9/10 diagnosis codes and procedural codes for retinopathy treatments. [DATA EXTRACTION] Exposures, covariates, and outcomes were obtained from structured claims fields. [ANALYTICAL APPROACH] Both cohorts were analyzed using propensity score matching (1:1) to control for confounding. Incidence rates (IRs), rate differences, and hazard ratios (HRs) were calculated. [RESULTS] After 1:1 propensity score matching, the study included 20,135 matched patient pairs in the incident NPDR cohort and 7,763 matched pairs in the DR progression cohort. For incident NPDR, there was no difference between SGLT2i and GLP1RA groups (IR 29.55 vs 30.38 per 1,000 person-years, respectively; HR 0.98 [95% CI, 0.87-1.10]). Similarly, DR progression was not different between groups (IR 32.73 vs 35.24 per 1,000 person-years; HR 0.92 [95% CI, 0.76-1.12]). Subgroup analyses showed no differences in HRs for both incident NPDR and DR progression across multiple predefined subgroups. [LIMITATIONS] Potential for residual confounding, outcome misclassification, and limited generalizability to non-U.S. populations. [CONCLUSIONS] Initiation of SGLT2i was not associated with a different risk of incident NPDR or DR progression compared with GLP1RA among patients with CKD stages 3-4 and T2D. Additional studies with extended follow-up are needed to better characterize long-term retinal safety profiles of these therapies.","url":"https://pubmed.ncbi.nlm.nih.gov/42935909/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"sodium-glucose cotransporter-2 inhibitors (SGLT2i)\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\", \"ophthalmologic\"]","outcome_type":"hard","primary_outcome":"incident nonproliferative diabetic retinopathy and diabetic retinopathy progression","endpoints":null,"effect_estimate":"Incident nonproliferative diabetic retinopathy: IR 29.55 versus 30.38 per 1,000 person-years, HR 0.98 [95% CI, 0.87-1.10] for SGLT2i against GLP1RA. Retinopathy progression: IR 32.73 versus 35.24 per 1,000 person-years, HR 0.92 [95% CI, 0.76-1.12]. Subgroup analyses showed no differences across predefined subgroups.","confidence_interval":"95% CI, 0.87-1.10 for incident nonproliferative diabetic retinopathy; 95% CI, 0.76-1.12 for retinopathy progression","p_value":null,"sample_size":40270,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD stages 3-4 required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease stages 3-4 with type 2 diabetes\", \"sample_size\": 40270, \"inclusion_exclusion\": \"adults with CKD stages 3-4 and type 2 diabetes starting SGLT2i or GLP1RA with no prior use in the preceding 365 days, in three US claims databases\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all patients had chronic kidney disease stages 3-4 and type 2 diabetes, conditions the target group does not have; no age, sex or BMI data are reported, and IN-063 puts chronic kidney disease on the INDIRECT side.","mediation":"unlikely","mediation_notes":"unlikely: both hazard ratios are null, so there is no effect whose mediation could be judged (IN-062). Propensity score matching addresses confounding between the two drug classes, not mediation, and no weight or HbA1c data are reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 40270, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"sodium-glucose cotransporter-2 inhibitors (SGLT2i)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% confidence intervals reported with incidence rates per 1,000 person-years; 20,135 matched pairs in the incident NPDR cohort and 7,763 in the progression cohort; no event counts given\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a population-based, new-user, active-comparator cohort across three US claims databases with 1:1 propensity score matching, coded hard outcomes and confidence intervals. Large and carefully designed, but an individual observational study, which section 1 rule 2 caps at study tier 3, with residual confounding and outcome misclassification acknowledged by the authors.","funding_source":"NIAMS NIH HHS; NIDDK NIH HHS; FDA HHS","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The retinal safety outcomes are the study's endpoints: no difference between SGLT2i and GLP1RA initiators in incident nonproliferative diabetic retinopathy (HR 0.98 [95% CI, 0.87-1.10]) or retinopathy progression (HR 0.92 [95% CI, 0.76-1.12]).","limitations":"The authors note residual confounding, outcome misclassification and limited generalisability beyond the United States; the design is an observational claims-based cohort with no follow-up duration or event counts reported, and the comparison is between two drug classes rather than against non-use.","plain_summary":"This claims-based study in three US databases compared adults with chronic kidney disease stages 3-4 and type 2 diabetes who started an SGLT2 inhibitor with those who started a GLP-1 receptor agonist, matched one to one. In 20,135 matched pairs, new non-proliferative diabetic retinopathy occurred at 29.55 against 30.38 per 1,000 person-years (HR 0.98 [95% CI, 0.87-1.10]), and in 7,763 matched pairs retinopathy progression was also no different (IR 32.73 vs 35.24 per 1,000 person-years; HR 0.92 [95% CI, 0.76-1.12]), with no differences across predefined subgroups. Being observational, it shows an absence of difference between two drug classes rather than an effect of GLP-1 treatment against non-use, and the authors note possible residual confounding.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1368,"doi":"10.1002/pds.70517","pmid":"42946127","nct_ids":"[]","title":"Semaglutide and Panic Attacks: Active-Comparator Disproportionality Analysis, Temporal Assessment of Notoriety Bias and Evidence Triangulation in Post-Marketing Pharmacovigilance","authors":"[\"Melamed B\", \"Parsi-Zahabi M\", \"Omrani MA\", \"Baskaran BS\", \"Eddin LE\", \"Kermanshahi N\", \"Chalabianloo N\", \"Muanda FT\"]","journal":"Pharmacoepidemiology and drug safety","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] To evaluate how confounding by indication and notoriety bias shape the apparent semaglutide-panic attack signal in the FDA Adverse Event Reporting System (FAERS) and to interpret this signal using an evidence-triangulation framework integrating randomized and observational studies. [METHODS] We conducted an active-comparator restricted disproportionality analysis of FAERS (2018Q1-2024Q4), including individual case safety reports in which semaglutide, dulaglutide or empagliflozin was the primary suspect drug. Panic attack was identified using the MedDRA preferred term. Crude and adjusted reporting odds ratios (RORs, aRORs) with 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age, sex and indication (Type 2 diabetes, obesity/weight management). Notoriety bias was assessed using prespecified temporal analyses (analyses restricted to reports received before July 1, 2023 and a drug-by-period comparison of 2018-2022 with 2023-2024) and reporting proportions per 10 000 reports. A sensitivity analysis used all other primary-suspect drugs in FAERS as the reference set. In parallel, we conducted a systematic review (MEDLINE, Embase, CENTRAL to November 24, 2025) of randomized trials, cohort and cross-sectional studies, pharmacovigilance analyses and case reports reporting panic attacks or acute anxiety outcomes with semaglutide. [RESULTS] Among 33 267 semaglutide, 54 282 dulaglutide and 25 380 empagliflozin reports, panic attacks were recorded in 87 (0.26%), 28 (0.05%) and 13 (0.05%) cases, respectively. Crude RORs were 5.08 (95% CI 3.32-7.78) versus dulaglutide and 5.12 (95% CI 2.86-9.17) versus empagliflozin, attenuating after adjustment to 2.82 (95% CI 1.74-4.56) and 2.75 (95% CI 1.41-5.36). In the pre-warning period crude RORs were 2.24 (95% CI 1.23-4.07) and 2.15 (95% CI 1.00-4.58), attenuating to 1.38 (95% CI 0.69-2.75) and 1.14 (95% CI 0.48-2.68) after adjustment. Panic-attack reports per 10 000 semaglutide reports rose from 6.7 in 2018-2022 to 42.0 in 2023-2024 (drug-by-period interaction p = 0.007). Against all other primary-suspect drugs, the aROR was 1.48 (95% CI 1.18-1.87) overall and 0.76 (95% CI 0.48-1.18) before July 1, 2023. Across 12 studies, randomized trials and active-comparator observational cohorts did not show a consistent increase in panic attacks or anxiety-related outcomes. [CONCLUSIONS] Crude FAERS analyses suggested a semaglutide-panic attack signal that attenuated after adjustment was no longer significant before the July 2023 regulatory communication and rose sharply thereafter in a pattern consistent with notoriety bias. Triangulation with randomized trials and active-comparator observational studies does not support a consistent pharmacological association. Disproportionality analyses are hypothesis-generating and cannot estimate incidence or establish causality. This case study illustrates how active-comparator design, temporal assessment of notoriety bias and evidence triangulation can improve the interpretation of post-marketing safety signals.","url":"https://pubmed.ncbi.nlm.nih.gov/42946127/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"dulaglutide and empagliflozin as active comparators, with all other primary-suspect drugs in FAERS as a sensitivity reference set\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"panic attack, identified by the MedDRA preferred term","endpoints":null,"effect_estimate":"Crude reporting odds ratios 5.08 versus dulaglutide and 5.12 versus empagliflozin, attenuating after adjustment to 2.82 and 2.75. Restricted to reports before July 1, 2023, crude RORs were 2.24 and 2.15, attenuating to 1.38 and 1.14 after adjustment. Against all other primary-suspect drugs the aROR was 1.48 overall and 0.76 before July 1, 2023. Reports per 10 000 semaglutide reports rose from 6.7 in 2018-2022 to 42.0 in 2023-2024 (drug-by-period interaction p = 0.007). Across 12 studies, trials and active-comparator cohorts showed no consistent increase.","confidence_interval":"95% CI 1.74-4.56 for the adjusted ROR versus dulaglutide and 95% CI 1.41-5.36 versus empagliflozin; 95% CI 0.69-2.75 and 95% CI 0.48-2.68 for the same comparisons before July 1, 2023","p_value":"drug-by-period interaction p = 0.007","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": \"individual case safety reports in FAERS from 2018Q1 to 2024Q4 in which semaglutide, dulaglutide or empagliflozin was the primary suspect drug\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the units are spontaneous FAERS reports and no age, sex, BMI or diabetes distribution is given for the reported cases; type 2 diabetes and obesity/weight management appear only as indication categories adjusted for, and a covariate is not the population (IN-062).","mediation":"possibly","mediation_notes":"possibly, by the no-data default: no weight change, HbA1c or mediation analysis is reported, and adjustment for age, sex and indication addresses confounding, not mediation. The authors' own explanation for the signal's rise is notoriety bias after the July 2023 regulatory communication.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"dulaglutide and empagliflozin as active comparators, with all other primary-suspect drugs in FAERS as a sensitivity reference set\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"95% confidence intervals reported throughout; panic attacks in 87, 28 and 13 reports for semaglutide, dulaglutide and empagliflozin\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a pharmacovigilance disproportionality analysis of spontaneous reports, which section 3 rates VERY_LOW. The active-comparator design and reported confidence intervals strengthen it against a crude signal, but reporting odds ratios cannot estimate incidence or establish causality, as the authors state, and the size of the signal moves with the reporting period.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Panic attacks were recorded in 87 (0.26%) semaglutide reports, 28 (0.05%) dulaglutide reports and 13 (0.05%) empagliflozin reports; adjusted reporting odds ratios were 2.82 and 2.75 over the whole period but 1.38 and 1.14 before July 1, 2023.","limitations":"A disproportionality analysis of spontaneous reports, which the authors say is hypothesis-generating and cannot estimate incidence or establish causality; reporting rose sharply after the July 2023 regulatory communication, a pattern consistent with notoriety bias, and residual confounding by indication remains despite adjustment.","plain_summary":"This analysis counted panic-attack reports in the FDA's adverse event reporting system from 2018Q1 to 2024Q4, comparing semaglutide with two drugs used for the same conditions. Panic attacks were recorded in 87 (0.26%) of 33 267 semaglutide reports, 28 (0.05%) of 54 282 dulaglutide reports and 13 (0.05%) of 25 380 empagliflozin reports. Crude reporting odds ratios of 5.08 and 5.12 fell after adjustment to 2.82 (95% CI 1.74-4.56) and 2.75 (95% CI 1.41-5.36), and to 1.38 (95% CI 0.69-2.75) and 1.14 (95% CI 0.48-2.68), no longer significant, among reports received before July 1, 2023; reports per 10 000 semaglutide reports then rose from 6.7 in 2018-2022 to 42.0 in 2023-2024. Across 12 studies, randomized trials and active-comparator observational cohorts did not show a consistent increase. Report counts cannot measure how often an event happens or show cause.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1444,"doi":"10.1111/1753-0407.70296","pmid":"42978062","nct_ids":"[]","title":"Body Mass Index, Cardiometabolic Treatment Patterns and Multifactorial Risk-Factor Control in Chinese Adults With Type 2 Diabetes: A Multicenter Cross-Sectional Study","authors":"[\"Yan J\", \"Yang W\", \"Cai X\", \"Liu M\", \"Li Y\", \"Ji Q\", \"Feng B\", \"Tong N\", \"Ji L\"]","journal":"Journal of diabetes","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] To examine medication use and simultaneous achievement of glycemic, blood pressure and lipid targets across body mass index (BMI) categories in Chinese adults with Type 2 diabetes. [METHODS] This BMI-focused secondary cross-sectional analysis included 8590 adults with evaluable BMI recruited from 60 hospitals in the iCaReMe China Registry. The primary comparison was obesity versus normal weight for simultaneous achievement of HbA1c < 7.0%, blood pressure < 130/80 mmHg and LDL cholesterol < 2.6 mmol/L. Missing data were handled by multiple imputation (20 datasets; 20 iterations per chain), and associations were estimated with center-clustered generalized estimating equations (GEE). [RESULTS] The cohort comprised 99 (1.2%) adults with underweight, 2725 (31.7%) normal weight, 3663 (42.6%) overweight, and 2103 (24.5%) obesity. Among 6683 with all three observed components, 332 (5.0%) achieved the composite. Compared with normal weight, the pooled adjusted OR for obesity was 0.55 (95% CI 0.39-0.78); each 1-kg/m2 higher BMI was associated with an OR of 0.93 (0.90-0.96). For obesity, component-specific ORs were 0.72 (0.61-0.85) for HbA1c, 0.47 (0.40-0.55) for blood pressure and 1.05 (0.91-1.22) for LDL-C. Sensitivity analyses supported the composite finding, with no evidence of nonlinearity (p = 0.904). [CONCLUSIONS] Obesity was associated with lower odds of simultaneous target attainment, with component-specific associations for glycemia and blood pressure but not LDL-C. GLP-1 receptor agonists and SGLT2 inhibitors were used more often at higher BMI; these prescribing patterns do not establish treatment effectiveness. [TRIAL REGISTRATION] ChiCTR2300073764.","url":"https://pubmed.ncbi.nlm.nih.gov/42978062/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1445,"doi":"10.1002/edm2.70383","pmid":"42977998","nct_ids":"[]","title":"Complication Prevention Beyond Glycaemic Control in Type 2 Diabetes: Cumulative Metabolic Exposure, Organ Vulnerability and Treatment Durability","authors":"[\"Sztanek F\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Type 2 diabetes is a progressive multisystem disorder in which long-term complication burden reflects more than contemporaneous glycaemic control. Age at onset, previous metabolic exposure, obesity-related risk, organ injury, treatment safety and the capacity to sustain effective care interact across the disease course. [METHODS] This critical narrative review synthesised targeted PubMed/MEDLINE searches, international guidance, landmark and contemporary randomised trials, longitudinal cohorts, validated risk models and clinically influential reviews. A targeted update search was completed through 22 September 2026. [RESULTS] The evidence supports a clinically ordered approach in which immediate treatment-related hazards are considered first, followed by established organ disease or a dominant preventable outcome, residual modifiable cardiometabolic exposure, treatment durability and the care systems required to translate evidence into sustained benefit. Historical trials established the importance of glycaemic, blood-pressure and lipid management and coordinated multifactorial intervention. Contemporary SGLT2 inhibitor and incretin-based trials add direct cardiovascular, heart-failure and kidney outcome evidence in defined populations, while MASH trials provide emerging histological evidence. HbA1c, validated risk equations and organ-specific pathways retain their established roles. [CONCLUSIONS] The proposed framework is interpretive rather than predictive. It does not assign numerical weights or treatment thresholds but aims to identify the preventable outcome that should take priority, the intervention supported by the most relevant evidence and whether that intervention can be implemented safely and durably.","url":"https://pubmed.ncbi.nlm.nih.gov/42977998/","source_name":"pubmed","source_tier":1,"coi_statement":"The author declares no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1480,"doi":"10.1111/sms.70393","pmid":"42986000","nct_ids":"[\"NCT06478173\"]","title":"Effects of Multicomponent Training on Body Composition and Cardiorespiratory Fitness in Adults With Type 2 Diabetes: A Randomized Controlled Trial","authors":"[\"Skoradal MB\", \"Kristiansen J\", \"Póvoas S\", \"Johannesen HL\", \"Ellingsgaard H\", \"Olsen HW\", \"Mohr M\", \"Sjúrðarson T\"]","journal":"Scandinavian journal of medicine & science in sports","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"We investigated whether 14 weeks of multicomponent training delivered as small-sided soccer improves body composition, cardiorespiratory fitness, and metabolic outcomes in adults with type 2 diabetes. Adults aged 40-70 years (n = 111) were randomized to exercise (n = 66; three 60-min sessions per week) or usual care (n = 45). Constrained linear mixed models estimated between-group differences in change. No between-group difference was detected in the primary outcome, lean body mass (0.04 kg, 95% CI -0.97 to 1.05), or in fat mass, body fat percentage, or HbA1c. Compared with usual care, exercise produced greater increases in relative VO2peak (between-group difference: 2.80 mL·kg-1·min-1, 95% CI 1.69 to 3.92), absolute VO2peak (237 mL/min, 95% CI 143 to 331), and Yo-Yo Intermittent Endurance Level 1 test performance (122 m, 95% CI 12 to 232). Exploratory analyses showed lower C-peptide (-10.3%, 95% CI -19.0 to -0.6) and HOMA2-IR (-10.8%, 95% CI -20.1 to -0.6), and higher HOMA2-%S (+12.2%, 95% CI 0.6 to 25.1), in the exercise group relative to usual care. Exploratory three-way interaction tests provided no clear evidence that glucagon-like peptide-1 receptor agonist (GLP-1RA) use modified the effects on lean body mass, fat mass, or absolute VO2peak. Small-sided soccer improved cardiorespiratory fitness, whereas a benefit for lean body mass was not demonstrated. The metabolic findings require confirmation. Trial Registration: ClinicalTrials.gov identifier: NCT06478173.","url":"https://pubmed.ncbi.nlm.nih.gov/42986000/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:16+00:00","study_design":"rct","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"lean_mass\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1512,"doi":"10.1111/jne.70308","pmid":"42985994","nct_ids":"[\"NCT04687514\"]","title":"Effects of glucagon-like peptide-1 analogs on prolactin levels: A secondary analysis of a randomized, double-blind, placebo-controlled crossover trial","authors":"[\"Reber V\", \"Mueller CD\", \"Lengsfeld S\", \"Probst L\", \"Werlen L\", \"Allen R\", \"Emara Y\", \"Bathelt C\", \"Winzeler B\"]","journal":"Journal of neuroendocrinology","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Prolactin (PRL) is involved in the modulation of sexual function. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been proposed to modulate reward-related processes beyond their effects on appetite, including sexual desire. In our previously published randomized parent trial of dulaglutide and sexual desire, we hypothesized that any potential effect on sexual desire could involve changes in PRL concentrations. Predefined secondary analysis of a single-center randomized, double blind, placebo-controlled, crossover trial involving 24 healthy eugonad men of normal weight (BMI 18.5-25 kg/m2 or BMI 25.1-30 kg/m2 and waist circumference <102 cm). PRL concentrations were the primary outcome of the present analysis and were measured at baseline and after 4 weeks of dulaglutide (1.5 mg s.c. weekly) and placebo treatment, alongside weight, appetite, and sexual desire. Median age of participants was 24.5 years (IQR [21.0, 29.0]), median BMI was 23.9 kg/m2 (IQR [22.2, 25.0]). PRL levels changed by -31.1 mU/L (SD 87.0 mU/L) on dulaglutide and +44.6 mU/L (SD 113.1 mU/L) on placebo over 4 weeks (estimated difference: -149.3 mU/L; 95% CI: [-298.5, -0.1]). On dulaglutide treatment, reductions in PRL correlated weakly with weight loss (r = 0.25), and more than half of participants (13/24) showed parallel decreases in PRL and appetite scores. Regarding sexuality, we found no association of PRL levels and sexual desire. Four weeks of dulaglutide treatment reduced PRL concentrations compared with placebo in healthy men. These findings may point to broader neuroendocrine effects of GLP-1 receptor activation and warrant further investigation. Trial registration: ClinicalTrials.gov NCT04687514.","url":"https://pubmed.ncbi.nlm.nih.gov/42985994/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:30+00:00","study_design":"crossover_trial","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"addiction\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1514,"doi":"10.1002/edm2.70381","pmid":"42967597","nct_ids":"[]","title":"Severe Infection Outcomes With SGLT2 Versus DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Active-Comparator Meta-Analysis of Real-World Cohorts","authors":"[\"Huang YM\", \"Wang JH\", \"Huang WT\", \"Hsu JZ\", \"Teh SH\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] To update and methodologically refine the synthesis of real-world evidence on severe infection outcomes with sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i), emphasising limits of causal interpretation. [METHODS] PubMed, Embase, Scopus and CENTRAL were searched from inception through 29 June 2026. Quantitative synthesis was restricted to DPP-4i active-comparator estimates. Incident pneumonia and sepsis were prespecified co-primary outcomes. Hazard ratios and incidence rate ratios were pooled as related but non-identical estimands using restricted maximum likelihood with modified Hartung-Knapp inference, with leave-one-out, prediction-interval and effect-measure-stratified analyses. ROBINS-I and GRADE were applied. [RESULTS] Eighteen cohorts were included; the 11 contributing quantitatively were all at moderate risk of bias. For incident pneumonia (five studies), the pooled ratio was 0.65 (95% CI: 0.55-0.75; prediction interval 0.45-0.93; I2 = 89.8%; very low certainty); omitting one multinational cohort whose follow-up began 2 years after drug initiation yielded 0.61 (0.56-0.67; I2 = 0%). For incident sepsis (five studies), the prediction interval crossed the null (0.38-1.13); the exploratory pooled ratio was 0.65 (0.53-0.80; I2 = 90.6%, and 88.1%-92.4% after every omission; very low certainty). Hazard-ratio-only point estimates were similar, although the sepsis estimate was imprecise (95% CI including 1.0). Two cohorts reported identical, unpooled estimates for infection-related hospitalisation (0.74 each; low certainty). Comparisons with GLP-1 receptor agonists did not show a consistent lower-risk pattern across four cohorts, two in selected populations, and randomised-trial syntheses have not shown a consistent class-wide preventive effect. [CONCLUSIONS] The available evidence did not suggest an increased average risk of severe infection with SGLT2i compared with DPP-4i. Given low to very low certainty and substantial heterogeneity, the lower pooled estimates should not be interpreted as a preventive effect. [REVIEW REGISTRATION] PROSPERO: CRD420261390509.","url":"https://pubmed.ncbi.nlm.nih.gov/42967597/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:33+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1274,"doi":"10.1016/j.biopha.2026.120029","pmid":"42966342","nct_ids":"[]","title":"Association of GLP-1 receptor agonist therapy with cardiovascular outcomes in patients with MASLD: A translational study","authors":"[\"Yang CC\", \"Wu JY\", \"Ko YM\", \"Wang SC\", \"Cheng YY\", \"Yu ML\", \"Chang WT\"]","journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","publication_date":"2026-10-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) are at increased risk of adverse cardiovascular outcomes, potentially involving systemic metabolic dysfunction and cardiac remodeling. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve metabolic dysfunction in MASLD; however, their associations with cardiovascular outcomes and effects on MASLD-associated cardiac remodeling remain incompletely understood. In this translational study, we integrated a real-world TriNetX cohort of patients with MASLD and T2D with complementary experimental studies in a mouse model of MASLD. Following propensity score matching, 42,910 patients were included in each treatment group. GLP-1 RA therapy was associated with a lower risk of the primary composite cardiovascular outcome compared with sulfonylurea therapy (hazard ratio 0.87, 95% confidence interval 0.84-0.91; P < 0.001), although this association was not statistically significant in 90-day and 180-day landmark analyses. In Western diet-fed mice, GLP-1 RA treatment improved selected indices of cardiac function and attenuated cardiomyocyte hypertrophy. Although myocardial fibrosis was numerically reduced, the difference compared with vehicle-treated mice was not statistically significant (P = 0.28). Molecular analyses showed reduced expression of fibrosis- and extracellular matrix remodeling-related markers, including CTGF, TGF-β1, and vimentin. Collectively, GLP-1 RA therapy was associated with lower cardiovascular risk in the primary observational analysis, although this finding was not consistently supported by sensitivity analyses. Complementary experimental findings suggest improvements in selected cardiac functional indices and changes in fibrosis-associated molecular remodeling, warranting further investigation.","url":"https://pubmed.ncbi.nlm.nih.gov/42966342/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest None","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"sulfonylurea therapy in the patient cohort; vehicle-treated mice in the animal experiments\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"liver\"]","outcome_type":"hard","primary_outcome":"composite cardiovascular outcome","endpoints":null,"effect_estimate":"GLP-1 RA therapy against sulfonylurea therapy: hazard ratio 0.87, 95% confidence interval 0.84-0.91; P < 0.001 for the primary composite cardiovascular outcome, not statistically significant in the 90-day and 180-day landmark analyses. In mice, improved selected indices of cardiac function and attenuated cardiomyocyte hypertrophy, with myocardial fibrosis numerically but not significantly reduced (P = 0.28) and reduced expression of CTGF, TGF-β1 and vimentin.","confidence_interval":"95% confidence interval 0.84-0.91","p_value":"P < 0.001 for the primary composite cardiovascular outcome; P = 0.28 for myocardial fibrosis in mice","sample_size":85820,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"metabolic dysfunction-associated steatotic liver disease with type 2 diabetes; Western diet-fed mice in the experimental arm\", \"sample_size\": 85820, \"inclusion_exclusion\": \"patients with MASLD and type 2 diabetes in TriNetX, propensity score matched between GLP-1 RA and sulfonylurea therapy\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all patients had metabolic dysfunction-associated steatotic liver disease with type 2 diabetes, conditions the target group does not have, and no age, sex or BMI data are reported; the experimental arm used Western diet-fed mice.","mediation":"possibly","mediation_notes":"possibly, by the no-data default: neither the cohort nor the animal experiments report weight change, HbA1c or a mediation analysis, and rule 6 presumes the effect is confounded with weight and metabolic change until a study separates them. Propensity score matching addresses confounding, not mediation, and the default applies to the animal work too.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 85820, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"sulfonylurea therapy in the patient cohort; vehicle-treated mice in the animal experiments\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% confidence interval 0.84-0.91 with P < 0.001 for the primary outcome; 42,910 patients in each matched group; no event counts and no group sizes for the mice\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: the primary evidence is one propensity-matched TriNetX cohort with 42,910 patients in each treatment group, a hard composite cardiovascular outcome and a tight confidence interval, but it is an individual observational study, capped at study tier 3 by section 1 rule 2, and its association did not hold in the 90-day and 180-day landmark analyses. The complementary mouse experiments are preclinical and would rate VERY_LOW on their own.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The human analysis is an observational cohort open to confounding by indication, and its benefit was not statistically significant in the 90-day and 180-day landmark analyses; no follow-up duration or event counts are reported; the mouse experiments carry no group sizes and their fibrosis result was not significant.","plain_summary":"This translational study paired a US electronic health record cohort of patients who had both metabolic dysfunction-associated steatotic liver disease and type 2 diabetes with experiments in a mouse model. After propensity score matching, 42,910 patients were included in each treatment group: GLP-1 receptor agonist therapy was associated with a lower risk of the primary composite cardiovascular outcome than sulfonylurea therapy (hazard ratio 0.87, 95% confidence interval 0.84-0.91; P < 0.001), but the association was not statistically significant in the 90-day and 180-day landmark analyses. In Western diet-fed mice, treatment improved selected indices of cardiac function and attenuated cardiomyocyte hypertrophy, while the reduction in myocardial fibrosis was not statistically significant (P = 0.28). The patient findings are associations and cannot show cause.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1453,"doi":"10.1093/bjs/znag139","pmid":"42975202","nct_ids":"[]","title":"Cardiovascular and diabetes outcomes after metabolic bariatric surgery versus obesity management medications: nationwide overlap-weighted cohort study of 379 858 patients","authors":"[\"Gillikin AP\", \"Rabinovich EP\", \"Nimeri AA\", \"Tavakkoli A\", \"Shin TH\"]","journal":"The British journal of surgery","publication_date":"2026-10-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic bariatric surgery (MBS) and incretin-based therapy (IBT) are effective treatments for obesity and type 2 diabetes (T2D). However, their comparative effectiveness in current practice remains incompletely defined. [METHODS] Adults aged ≥18 years with obesity and T2D who underwent MBS or initiated obesity management medications (OMMs) were identified. The median follow-up was 4.9 (interquartile range (i.q.r.) 3.6-6.7) years for MBS and 4.3 (i.q.r. 3.4-5.8) years for IBT. Overlap weighting balanced baseline covariates between groups. Five-year outcomes included nephropathy, retinopathy, major adverse cardiovascular events (MACE), and all-cause mortality. One-year outcomes included percentage total weight loss (%TWL) and rates of haemoglobin A1c (HbA1c) <6.5%. [RESULTS] In total, 379 858 adults met the inclusion criteria (32 401 underwent MBS and 347 457 initiated OMMs). After overlap weighting, baseline covariates were well balanced. Compared with OMMs, MBS was associated with lower 5-year cumulative incidences of nephropathy (4.5% versus 8.3%; -3.8% points; HR 0.55 (95% c.i. 0.52 to 0.60)), retinopathy (3.6% versus 7.4%; -3.8% points; HR 0.60 (95% c.i. 0.55 to 0.65)), MACE (6.1% versus 8.1%; -2.0% points; HR 0.78 (95% c.i. 0.73 to 0.84)), and all-cause mortality (2.1% versus 3.7%; -1.6% points; HR 0.61 (95% c.i. 0.55 to 0.69)). At 1 year, the mean %TWL was greater after MBS (25.4% (95% c.i. 25.3% to 25.5%)) than after OMMs (6.4% (95% c.i. 6.3% to 6.5%)). Among patients with baseline HbA1c ≥6.5%, the proportion achieving HbA1c <6.5% at 1 year was higher after MBS (76.7% (95% c.i. 75.3% to 78.0%)) than after OMMs (47.2% (95% c.i. 46.2% to 48.1%); P < 0.001). Findings were consistent across agent-stratified, competing-risk, landmark, and no-censoring sensitivity analyses. [CONCLUSION] Among adults with obesity and T2D, MBS was associated with greater %TWL, higher glycaemic normalization, and lower 5-year risks of nephropathy, retinopathy, MACE, and all-cause mortality compared with real-world initiation of OMMs among patients in clinical equipoise, supporting the role of MBS as a durable therapy in multimodal obesity management.","url":"https://pubmed.ncbi.nlm.nih.gov/42975202/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"metabolic\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1283,"doi":"10.1161/jaha.126.050387","pmid":"42960821","nct_ids":"[]","title":"Glucagon-Like Peptide-1 Receptor Agonists in Obese Heart Failure With Preserved Ejection Fraction","authors":"[\"Selvaganesan P\", \"Karnib M\", \"Helmy I\", \"Zakeri R\", \"Saeed YB\", \"Sahadevan J\", \"Osman MN\", \"Mondal A\", \"Milfred-LaForest S\", \"Fang JC\", \"Reddy YNV\", \"Sundaram V\"]","journal":"Journal of the American Heart Association","publication_date":"2026-10-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] To evaluate whether GLP-1 (glucagon-like peptide-1) receptor agonists (GLP-1RAs), compared with DPP4 (dipeptidyl peptidase-4) inhibitors or sulfonylureas, are associated with reduced all-cause mortality or heart failure hospitalizations in patients with obesity and type 2 diabetes, and heart failure with preserved ejection fraction. [METHODS] PRAISE-HFpEF (Glucagon-Like Peptide-1 Receptor Agonist in Obese Heart Failure With Preserved Ejection Fraction) was a nationwide multicenter cohort study using a new-user, active-comparator design within the national Veterans Affairs Health System (170 US hospitals). Adults with type 2 diabetes between January 1, 2000 and December 31, 2021, were identified from centralized electronic health records. Patients with heart failure with preserved ejection fraction and a body mass index ≥30 kg/m2 were selected using a validated diagnostic algorithm. Exposure was initiation of a GLP-1RA versus DPP4 inhibitors/sulfonylurea from January 1, 2015 to December 31, 2021. The primary outcome was time to all-cause mortality or heart failure hospitalization. Inverse probability of treatment weighting based on the propensity score was used to balanced baseline characteristics. [RESULTS] Among 179 288 patients with type 2 diabetes, obesity, and heart failure with preserved ejection fraction, 1024 GLP-1RA users and 796 DPP4 inhibitors/sulfonylurea users met inclusion criteria. Over a median follow-up of 1.5 years, GLP-1RA use was associated with a lower risk of the primary outcome (adjusted hazard ratio, 0.78 [95% CI, 0.64-0.95], P=0.01). Weight loss was modestly greater with GLP-1RAs compared with DPP4 inhibitors/sulfonylurea (-12.9% versus -10.1%). [CONCLUSIONS] Among patients with obese heart failure with preserved ejection fraction and type 2 diabetes, GLP-1RA initiation was associated with a lower incidence of death or heart failure hospitalization compared with alternative oral agents.","url":"https://pubmed.ncbi.nlm.nih.gov/42960821/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"DPP4 inhibitors/sulfonylurea\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"time to all-cause mortality or heart failure hospitalization","endpoints":null,"effect_estimate":"Primary outcome (all-cause mortality or heart failure hospitalization) adjusted hazard ratio 0.78 [95% CI, 0.64-0.95], P=0.01; weight loss -12.9% with GLP-1RAs versus -10.1% with DPP4 inhibitors/sulfonylurea","confidence_interval":"95% CI, 0.64-0.95","p_value":"P=0.01","sample_size":1820,"follow_up":"median 1.5 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"obesity required (body mass index ≥30 kg/m2)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"heart failure with preserved ejection fraction required\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure with preserved ejection fraction, obesity and type 2 diabetes\", \"sample_size\": 1820, \"inclusion_exclusion\": \"adults with type 2 diabetes, heart failure with preserved ejection fraction and body mass index ≥30 kg/m2, newly initiating a GLP-1RA or a DPP4 inhibitor/sulfonylurea\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes, a body mass index of 30 kg/m2 or more and heart failure with preserved ejection fraction.","mediation":"possibly","mediation_notes":"Weight fell in both groups, by -12.9% with the GLP-1 drugs and -10.1% with the comparator drugs, so the difference between the groups is small, and nothing in the study separates weight change from the drug itself. Propensity weighting balanced baseline characteristics, which addresses confounding rather than mediation. The outcome is death or heart failure hospitalisation rather than a symptom measure that weight loss is known to improve.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 1820, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"DPP4 inhibitors/sulfonylurea\", \"follow_up_duration\": \"median 1.5 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CI reported (0.64-0.95); no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational cohort, which the model caps at the observational-study ceiling; the new-user active-comparator design, propensity weighting and nationwide coverage are strengths, but the analysis rests on 1024 treated and 796 comparator patients and reports no event counts.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"An observational new-user comparison weighted by propensity score rather than randomised, so confounding by indication cannot be excluded; it rests on 1024 GLP-1RA and 796 comparator users in one national health system over a median 1.5 years, and reports no event counts or absolute risks.","plain_summary":"A nationwide US Veterans Affairs cohort compared 1024 adults who started a GLP-1 receptor agonist with 796 who started a DPP4 inhibitor or sulfonylurea, all with type 2 diabetes, a body mass index of 30 kg/m2 or more and heart failure with preserved ejection fraction. Over a median 1.5 years, starting a GLP-1 drug was associated with a lower risk of death or heart failure hospitalisation (adjusted hazard ratio 0.78, 95% CI 0.64-0.95, P=0.01). Weight loss was somewhat greater with the GLP-1 drugs, -12.9% against -10.1%. Because treatment was not randomised, this is an association rather than a demonstrated effect.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1327,"doi":"10.1113/jp291770","pmid":"42958899","nct_ids":"[]","title":"Combined time-restricted feeding and resistance training enhance tirzepatide-induced improvements in adiposity and whole-body insulin sensitivity in female mice","authors":"[\"Macêdo APA\", \"da Conceição de Mattis LR\", \"de Lima RD\", \"Barbosa LA\", \"Pinotti CB\", \"Brisque GD\", \"Dias LM\", \"Pitoli BS\", \"Avelino AA\", \"Antonio GCF\", \"Muñoz VR\", \"Antunes GC\", \"Figueiredo LS\", \"Cintra DE\", \"da Silva ASR\", \"Ropelle ER\", \"Pauli JR\"]","journal":"The Journal of physiology","publication_date":"2026-10-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors with potent effects on body weight regulation, glucose homeostasis and metabolic health. However, its interaction with dietary and exercise interventions as well as its impact on obesity and hepatic metabolic pathways, particularly in females, remain unclear. Here, we tested whether tirzepatide, alone or combined with time-restricted feeding (TRF) or resistance training, modulates energy balance, strength performance, adipose tissue remodelling, insulin sensitivity and hepatic lipid accumulation in female mice. Female Swiss mice after 10 weeks of obesity induction were treated with tirzepatide, TRF or resistance training for 8 weeks. Tirzepatide was administered subcutaneously using a dose-escalation protocol. TRF consisted of a 12 h feeding window, and resistance training was performed as stair climbing on alternating days. Body weight, caloric intake and feed efficiency were monitored longitudinally. Glucose homeostasis was assessed by intraperitoneal glucose and insulin tolerance tests. Adipose depots, skeletal muscle and liver mass were quantified, and hepatic lipid accumulation was evaluated by histology and RT-qPCR of lipogenic metabolism genes. Tirzepatide reduced body weight gain and feed efficiency, consistent with a negative energy balance. When combined with TRF and resistance training, tirzepatide accelerated weight loss, and the addition of resistance training further enhanced this effect, bringing body weight close to control levels. These effects were associated with reduced adipose mass and adipocyte hypertrophy, indicating improved adipose tissue remodelling. Resistance training improved strength performance and increased skeletal muscle mass. Tirzepatide combined with TRF, with or without resistance training, improved glucose tolerance in female mice. All interventions reduced hepatic lipid accumulation. Collectively, tirzepatide, particularly in combination with TRF and resistance training, exerts enhanced metabolic benefits on obesity, insulin sensitivity and metabolic regulation in female mice. KEY POINTS: Tirzepatide combined with time-restricted feeding and resistance training produced greater reductions in body weight and adiposity in obese female mice. Combined interventions improved whole-body insulin sensitivity more effectively than isolated strategies. Resistance training preserved skeletal muscle mass during tirzepatide-induced weight loss. All interventions similarly reduced hepatic lipid accumulation and lipogenic gene expression. Tirzepatide-based therapies enhanced systemic metabolic health without additional hepatic benefits from combined interventions.","url":"https://pubmed.ncbi.nlm.nih.gov/42958899/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":"{\"treatment_duration\": \"8 weeks\", \"route\": \"subcutaneous\", \"dose\": null, \"comparator\": \"control mice, and time-restricted feeding or resistance training given alone or combined with tirzepatide\"}","domains":"[\"muscle\", \"body_composition\", \"liver\", \"metabolic\", \"nutrition\"]","outcome_type":"intermediate","primary_outcome":"adiposity and whole-body insulin sensitivity, with body weight","endpoints":null,"effect_estimate":"No numerical results are given. Tirzepatide reduced body weight gain and feed efficiency; combined with time-restricted feeding and resistance training it accelerated weight loss, bringing body weight close to control levels; adipose mass and adipocyte hypertrophy fell; resistance training improved strength and increased skeletal muscle mass; tirzepatide with time-restricted feeding improved glucose tolerance; all interventions reduced hepatic lipid accumulation, with no additional hepatic benefit from combining them.","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"female mice only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required: obesity induced over 10 weeks before treatment\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"induced obesity in female Swiss mice\", \"sample_size\": null, \"inclusion_exclusion\": \"female Swiss mice after 10 weeks of obesity induction\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: the subjects are female Swiss mice made obese over 10 weeks, not people; section 1 rule 4 makes animal evidence VERY_INDIRECT.","mediation":"not_applicable","mediation_notes":"not_applicable: the outcomes the record is built on, body weight, adiposity and whole-body insulin sensitivity, are weight, body composition and glycaemic measures themselves, so whether weight loss explains them is not a question (IN-062). The fall in liver fat is an outcome weight loss is known to improve and the record does not separate it from the accompanying weight loss, so no independent mediation claim is made for it either.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"control mice, and time-restricted feeding or resistance training given alone or combined with tirzepatide\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI or p-value reported in the abstract; number of animals not stated\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical study in female Swiss mice, which section 3 rates VERY_LOW. The abstract gives no group sizes, no estimates, no confidence intervals and no p values, and the allocation of animals to groups and any blinding are not described.","funding_source":"Coordination for the Improvement of Higher Education Personnel; Fundação de Amparo à Pesquisa do Estado de São Paulo; Conselho Nacional de Desenvolvimento Científico e Tecnológico","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"An animal study in female Swiss mice made obese over 10 weeks and treated for 8 weeks, reporting body composition, glucose tolerance, strength and liver fat with no group sizes and no statistics of any kind; allocation and blinding are not described, and the combination arms are not separated from the drug's own effect.","plain_summary":"Female Swiss mice were made obese over 10 weeks, then treated for 8 weeks with subcutaneous tirzepatide, a 12 h feeding window, resistance training as stair climbing, or combinations of these. Tirzepatide reduced body weight gain and feed efficiency and lowered adipose mass and adipocyte hypertrophy; combined with the feeding window and resistance training it accelerated weight loss, bringing body weight close to control levels, and resistance training increased skeletal muscle mass. Tirzepatide with the feeding window improved glucose tolerance, and all the interventions reduced liver fat, with no additional hepatic benefit from combining them. This is an animal study and the abstract reports no group sizes and no statistics of any kind.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1358,"doi":"10.1016/s2213-8587(26)00232-9","pmid":"42962687","nct_ids":"[\"NCT05931380\"]","title":"Efficacy and safety of oral orforglipron in Japanese participants with obesity disease (ATTAIN-J): a double-blind, randomised, placebo-controlled, parallel-group, phase 3 trial","authors":"[\"Yokote K\", \"Yamauchi T\", \"Shingaki T\", \"Chin R\", \"Oura T\", \"Nagai Y\", \"Shimomura I\", \"Kadowaki T\"]","journal":"The lancet. Diabetes & endocrinology","publication_date":"2026-10-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Orforglipron, a small-molecule, non-peptide, oral GLP-1 receptor agonist, has shown bodyweight reduction and cardiometabolic benefits in adults with obesity across phase 3 trials globally. We aimed to assess the efficacy and safety of orforglipron versus placebo for treating obesity disease in Japanese adults. [METHODS] ATTAIN-J was a double-blind, randomised, placebo-controlled, parallel-group, phase 3 trial conducted across 16 medical research centres and hospitals in Japan and included adults aged 18 years or older with a BMI between 27 kg/m2 and less than 35 kg/m2 and two or more obesity-related health disorders, or a BMI of 35 kg/m2 or higher and one or more obesity-related health disorder, with one or more of the obesity-related health disorders being hypertension, dyslipidaemia, or type 2 diabetes (targeted at about 25% of participants), consistent with Japanese indications for tirzepatide and semaglutide for obesity disease; and at least one unsuccessful dietary attempt to lose weight. Participants were randomly assigned (1:1:1:1) via a computer-generated sequence to once-daily oral orforglipron (6 mg, 12 mg, or 36 mg) or placebo. Co-primary endpoints were mean percentage change in bodyweight and percentage of participants with at least 5% bodyweight reduction from baseline to week 72. Efficacy endpoints were primarily evaluated by the treatment regimen estimand in all randomly assigned participants. Safety was assessed in participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT05931380 (completed). [FINDINGS] Between July 31, 2023, and June 19, 2025, 291 participants were screened, of whom 238 (144 [61%] males and 94 [39%] females; mean age 54·1 years [SD 11·2]) were randomly assigned to receive orforglipron 6 mg (n=61), 12 mg (n=57), or 36 mg (n=60), or placebo (n=60); 214 (90%) participants completed the study. At week 72, mean percentage change in bodyweight was -5·9% (95% CI -7·6 to -4·2) with orforglipron 6 mg, -8·7% (-10·9 to -6·5) with 12 mg, and -7·9% (-10·0 to -5·8) with 36 mg, compared with -0·6% (-2·1 to 0·8) with placebo (all p<0·0001 vs placebo). At week 72, a bodyweight reduction of at least 5% was seen in 15·2% (SE 4·8; nine of 60) of participants in the placebo group compared with 45·6% (6·1; 28 of 61; p=0·0001) of participants in the orforglipron 6 mg group, 60·8% (6·4; 35 of 57; p<0·0001) of participants in the orforglipron 12 mg group, and 58·8% (6·5; 35 of 60; p<0·0001) of participants in the orforglipron 36 mg group. Adverse events with orforglipron were mostly mild-to-moderate gastrointestinal symptoms. Across all orforglipron groups, treatment-emergent adverse events that most frequently led to study treatment discontinuation were nausea (one [2%] of 61 in the 6 mg group, one [2%] of 57 in the 12 mg group, and five [8%] of 60 in the 36 mg group vs none with placebo) and vomiting (none in the 6 mg group, two [4%] in the 12 mg group, and one [2%] in the 36 mg group vs none in the placebo group). [INTERPRETATION] In Japanese adults with obesity disease, once-daily orforglipron resulted in statistically superior reductions in bodyweight versus placebo, with a safety profile consistent with that of other GLP-1 receptor agonists. [FUNDING] Eli Lilly and Company. [TRANSLATION] For the Japanese translation of the abstract see Supplementary Materials section.","url":"https://pubmed.ncbi.nlm.nih.gov/42962687/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests All authors declare medical writing and editorial support paid for by the study funder (Eli Lilly and Company). KY declares research grants from Sumitomo Pharma, Takeda Pharmaceutical, Tanabe Pharma, and Nippon Boehringer Ingelheim; consulting fees from Nippon Boehringer Ingelheim, Novo Nordisk Pharma, and Eli Lilly Japan; and honoraria for lectures from Astellas Pharma, Kowa Pharmaceutical, Sanofi, Sumitomo Pharma, Daiichi Sankyo, Taisho Pharmaceutical, Tanabe Pharma, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, and Eli Lilly Japan. TY declares research grants from Novo Nordisk Pharma, Tanabe Pharma, Takeda Pharmaceutical, Ono Pharmaceutical, Sumitomo Pharma, Nipro, Med Mirai, Boehringer Ingelheim Japan, Kowa Pharmaceutical, Nitto Boseki, Asahi Mutual Life Insurance Company, and Sanwa Kagaku Kenkyusho; and honoraria for lectures from Abbott Japan, Daiichi Sankyo, Sanofi, Medtronic Japan, Astellas Pharma, AstraZeneca, Terumo, Taisho Pharmaceutical, Amgen, Arkray Marketing, Bayer Yakuhin, Lindsay Advice, Kyowa Kirin, Sanwa Kagaku Kenkyusho, GSK, Ono Pharmaceutical, Merck Sharp & Dohme (MSD), Sumitomo Pharma, Teijin Pharma, Boehringer Ingelheim Japan, Novo Nordisk Pharma, Eli Lilly and Company, Kowa Pharmaceutical, Nipro, Tanabe Pharma, Amgen, Dexcom Japan, Nitto Boseki, View Send ICT, Chugai Pharmaceutical, and Pfizer. IS declares research grants from Teijin Pharma, Mochida Pharmaceutical, Kowa Pharmaceutical, Kyowa Kirin, Sumitomo Pharma, Rohto Pharmaceutical, Kobayashi Pharmaceutical, Nissin Foods Holdings, CancerScan, Osaka Central Hospital, Hakuhokai Central Hospital, Midori Health Care Center, Kyowakai Medical Corporation, Ono Medical Research Foundation, Suzuken Memorial Foundation, Manpei Suzuki Diabetes Foundation, the Japan Agency for Medical Research and Development, and the Japan Endocrine Society; consulting fees from Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Chugai Pharmaceutical, Amgen, Shionogi & Co, and Nissin Foods Holdings; honoraria for lectures from Eli Lilly Japan, Arkray, MSD, Astellas Pharma, AstraZeneca, Abbott Japan, Ono Pharmaceutical, Otsuka Pharmaceutical, Johnson & Johnson, Kyowa Kirin, Kowa Pharmaceutical, Sanofi, Sumitomo Pharma, Sanwa Kagaku Kenkyusho, Teijin Pharma, Daiichi Sankyo, Tanabe Pharma, Chugai Pharmaceutical, Nipro, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Mochida Pharmaceutical, Bayer Yakuhin, Pfizer Japan, Lotte, Taisho Pharmaceutical, Tsumura & Co, Sawai Pharmaceutical, PDR Pharma, and Miyarisan Pharmaceutical; participation on a data safety monitoring or advisory board for Novo Nordisk Pharma, Eli Lilly Japan, Amgen, Sumitomo Pharma, Nippon Boehringer Ingelheim, and Sanofi; and leadership or fiduciary role for the Japan Society for the Study of Obesity, the Japan Endocrine Society, the Japan Diabetes Society, the Japanese Society for the Treatment of Obesity, the Japanese Society of Molecular Medicine, the Japanese Society of Internal Medicine, the Japan Atherosclerosis Society, the Japan Society of Metabolism and Clinical Nutrition, and the Japanese Society of Anti-Aging Medicine. TK declares research grants from Nippon Boehringer Ingelheim and Sumitomo Pharma; consulting fees from Taisho Pharmaceutical, Eli Lilly Japan, and Novo Nordisk Pharma; and honoraria for lectures from Nippon Boehringer Ingelheim, Sumitomo Pharma, Teijin Pharma, MSD, Eli Lilly Japan, Tanabe Pharma, Taisho Pharmaceutical, and Novo Nordisk Pharma. TS, RC, TO, and YN are employees of Eli Lilly Japan and shareholders in Eli Lilly and Company.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"rct","drugs":"[\"orforglipron\"]","drug_details":"{\"dose\": \"6 mg, 12 mg, or 36 mg once daily\", \"route\": \"oral\", \"comparator\": \"placebo\", \"treatment_duration\": \"to week 72\"}","domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"co-primary: mean percentage change in bodyweight, and percentage of participants with at least 5% bodyweight reduction, from baseline to week 72","endpoints":null,"effect_estimate":"Mean percentage change in bodyweight at week 72: -5·9% with orforglipron 6 mg, -8·7% with 12 mg and -7·9% with 36 mg against -0·6% with placebo, all p<0·0001. At least 5% bodyweight reduction in 45·6% (6 mg), 60·8% (12 mg) and 58·8% (36 mg) against 15·2% on placebo.","confidence_interval":"95% CI -7·6 to -4·2 (6 mg), -10·9 to -6·5 (12 mg), -10·0 to -5·8 (36 mg) and -2·1 to 0·8 (placebo)","p_value":"all p<0·0001 vs placebo for mean percentage bodyweight change; p=0·0001 (6 mg) and p<0·0001 (12 mg and 36 mg) for at least 5% bodyweight reduction","sample_size":238,"follow_up":"to week 72","direction":"benefit","population":"{\"mean_age\": 54.1, \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"144 [61%] males and 94 [39%] females\", \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"required: BMI between 27 kg/m2 and less than 35 kg/m2 with two or more obesity-related health disorders, or BMI 35 kg/m2 or higher with one or more\", \"diabetes_status\": \"mixed: type 2 diabetes was one of the qualifying obesity-related disorders, targeted at about 25% of participants\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity disease in Japanese adults\", \"sample_size\": 238, \"inclusion_exclusion\": \"adults 18 or older, BMI 27 to under 35 with two or more obesity-related disorders or BMI 35 or higher with one or more, one being hypertension, dyslipidaemia or type 2 diabetes, and at least one unsuccessful dietary attempt to lose weight\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 238 participants were Japanese adults with obesity disease, BMI between 27 kg/m2 and less than 35 kg/m2 with two or more obesity-related health disorders or BMI 35 kg/m2 or higher with one or more, with type 2 diabetes targeted at about 25%; mean age was 54·1 years.","mediation":"not_applicable","mediation_notes":"not_applicable: the co-primary endpoints are mean percentage change in bodyweight and the proportion reaching at least 5% bodyweight reduction, so the outcome is weight itself and no mediation question arises (IN-062).","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 238, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"to week 72\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported for every bodyweight endpoint with standard errors for the responder analysis; 238 randomly assigned and 214 (90%) completed\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a double-blind, randomised, placebo-controlled, parallel-group phase 3 trial with computer-generated allocation, 90% completion and confidence intervals on every bodyweight endpoint. It sits at study tier 2 rather than tier 1 because it randomised 238 participants at 16 Japanese centres and its co-primary endpoints are bodyweight, an intermediate outcome, not clinical events.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly and Company","author_conflicts":"All authors report medical writing and editorial support paid for by the study funder, four academic authors report research grants, consulting fees and lecture honoraria from many pharmaceutical companies including Eli Lilly and Novo Nordisk, and four authors are Eli Lilly Japan employees and Eli Lilly shareholders.","sponsor_role":"The study funder paid for medical writing and editorial support; no other sponsor role is stated.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly and Company, named in the abstract as the study funder; four authors are Eli Lilly Japan employees and Eli Lilly shareholders, all authors received medical writing and editorial support paid for by it, and four academic authors report its consulting fees or honoraria.","adverse_events":"Adverse events were mostly mild-to-moderate gastrointestinal symptoms. Discontinuation from nausea in one [2%] of 61 (6 mg), one [2%] of 57 (12 mg) and five [8%] of 60 (36 mg) versus none with placebo; from vomiting in two [4%] (12 mg) and one [2%] (36 mg) versus none with placebo.","limitations":"A single-country trial of 238 participants over 72 weeks whose co-primary endpoints are bodyweight rather than clinical events; the 36 mg dose produced less weight loss than the 12 mg dose and more discontinuations, 214 of 238 completed, and the manufacturer funded the trial and employs four of the authors.","plain_summary":"ATTAIN-J randomly assigned 238 Japanese adults with obesity disease and obesity-related health disorders to a once-daily tablet of orforglipron at 6 mg, 12 mg or 36 mg, or to placebo, for 72 weeks, with neither participants nor staff knowing the assignment. Mean age was 54·1 years and 144 (61%) were male. At week 72, mean percentage change in bodyweight was -5·9% (95% CI -7·6 to -4·2) with 6 mg, -8·7% (-10·9 to -6·5) with 12 mg and -7·9% (-10·0 to -5·8) with 36 mg, against -0·6% (-2·1 to 0·8) with placebo (all p<0·0001), and at least 5% bodyweight reduction was reached by 45·6%, 60·8% and 58·8% of participants against 15·2% on placebo. Adverse events were mostly mild-to-moderate gastrointestinal symptoms, with nausea leading five [8%] of 60 participants on 36 mg to discontinue against none on placebo. Eli Lilly and Company funded the trial.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1286,"doi":"10.1016/j.diabres.2026.113618","pmid":"42956842","nct_ids":"[]","title":"Semaglutide versus other GLP-1 RAs and cardiovascular risk in obesity-related cancer survivors","authors":"[\"Abdelgadir O\", \"Hernández-Pérez JG\", \"Hussain MR\", \"Mendoza K\", \"Mian RK\", \"Albayyaa M\", \"Hughes A\", \"Almandoz JP\", \"Cowell LG\", \"Messiah SE\", \"Lopez DS\"]","journal":"Diabetes research and clinical practice","publication_date":"2026-10-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Obesity-related cancer (ORCa) survivors are a unique population often excluded from landmark GLP-1 receptor agonist (GLP-1 RA) trials. Given their cardiovascular risks, we investigated whether semaglutide initiation, compared with other GLP-1 RA, was associated with modified 3-point major adverse cardiovascular events (MACE) among ORCa survivors with type 2 diabetes (T2D). [METHODS] We emulated a target trial using PCORnet-UTSW electronic health records (2016-2025). Adults with ORCa and T2D initiating semaglutide versus other GLP-1 RA were included. The primary outcome was modified 3-point MACE (myocardial infarction, stroke, or all-cause mortality). Cumulative incidence risk (CIR), risk difference (RD), and hazard ratio (HR) were estimated in 1:1 propensity score-matched cohort. [RESULTS] Among 918 matched patients (semaglutide, n = 459; other GLP-1 RA, n = 459), 124 modified 3-point MACE occurred. The 5-year CIR% was 17.6 (95% CI, 12.3-22.9) for semaglutide and 26.6 (95% CI, 20.7-32.6) for other GLP-1 RA. Semaglutide was associated with lower modified 3-point MACE risk (RD%, -7.41 [95% CI, -11.83 to - 2.98];HR, 0.65 [95% CI, 0.44-0.94]) than other GLP-1 RA. Findings were largely consistent across high-risk subgroups. [CONCLUSIONS] Semaglutide was associated with a lower modified 3-point MACE risk than other GLP-1 RA. These findings suggest potential heterogeneity in cardioprotective effects and warrant confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42956842/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"other GLP-1 RA\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"cancer\", \"mortality\"]","outcome_type":"hard","primary_outcome":"modified 3-point MACE (myocardial infarction, stroke, or all-cause mortality)","endpoints":null,"effect_estimate":"5-year cumulative incidence 17.6% (95% CI, 12.3-22.9) with semaglutide versus 26.6% (95% CI, 20.7-32.6) with other GLP-1 RA; risk difference -7.41% and hazard ratio 0.65 (95% CI, 0.44-0.94); 124 events among 918 matched patients","confidence_interval":"95% CI, 0.44-0.94","p_value":null,"sample_size":918,"follow_up":"5 years (5-year cumulative incidence reported)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity-related cancer survivors with type 2 diabetes\", \"sample_size\": 918, \"inclusion_exclusion\": \"adults with obesity-related cancer and type 2 diabetes initiating semaglutide or another GLP-1 RA in PCORnet-UTSW records, 2016-2025\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and were survivors of an obesity-related cancer; no BMI data are reported.","mediation":"possibly","mediation_notes":"No weight change, HbA1c or mediation analysis is reported, so the difference between semaglutide and the other GLP-1 drugs cannot be separated from weight or metabolic change; propensity matching addressed baseline differences rather than mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 918, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"other GLP-1 RA\", \"follow_up_duration\": \"5 years (5-year cumulative incidence reported)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% confidence intervals reported; 124 modified 3-point MACE events among 918 matched patients\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational cohort study, which the model caps at the observational-study ceiling; it uses an active-comparator target-trial emulation with 1:1 propensity matching, but rests on 124 events in one health system's records.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no known competing financial interests or personal relationships that could have influenced the work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"An observational target-trial emulation in one health system's records: propensity matching cannot remove confounding by indication, both arms received GLP-1 drugs so there is no untreated comparison, and the result rests on 124 events in 918 matched patients; the authors say it warrants confirmation.","plain_summary":"Using one US health system's electronic records from 2016 to 2025, researchers emulated a trial in adults who had survived an obesity-related cancer and had type 2 diabetes, matching 459 who started semaglutide with 459 who started another GLP-1 receptor agonist. Over five years 124 heart attacks, strokes or deaths occurred; the risk was 17.6% with semaglutide and 26.6% with the other drugs (hazard ratio 0.65, 95% CI 0.44-0.94; risk difference -7.41%). Because treatment was not randomised this is an association, and the comparison is between GLP-1 drugs rather than against no treatment.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1287,"doi":"10.1007/s40265-026-02409-8","pmid":"42955666","nct_ids":"[]","title":"Comparative Effects of Pharmacological Treatment on Heart Failure with Mildly Reduced or Preserved Ejection Fraction: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials","authors":"[\"Zhang J\", \"Wang Y\", \"Li J\", \"Chen Y\", \"Peng X\", \"Thabane L\", \"Lip GYH\", \"Li G\"]","journal":"Drugs","publication_date":"2026-10-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The comparative efficacy and safety of the new drugs (including sodium-glucose cotransporter-2 inhibitors [SGLT-2Is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], non-steroidal mineralocorticoid receptor antagonists [nsMRAs], and soluble guanylate cyclase stimulators [sGCs]) for heart failure with mildly reduced or preserved (HFmrEF/HFpEF) ejection fraction remains largely unclear. We conducted a systematic review and network meta-analysis to evaluate their comparative effects on HFmrEF/HFpEF, aiming to provide evidence-based guidance for treatment selection. [METHODS] MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were comprehensively searched. We included randomized controlled trials that compared nsMRA, sGC, SGLT-2I, and GLP-1RA with placebo for patients with HFmrEF/HFpEF. Primary efficacy outcomes were cardiovascular (CV) death, hospitalization for heart failure (HF hospitalization), and all-cause mortality, while primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs). The main analysis was conducted to compare the effects on HFmrEF/HFpEF between individual drugs. A frequentist network meta-analysis with random-effects models was used to calculate risk ratios (RRs) for dichotomous outcomes and standardized mean differences (SMDs) for continuous outcomes. [RESULTS] A total of 20 randomized controlled trials (RCTs, including 10 drugs from 35 publications) were included for analyses, but none provided head-to-head direct comparisons. No significant differences among all the individual drugs were found in risks of CV death or all-cause mortality. Compared with exenatide, low or moderate certainty evidence showed that dapagliflozin (RR 0.57, 95% CI 0.36-0.91), empagliflozin (RR 0.54, 95% CI 0.34-0.86), and semaglutide (RR 0.43, 95% CI 0.20-0.91) were related to decreased risk of HF hospitalization. No significant differences in the risk of SAEs were found among the individual drugs. Compared with empagliflozin, very low certainty evidence showed that tirzepatide (RR 1.17, 95% CI 1.04-1.32) was related to increased risk of AEs. When comparing the four drug classes (nsMRA, sGC, SGLT-2I, and GLP-1RA), no significant differences in efficacy outcomes were found, while SGLT-2I (RR 0.87, 95% CI 0.78-0.96) was associated with a decreased risk of AEs compared with GLP-1RA. [CONCLUSIONS] No significant differences among the individual SGLT-2I, GLP-1RA, nsMRA, and sGC drugs were found in risks of CV death, all-cause mortality or SAEs in patients with HFmrEF/HFpEF. Further evidence is needed to support these comparative effects and update guidance on medication choice for HFmrEF/HFpEF. [REGISTRATION] PROSPERO identifier number CRD420251143542.","url":"https://pubmed.ncbi.nlm.nih.gov/42955666/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of Interest: Jingyi Zhang, Yongjian Wang, Jianfeng Li, Yujiong Chen, Xinru Peng, Lehana Thabane, Gregory Y.H. Lip, and Guowei Li declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Data Availability: Not applicable because this study was based exclusively on published literature. Ethical Approval: Not applicable. Code Availability: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. AI use: No AI tools were used for this article. Author Contributions: JZ and GL conceived the idea of the study and designed the study. JZ, YW, JL, YC, XP, and GL contributed to record screening and data collection. JZ and GL performed statistical analyses and interpretation, and drafted the manuscript. GYHL and LT provided professional support and made several critical revisions to the manuscript. All authors read and approved the final manuscript. GL acts as the guarantor of this work.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo in the included trials; the network also yielded indirect drug-versus-drug and class-versus-class comparisons\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"cardiovascular death, hospitalization for heart failure and all-cause mortality (efficacy); adverse events and serious adverse events (safety)","endpoints":null,"effect_estimate":"No significant differences among the individual drugs for CV death, all-cause mortality or serious adverse events; versus exenatide, HF hospitalization was lower with semaglutide (RR 0.43, 95% CI 0.20-0.91), dapagliflozin (0.57, 0.36-0.91) and empagliflozin (0.54, 0.34-0.86); versus empagliflozin, tirzepatide had a higher risk of adverse events (1.17, 1.04-1.32); by class, SGLT-2I had a lower risk of adverse events than GLP-1RA (0.87, 0.78-0.96), with no class differences in efficacy","confidence_interval":"95% CI 0.20-0.91 (semaglutide versus exenatide, HF hospitalization)","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"heart failure with mildly reduced or preserved ejection fraction required\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure with mildly reduced or preserved ejection fraction\", \"sample_size\": null, \"inclusion_exclusion\": \"randomized controlled trials comparing a non-steroidal mineralocorticoid receptor antagonist, soluble guanylate cyclase stimulator, SGLT-2 inhibitor or GLP-1 receptor agonist with placebo in patients with HFmrEF/HFpEF\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all included trials enrolled patients with heart failure with mildly reduced or preserved ejection fraction, with no BMI or diabetes data reported.","mediation":"possibly","mediation_notes":"No weight, body mass index or HbA1c data are reported for the pooled trials, and nothing separates a drug effect from weight or metabolic change. The primary efficacy comparisons were null for cardiovascular death and all-cause mortality, but one GLP-1 result was not: heart failure hospitalisation was lower with semaglutide than with exenatide, so there is a result whose mediation can be asked about.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo in the included trials; the network also yielded indirect drug-versus-drug and class-versus-class comparisons\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"risk ratios with 95% confidence intervals from a frequentist random-effects network meta-analysis of 20 randomized trials, none of them head-to-head; no pooled sample size, follow-up or event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a random-effects network meta-analysis that pools 20 randomized trials with hard outcomes, rated down because none of the trials provided head-to-head comparisons and the authors themselves grade the reported comparisons as low or very low certainty in places.","funding_source":"the National Natural Science Foundation of China; the Natural Science Foundation of Guangdong Province of China; the Science Foundation of Guangdong Second Provincial General Hospital; the Young Top Talent Project in the Special Support Plan for Training High-level Talents in Guangdong","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"The named authors declare no potential conflicts of interest relevant to the manuscript.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No significant differences in serious adverse events among the individual drugs; tirzepatide had a higher risk of adverse events than empagliflozin (RR 1.17, 95% CI 1.04-1.32), and SGLT-2I a lower risk than GLP-1RA as classes (RR 0.87, 95% CI 0.78-0.96)","limitations":"None of the 20 trials provided head-to-head comparisons, so every drug-versus-drug estimate is indirect and the authors grade the certainty of these comparisons from moderate down to very low; no pooled sample size, follow-up or event counts are reported.","plain_summary":"A systematic review and network meta-analysis pooled 20 randomized placebo-controlled trials, covering 10 drugs across 35 publications, in people with heart failure with mildly reduced or preserved ejection fraction. No drug differed from another in cardiovascular death, all-cause mortality or serious adverse events. Heart failure hospitalisation was lower with semaglutide (risk ratio 0.43, 95% CI 0.20-0.91), dapagliflozin (0.57) and empagliflozin (0.54) than with exenatide, while adverse events were more frequent with tirzepatide than empagliflozin (1.17, 1.04-1.32) and, by class, with GLP-1 drugs than SGLT-2 inhibitors (0.87, 0.78-0.96). None of the comparisons came from head-to-head trials, so all are indirect.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1312,"doi":"10.1007/s12020-026-04840-z","pmid":"42955519","nct_ids":"[]","title":"Comparative adverse-event reporting patterns of semaglutide and tirzepatide: a disproportionality analysis of FAERS","authors":"[\"Arslan T\"]","journal":"Endocrine","publication_date":"2026-10-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide and tirzepatide are widely used for type 2 diabetes and obesity, but comparative post-marketing safety data remain limited. [OBJECTIVE] To compare adverse-event reporting patterns for semaglutide and tirzepatide in the FDA Adverse Event Reporting System (FAERS), focusing on gastrointestinal, renal and ocular events, alopecia, serious outcomes, mortality, and reporting chronology. [METHODS] This retrospective pharmacovigilance study analyzed FAERS reports submitted from January 2022 through June 2026. After deduplication, 215,337 unique reports remained; predefined exposure criteria identified 60,423 semaglutide-only reports, 143,126 tirzepatide-only reports, and 853 reports listing both drugs without additional suspect active ingredients. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals. Multivariable logistic regression, false discovery rate adjustment, and reporting-latency analyses were also performed. [RESULTS] Semaglutide showed higher reporting odds than tirzepatide for impaired gastric emptying (ROR 6.39), intestinal obstruction/ileus (ROR 4.56), acute kidney injury (ROR 2.51), pancreatitis (ROR 2.18), vomiting (ROR 2.11), and optic ischaemic neuropathy (ROR 15.77). Alopecia was relatively more frequently reported with tirzepatide (ROR 0.74). Semaglutide reports had higher adjusted reporting odds of hospitalization (aOR 2.80) and death (aOR 1.21). In an exploratory analysis restricted to male reports, erectile dysfunction was reported in 92 of 16,673 semaglutide reports and 46 of 27,321 tirzepatide reports (ROR 3.29, 95% CI 2.31-4.69; q < 0.001). [CONCLUSIONS] Semaglutide and tirzepatide exhibited distinct post-marketing reporting patterns. The erectile-dysfunction finding was exploratory and hypothesis-generating. All findings reflect spontaneous reporting rather than comparative clinical risk or causality and require confirmation in population-based studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42955519/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics Approval: The present study analyzed anonymized publicly available data obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Institutional Review Board approval and informed consent were therefore not required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Use of AI-assisted Technology: During the preparation of this manuscript, the author used generative artificial intelligence solely to improve the clarity, grammar, and readability of the language. The author critically reviewed and edited all AI-assisted content and accepts full responsibility for the accuracy, integrity, and originality of the manuscript.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"tirzepatide (semaglutide reports compared with tirzepatide reports)\", \"treatment_duration\": null}","domains":"[\"kidney\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":"reporting odds for gastrointestinal, renal and ocular events, alopecia, serious outcomes, mortality and reporting chronology","endpoints":null,"effect_estimate":"Semaglutide versus tirzepatide: impaired gastric emptying ROR 6.39, intestinal obstruction/ileus 4.56, acute kidney injury 2.51, pancreatitis 2.18, vomiting 2.11, optic ischaemic neuropathy 15.77, hospitalization aOR 2.80 and death aOR 1.21; alopecia was reported relatively more often with tirzepatide (ROR 0.74); exploratory male-only erectile dysfunction ROR 3.29 (95% CI 2.31-4.69)","confidence_interval":"95% CI 2.31-4.69 (erectile dysfunction ROR 3.29, exploratory)","p_value":"q < 0.001 (erectile dysfunction, false discovery rate adjusted)","sample_size":215337,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 215337, \"inclusion_exclusion\": \"FAERS reports submitted January 2022 through June 2026; after deduplication, predefined exposure criteria selected semaglutide-only, tirzepatide-only and both-drug reports without additional suspect active ingredients\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the analysis counts spontaneous reports and gives no age, BMI or diabetes data for the people behind them.","mediation":"possibly","mediation_notes":"No weight change, HbA1c or mediation analysis is reported, so the reported differences cannot be separated from weight and metabolic change; both drugs compared lower weight, which further confounds the contrast.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": 215337, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"tirzepatide (semaglutide reports compared with tirzepatide reports)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"reporting odds ratios with 95% confidence intervals and false discovery rate adjustment; the abstract prints an interval only for the exploratory erectile-dysfunction result; 60,423 semaglutide-only and 143,126 tirzepatide-only reports\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a single disproportionality analysis of spontaneous reports, which the model places at its lowest tier, and whose authors state the findings reflect reporting patterns rather than comparative clinical risk or causality.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Semaglutide reports showed higher reporting odds than tirzepatide for impaired gastric emptying (ROR 6.39), intestinal obstruction/ileus (4.56), acute kidney injury (2.51), pancreatitis (2.18), vomiting (2.11), optic ischaemic neuropathy (15.77), hospitalization (aOR 2.80) and death (aOR 1.21); alopecia was reported relatively more often with tirzepatide (ROR 0.74)","limitations":"Spontaneous reporting data cannot give incidence or causality, as the authors state; a comparison of reporting between two drugs is shaped by differential reporting and by how long each has been on the market, no characteristics of the people behind the reports are available, and the erectile-dysfunction finding is explicitly exploratory.","plain_summary":"This study compared spontaneous adverse-event reports for semaglutide and tirzepatide in the US FDA reporting system from January 2022 through June 2026, using 215,337 deduplicated reports, of which 60,423 named semaglutide only and 143,126 tirzepatide only. Semaglutide reports more often described impaired gastric emptying (reporting odds ratio 6.39), intestinal obstruction or ileus (4.56), acute kidney injury (2.51), pancreatitis (2.18), vomiting (2.11), optic ischaemic neuropathy (15.77), hospitalization (adjusted odds ratio 2.80) and death (1.21), while alopecia was reported relatively more often with tirzepatide (0.74). An exploratory male-only analysis found erectile dysfunction in 92 of 16,673 semaglutide reports against 46 of 27,321 tirzepatide reports (3.29, 95% CI 2.31-4.69). The authors state these are reporting patterns, not comparative clinical risk or causality.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1379,"doi":"10.1111/dom.71494","pmid":"42957440","nct_ids":"[]","title":"Digital Food Purchase Signatures and Their Response to GLP-1-Based Treatment in People With Obesity","authors":"[\"Orban F\", \"Cerro LF\", \"Stoll M\", \"Rupp M\", \"Herzig D\", \"Bally L\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To characterise digital food purchase signatures in adults with obesity (OB) versus normal-weight (NW) controls and explore changes from pre-treatment to early (5-month) and later (10-month) phases of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, including high and low weight-loss responders. [MATERIALS AND METHODS] We obtained household-level loyalty-card food purchase data at two major Swiss grocery retailers for 56 OB adults and 92 NW controls, covering 12-24 months. Purchases were matched to a nutritional database and analysed by purchase patterns using nutrient profiles, food group distributions, and composite diet quality scores, comparing OB and NW cross-sectionally and, within the OB group, longitudinally following GLP-1RA initiation. [RESULTS] Compared to NW (BMI 22.0 ± 1.7 kg/m2), OB participants (BMI 37.8 ± 5.2 kg/m2) purchased a higher proportion of energy from protein (mainly animal-based), higher energy-adjusted salt content, but smaller energy shares of fruit, vegetables, nuts, whole foods and scored lower on the Dietary Phytochemical Index, Simplified Healthy Food Diversity Index and alternate Mediterranean Diet Score (all p < 0.05). GLP-1RA initiation was followed by early increases in protein-derived energy, fibre content, energy from fruit, vegetables and unprocessed foods (all p < 0.05). However, by 10 months, purchasing patterns no longer differed meaningfully from pre-treatment levels in the full cohort. High/low weight-loss responders did not differ in food purchase patterns, except for a greater increase in salt content among low responders at 5 months. [CONCLUSIONS] Distinct digital food purchase signatures were observed in OB versus NW adults. Within OB, no clear longitudinal shift was evident after 10 months of GLP-1RA treatment, although the sample size and household-level data limited individual-level precision and interpretability.","url":"https://pubmed.ncbi.nlm.nih.gov/42957440/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"pre-treatment purchasing in the same participants for the longitudinal analysis; normal-weight controls for the cross-sectional comparison\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": \"early (5-month) and later (10-month) phases\"}","domains":"[\"nutrition\"]","outcome_type":"surrogate","primary_outcome":"food purchase patterns: nutrient profiles, food group distributions and composite diet quality scores","endpoints":null,"effect_estimate":"After GLP-1RA initiation there were early increases in protein-derived energy, fibre content and energy from fruit, vegetables and unprocessed foods (all p < 0.05), but by 10 months purchasing patterns no longer differed meaningfully from pre-treatment; high and low weight-loss responders did not differ except for a greater salt increase among low responders at 5 months","confidence_interval":"not reported in abstract","p_value":"all p < 0.05","sample_size":148,"follow_up":"10 months after GLP-1RA initiation","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 37.8, \"bmi_min\": null, \"obesity_status\": \"mixed: 56 adults with obesity (BMI 37.8 ± 5.2 kg/m2) received GLP-1RA therapy; 92 normal-weight controls (BMI 22.0 ± 1.7 kg/m2) were untreated\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity in the treated group; normal weight in the control group\", \"sample_size\": 148, \"inclusion_exclusion\": \"adults with obesity starting GLP-1RA therapy and normal-weight controls, with household loyalty-card purchase data at two Swiss grocery retailers covering 12-24 months\", \"healthy_volunteers\": false, \"normal_weight_included\": true, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all GLP-1RA-treated participants had obesity, with mean BMI 37.8 kg/m2; the 92 normal-weight participants were untreated controls.","mediation":"possibly","mediation_notes":"No weight-change values, HbA1c or mediation analysis are reported; participants were only grouped as high or low weight-loss responders, and their purchase patterns largely did not differ. An unreported weight change is not a separation of the drug effect from weight and metabolic change, so weight could contribute.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 148, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"pre-treatment purchasing in the same participants for the longitudinal analysis; normal-weight controls for the cross-sectional comparison\", \"follow_up_duration\": \"10 months after GLP-1RA initiation\", \"outcome_type\": \"surrogate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no confidence intervals reported, p values only (all p < 0.05); 56 treated adults and 92 controls\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: the GLP-1RA part of the study is an uncontrolled before-and-after analysis in 56 treated adults with no untreated comparator, equivalent to a case series under the model, and the outcome is household purchasing, a proxy the authors say limited individual-level precision.","funding_source":"Bernischer Hilfsbund; Swiss Heart Foundation; Johanna Dürmüller-Bol Foundation; Novo Nordisk; Vontobel Foundation; Inselheim-Stiftung","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The authors state that the sample size and household-level data limited individual-level precision and interpretability; the GLP-1RA analysis is an uncontrolled before-and-after comparison in 56 treated adults with no untreated comparison group, and grocery purchases are a proxy for what people actually ate.","plain_summary":"Household loyalty-card data from two Swiss grocery chains were used to compare food purchases of 56 adults with obesity (BMI 37.8 kg/m2) with 92 normal-weight controls (BMI 22.0 kg/m2), and then to follow the group with obesity before and after starting a GLP-1 receptor agonist. Purchases by the group with obesity carried more protein energy and salt and smaller shares of fruit, vegetables and nuts, and scored lower on the diet-quality indices used (all p < 0.05). After treatment started, purchases shifted at 5 months towards more fibre, fruit, vegetables and unprocessed foods, but by 10 months they no longer differed meaningfully from before treatment, and high and low weight-loss responders differed only in a greater salt increase among low responders at 5 months. With no untreated comparison group, these are changes observed in treated people rather than a measured drug effect.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1290,"doi":"10.1177/19322968261498914","pmid":"42949133","nct_ids":"[]","title":"Multisystem Outcomes of GLP-1 Receptor Agonists Versus Active Comparators in Type 2 Diabetes: A Multicenter Target Trial Emulation","authors":"[\"Vashisht R\", \"Dhruva SS\", \"Patel A\", \"Dahm L\", \"Morris P\", \"Gonzalez D\", \"Follett R\", \"Sirota M\", \"Singh K\", \"Koliwad S\", \"Han C\"]","journal":"Journal of diabetes science and technology","publication_date":"2026-10-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Multisystem effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond cardiometabolic outcomes are incompletely characterized against active comparators in type 2 diabetes (T2D). We compared GLP-1RA with sulfonylureas (SUs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), and dipeptidyl peptidase-4 inhibitors (DPP4is) in adults with T2D. [METHOD] In a multicenter target trial emulation across 5 University of California academic medical centers (2012-2025) using harmonized electronic health record data, adults with T2D newly initiating GLP-1RA, SU, SGLT2i, or DPP4i were propensity score-matched 1-to-1 within site via least absolute shrinkage and selection operator (>11 000 covariates), with up to 5-year follow-up. We screened 181 prespecified incident outcomes across 15 body systems, pooling hazard ratios by random-effects meta-analysis. Robustness required leave-one-medical-center-out stability, E-value ≥1.5, and false discovery rate-adjusted P < .10. [RESULTS] Among 70 982 matched adults, 118 robust associations were identified (65 for reduced risk and 53 for increased risk). Risk reductions were most consistent for cardiovascular outcomes, including myocarditis/cardiomyopathy (summary hazard ratio, 0.38 [95% CI, 0.32-0.44] vs SGLT2i), acute myocardial infarction (0.53 [0.42-0.66]), heart failure (0.71 [0.58-0.88] vs DPP4i), and thromboembolism (0.69-0.72), and for nephritis/nephrosis (0.73 [0.67-0.79]), nutritional anemia (0.70-0.81), coagulation disorders (0.73-0.81), and tobacco-related disorders (0.60 [0.49-0.74]). Risk increases were found for musculoskeletal conditions (22 associations); osteoarthritis 1.48 (1.29-1.68), stress fractures 1.68 (1.15-2.47), diverticular disease (1.18-1.33), sleep-wake disorders (1.27-1.54), and menopausal disorders (1.32-1.52). [CONCLUSIONS] Glucagon-like peptide-1 receptor agonist initiation was associated with reduced cardiovascular, renal, hematologic, and tobacco-related risk, consistent with outcome trials. Increased risks for musculoskeletal, gastrointestinal, and sleep-wake disorders warrant monitoring as the clinical use of GLP-1RAs continues to expand.","url":"https://pubmed.ncbi.nlm.nih.gov/42949133/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"sulfonylureas, SGLT2 inhibitors, DPP4 inhibitors\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"osteoarthritis\", \"bone\", \"sleep\", \"nutrition\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"181 prespecified incident outcomes across 15 body systems","endpoints":null,"effect_estimate":"118 robust associations, 65 for reduced risk and 53 for increased risk: myocarditis/cardiomyopathy summary hazard ratio 0.38 (95% CI, 0.32-0.44) versus SGLT2i, acute myocardial infarction 0.53 (0.42-0.66), heart failure 0.71 (0.58-0.88) versus DPP4i, thromboembolism 0.69-0.72, nephritis/nephrosis 0.73 (0.67-0.79), nutritional anemia 0.70-0.81, coagulation disorders 0.73-0.81, tobacco-related disorders 0.60 (0.49-0.74); osteoarthritis 1.48 (1.29-1.68), stress fractures 1.68 (1.15-2.47), diverticular disease 1.18-1.33, sleep-wake disorders 1.27-1.54, menopausal disorders 1.32-1.52","confidence_interval":"95% CI, 0.32-0.44 (myocarditis/cardiomyopathy vs SGLT2i)","p_value":null,"sample_size":70982,"follow_up":"up to 5-year follow-up","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 70982, \"inclusion_exclusion\": \"adults with type 2 diabetes newly initiating a GLP-1RA, sulfonylurea, SGLT2 inhibitor or DPP-4 inhibitor at five University of California academic medical centers, 2012-2025\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were adults with type 2 diabetes newly starting a glucose-lowering drug, with no BMI data reported.","mediation":"possibly","mediation_notes":"No weight change, HbA1c or mediation analysis is reported, so these associations cannot be separated from weight and metabolic change; the matching on more than 11 000 baseline covariates addresses confounding rather than mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 70982, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"sulfonylureas, SGLT2 inhibitors, DPP4 inhibitors\", \"follow_up_duration\": \"up to 5-year follow-up\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% confidence intervals with random-effects pooling across sites; robustness required leave-one-medical-center-out stability, E-value ≥1.5 and false discovery rate-adjusted P < .10; 70 982 matched adults\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational cohort, which the model caps at the observational-study ceiling; its size, active comparators, leave-one-centre-out stability requirement and E-value threshold are strengths, but 181 screened outcomes make individual associations hypothesis-generating.","funding_source":"FDA HHS; NCATS NIH HHS","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"The authors declared no potential conflicts of interest with respect to the research, authorship or publication of this article.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Risk increases for musculoskeletal conditions (22 associations), including osteoarthritis 1.48 (1.29-1.68) and stress fractures 1.68 (1.15-2.47), and for diverticular disease (1.18-1.33), sleep-wake disorders (1.27-1.54) and menopausal disorders (1.32-1.52)","limitations":"An observational emulation in matched electronic health records: despite matching on more than 11 000 covariates and the robustness checks, confounding by indication remains possible; the active comparator differs between outcomes and 181 outcomes were screened, so individual associations are hypothesis-generating; all five sites are University of California academic medical centres.","plain_summary":"Across five University of California medical centres from 2012 to 2025, adults with type 2 diabetes starting a GLP-1 receptor agonist were matched one-to-one with adults starting a sulfonylurea, SGLT2 inhibitor or DPP-4 inhibitor, giving 70 982 matched adults followed up to 5 years while 181 prespecified outcomes across 15 body systems were screened. Of 118 robust associations, 65 pointed to lower risk, most consistently myocarditis or cardiomyopathy (hazard ratio 0.38, 95% CI 0.32-0.44 against SGLT2 inhibitors), myocardial infarction (0.53), heart failure (0.71 against DPP-4 inhibitors) and nephritis or nephrosis (0.73). The other 53 pointed to higher risk, including osteoarthritis (1.48), stress fractures (1.68), diverticular disease, sleep-wake disorders and menopausal disorders. Treatment was not randomised, so these are associations rather than demonstrated effects.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1353,"doi":"10.1111/bph.70720","pmid":"42950887","nct_ids":"[]","title":"GLP-1 receptor activation attenuates chronic migraine-like behaviour: Sex-specific modulation of opioid- and endocannabinoid-related pathways","authors":"[\"Sićović K\", \"Nastić K\", \"Dinić M\", \"Brdarić E\", \"Pecikoza U\", \"Tomić M\", \"Micov A\"]","journal":"British journal of pharmacology","publication_date":"2026-10-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND PURPOSE] Chronic migraine (CM) is a highly disabling condition that remains suboptimally treated. Metabolic disturbances may trigger migraine chronification, whereas impaired endogenous pain inhibition contributes to CM development. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), used for type 2 diabetes and obesity, show efficacy in chronic pain models. We evaluated the prophylactic effects of liraglutide, semaglutide and dulaglutide compared with propranolol (reference drug), potential opioidergic/endocannabinoid involvement and sex differences in a CM model. [EXPERIMENTAL APPROACH] Chronic migraine-like hypersensitivity was induced by repeated nitroglycerin administration in male and female mice. The prophylactic effects of GLP-1RAs and propranolol were examined using von Frey, acetone and orofacial glutamate tests. Body weight and glucose tolerance were monitored to evaluate metabolic safety. Potential opioidergic/endocannabinoid involvement in semaglutide-induced antinociception (selected GLP-1RA class representative) was assessed by pharmacological blockade and/or quantitative polymerase chain reaction (qPCR) analysis of pain-related neurobiomarker mRNA expression in brainstem and trigeminal ganglia. [KEY RESULTS] Liraglutide, semaglutide and dulaglutide dose-dependently attenuated CM-like hypersensitivity in both sexes, with efficacy comparable to propranolol. GLP-1RAs did not affect metabolic parameters, whereas propranolol induced male-specific hyperglycaemia. Semaglutide-induced antinociception was partially sensitive to naloxone and was associated with sex-dimorphic, brainstem-specific transcriptional changes in opioid- and endocannabinoid-related pathways. Semaglutide increased Glp1r, Cnr1, Pomc, Pcsk1 and Pcsk2 mRNA expression in males, whereas it up-regulated Glp1r and down-regulated Faah and Mgll in females. [CONCLUSIONS AND IMPLICATIONS] GLP-1RAs exert class-wide antinociceptive effects in a preclinical CM model, with semaglutide-based analyses suggesting sex-specific modulation of central opioid- and endocannabinoid-related pathways. These findings support further investigation of GLP-1RAs as prophylactic strategies for migraine, particularly in individuals with metabolic comorbidities.","url":"https://pubmed.ncbi.nlm.nih.gov/42950887/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\", \"semaglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"propranolol (reference drug)\", \"treatment_duration\": null}","domains":"[\"addiction\", \"adverse_effects\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":"attenuation of nitroglycerin-induced chronic migraine-like hypersensitivity (von Frey, acetone and orofacial glutamate tests)","endpoints":null,"effect_estimate":"Liraglutide, semaglutide and dulaglutide dose-dependently attenuated migraine-like hypersensitivity in both sexes, comparable to propranolol; the GLP-1RAs did not affect metabolic parameters while propranolol caused male-specific hyperglycaemia; semaglutide's antinociception was partially blocked by naloxone and came with sex-dimorphic brainstem changes in opioid- and endocannabinoid-related gene expression","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male and female mice\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"nitroglycerin-induced chronic migraine-like hypersensitivity in mice\", \"sample_size\": null, \"inclusion_exclusion\": \"male and female mice given repeated nitroglycerin to induce chronic migraine-like hypersensitivity, then treated with a GLP-1RA or propranolol\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: the subjects are male and female mice in a nitroglycerin model of chronic migraine, not people.","mediation":"unlikely","mediation_notes":"Body weight and glucose tolerance were monitored and the GLP-1RAs left them unchanged, while propranolol raised glucose in males, so the antinociceptive effect cannot be attributed to weight loss or improved glycaemia; the outcome is a behavioural pain measure. No formal mediation analysis was done.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"propranolol (reference drug)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no confidence intervals, p values or animal numbers reported; effects described as dose-dependent\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical animal study, which the model places at its lowest tier; no animal numbers, doses, confidence intervals or p values are reported.","funding_source":"Ministry of Science, Technological Development, and Innovation of the Republic of Serbia","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"GLP-1RAs did not affect metabolic parameters; propranolol, the comparator, induced male-specific hyperglycaemia","limitations":"A preclinical study in a nitroglycerin mouse model of chronic migraine with no animal numbers, doses, confidence intervals or p values reported; the endpoints are behavioural pain tests and brain mRNA measures rather than clinical migraine outcomes, and the mechanistic work used semaglutide alone as the class representative.","plain_summary":"In male and female mice given repeated nitroglycerin to produce chronic migraine-like pain sensitivity, liraglutide, semaglutide and dulaglutide each reduced that sensitivity dose-dependently, about as well as the reference drug propranolol. The GLP-1 drugs did not change body weight or glucose tolerance, while propranolol raised blood glucose in males only. Semaglutide's effect was partly blocked by naloxone and came with sex-specific changes in opioid- and endocannabinoid-related gene expression in the brainstem. This is a preclinical animal study, and the abstract gives no animal numbers, doses or statistical estimates.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1363,"doi":"10.1016/j.molmet.2026.102464","pmid":"42951207","nct_ids":"[]","title":"Continued CagriSema treatment preserves weight loss by reducing energy intake and maintaining energy expenditure in rats","authors":"[\"Petersen LM\", \"Knop FK\", \"le Roux CW\", \"Raun K\", \"Reitman ML\", \"Kuhre RE\"]","journal":"Molecular metabolism","publication_date":"2026-10-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] CagriSema (CS), combining the amylin receptor agonist cagrilintide with the glucagon-like peptide 1 receptor agonist semaglutide, is being developed for obesity and type 2 diabetes. We quantified CS effects on energy balance during initial treatment, weight maintenance, and after discontinuation. [METHODS] Male diet-induced obese rats underwent indirect calorimetry during 6 weeks of treatment and for 4 weeks after discontinuation. Treatments were a) vehicle, b) CS, c) calorie-restriction to match CS body weight loss (weight matched, WM), and d) calorie-restriction to match CS food intake (pair-feeding, PF). [RESULTS] CS effects occurred in four phases. During days 1-10 (Phase I), CS induced rapid weight loss mainly through reduced energy intake (EI), while energy expenditure (EE) was relatively preserved. EE was significantly lower in WM rats, consistent with metabolic adaptation. During days 11-42 (Phase II), reduced body weight was maintained in the CS, WM, and PF groups, and respiratory exchange ratio converged across groups, indicating metabolic steady state had been reached. Reduced EI and preserved total EE respectively explained 86% and 14% of CS weight loss efficacy. Maintained resting/sleeping EE contributed to the total EE preservation. Treatment discontinuation (days 43-52, Phase III) caused hyperphagia and rapid weight regain. During days 53-68 (Phase IV), all groups reached metabolic steady state and weight gain returned to pretreatment rates. Body weight plateaued in approximately half the time needed to reach metabolic steady state, and metabolic adaptation reversed within ∼7 days after discontinuation. [CONCLUSIONS] By persistently lowering EI and attenuating metabolic adaptation, CS enables sustained weight loss in rats; however, the reversal after treatment cessation suggests that chronic pharmacological therapy may be required to maintain weight loss.","url":"https://pubmed.ncbi.nlm.nih.gov/42951207/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rune Ehrenreich Kuhre reports a relationship with Novo Nordisk that includes: employment. Lisbeth M Pedersen, Filip K Knop, Kirsten Raun, and Rune E Kuhre are employed by Novo Nordisk A/S and are minor shareholders. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"treatment_duration\": \"6 weeks\", \"dose\": null, \"route\": null, \"comparator\": \"vehicle, calorie restriction weight-matched to CagriSema weight loss, and pair-feeding matched to CagriSema food intake\"}","domains":"[\"adverse_effects\", \"discontinuation\"]","outcome_type":"intermediate","primary_outcome":"energy balance (energy intake and energy expenditure) during treatment, weight maintenance and after discontinuation","endpoints":null,"effect_estimate":"Reduced energy intake and preserved total energy expenditure explained 86% and 14% of CagriSema weight-loss efficacy; energy expenditure was significantly lower in the weight-matched calorie-restricted rats; stopping treatment caused hyperphagia and rapid weight regain, with metabolic adaptation reversing within about 7 days","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":"4 weeks after discontinuation","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"all male\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required (male diet-induced obese rats)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diet-induced obesity in male rats\", \"sample_size\": null, \"inclusion_exclusion\": \"male diet-induced obese rats allocated to vehicle, CagriSema, weight-matched calorie restriction or pair-feeding\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: the subjects are male diet-induced obese rats, not people.","mediation":"not_applicable","mediation_notes":"The outcomes are body weight, energy intake and energy expenditure themselves, so mediation by weight loss does not arise. The design did include weight-matched and pair-fed calorie-restricted comparison groups, which is why the split of 86% intake and 14% expenditure can be reported.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"vehicle, calorie restriction weight-matched to CagriSema weight loss, and pair-feeding matched to CagriSema food intake\", \"follow_up_duration\": \"4 weeks after discontinuation\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no confidence intervals, p values or group sizes reported; one difference described as significant\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical study in rats, the model's lowest tier, reporting no group sizes, doses, confidence intervals or p values.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Named authors are employed by Novo Nordisk A/S and are minor shareholders, one of them also reporting that employment relationship; any other authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk A/S (employment, minor shareholdings)","adverse_events":"not reported in abstract","limitations":"A preclinical experiment in male diet-induced obese rats only, with no group sizes, doses, confidence intervals or p values reported, measuring energy balance rather than clinical outcomes; the drug was given only as the cagrilintide-semaglutide combination, so the GLP-1 component's own contribution cannot be separated.","plain_summary":"Male diet-induced obese rats received CagriSema, the amylin agonist cagrilintide combined with semaglutide, for 6 weeks and were followed for 4 weeks after it stopped, alongside a vehicle group, a calorie-restricted group matched to the drug's weight loss and a pair-fed group matched to its food intake. Lower food intake accounted for 86% of the drug's weight-loss effect and preserved energy expenditure for 14%, whereas the weight-matched calorie-restricted rats showed the expected fall in energy expenditure. Stopping treatment brought overeating and rapid weight regain, with the metabolic adaptation reversing within about 7 days. This is an animal study with no group sizes reported, and the GLP-1 drug was given only as part of the combination.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1380,"doi":"10.1111/dom.71480","pmid":"42951303","nct_ids":"[]","title":"Tirzepatide Use Resulted in Clinically Meaningful Weight Reduction in Individuals With Obesity or Overweight: 12-Month Real-World Results","authors":"[\"Chinthammit C\", \"Gibble TH\", \"Dehghan M\", \"Mojdami D\", \"Huang A\", \"Schapiro D\", \"Bays H\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] This study assessed the real-world effectiveness of tirzepatide in commercially insured individuals without diabetes, eligible for obesity medications (OMs), including glucagon like-peptide-1 receptor agonist (GLP-1 RA)-naïve individuals (i.e., no GLP-1 RA prescription during the 12-month pre-index period) and GLP-1 RA-experienced individuals. [METHODS] This retrospective, observational cohort study used Optum's de-identified Market Clarity Data (Optum Market Clarity). Adults with ≥ 1 prescription claim for tirzepatide between November 2023 and March 2024, with continuous medical/pharmacy enrollment for ≥ 12 months pre-index and post-index and available pre- and post-index data were included. Baseline demographics, clinical characteristics, and treatment effectiveness (change from baseline in weight, body mass index, and cardiometabolic risk factors) were assessed among OM-eligible individuals who were persistent on tirzepatide for ≥ 12 months. [RESULTS] The GLP-1 RA-naïve and experienced cohorts included 230 individuals (mean age: 49.5 years, 72.2% female) and 123 individuals (mean age: 48.9 years, 81.3% female), respectively, who were persistent on tirzepatide for 12 months with documented pre- and post-index weight measurements. At baseline, more than 85% of individuals in each cohort had ≥ 1 obesity-related complication, most commonly dyslipidemia, hypertension, and prediabetes. At 12 months post-index, the GLP-1 RA-naïve cohort achieved a mean weight reduction of 19.3%, while the GLP-1 RA-experienced cohort achieved a mean weight reduction of 13.1%. [CONCLUSIONS] After 12 months of persistent tirzepatide use, individuals experienced clinically meaningful weight reduction, comparable to outcomes reported in clinical trials. These real-world findings were observed both in GLP-1 RA-naïve and experienced individuals.","url":"https://pubmed.ncbi.nlm.nih.gov/42951303/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1293,"doi":"10.1111/dom.71496","pmid":"42946897","nct_ids":"[]","title":"Cardiovascular Effects of GLP-1 Receptor Agonists Across Age Groups: An Updated Meta-Analysis of Randomized Controlled Trials","authors":"[\"Fujii A\", \"Hasebe M\", \"Furuichi K\", \"Yabe D\", \"Yoshiji S\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To evaluate whether cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) differ by age. [MATERIALS AND METHODS] PubMed and Embase were searched to 1 July 2026 for randomized placebo-controlled GLP-1RA trials in adults with type 2 diabetes or overweight/obesity reporting age-stratified major adverse cardiovascular events (MACE; a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). Hazard ratios (HRs) for participants aged < 65 and ≥ 65 years were pooled using random-effects models with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Effect modification was assessed by pooling trial-specific ratios of HRs (RHRs) for ≥ 65 versus < 65 years. Where reported, effects were assessed across < 65, 65 to < 75 and ≥ 75 years. [RESULTS] Eight trials (SUSTAIN-6, EXSCEL, Harmony Outcomes, PIONEER 6, REWIND, AMPLITUDE-O, SELECT and SOUL) comprising 71 926 participants were included. GLP-1RAs reduced MACE at < 65 years and ≥ 65 years, with pooled HRs of 0.81 (95% CI 0.69-0.94; I2 = 64.1%) and 0.84 (95% CI 0.79-0.90; I2 = 0.0%), respectively. The pooled RHR showed no clear evidence of effect modification (1.03, 95% CI 0.85-1.25), although between-trial heterogeneity was high (I2 = 59.3%). Among trials reporting three age strata, RHRs showed no clear evidence of effect modification for 65 to < 75 or ≥ 75 years versus < 65 years, but data were available from only four trials, and the ≥ 75-year group was relatively small. [CONCLUSIONS] Across the included trial populations, GLP-1RAs lowered MACE in the age groups examined, with no clear evidence that relative cardiovascular effects differed by age.","url":"https://pubmed.ncbi.nlm.nih.gov/42946897/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\"]","outcome_type":"hard","primary_outcome":"major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), stratified by age","endpoints":null,"effect_estimate":"Pooled HR for MACE 0.81 (95% CI 0.69-0.94; I2 = 64.1%) at < 65 years and 0.84 (95% CI 0.79-0.90; I2 = 0.0%) at ≥ 65 years; pooled ratio of hazard ratios for ≥ 65 versus < 65 years 1.03 (95% CI 0.85-1.25), no clear effect modification, with high between-trial heterogeneity (I2 = 59.3%); ratios of hazard ratios for 65 to < 75 and ≥ 75 years versus < 65 years also showed no clear effect modification, from only four trials.","confidence_interval":"95% CI 0.69-0.94 for the pooled HR of 0.81 at < 65 years; 95% CI 0.79-0.90 for 0.84 at ≥ 65 years","p_value":null,"sample_size":71926,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (trials in adults with type 2 diabetes or overweight/obesity; no BMI criterion given)\", \"diabetes_status\": \"mixed (trials in adults with type 2 diabetes or overweight/obesity)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes or overweight/obesity\", \"sample_size\": 71926, \"inclusion_exclusion\": \"randomized placebo-controlled GLP-1RA trials in adults with type 2 diabetes or overweight/obesity that report age-stratified MACE, searched to 1 July 2026\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the eight pooled trials enrolled adults with type 2 diabetes or overweight/obesity; no BMI or age values are reported, although results are presented for participants aged 65 and over.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight change, HbA1c or mediation analysis, so the reduction in major adverse cardiovascular events cannot be separated from weight loss and glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 71926, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs for every pooled estimate, with I2 = 64.1% at < 65 years, I2 = 0.0% at ≥ 65 years and I2 = 59.3% for the ratio of hazard ratios; no event counts given\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis pooling eight randomized placebo-controlled trials (71 926 participants) with a hard composite outcome and confidence intervals, but it pools age-stratified subgroup estimates rather than individual participant data, heterogeneity is high (I2 = 64.1% in the younger stratum, 59.3% for the ratio of hazard ratios), and the finer age strata rest on four trials.","funding_source":"Canada Research Chairs Program; Japan Society for the Promotion of Science;  CIHR; DNA to RNA (D2R) Foundational Program; McGill University","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"It pools trial-level age-stratified estimates rather than individual participant data, and between-trial heterogeneity is high (I2 = 64.1% in the younger stratum and 59.3% for the ratio of hazard ratios); the three-stratum analysis rests on four trials and the authors note the oldest group was relatively small.","plain_summary":"A meta-analysis pooled eight randomised placebo-controlled trials of GLP-1 receptor agonists - SUSTAIN-6, EXSCEL, Harmony Outcomes, PIONEER 6, REWIND, AMPLITUDE-O, SELECT and SOUL - covering 71 926 adults with type 2 diabetes or overweight/obesity, to see whether the cardiovascular effect changes with age. Major cardiovascular events were lower with the drugs both below 65 years (hazard ratio 0.81, 95% CI 0.69-0.94) and at 65 and over (0.84, 95% CI 0.79-0.90), and the comparison between those age groups showed no clear difference (1.03, 95% CI 0.85-1.25). Variation between trials was high in the younger estimate, and only four trials reported the finer age strata, where the group aged 75 and over was small.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1304,"doi":"10.1177/23800844261491724","pmid":"42935458","nct_ids":"[]","title":"Oral Health-Related Adverse Events of GLP-1 Receptor Agonists","authors":"[\"Massarotto FC\", \"Mahmoud AH\", \"Watson GE\", \"Arany S\"]","journal":"JDR clinical and translational research","publication_date":"2026-10-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] As the clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) continues to grow for the management of type 2 diabetes, cardiovascular and renal protection, noncirrhotic fatty liver disease, and weight management, their potential implications for oral health need to be considered. [OBJECTIVES] This study examined oral health-related adverse events (AEs) associated with GLP-1 RAs using postmarketing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). [METHODS] FAERS reports for available GLP-1 RAs, exenatide, liraglutide, semaglutide, dulaglutide, and tirzepatide, were screened from their initial market introduction through December 2025, identifying 364,274 total AE reports, of which 31,195 (8.6%) involved oral, craniofacial, or dental manifestations. [RESULTS] Tirzepatide, despite being one of the most recently approved GLP-1 RAs, accounted for the highest overall AE volume, and semaglutide demonstrated the largest proportion of oral health-related AEs. A disproportionality analysis revealed a significant drug-specific signal for dry mouth of semaglutide, while vomiting, regurgitation, and reflux-related events produced a significant signal across all 5 drugs. Sensory disorders, including dysgeusia and taste disturbances, also demonstrated significant proportional reporting ratios (PRRs) and reporting odds ratios (RORs) for several GLP-1 RAs. Association analysis of AEs showed significant associations between vomiting and taste disturbances, as well as between dry mouth and dysgeusia, particularly with semaglutide and dulaglutide. [CONCLUSION] This analysis highlights emerging safety signals in oral health and underscores the need for heightened clinical awareness and prospective studies to characterize the incidence, timing, and mechanisms of oral AEs associated with GLP-1 RA therapy.Knowledge Transfer Statement:Understanding the oral adverse effects associated with GLP-1 receptor agonists allows clinicians and dental providers to more effectively counsel patients initiating or continuing these medications. By recognizing early symptoms such as dry mouth, dysgeusia, and reflux-related irritation, providers can implement targeted preventive strategies-including hydration guidance, salivary substitutes, dietary modifications, and closer oral health monitoring-to reduce complications and improve patient comfort, adherence, and overall treatment outcomes. This knowledge enhances interdisciplinary management of individuals using GLP-1 RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/42935458/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"pharmacovigilance","drugs":"[\"exenatide\", \"liraglutide\", \"semaglutide\", \"dulaglutide\", \"tirzepatide\"]","drug_details":"{\"route\": null, \"dose\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"oral, craniofacial and dental adverse events reported for GLP-1 receptor agonists (dry mouth, vomiting, regurgitation, reflux, dysgeusia and taste disturbance)","endpoints":null,"effect_estimate":"No effect sizes are reported. Of 364,274 total AE reports, 31,195 (8.6%) involved oral, craniofacial or dental manifestations; a significant drug-specific signal for dry mouth with semaglutide; significant signals for vomiting, regurgitation and reflux-related events across all 5 drugs; significant proportional reporting ratios and reporting odds ratios for dysgeusia and taste disturbances for several drugs; tirzepatide had the highest overall AE volume and semaglutide the largest proportion of oral AEs.","confidence_interval":"not reported in abstract","p_value":null,"sample_size":364274,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 364274, \"inclusion_exclusion\": \"FAERS reports for exenatide, liraglutide, semaglutide, dulaglutide and tirzepatide, screened from each drug's initial market introduction through December 2025\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the analysis counts adverse-event reports rather than describing people, and gives no age, sex, BMI or diabetes data, so the population is not determinable.","mediation":"possibly","mediation_notes":"Possibly: no weight, HbA1c or mediation data are reported, so the oral events cannot be separated from weight loss, reduced food and fluid intake or metabolic change.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": 364274, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no confidence intervals or values for the proportional reporting ratios and reporting odds ratios; 31,195 of 364,274 reports involved oral, craniofacial or dental manifestations\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a pharmacovigilance disproportionality analysis of spontaneous FAERS reports, which sits at study tier 4. It has no denominator, no comparator group and no effect sizes, so it can show what gets reported, not how often events occur or whether the drugs cause them.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Dry mouth signalled for semaglutide; vomiting, regurgitation and reflux-related events signalled across all 5 drugs; dysgeusia and taste disturbances showed significant proportional reporting ratios and reporting odds ratios for several drugs; vomiting was associated with taste disturbances and dry mouth with dysgeusia, particularly for semaglutide and dulaglutide.","limitations":"Spontaneous reports give no denominator, incidence or causal inference, and no comparator, effect size or interval is reported; reporting is open to notoriety and channelling bias, and no age, sex or clinical data for the reported cases are given. The authors call for prospective studies to characterise incidence, timing and mechanisms.","plain_summary":"Researchers screened reports sent to the US FDA's adverse-event system for five GLP-1 drugs - exenatide, liraglutide, semaglutide, dulaglutide and tirzepatide - from each drug's market introduction through December 2025, finding 364,274 reports of which 31,195 (8.6%) involved the mouth, face or teeth. Dry mouth stood out for semaglutide, vomiting, regurgitation and reflux across all five drugs, and taste disturbances for several of them. Spontaneous reports show what gets reported rather than how often problems happen or whether the drug caused them, and the analysis gives no figures for the signals it calls significant.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1354,"doi":"10.1016/j.neuropharm.2026.111240","pmid":"42946204","nct_ids":"[]","title":"The GLP-1 receptor agonist semaglutide reduces alcohol consumption and anxiety-like behaviors during withdrawal in Marchigian Sardinian alcohol-preferring rats","authors":"[\"Palmisano M\", \"Mrizak H\", \"Gonzalez AE\", \"Onge CMS\", \"Erikson CM\", \"Cruz B\", \"Flores-Bonilla A\", \"Vlkolinsky R\", \"Sharlai O\", \"Benedict J\", \"Bajo M\", \"Leggio L\", \"Ciccocioppo R\", \"Roberto M\"]","journal":"Neuropharmacology","publication_date":"2026-10-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising pharmacotherapeutics for alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 receptor agonist, on alcohol intake and anxiety-related behaviors in Marchigian Sardinian alcohol-preferring rats, a model characterized by excessive alcohol intake and pronounced anxious and depressive-like phenotypes. Male and female rats were treated with semaglutide (0.001, 0.01 and 0.1 mg/kg, s.c.) and vehicle. Voluntary alcohol consumption was assessed using the two-bottle choice paradigm. Locomotion, anxiety, and stress responses were evaluated during withdrawal and in naïve rats, following administration of the highest dose of semaglutide (0.1 mg/kg). Furthermore, the acute effects of semaglutide on GABAergic transmission were assessed in the central nucleus of the amygdala and in the infralimbic (IL) medial pre-frontal cortex (mPFC) of naïve rats. Semaglutide reduced voluntary alcohol consumption in a dose-dependent manner, and it produced anxiolytic-like behaviors during withdrawal in the open field test. In naïve animals, semaglutide reduced locomotor activity, lowered blood glucose levels, and decreased fat mass and GABAergic transmission in the IL mPFC. Our findings support the use of the GLP-1 receptor agonist semaglutide as a promising pharmacotherapy for the treatment of AUD and its associated psychiatric symptoms.","url":"https://pubmed.ncbi.nlm.nih.gov/42946204/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"0.001, 0.01 and 0.1 mg/kg\", \"route\": \"subcutaneous\", \"comparator\": \"vehicle\", \"treatment_duration\": null}","domains":"[\"body_composition\", \"addiction\", \"adverse_effects\", \"psychiatric\"]","outcome_type":"mixed","primary_outcome":"voluntary alcohol consumption in the two-bottle choice paradigm, with anxiety-related behaviour during withdrawal","endpoints":null,"effect_estimate":"No numerical estimates are given. Semaglutide reduced voluntary alcohol consumption dose-dependently and produced anxiolytic-like behaviour during withdrawal in the open field test; in naïve animals it reduced locomotor activity, lowered blood glucose, and decreased fat mass and GABAergic transmission in the infralimbic medial prefrontal cortex.","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male and female rats\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Marchigian Sardinian alcohol-preferring rats, a line with excessive alcohol intake and pronounced anxious and depressive-like phenotypes\", \"sample_size\": null, \"inclusion_exclusion\": \"male and female Marchigian Sardinian alcohol-preferring rats; naïve rats for the locomotor, stress and electrophysiology experiments\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: the study is in Marchigian Sardinian alcohol-preferring rats, a bred animal model, not in people.","mediation":"possibly","mediation_notes":"Possibly: the record itself reports that semaglutide lowered blood glucose and decreased fat mass in naïve animals, and nothing separates those metabolic changes from the fall in alcohol intake or the anxiolytic-like behaviour. No mediation analysis, weight-matched comparison or measurement before weight change is reported.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"vehicle\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no estimates, confidence intervals, p values or animal numbers reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical animal experiment, which sits at study tier 4; the abstract also gives no animal numbers, effect sizes, intervals or p values.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no known competing financial interests or personal relationships that could have influenced the work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"In naïve animals semaglutide reduced locomotor activity, lowered blood glucose levels, and decreased fat mass and GABAergic transmission in the infralimbic medial prefrontal cortex; no other safety findings are reported.","limitations":"Animal study in a selectively bred alcohol-preferring rat line, with no animal numbers, effect sizes or statistics in the abstract and no randomization or blinding described; semaglutide reduced locomotor activity at the dose used for the behavioural tests, which could affect those readouts. The authors state no limitations.","plain_summary":"Male and female Marchigian Sardinian alcohol-preferring rats, a line bred to drink heavily and to be anxious, were given semaglutide under the skin at 0.001, 0.01 or 0.1 mg/kg, or vehicle. Semaglutide cut voluntary alcohol drinking dose by dose and reduced anxiety-like behaviour during withdrawal. In rats not drinking alcohol it also lowered movement and blood glucose, reduced fat mass, and damped GABA signalling in one part of the prefrontal cortex. The abstract reports no animal numbers, effect sizes or statistics, and this is animal evidence, not evidence in people.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1373,"doi":"10.1111/dom.71485","pmid":"42935221","nct_ids":"[]","title":"Efficacy and Safety of CagriSema in Type 2 Diabetes: A Dose- and Comparator-Specific Systematic Review and Bayesian Meta-Analysis","authors":"[\"Kow CS\", \"Zaihan AF\", \"Ramachandram DS\", \"Thiruchelvam K\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] CagriSema combines cagrilintide with semaglutide and may improve glycaemic control and body weight in Type 2 diabetes. We evaluated its dose- and comparator-specific efficacy and safety. [METHODS] PubMed, Embase, CENTRAL and ClinicalTrials.gov were searched through 30 June 2026 for randomized controlled trials. Analyses were stratified by CagriSema dose and comparator. For HbA1c and body weight, efficacy/trial-product estimands were aligned where sufficiently reported, with treatment-policy estimates examined in sensitivity analyses. Bayesian random-effects models generated posterior medians and 95% credible intervals (CrIs). [RESULTS] Six trials representing 4554 potentially eligible participants with Type 2 diabetes were included. Compared with placebo, CagriSema 2.4 mg produced between-group differences of -1.87 percentage points in HbA1c (95% CrI, -2.08 to -1.62) and -12.69 percentage points in percentage body-weight change (95% CrI, -13.78 to -11.61). Versus semaglutide 2.4 mg, the additional HbA1c reduction was modest and uncertain (-0.21 percentage points; 95% CrI, -0.62 to 0.11), whereas additional body-weight reduction remained probable (-5.84 percentage points; 95% CrI, -10.08 to -2.15). Gastrointestinal adverse events and adverse-event-related discontinuation were increased versus placebo (RR, 2.27 [95% CrI, 1.81 - 3.00] and 3.16 [1.50 to 6.87], respectively), while estimates versus semaglutide were less precise. [CONCLUSIONS] CagriSema provides substantial glycaemic and body-weight benefits versus placebo. Its incremental advantage over dose-matched semaglutide is more evident for body-weight reduction, while comparative gastrointestinal tolerability and discontinuation risk remain uncertain.","url":"https://pubmed.ncbi.nlm.nih.gov/42935221/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"meta_analysis","drugs":"[\"cagrilintide-semaglutide\"]","drug_details":"{\"dose\": \"CagriSema 2.4 mg (analyses stratified by dose)\", \"comparator\": \"placebo and semaglutide 2.4 mg\", \"route\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"HbA1c and percentage body-weight change, with gastrointestinal adverse events and adverse-event-related discontinuation for safety","endpoints":null,"effect_estimate":"Versus placebo, CagriSema 2.4 mg: HbA1c -1.87 percentage points (95% CrI, -2.08 to -1.62) and percentage body-weight change -12.69 percentage points (95% CrI, -13.78 to -11.61). Versus semaglutide 2.4 mg: HbA1c -0.21 percentage points (95% CrI, -0.62 to 0.11), an uncertain difference, and body weight -5.84 percentage points (95% CrI, -10.08 to -2.15). Gastrointestinal adverse events RR 2.27 (95% CrI, 1.81 - 3.00) and adverse-event-related discontinuation 3.16 (1.50 to 6.87) versus placebo.","confidence_interval":"95% CrI, -2.08 to -1.62 for the HbA1c difference of -1.87 percentage points versus placebo","p_value":null,"sample_size":4554,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Type 2 diabetes\", \"sample_size\": 4554, \"inclusion_exclusion\": \"randomized controlled trials of CagriSema in Type 2 diabetes, searched to 30 June 2026, analysed by dose and comparator\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants in the six pooled trials had Type 2 diabetes; no BMI or age values are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the pooled outcomes are HbA1c and percentage body-weight change themselves, and whether weight loss explains weight loss is not a question.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 4554, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo and semaglutide 2.4 mg\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% credible intervals for every estimate; the comparisons with semaglutide 2.4 mg are imprecise (HbA1c -0.21; 95% CrI, -0.62 to 0.11; discontinuation 3.16 [1.50 to 6.87]); no event counts given\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a Bayesian meta-analysis pooling six randomized controlled trials, with credible intervals on every estimate, but the outcomes are intermediate (HbA1c, body weight), the evidence base is small, and the comparison against dose-matched semaglutide is imprecise.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Gastrointestinal adverse events and adverse-event-related discontinuation were increased versus placebo (RR 2.27 [95% CrI, 1.81 - 3.00] and 3.16 [1.50 to 6.87]); the estimates against semaglutide were less precise and the authors call comparative tolerability uncertain.","limitations":"Only six trials, all in Type 2 diabetes, and the abstract gives a count of potentially eligible rather than analysed participants; estimands could be aligned only where trials reported enough detail; the comparisons with dose-matched semaglutide are imprecise and the authors call comparative gastrointestinal tolerability and discontinuation risk uncertain.","plain_summary":"A Bayesian meta-analysis pooled six randomised trials of CagriSema, which combines cagrilintide with semaglutide, in people with Type 2 diabetes; the six trials cover 4554 participants the authors describe as potentially eligible. Against placebo, CagriSema 2.4 mg lowered HbA1c by 1.87 percentage points and body weight by 12.69 percentage points. Against semaglutide 2.4 mg the extra HbA1c effect was small and uncertain (-0.21 percentage points, credible interval -0.62 to 0.11), while the extra weight loss was clearer (-5.84 percentage points). Gastrointestinal side effects and discontinuation were more common than with placebo (RR 2.27 and 3.16).","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1381,"doi":"10.1016/j.cmi.2026.10.021","pmid":"42946163","nct_ids":"[]","title":"SGLT2 Inhibitors and risk of bacteriuria, candiduria, and UTI-related hospitalization: A Nationwide Cohort Study","authors":"[\"Biham O\", \"Burrack N\", \"Hassan L\", \"Nesher L\"]","journal":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","publication_date":"2026-10-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] SGLT2 inhibitors induce glycosuria; however, pathogen-specific real-world data on UTI risk are scarce, particularly in individuals without diabetes. We compared positive urine cultures, UTI-related hospitalizations, and Gram-negative, Gram-positive, and yeast-positive cultures after the initiation of SGLT2 inhibitors vs. GLP-1 receptor agonists in adults with and without type 2 diabetes. [METHODS] We conducted parallel propensity score-matched, active-comparator, new-user cohort studies within Clalit Health Services, Israel (2015-2024). Matching and Poisson regression were performed separately in all patients and in the strata with and without documented UTI in the preceding two years. [RESULTS] We analyzed 153,660 SGLT2 inhibitor initiators (134,060 with diabetes) and 172,262 GLP-1 receptor agonist initiators (93,086 with diabetes). Yeast-positive cultures were markedly more frequent with SGLT2 inhibitors (diabetes IRR 3.31, 95% CI 2.79-3.94; no diabetes 7.76, 2.34-47.99), as were Gram-positive uropathogens (1.34, 1.23-1.45; 1.53, 1.13-2.10), whereas Gram-negative uropathogens were not (0.74, 0.72-0.77; 1.05, 0.94-1.18). Overall culture positivity was lower with SGLT2 inhibitors in patients with diabetes (0.84, 0.81-0.86), but not in those without prior UTI (1.00, 0.96-1.04), and higher in patients without diabetes (1.14, 1.03-1.27). UTI-related hospitalization was uncommon (0.85, 0.74-0.97; 1.01, 0.58-1.83). [CONCLUSIONS] Compared with GLP-1 receptor agonists, SGLT2 inhibitor initiation was associated with a marked increase in yeast-positive urine cultures irrespective of diabetes status, a smaller increase in Gram-positive uropathogens, and no increase in Gram-negative uropathogens. Culture positivity was higher in patients without diabetes, and UTI-related hospitalization remained uncommon. These findings support the continued use of SGLT2 inhibitors when indicated, with candiduria as a specific safety signal warranting further characterization.","url":"https://pubmed.ncbi.nlm.nih.gov/42946163/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations of interest All authors have no financial or potential conflicts of interest to declare.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:52+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1291,"doi":"10.4081/monaldi.2026.3980","pmid":"42948977","nct_ids":"[]","title":"Effect of glucagon-like-peptide-1 receptor agonists on major cardiovascular outcomes: a systematic review and meta-analysis","authors":"[\"Saleem MF\", \"Mansoor A\", \"Shahid E\", \"Lohana M\", \"Ghafoor MS\", \"Khan MU\", \"Abbas F\", \"Hirpara H\", \"Khalid A\", \"Hassan F\", \"Rehman MEU\", \"Rizwan D\", \"Mohammad AM\", \"Vats V\"]","journal":"Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace","publication_date":"2026-10-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like-peptide-1 (GLP-1) receptor agonists are an antihyperglycemic group of drugs that have emerged as potentially preventing the risk of cardiovascular events. This meta-analysis assesses the effect of GLP-1 receptor agonists on cardiovascular outcomes. A detailed search of existing literature was based on MEDLINE, the Cochrane Library, Embase, and ClinicalTrials.gov. The search included all the studies from inception to February 2026. Statistical analyses were performed using the RevMan software, and a random-effects model was used to conduct the meta-analysis. Data were represented via forest plots, and dichotomous outcomes were evaluated using the Mantel-Haenszel method. This meta-analysis includes 12 randomized control trials (RCTs) with 82,669 patients. The analysis showed that GLP-1 receptor agonists reduce risk of cardiac death [relative risk (RR): 0.89, 95% confidence interval (CI): 0.82-0.96, p=0.003, I²=0%], all-cause mortality (RR: 0.88, 95% CI: 0.84-0.93, p<0.00001, I²=0%), stroke (RR: 0.85, 95% CI: 0.77-0.94, p=0.001, I²=0%), non-fatal stroke (RR: 0.87, 95% CI: 0.79-0.96, p=0.005, I²=0%) and revascularization (RR: 0.82, 95% CI: 0.72-0.95, p=0.007, I²=59%). There was no statistically significant reduction in myocardial infarction (MI) (RR: 0.92, 95% CI: 0.84-1.01, p=0.09, I²=42%), fatal MI (RR: 1.15, 95% CI: 0.80-1.66, p=0.44, I²=0%), non-fatal MI (RR: 0.91, 95% CI: 0.82-1.01, p=0.09, I²=51%), fatal stroke (RR: 0.75, 95% CI: 0.55-1.00, p=0.05, I²=0%), heart failure hospitalization (RR: 0.94, 95% CI: 0.85-1.03, p=0.20, I²=17%), or hospitalization for unstable angina (RR: 0.97, 95% CI: 0.85-1.12, p=0.71, I²=0%). This meta-analysis demonstrates that GLP-1 receptor agonists have a significant impact on cardiovascular death. More thorough RCTs with longer follow-up periods are required to completely understand the possible cardiovascular advantages of GLP-1 receptor agonists.","url":"https://pubmed.ncbi.nlm.nih.gov/42948977/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\", \"metabolic\"]","outcome_type":"hard","primary_outcome":"major cardiovascular outcomes: cardiac death, all-cause mortality, stroke, myocardial infarction, revascularization and heart failure hospitalization","endpoints":null,"effect_estimate":"Cardiac death RR 0.89; all-cause mortality RR 0.88; stroke RR 0.85; non-fatal stroke RR 0.87; revascularization RR 0.82; no significant reduction in myocardial infarction RR 0.92, fatal MI RR 1.15, non-fatal MI RR 0.91, fatal stroke RR 0.75, heart failure hospitalization RR 0.94 or hospitalization for unstable angina RR 0.97","confidence_interval":"95% CI: 0.82-0.96 (cardiac death)","p_value":"p=0.003 (cardiac death); p<0.00001 (all-cause mortality)","sample_size":82669,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 82669, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract reports no age, sex, BMI, diabetes status or baseline condition for the 82,669 pooled patients, so the population cannot be determined.","mediation":"possibly","mediation_notes":"The pooled outcomes are cardiovascular events rather than weight or glycaemia. No weight change, HbA1c or mediation analysis is reported, so under the presumption that GLP-1 effects are confounded with weight and metabolic change, mediation stays possible.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 82669, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"95% CIs, p-values and I² reported for every outcome; 12 trials with 82,669 patients; no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A meta-analysis that pools 12 randomized trials and 82,669 patients on hard cardiovascular outcomes, which puts it above the single-study tiers. It is held at MODERATE rather than HIGH because no risk-of-bias or certainty assessment is reported, the comparators and the pooled population are not described, and heterogeneity was substantial for revascularization (I²=59%) and non-fatal myocardial infarction (I²=51%).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The authors call for more thorough trials with longer follow-up. The abstract describes neither the comparators nor the pooled population, gives no risk-of-bias or certainty assessment, and heterogeneity was substantial for revascularization and non-fatal myocardial infarction.","plain_summary":"This meta-analysis pooled 12 randomized controlled trials with 82,669 patients to test what GLP-1 receptor agonists do to cardiovascular outcomes. Cardiac death (RR: 0.89, 95% CI: 0.82-0.96), all-cause mortality (RR: 0.88), stroke (RR: 0.85) and revascularization (RR: 0.82) were less frequent with the drugs, but there was no significant reduction in myocardial infarction (RR: 0.92), fatal or non-fatal MI, fatal stroke, heart failure hospitalization or hospitalization for unstable angina. The abstract does not say who the patients were, what they were compared with, or how long they were followed.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1307,"doi":"10.1002/cpt.70536","pmid":"42935015","nct_ids":"[]","title":"Use of SGLT2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors in Incident Hyponatremia in Patients with Type 2 Diabetes: Multicenter Target Trial Emulations","authors":"[\"Lin YH\", \"Tsai DH\", \"Hsieh MH\", \"Lee CC\", \"Tseng CC\", \"Wang MC\", \"Lai EC\", \"Liu KH\"]","journal":"Clinical pharmacology and therapeutics","publication_date":"2026-10-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Hyponatremia poses risks in type 2 diabetes, yet comparative electrolyte safety across glucose-lowering therapies remains unclear. We evaluated the risk of incident hyponatremia associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 (DPP-4) inhibitors in real-world practice. Using electronic health records from 155 healthcare organizations in the TriNetX Global Collaborative Network, we conducted multicenter active-comparator, new-user target trial emulations with 1:1 propensity score matching. For each pairwise comparison, adults with type 2 diabetes initiating either drug class, with no record of either class during the preceding 365 days, were included. The primary outcome was incident hyponatremia (ICD-10-CM E87.1 or serum sodium ≤ 135 mmol/L); sensitivity outcomes included diagnosis-only, laboratory-only, and stricter laboratory thresholds. Among more than 300,000 matched pairs per comparison, SGLT2 inhibitors and GLP-1 RAs were each associated with a 15% lower hazard of hyponatremia than DPP-4 inhibitors (hazard ratio [HR], 0.850; 95% confidence interval [CI], 0.842-0.858 and HR, 0.847; 95% CI: 0.838-0.856). The lower risk persisted at stricter sodium thresholds and across clinically relevant subgroups, including patients with heart failure, chronic kidney disease, or high-risk medications use. SGLT2 inhibitors and GLP-1 RAs were broadly comparable (HR, 0.962; 95% CI: 0.952-0.971). Positive and negative control outcomes were consistent with expectations. Overall, SGLT2 inhibitors and GLP-1 RAs were associated with a lower risk of incident hyponatremia than DPP-4 inhibitors. These real-world findings provide reassurance regarding the electrolyte safety of SGLT2 inhibitors and GLP-1 RAs, complementing their established cardiorenal benefits.","url":"https://pubmed.ncbi.nlm.nih.gov/42935015/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declared no competing interests for this work.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"DPP-4 inhibitors; GLP-1 RAs were also compared with SGLT2 inhibitors\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"incident hyponatremia (ICD-10-CM E87.1 or serum sodium ≤ 135 mmol/L)","endpoints":null,"effect_estimate":"GLP-1 RAs vs DPP-4 inhibitors: HR 0.847 for incident hyponatremia; SGLT2 inhibitors vs DPP-4 inhibitors HR 0.850; GLP-1 RAs and SGLT2 inhibitors broadly comparable, HR 0.962","confidence_interval":"95% CI: 0.838-0.856 (GLP-1 RAs vs DPP-4 inhibitors, HR 0.847)","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"mixed (heart failure present in a reported subgroup)\", \"ckd_status\": \"mixed (chronic kidney disease present in a reported subgroup)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": null, \"inclusion_exclusion\": \"adults with type 2 diabetes initiating either drug class, with no record of either class in the preceding 365 days\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were adults with type 2 diabetes initiating a glucose-lowering drug class, and no BMI or age data are reported.","mediation":"possibly","mediation_notes":"The outcome is incident hyponatremia, and the record reports no body-weight change, no HbA1c and no mediation analysis, so weight and metabolic change cannot be separated from the drug effect. The 1:1 propensity score matching addresses baseline confounding rather than mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"DPP-4 inhibitors; GLP-1 RAs were also compared with SGLT2 inhibitors\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported for every hazard ratio; more than 300,000 matched pairs per comparison; no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A single observational study, so capped at LOW. It is a multicentre new-user active-comparator analysis of electronic health records from 155 healthcare organizations with very narrow confidence intervals, which keeps it above VERY_LOW, but the outcome is coded in routine records and the exact analysed numbers, follow-up and population characteristics are not reported.","funding_source":"National Science and Technology Council; National Cheng Kung University","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare no competing interests for this work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The safety outcome itself: incident hyponatremia was less frequent with GLP-1 RAs than with DPP-4 inhibitors (HR 0.847) and comparable with SGLT2 inhibitors (HR 0.962); no other adverse events reported","limitations":"Observational use of routinely coded electronic health records: the outcome is defined by diagnosis codes or a single sodium value, confounding by indication and by unmeasured factors remains after propensity matching, and the abstract reports no follow-up time, no exact analysed numbers, no ages and no BMI.","plain_summary":"Researchers used electronic health records from 155 healthcare organizations to compare adults with type 2 diabetes who started GLP-1 receptor agonists, SGLT2 inhibitors or DPP-4 inhibitors, matching them in pairs. GLP-1 receptor agonists were linked to a lower risk of newly recorded low blood sodium than DPP-4 inhibitors (hazard ratio 0.847, 95% CI: 0.838-0.856), and were broadly comparable with SGLT2 inhibitors (hazard ratio 0.962). Because the study is observational, this is an association rather than proof that the drugs prevent low sodium. The abstract gives no ages, no BMI and no follow-up time, and only an approximate number of matched pairs.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1334,"doi":"10.1007/s10549-026-08096-z","pmid":"42932003","nct_ids":"[]","title":"GLP-1 receptor agonist-associated weight loss in breast cancer patients receiving concurrent endocrine therapy: a retrospective cohort analysis","authors":"[\"Cronin KM\", \"Tiersten A\"]","journal":"Breast cancer research and treatment","publication_date":"2026-10-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Endocrine therapy for hormone receptor-positive breast cancer is associated with adverse metabolic effects - including increased fat mass, decreased lean muscle mass, and insulin resistance - that may attenuate the efficacy of GLP-1 receptor agonists (GLP-1 RAs). This study evaluated GLP-1 RA-associated weight loss outcomes in breast cancer patients receiving concurrent endocrine therapy. [METHODS] We conducted a retrospective cohort analysis of 269 breast cancer patients at a single academic center receiving concurrent GLP-1 RA and adjuvant endocrine therapy. GLP-1 RA and endocrine therapy data were obtained from electronic medication reconciliation lists and pharmacy dispense reports. Patients were required to have initiated GLP-1 therapy during the study period and to have received concurrent GLP-1 RA and endocrine therapy for at least one year. The primary outcome was percentage weight change from GLP-1 initiation to 12 months (± 2 months). Secondary outcomes included proportions achieving ≥ 5%, ≥ 10%, and ≥ 15% weight loss. [RESULTS] Mean one-year percentage weight loss was - 4.5% (95% CI: -6.0% to - 3.0%; -3.9 kg; 95% CI: -4.96 to - 2.93 kg), significantly below the 10-20% observed in postmenopausal subgroups of GLP-1 randomized trials (all p < 0.001). Only 21.3% achieved ≥ 10% and 10.4% achieved ≥ 15% weight loss. Weight loss differed significantly by GLP-1 agent (p = 0.003); semaglutide (- 5.8%) and tirzepatide (- 4.7%) outperformed dulaglutide (+ 0.1%), which is approved for type 2 diabetes only. Higher baseline weight was associated with greater absolute loss (r = - 0.19, p = 0.002), though percentage weight loss did not differ significantly by baseline BMI category (p = 0.303). PR-negative patients lost more than PR-positive patients (- 8.2% vs. -4.2%; p = 0.021, d = 0.46). Type 2 diabetes was present in 70.6% of patients; T2DM status was not significantly associated with weight loss on t-test (p = 0.288), though patients without T2DM were numerically more likely to achieve ≥ 15% loss (21.5% vs. 5.8%). [CONCLUSIONS] GLP-1 RAs produce statistically significant but substantially attenuated weight loss in breast cancer patients on concurrent endocrine therapy. GLP-1 agent selection significantly influences outcomes. Given emerging evidence of oncologic benefit, prospective trials are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42932003/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:29+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"muscle\", \"body_composition\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1361,"doi":"10.5041/rmmj.10585","pmid":"42957176","nct_ids":"[]","title":"Neuropsychiatric Safety of GLP-1 Receptor Agonists and Tirzepatide in Adults with Type 2 Diabetes Mellitus or Obesity","authors":"[\"Jani HT\", \"Levine H\", \"Patel A\", \"Trivedi R\", \"Patel XD\"]","journal":"Rambam Maimonides medical journal","publication_date":"2026-10-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Neuropsychiatric safety concerns about glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide prompted regulatory review by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). We synthesized the contemporary evidence in adults with type 2 diabetes mellitus or obesity, emphasizing study design, risk of bias, and the distinction between signal detection and causal inference. [METHODS] The PubMed/MEDLINE, Embase, Web of Science, and Scopus databases were searched without a lower date limit through March 15, 2026 (English, adults ≥18 years). The review was reported with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, and the PRISMA-S and PRISMA-Harms extensions. Evidence was grouped into prespecified categories: randomized syntheses, comparative observational studies and target-trial emulations, outlier non-active-comparator studies, pharmacovigilance analyses, and regulatory reviews. Risk of bias was appraised with the Cochrane Risk of Bias 2 tool and with Risk of Bias in Non-randomised Studies of Interventions; certainty was summarized using Grading of Recommendations Assessment, Development and Evaluation. [RESULTS] Twenty studies and two regulatory reviews met the inclusion criteria. Randomized evidence, including two large 2025 meta-analyses and post hoc pooled analyses of semaglutide and tirzepatide, showed no increased risk of suicidality, depression, or anxiety, though psychiatric exclusion criteria limited generalizability. Active-comparator cohorts from the United States, Scandinavia, and the United Kingdom likewise showed no clear increase after confounding control. Passive-comparator and disproportionality analyses generated signals but could not separate drug effects from baseline psychiatric risk, obesity-related distress, or reporting bias. The EMA and FDA conclusions do not support a causal class-wide association between GLP-1 RAs and suicidal ideation or behavior. [CONCLUSIONS] Evidence does not support a clinically meaningful increase in neuropsychiatric harm with GLP-1 RAs or tirzepatide in the populations studied. Surveillance remains warranted for patients with substantial psychiatric morbidity, for obesity-only populations, and for long-term rare outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42957176/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\", \"tirzepatide\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"active comparators in the comparative cohorts and target-trial emulations; passive comparators in the disproportionality analyses\", \"treatment_duration\": null}","domains":"[\"adverse_effects\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"neuropsychiatric safety: suicidality, depression and anxiety","endpoints":null,"effect_estimate":"No pooled estimate or numerical result is reported. Randomized evidence, including two large 2025 meta-analyses and post hoc pooled analyses of semaglutide and tirzepatide, showed no increased risk of suicidality, depression or anxiety; active-comparator cohorts from the United States, Scandinavia and the United Kingdom showed no clear increase after confounding control; passive-comparator and disproportionality analyses generated signals that could not be separated from baseline psychiatric risk, obesity-related distress or reporting bias.","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (the review covers adults with type 2 diabetes mellitus or obesity)\", \"diabetes_status\": \"mixed (the review covers adults with type 2 diabetes mellitus or obesity)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes mellitus or obesity\", \"sample_size\": null, \"inclusion_exclusion\": \"studies in adults aged 18 and over with type 2 diabetes mellitus or obesity, English language, searched through March 15, 2026; evidence grouped into randomized syntheses, comparative observational studies and target-trial emulations, outlier non-active-comparator studies, pharmacovigilance analyses and regulatory reviews\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review covers adults with type 2 diabetes mellitus or obesity, and the randomized evidence it rests on came from trials with psychiatric exclusion criteria; no BMI or age values are reported.","mediation":"unlikely","mediation_notes":"Unlikely: the main result is null, so there is no effect to attribute to weight loss or metabolic change. No weight, HbA1c or mediation analysis is reported either.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"active comparators in the comparative cohorts and target-trial emulations; passive comparators in the disproportionality analyses\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no pooled estimate, confidence interval or event count reported; risk of bias appraised with Cochrane Risk of Bias 2 and ROBINS-I and certainty summarized with GRADE\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review with a narrative synthesis only. It appraises risk of bias with RoB 2 and ROBINS-I and summarises certainty with GRADE, but pools nothing itself and reports no new primary outcome data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The review's subject is safety: randomized evidence showed no increased risk of suicidality, depression or anxiety, active-comparator cohorts showed no clear increase after confounding control, and passive-comparator and disproportionality analyses generated signals the authors could not separate from baseline psychiatric risk, obesity-related distress or reporting bias.","limitations":"A narrative synthesis of twenty studies and two regulatory reviews with no pooled estimate of its own; the randomized evidence came from trials with psychiatric exclusion criteria, which the authors say limits generalizability, and they note that surveillance is still needed for people with substantial psychiatric morbidity, for obesity-only populations and for long-term rare outcomes.","plain_summary":"A systematic review searched four databases to March 15, 2026 and brought together twenty studies and two regulatory reviews on whether GLP-1 receptor agonists and tirzepatide raise neuropsychiatric risk in adults with type 2 diabetes or obesity. Randomised evidence, including two large 2025 meta-analyses, showed no increased risk of suicidality, depression or anxiety, and cohort studies with active comparators showed no clear increase once confounding was controlled. Analyses using passive comparators or spontaneous reports did produce signals, which the authors could not separate from existing psychiatric risk, obesity-related distress or reporting bias. The review pools nothing of its own, and the trials it draws on excluded people with psychiatric illness, so it does not settle the question for that group.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1375,"doi":"10.1016/j.cmet.2026.10.010","pmid":"42933400","nct_ids":"[\"NCT07163624\"]","title":"UBT251, a novel triple GLP-1, GIP, and glucagon receptor agonist, in adults with type 2 diabetes: A multicenter, randomized phase 2 trial","authors":"[\"Zhou Z\", \"Shi X\", \"Jiang S\", \"Wang S\", \"Shu H\", \"Sun W\", \"Wang H\", \"Cong L\", \"Mao L\", \"Fu L\", \"Gan S\", \"Zhang L\", \"Han J\", \"Gao Y\", \"Wang W\", \"Zhang L\", \"Wang F\", \"Cao C\", \"Yan X\", \"Zhang H\", \"Su T\", \"Ling W\", \"Jakobsen LHK\", \"Belmar Nazal N\", \"Yan H\"]","journal":"Cell metabolism","publication_date":"2026-10-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"This phase 2 trial included 211 Chinese participants with type 2 diabetes mellitus (mean age 48.4 years; 131 participants were male). Participants received once-weekly subcutaneous UBT251 (2 mg, 4 mg [initial dose 0.5 mg], 4 mg [initial dose 1 mg], or 6 mg), 1 mg semaglutide, or placebo for 24 weeks. At week 24, UBT251 achieved least-squares mean changes in glycated hemoglobin of -2.16% (95% CI, -2.39 to -1.92) to -1.98% (95% CI, -2.31 to -1.64), versus -1.77% (95% CI, -1.99 to -1.54) for semaglutide and -0.66% (95% CI, -0.90 to -0.41) for placebo (placebo-adjusted differences: -1.50% to -1.32%; all p < 0.001). UBT251 significantly reduced fasting blood glucose, 2-h postprandial glucose, and waist circumference versus placebo (all p < 0.001). Weight reduction with UBT251 was significantly greater than both placebo and semaglutide (all p < 0.05). Gastrointestinal events were the most common treatment-emergent adverse events. These findings support further phase 3 evaluation of UBT251. Registration: CTR20250029; NCT07163624.","url":"https://pubmed.ncbi.nlm.nih.gov/42933400/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests H.Z., T.S., W.L., and H.Y. are employees of Zhuhai United Laboratories Co., Ltd. and provide clinical affairs services to United Bio-Technology (Hengqin) Co., Ltd., which is the sponsor of this clinical trial and an affiliated entity of the employer. United Bio-Technology (Hengqin) Co., Ltd. filed a patent application in part based on results reported in this study, with H.Y., H.Z., T.S., and W.L. listed as inventors. L.H.K.J. and N.B.N. are employees of Novo Nordisk. All other authors received research funds from United Bio-Technology (Hengqin) Co., Ltd.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"rct","drugs":"[\"ubt251\"]","drug_details":"{\"dose\": \"2 mg, 4 mg [initial dose 0.5 mg], 4 mg [initial dose 1 mg], or 6 mg\", \"treatment_duration\": \"24 weeks\", \"route\": \"subcutaneous\", \"comparator\": \"1 mg semaglutide, or placebo\"}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"change in glycated hemoglobin at week 24","endpoints":null,"effect_estimate":"At week 24, least-squares mean HbA1c changes with UBT251 of -2.16% (95% CI, -2.39 to -1.92) to -1.98% (95% CI, -2.31 to -1.64), versus -1.77% (95% CI, -1.99 to -1.54) for semaglutide and -0.66% (95% CI, -0.90 to -0.41) for placebo; placebo-adjusted differences -1.50% to -1.32%, all p < 0.001. Fasting blood glucose, 2-h postprandial glucose and waist circumference also fell versus placebo (all p < 0.001), and weight reduction was greater than with both placebo and semaglutide (all p < 0.05).","confidence_interval":"95% CI, -2.39 to -1.92 for the HbA1c change of -2.16%","p_value":"all p < 0.001 for the placebo-adjusted HbA1c differences; all p < 0.05 for the weight reduction against placebo and semaglutide","sample_size":211,"follow_up":"24 weeks","direction":"benefit","population":"{\"mean_age\": 48.4, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"131 participants were male (of 211)\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes mellitus\", \"sample_size\": 211, \"inclusion_exclusion\": \"Chinese adults with type 2 diabetes mellitus in a multicenter phase 2 trial\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 211 participants were Chinese adults with type 2 diabetes mellitus and mean age was 48.4 years, below the 55-75 reference range; no BMI data are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcomes are HbA1c, fasting and 2-h postprandial glucose, waist circumference and body weight, which are the weight and glycaemic measures the mediation question excludes.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 211, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"1 mg semaglutide, or placebo\", \"follow_up_duration\": \"24 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs for each arm's HbA1c change (for example 95% CI, -2.39 to -1.92) with p values for the comparisons; 211 participants spread across the four UBT251 dose groups, semaglutide and placebo\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a randomized multicentre phase 2 trial of 211 participants over 24 weeks, with both placebo and an active comparator and confidence intervals on every arm, but the outcomes are intermediate (HbA1c, glucose, waist circumference, weight) rather than clinical events, blinding is not stated, and the trial is industry-sponsored.","funding_source":"United Bio-Technology (Hengqin) Co., Ltd., named as the sponsor of this clinical trial; all other authors received research funds from it","industry_funded":"yes","manufacturer":"United Bio-Technology (Hengqin) Co., Ltd.","author_conflicts":"Four authors are employees of Zhuhai United Laboratories and provide clinical affairs services to the trial's sponsor, United Bio-Technology (Hengqin), which filed a patent application based in part on these results with those four as inventors; two authors are employees of Novo Nordisk; all other authors received research funds from the sponsor.","sponsor_role":"United Bio-Technology (Hengqin) Co., Ltd. is named as the sponsor of this clinical trial and filed a patent application based in part on the results; its role in design, conduct, analysis or reporting is not described.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: four are employees of Zhuhai United Laboratories Co., Ltd. and provide clinical affairs services to the sponsor United Bio-Technology (Hengqin) Co., Ltd., which filed a patent application based in part on these results with those four as inventors, and all other authors received its research funds; two authors are employees of Novo Nordisk, the maker of the active comparator semaglutide.","adverse_events":"Gastrointestinal events were the most common treatment-emergent adverse events; no rates or between-group comparison are given.","limitations":"A 24-week phase 2 trial in 211 Chinese participants with type 2 diabetes, reporting glycaemic, weight and waist outcomes rather than clinical events; HbA1c results are given as ranges across four dose groups, adverse events without rates, and blinding is not stated. The sponsor is the drug's company and several authors are its or its affiliate's employees. The authors state no limitations.","plain_summary":"A multicentre randomised phase 2 trial gave 211 Chinese adults with type 2 diabetes (mean age 48.4 years; 131 male) weekly injections under the skin of UBT251, a triple GLP-1, GIP and glucagon receptor agonist, at 2, 4 or 6 mg, or semaglutide 1 mg, or placebo, for 24 weeks. HbA1c fell by between 2.16% and 1.98% on UBT251, against 1.77% on semaglutide and 0.66% on placebo, and weight loss was greater than with either comparator; fasting and post-meal glucose and waist circumference also fell against placebo. Gastrointestinal events were the most common side effects, with no rates given, and the trial's sponsor is the company behind the drug, with several authors employed by it or its affiliate.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1391,"doi":"10.21203/rs.3.rs-11332760/v1","pmid":null,"nct_ids":"[]","title":"Postoperative Glucagon-Like Peptide-1 Receptor Agonist Use and Long-Term Outcomes Following Breast Reconstruction: A Retrospective Cohort Study Using a U.S. Collaborative Network","authors":"[\"Brito EM\", \"Ogbonnah C\", \"Gaston JO\", \"Phuyal D\", \"Almeida V\", \"Ha J\", \"Duraes EFR\", \"Djohan R.\"]","journal":"preprint server","publication_date":"2026-10-26","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>Background  Weight gain is common among breast cancer patients. Increasing use of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss has raised concerns regarding long-term breast reconstruction outcomes. This study evaluated long-term breast reconstruction outcomes among overweight and obese GLP-1 users. Methods  TriNetX was queried to identify patients undergoing breast reconstruction between 2015 and 2023. Cohorts comprised users of GLP-1 receptor agonists within 2 years after reconstruction and non-users. Propensity score matching included demographic and clinical covariates. Outcomes at 2 and 3 years included revisions and capsular contracture outcomes, reconstruction revisions, aesthetic reoperations, fat grafting, lymphedema, and implant-based capsular contracture. Results  After matching, 304 patients per group were analyzed at 2 years and 314 at 3 years. Revisions and capsular contracture outcomes were lower with GLP-1 use at 2 and 3 years (22% vs 50%, risk ratio [RR] 0.44, and 26% vs 53%, RR 0.49, both p < 0.001), as was reconstruction revision (15% vs 34% and 19% vs 35%, both p < 0.001). Aesthetic reoperation was lower (13% vs 18%, p = 0.043, and 14% vs 24%, p = 0.001). Capsular contracture was lower with GLP-1 use in implant-based reconstruction (13% vs 26%, p < 0.001, and 15% vs 25%, p = 0.002), preserved in a procedure-only analysis. Lymphedema did not differ, while fat grafting was lower only at 3 years. Conclusions  GLP-1 receptor agonist use was associated with lower revisions and capsular contracture outcomes after breast reconstruction and lower capsular contracture in implant-based reconstruction. Given the observational design and potential confounding by indication, these associations are hypothesis-generating and warrant prospective evaluation.</p>","url":"https://doi.org/10.21203/rs.3.rs-11332760/v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"non-users\", \"treatment_duration\": null}","domains":"[\"cancer\"]","outcome_type":"hard","primary_outcome":"revisions and capsular contracture outcomes after breast reconstruction","endpoints":null,"effect_estimate":"Revisions and capsular contracture outcomes 22% vs 50% (RR 0.44) at 2 years and 26% vs 53% (RR 0.49) at 3 years, both p < 0.001; reconstruction revision 15% vs 34% and 19% vs 35%, both p < 0.001; aesthetic reoperation 13% vs 18% (p = 0.043) and 14% vs 24% (p = 0.001); capsular contracture in implant-based reconstruction 13% vs 26% (p < 0.001) and 15% vs 25% (p = 0.002); lymphedema did not differ; fat grafting was lower only at 3 years.","confidence_interval":"not reported in abstract","p_value":"both p < 0.001 for revisions and capsular contracture outcomes at 2 and 3 years","sample_size":608,"follow_up":"2 and 3 years","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (the population is described as overweight and obese GLP-1 users; no BMI value or threshold is given)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"patients undergoing breast reconstruction between 2015 and 2023\", \"sample_size\": 608, \"inclusion_exclusion\": \"patients undergoing breast reconstruction between 2015 and 2023; GLP-1 receptor agonist use within 2 years after reconstruction versus non-users, propensity-score matched on demographic and clinical covariates\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the study population is described as overweight and obese GLP-1 users undergoing breast reconstruction; no BMI values, ages or diabetes data are reported.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight change, BMI or mediation analysis, so the lower revision and capsular contracture rates cannot be separated from the weight loss these drugs produce. Propensity matching on baseline covariates addresses confounding, not mediation.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 608, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"non-users\", \"follow_up_duration\": \"2 and 3 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no confidence intervals reported; risk ratios with p values only; 304 patients per group at 2 years and 314 at 3 years\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a preprint, not peer reviewed. It is also a single retrospective records-network cohort (304 matched patients per group at 2 years, 314 per group at 3 years) with no confidence intervals and confounding by indication that the authors themselves flag.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The outcomes are surgical complications: revisions, capsular contracture, aesthetic reoperation and implant-based capsular contracture were all lower among GLP-1 users, lymphedema did not differ, and fat grafting was lower only at 3 years.","limitations":"A retrospective records-network study of 304 matched patients per group, not peer reviewed, with no confidence intervals and no weight or BMI values; the authors note that the observational design and potential confounding by indication make the associations hypothesis-generating.","plain_summary":"A preprint used the TriNetX records network to compare patients who used GLP-1 receptor agonists in the 2 years after breast reconstruction with matched non-users: 304 per group at 2 years and 314 per group at 3 years. Revisions and capsular contracture outcomes were lower among GLP-1 users (22% vs 50% at 2 years, risk ratio 0.44; 26% vs 53% at 3 years), as were reconstruction revisions, aesthetic reoperations and implant capsular contracture, while lymphedema did not differ and fat grafting was lower only at 3 years. These are associations from an observational study that has not been peer reviewed, and the authors say confounding by indication makes them hypothesis-generating.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1395,"doi":"10.64898/2026.10.23.26366288","pmid":null,"nct_ids":"[]","title":"Interventions for Cognitive Impairment in Type 2 Diabetes Mellitus: An Umbrella Review of Pharmacological and Lifestyle Strategies, Mechanisms, and Clinical Implications","authors":"[\"Ninsiima, H. I.\", \"Daniel, E. E.\", \"Kisakye, N. I.\", \"Mandera, I.\", \"Ainamani, H. E.\", \"Akambasisa, M.\", \"Ayebazibwe, G.\", \"Matovu, D.\"]","journal":"medrxiv (preprint)","publication_date":"2026-10-26","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"AbstractO_ST_ABSBackgroundC_ST_ABSType 2 diabetes mellitus (T2DM) is one of the fastest-growing epidemics associated with cognitive impairment and dementia. This reduces quality of life among patients with diabetes. Several trials on the management of cognitive impairment have been done although their effectiveness and mechanisms are still unclear.\n\nAimTo synthesize evidence from systematic reviews and meta-analyses of RCTs examining interventions for cognitive impairment in T2DM, stratified by intervention category, comparator, patient characteristics, mechanisms and clinical outcomes.\n\nMethodsWe identified eleven systematic reviews (n = 213,604 participants) reporting effects of cognitive impairment interventions through comprehensive literature search. Using random effect models, a meta-meta-analysis was conducted and heterogeneity assessed using I{superscript 2} statistics. AMSTAR and GRADE were used to assess for quality of reviews. Subgroup analyses were conducted for intervention category, cognitive severity, age, diabetes duration, sex, and follow-up duration.\n\nResultSodium glucose co-transporter inhibitors showed the strongest cognitive improvement effect (pooled OR = 0.44, 95% CI: 0.35-0.55; SUCRA = 94.5%), followed by GLP-1 receptor agonists (RR/OR = 0.60, 95% CI: 0.50-0.72; SUCRA = 92.1%). Among lifestyle interventions, multi-component exercise was the most effective (SMD = 0.69-1.04). The lower baseline cognition (MMSE < 23) benefited more from GLP-1 receptor agonists (Cohens d = -3.00, p < 0.001). Advanced age ([&ge;]60 years) and prolonged intervention time ([&ge;]24 weeks for medications; [&ge;]6 months for exercise) were associated with greater effects. Female gender showed greater benefit from GLP-1 receptor agonists (HR = 0.63 vs 0.81 for male gender).\n\nConclusionsSGLT2 inhibitors and GLP-1 receptor agonists have the greatest effect on cognition in T2DM, and the multi-component exercise as the most effective lifestyle component. The review therefore recommends individualized intervention selection based on patient characteristics and baseline cognitive status. This calls for high quality trials with prolonged follow-up to strengthen the evidence base.\n\nPROSPERO RegistrationThe trial was registered in PROSPERO under number CRD420261453178","url":"https://www.medrxiv.org/content/10.64898/2026.10.23.26366288","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"umbrella_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cognition\", \"dementia\"]","outcome_type":"intermediate","primary_outcome":"cognitive outcomes in type 2 diabetes (cognitive improvement, pooled as odds or risk ratios and standardised mean differences)","endpoints":null,"effect_estimate":"GLP-1 receptor agonists RR/OR = 0.60 (95% CI: 0.50-0.72; SUCRA = 92.1%), second to sodium glucose co-transporter inhibitors (pooled OR = 0.44, 95% CI: 0.35-0.55; SUCRA = 94.5%); multi-component exercise was the most effective lifestyle intervention (SMD = 0.69-1.04); greater GLP-1 effect at lower baseline cognition (MMSE < 23: Cohens d = -3.00, p < 0.001) and in women (HR = 0.63 vs 0.81 for male gender).","confidence_interval":"95% CI: 0.50-0.72 for the GLP-1 receptor agonist estimate of 0.60","p_value":"p < 0.001 for the greater GLP-1 effect at lower baseline cognition (MMSE < 23); no p value is given for the main pooled GLP-1 estimate","sample_size":213604,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes mellitus with cognitive impairment\", \"sample_size\": 213604, \"inclusion_exclusion\": \"systematic reviews and meta-analyses of randomised trials of interventions for cognitive impairment in type 2 diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all of the pooled reviews studied interventions for cognitive impairment in people with type 2 diabetes mellitus; no BMI or age values are reported.","mediation":"possibly","mediation_notes":"Possibly: no weight, HbA1c or mediation analysis is reported for the GLP-1 estimate, so the cognitive effect cannot be separated from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Umbrella review\", \"sample_size\": 213604, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs for the pooled estimates (GLP-1 receptor agonists 0.60, 95% CI: 0.50-0.72); heterogeneity assessed with I2 statistics but no value reported; no event counts\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a preprint, not peer reviewed. It does pool, as a meta-meta-analysis of eleven systematic reviews with pooled estimates and confidence intervals, so it is not NOT_RATED for want of a pooled result, but it adds no new primary data and its subgroup findings are exploratory.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A preprint that pools eleven published reviews rather than primary data, so the same trials may be counted more than once; the GLP-1 estimate is printed as a combined risk or odds ratio, no comparator is named, and the findings by cognition, age, sex and duration are subgroup analyses. The authors call for high-quality trials with longer follow-up.","plain_summary":"This preprint umbrella review pooled eleven published systematic reviews, covering 213,604 participants, of treatments for cognitive impairment in people with type 2 diabetes. GLP-1 receptor agonists came second to SGLT2 inhibitors for cognitive improvement (0.60, 95% CI 0.50-0.72, against 0.44 for SGLT2 inhibitors), with larger effects reported for people whose cognition was already poorer, for women, and for longer treatment. It is not peer reviewed, it pools published reviews rather than patient data, and the GLP-1 figure is printed as a combined risk or odds ratio, so the result is exploratory.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1324,"doi":"10.1111/dom.71459","pmid":"42928425","nct_ids":"[]","title":"Neuropsychiatric Outcomes Associated With GLP-1 Receptor Agonist Use in Medicare Beneficiaries With Type 2 Diabetes: Variation by Treatment Pattern and Obesity Status","authors":"[\"Baik SH\", \"Baye F\", \"Xian H\", \"Fung KW\", \"McDonald CJ\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-25","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Glucagon-like peptide-1 (GLP-1) receptors are expressed in brain regions governing mood, reward and stress, yet the neuropsychiatric effects of GLP-1 receptor agonist (GLP-1 RA) therapy remain poorly characterized. We estimated associations between GLP-1 RA use and neuropsychiatric disorders and variation by obesity status and treatment pattern. [MATERIAL AND METHODS] This population-based cohort study used claims data from Medicare enrolees with Type 2 diabetes mellitus. GLP-1 RAs were compared with other second-line glucose-lowering medications and evaluated across four treatment patterns: monotherapy, switch, escalation and augmentation. Eight neuropsychiatric outcomes were examined using 1:1 propensity score-matched, covariate-adjusted stratified Cox regression with time-varying covariates. [RESULTS] GLP-1 RA use was associated with a small increase in aggregate psychiatric disorder risk (Hazard Ratio [HR] = 1.04; 95% Confidence Interval: 1.03-1.06; 1.7 excess events/1000 person-years), of uncertain clinical significance given the large cohort size. Risk was elevated for depression (HR = 1.11; 3.0 excess events/1000 person-years) but reduced for substance use disorders (HR = 0.84; 4.1 fewer events/1000 person-years), dementia (HR = 0.87; 2.8 fewer) and suicidal/self-harm (HR = 0.81; 0.4 fewer events/1000 person-years). Associations varied by treatment pattern: monotherapy showed elevated psychiatric (HR = 1.43) and elevated emotional symptom (HR = 1.32) risks; escalation also exhibited elevated psychiatric risk, whereas switch and augmentation demonstrated reduced or null risks. [CONCLUSIONS] Rather than a uniform class effect, the neuropsychiatric profile of GLP-1 RA appears context-dependent, differing by treatment pattern, obesity status and outcome examined. Elevated risk with monotherapy or escalation may reflect baseline clinical differences rather than pharmacological effect. Reduced risks of substance use disorders, dementia and suicidal/self-harm are reassuring.","url":"https://pubmed.ncbi.nlm.nih.gov/42928425/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"other second-line glucose-lowering medications\", \"treatment_duration\": null}","domains":"[\"dementia\", \"addiction\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"eight neuropsychiatric outcomes, including aggregate psychiatric disorder, depression, substance use disorders, dementia and suicidal/self-harm","endpoints":null,"effect_estimate":"Aggregate psychiatric disorder HR = 1.04 (1.7 excess events/1000 person-years); depression HR = 1.11; substance use disorders HR = 0.84; dementia HR = 0.87; suicidal/self-harm HR = 0.81; monotherapy psychiatric HR = 1.43 and emotional symptom HR = 1.32","confidence_interval":"95% Confidence Interval: 1.03-1.06 (aggregate psychiatric disorder, HR = 1.04)","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (analyses were stratified by obesity status; no BMI values reported)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes mellitus\", \"sample_size\": null, \"inclusion_exclusion\": \"Medicare enrolees with type 2 diabetes receiving GLP-1 RAs or other second-line glucose-lowering medications\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were Medicare enrolees with type 2 diabetes receiving second-line glucose-lowering medication, and no age or BMI values are reported.","mediation":"possibly","mediation_notes":"The outcomes are neuropsychiatric diagnoses rather than weight or glycaemia, and no weight change, HbA1c or mediation analysis is reported, so weight and metabolic change cannot be separated from the drug effect. Obesity status was used to stratify the analysis, which is not a mediation test.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"other second-line glucose-lowering medications\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"a 95% CI is given for the aggregate psychiatric outcome only; the individual outcomes carry hazard ratios and events per 1000 person-years without CIs; no cohort size reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A single observational study, so capped at LOW. It is a population-based Medicare claims cohort with propensity score matching, covariate adjustment and time-varying covariates, which keeps it above VERY_LOW, but the cohort size and follow-up are not reported, outcomes come from diagnosis codes, and the authors themselves say the elevated risks may reflect baseline clinical differences.","funding_source":"U.S. National Library of Medicine, Intramural Research Program","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Neuropsychiatric safety outcomes: a small increase in aggregate psychiatric disorder risk (HR = 1.04) and elevated depression risk (HR = 1.11), with reduced substance use disorder (HR = 0.84), dementia (HR = 0.87) and suicidal/self-harm (HR = 0.81) risk","limitations":"An observational claims analysis: the authors note that elevated risk with monotherapy or escalation may reflect baseline clinical differences rather than a drug effect, outcomes are identified from diagnosis codes, eight outcomes are tested across four treatment patterns, and no cohort size or follow-up duration is reported.","plain_summary":"This study followed Medicare enrolees with type 2 diabetes in insurance claims, comparing those who used GLP-1 receptor agonists with those on other second-line glucose-lowering medicines across eight neuropsychiatric outcomes. GLP-1 use was linked to a small increase in overall psychiatric disorder risk (HR = 1.04; 1.7 excess events/1000 person-years) and to higher depression risk (HR = 1.11), but to lower risk of substance use disorders (HR = 0.84), dementia (HR = 0.87) and suicidal or self-harm events (HR = 0.81). Associations varied by treatment pattern, with raised psychiatric risk for monotherapy (HR = 1.43). Because this is an observational claims analysis, these are associations, and the authors note the raised risks may reflect baseline differences between patients rather than the drug.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1378,"doi":"10.3760/cma.j.cn441530-20260715-00287","pmid":"42927970","nct_ids":"[]","title":"[Efficacy and safety of GLP-1 receptor agonists combined with bariatric surgery for obesity: a timing-stratified systematic review]","authors":"[\"He MC\", \"Hua R\", \"Shao YK\", \"Xu B\", \"Shen QW\", \"Fu XJ\", \"Zhan CW\", \"Huang XJ\", \"Yao QY\"]","journal":"Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery","publication_date":"2026-10-25","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Objective: To systematically evaluate the efficacy and safety of GLP-1 receptor agonists applied at different stages before and after bariatric surgery, and to compare the clinical benefits of preoperative use, early postoperative use, and rescue use after insufficient weight loss or weight regain according to medication timing. Methods: PubMed, Web of Science, and Embase via Ovid were searched from inception to June 20, 2026. A relatively strict three-concept search strategy was used, consisting of terms related to bariatric surgery, GLP-1 receptor agonists and specific drug names, and perioperative or weight-management scenarios. Searches were mainly restricted to title and abstract fields, and animal-only studies were excluded. Clinical studies involving patients who underwent metabolic and bariatric surgery and received GLP-1 receptor agonists before or after surgery were included. Studies were classified into three groups according to medication timing: preoperative use, early postoperative use, and rescue use after insufficient weight loss or weight regain. Mean difference or standardized mean difference was used for continuous variables, and odds ratio was used for categorical variables. Meta-analysis was performed using a random-effects model. Results: A total of 27 studies were included in the systematic review, including 10 studies on preoperative use, 4 on early postoperative use, and 13 on rescue use after insufficient weight loss or weight regain. Among them, 13 studies were included in efficacy meta-analyses. Preoperative use of GLP-1 receptor agonists improved preoperative weight loss, with a pooled SMD of 0.52 (95%CI: 0.25-0.79, I²=0%, P<0.05). However, when postoperative weight loss at 12 months was assessed using body weight at surgery as the baseline, the percentage of total body weight loss at 12 months was 2.85 percentage points lower in the preoperative medication group than in the non-medication group (95%CI: -4.35 to -1.36, I²=37.7%, P<0.05). Active addition of GLP-1 receptor agonists around 1 month after surgery increased the percentage of total body weight loss at 6 months by an additional 3.62 percentage points (95%CI: 1.88-5.37, I²=0%, P<0.05). Initiation of GLP-1 receptor agonists around 6 months after surgery resulted in an additional weight loss of 7.48 kg during subsequent follow-up compared with controls (95%CI: 5.35-9.60, I²=34.6%, P<0.05). For rescue therapy, four randomized controlled trials showed that GLP-1 receptor agonists resulted in an additional 10.30 percentage points of endpoint percentage weight loss compared with placebo or usual care (95%CI: 6.40-14.20, I²=89.2%, P<0.05). Regarding safety, among studies that clearly reported event numbers, the pooled incidences of nausea, constipation, diarrhea, and vomiting were 25.3%, 19.0%, 9.2%, and 8.6%, respectively. Serious adverse events were uncommon. Conclusion: GLP-1 receptor agonists have timing-specific value in the comprehensive management of metabolic and bariatric surgery. Preoperative use can increase preoperative weight loss but does not enhance postoperative weight loss when body weight at surgery is used as the baseline. Early postoperative use may further amplify weight-loss benefits within the first postoperative year. Rescue use after insufficient weight loss or weight regain is supported by the strongest evidence. In terms of safety, adverse events are mainly gastrointestinal, and serious adverse events are uncommon.","url":"https://pubmed.ncbi.nlm.nih.gov/42927970/","source_name":"pubmed","source_tier":1,"coi_statement":"所有作者声明不存在利益冲突","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"non-medication group; controls; placebo or usual care\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"adverse_effects\", \"gastrointestinal\", \"perioperative\", \"discontinuation\"]","outcome_type":"intermediate","primary_outcome":"weight loss around metabolic and bariatric surgery (preoperative weight loss and percentage of total body weight loss), with gastrointestinal safety","endpoints":null,"effect_estimate":"Preoperative use improved preoperative weight loss, pooled SMD 0.52; at 12 months, total body weight loss was 2.85 percentage points lower in the preoperative medication group than in the non-medication group; starting around 1 month after surgery added 3.62 percentage points at 6 months; starting around 6 months after surgery added 7.48 kg; rescue use added 10.30 percentage points versus placebo or usual care","confidence_interval":"95%CI: 0.25-0.79 (pooled SMD 0.52 for preoperative weight loss)","p_value":"P<0.05","sample_size":null,"follow_up":"weight loss assessed at 12 months and at 6 months after surgery","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (patients undergoing metabolic and bariatric surgery for obesity; no BMI criterion stated)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity treated with metabolic and bariatric surgery\", \"sample_size\": null, \"inclusion_exclusion\": \"clinical studies of patients who underwent metabolic and bariatric surgery and received GLP-1 receptor agonists before or after surgery; animal-only studies excluded\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the included studies enrolled patients undergoing metabolic and bariatric surgery for obesity, and no age, BMI or diabetes data are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the pooled outcomes are preoperative weight loss and percentage of total body weight loss, so weight change is the outcome rather than a possible explanation for it.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"non-medication group; controls; placebo or usual care\", \"follow_up_duration\": \"weight loss assessed at 12 months and at 6 months after surgery\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs and I² reported for each pooled estimate (I²=89.2% for rescue use); no participant totals or event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A systematic review with pooled random-effects estimates, so it is rated rather than left unrated, but held at MODERATE: the 27 included studies are clinical studies of mixed design, only 13 contributed to the efficacy analyses, heterogeneity reached 89.2% for rescue use, the timing subgroups are small, and no participant totals are reported.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"All authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Pooled incidences of nausea 25.3%, constipation 19.0%, diarrhea 9.2% and vomiting 8.6% among studies that clearly reported event numbers; serious adverse events were uncommon","limitations":"The pooled studies are clinical studies of mixed design rather than trials only, just 13 of the 27 contributed to the efficacy analyses, the timing subgroups are small (4 studies on early postoperative use), heterogeneity was high for rescue therapy, and no participant totals, ages or BMI values are reported.","plain_summary":"This systematic review pooled 27 studies of GLP-1 receptor agonists used before or after metabolic and bariatric surgery for obesity, grouped by when the drug was started, with 13 studies in the efficacy analyses. Starting the drug before surgery increased weight loss beforehand (pooled SMD 0.52) but left total body weight loss 2.85 percentage points lower at 12 months than in the non-medication group, while starting about 1 month after surgery added 3.62 percentage points at 6 months and rescue use after insufficient weight loss or weight regain added 10.30 percentage points over placebo or usual care. Nausea (25.3%), constipation (19.0%), diarrhea (9.2%) and vomiting (8.6%) were common, and serious adverse events were uncommon. The abstract names four randomized trials for rescue use and does not give the designs of the other included studies, so some of these comparisons are associations rather than randomized treatment effects.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1208,"doi":"10.1016/j.euroneuro.2026.113886","pmid":"42925811","nct_ids":"[]","title":"Efficacy and safety of GLP-1 receptor agonists in patients with schizophrenia spectrum disorders treated with antipsychotics: a systematic review and meta-analysis","authors":"[\"Gędek A\", \"Modrzejewski S\", \"Polański K\", \"Waśniewska L\", \"Molero P\", \"Wichniak A\", \"Dominiak M\", \"McIntyre RS\"]","journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","publication_date":"2026-10-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Weight gain and impaired glucose metabolism are common complications of antipsychotic treatment in schizophrenia spectrum disorders (SSD). While beneficial in other populations, the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in SSD remain unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1 RAs versus placebo in SSD patients treated with antipsychotics. PubMed, Scopus, and Web of Science were searched until January 2026. Random-effects models were used to pool mean differences (MDs), standardized mean differences (SMDs), and risk ratios (RRs), as appropriate. Seven RCTs including 481 participants were included. Compared with placebo, GLP-1 RAs significantly reduced body weight (MD -6.98 kg; 95% CI -10.53 to -3.43), BMI (MD -2.51 kg/m²; 95% CI -3.51 to -1.51), waist circumference (MD -5.05 cm; 95% CI -6.66 to -3.44), HbA1c (MD -0.32 percentage points; 95% CI -0.38 to -0.26), and fasting blood glucose (MD -0.54 mmol/L; 95% CI -0.83 to -0.25). Heterogeneity was substantial for body weight (I²=93%) and BMI (I²=80%). No significant effects emerged for blood pressure or lipid parameters. Psychiatric symptom severity did not differ between GLP-1 RAs and placebo (SMD -0.05; 95% CI -0.36 to 0.25). Gastrointestinal adverse events were more frequent with GLP-1 RAs than with placebo, while overall study drop-out did not differ between groups. GLP-1 RAs improve short-term anthropometric and glycemic outcomes in SSD patients treated with antipsychotics. However, the limited number of trials, substantial heterogeneity in weight-related outcomes, and relatively short follow-up warrant cautious interpretation and further large-scale RCTs.","url":"https://pubmed.ncbi.nlm.nih.gov/42925811/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute, and speaker and/or consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, Eli Lilly, NewBridge Pharmaceuticals, Viatris, AbbVie, Bristol Myers Squibb (BMS), Teva, Adhere Tech, GH Research, Autobahn Therapeutics, and Atai Life Sciences. Adam Wichniak has received speaker and/or consultation fees from Aflofarm, Adamed, Angelini, Bausch Health, Biofarm, Celon Pharma, Eli Lilly, GL Pharma, Gedeon Richter, Krka, Lekam, Lundbeck, Polski Lek, Stada, Swixx Biopharma, and Viatris. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"body weight, with BMI, waist circumference, HbA1c, fasting blood glucose and psychiatric symptom severity (no primary outcome designated in the abstract)","endpoints":null,"effect_estimate":"Body weight MD -6.98 kg; BMI MD -2.51 kg/m2; waist circumference MD -5.05 cm; HbA1c MD -0.32 percentage points; fasting blood glucose MD -0.54 mmol/L; no significant effects for blood pressure or lipid parameters; psychiatric symptom severity SMD -0.05, no difference; gastrointestinal adverse events more frequent","confidence_interval":"95% CI -10.53 to -3.43 (body weight MD -6.98 kg)","p_value":null,"sample_size":481,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"schizophrenia spectrum disorders treated with antipsychotics\", \"sample_size\": 481, \"inclusion_exclusion\": \"randomized controlled trials of GLP-1 RAs versus placebo in patients with schizophrenia spectrum disorders treated with antipsychotics\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: participants were adults with schizophrenia spectrum disorders treated with antipsychotics, a disease selected for itself, and no BMI, age or diabetes data are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcomes are body weight, BMI, waist circumference, HbA1c and fasting glucose, so weight and glycaemic change are the results themselves. The one non-metabolic outcome, psychiatric symptom severity, showed no difference from placebo.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 481, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"95% CIs reported for every pooled estimate; heterogeneity substantial for body weight (I²=93%) and BMI (I²=80%); no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A meta-analysis of seven randomized placebo-controlled trials, which puts it above the single-study tiers, but held at MODERATE: only 481 participants, heterogeneity of I²=93% for body weight and 80% for BMI, follow-up the authors call relatively short, and outcomes that are anthropometric and glycaemic measures rather than clinical events.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Two of the authors report research grant support and speaker or consultation fees from a long list of pharmaceutical companies; all other authors declare none.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with manufacturers of GLP-1 receptor agonists: Novo Nordisk and Eli Lilly, among many other companies.","adverse_events":"Gastrointestinal adverse events were more frequent with GLP-1 RAs than with placebo, and overall study drop-out did not differ between groups; no event numbers given","limitations":"The authors point to the limited number of trials, substantial heterogeneity in the weight outcomes and relatively short follow-up, and call for larger trials. Only seven trials and 481 participants were pooled, and the abstract gives no ages, BMI values or follow-up length.","plain_summary":"Seven randomized trials with 481 participants who had schizophrenia spectrum disorders and were taking antipsychotics were pooled to compare GLP-1 receptor agonists with placebo. Body weight fell by 6.98 kg (95% CI -10.53 to -3.43), BMI by 2.51 kg/m2, waist circumference by 5.05 cm, HbA1c by 0.32 percentage points and fasting glucose by 0.54 mmol/L, while blood pressure, lipids and psychiatric symptom severity (SMD -0.05) showed no difference. Gastrointestinal side effects were more common with the drugs, though drop-out was not. The trials were few, short and very inconsistent with each other, with heterogeneity of I²=93% for body weight.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1212,"doi":"10.1007/s00228-026-04206-4","pmid":"42920001","nct_ids":"[]","title":"Efficacy and safety of GLP-1 receptor agonists for antipsychotic-related overweight and metabolic dysregulation: a systematic review and meta-analysis","authors":"[\"Zhou L\", \"Zhang Y\", \"Shen C\", \"Wu F\"]","journal":"European journal of clinical pharmacology","publication_date":"2026-10-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Antipsychotic-related overweight and metabolic dysregulation are highly prevalent among patients with severe mental illness. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial metabolic benefits in the general population, their efficacy and safety in antipsychotic-treated patients remain unclear. This review aimed to systematically evaluate the efficacy and safety of GLP-1RAs in patients with antipsychotic-related overweight and metabolic dysregulation. [METHODS] We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1RAs in adults receiving antipsychotic treatment. PubMed, Web of Science, Embase, MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to September 13, 2026. Primary outcomes included changes in body weight, body mass index (BMI), HbA1c, and total cholesterol. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs). This study was registered with PROSPERO (CRD420261290294). [RESULTS] Eight RCTs involving 535 randomized participants were included. GLP-1RAs treatment was associated with significant reductions in body weight (MD = -6.54 kg, 95% CI: -9.80 to -3.29, P < 0.001, I2 = 92%), BMI (MD = -2.34 kg/m2, 95% CI: -3.34 to -1.34, P < 0.001, I² = 85%), HbA1c (MD = -0.32%, 95% CI: -0.39 to -0.26, P < 0.001, I² = 52%), waist circumference (MD = -5.22 cm, 95% CI: -6.55 to -3.88, P < 0.001, I2 = 27%), visceral fat mass (MD = -0.31 kg, 95% CI: -0.46 to -0.16, P < 0.001, I2 = 11%), and LDL-C (MD = -0.16 mmol/L, 95% CI: -0.31 to -0.01, P = 0.03, I2 = 54%), whereas no significant effects were observed for total cholesterol, triglycerides, or HDL-C. Weight reduction was greatest with semaglutide, followed by liraglutide, and increased with longer treatment duration (both P for subgroup differences < 0.05). GLP-1RAs were associated with higher risks of nausea (RR = 1.61, 95% CI: 1.20 to 2.16), vomiting (RR = 2.10, 95% CI: 1.32 to 3.35), and constipation (RR = 2.34, 95% CI: 1.23 to 4.47), but not of diarrhea, serious adverse events (RR = 0.72, 95% CI: 0.49 to 1.06), all-cause discontinuation (RR = 1.05, 95% CI: 0.60 to 1.85), or discontinuation due to adverse events (RR = 2.14, 95% CI: 0.72 to 6.33). Psychiatric adverse events were infrequent and could not be pooled. [CONCLUSION] GLP-1RAs significantly improve weight-related and glycemic outcomes in antipsychotic-treated patients, at the cost of an increased risk of gastrointestinal adverse events. Their psychiatric safety could not be established owing to sparse data. Longer-term trials with standardized safety reporting are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42920001/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval: Given that this systematic review and meta-analysis did not utilize primary data from individual participants, formal ethical approval was not sought. The protocol has been registered with PROSPERO (CRD420261290294). Consent for publication: All authors have reviewed and approved the final version of this manuscript and consent to its submission and publication in European Journal of Clinical Pharmacology. Competing interests: The authors declare no competing interests.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"body_composition\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"changes in body weight, body mass index (BMI), HbA1c, and total cholesterol","endpoints":null,"effect_estimate":"Body weight MD = -6.54 kg; BMI MD = -2.34 kg/m2; HbA1c MD = -0.32%; waist circumference MD = -5.22 cm; visceral fat mass MD = -0.31 kg; LDL-C MD = -0.16 mmol/L; no significant effects for total cholesterol, triglycerides or HDL-C; nausea RR = 1.61, vomiting RR = 2.10, constipation RR = 2.34; serious adverse events RR = 0.72, not significant","confidence_interval":"95% CI: -9.80 to -3.29 (body weight MD = -6.54 kg)","p_value":"P < 0.001 (body weight, BMI and HbA1c); P = 0.03 (LDL-C)","sample_size":535,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (antipsychotic-related overweight; no BMI threshold or obesity criterion stated)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"antipsychotic-related overweight and metabolic dysregulation\", \"sample_size\": 535, \"inclusion_exclusion\": \"randomized controlled trials of GLP-1RAs in adults receiving antipsychotic treatment\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the pooled trials enrolled adults receiving antipsychotic treatment who had antipsychotic-related overweight and metabolic dysregulation, a cardiometabolic problem the target group does not have, and no ages or BMI values are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the primary outcomes are body weight, BMI, HbA1c and total cholesterol, so weight and metabolic change are the results rather than a possible explanation for them.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 535, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs and I² reported for every pooled estimate; heterogeneity high for body weight (I2 = 92%); no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"A meta-analysis that pools randomized trials, which puts it above the single-study tiers, but held at MODERATE: only eight trials and 535 participants, heterogeneity of I2 = 92% for body weight and 85% for BMI, outcomes that are weight, glycaemic and lipid measures rather than clinical events, and psychiatric safety that the authors say could not be established.","funding_source":"Sichuan Provincial Science and Technology Support Program; Chengdu Pharmaceutical Association","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Higher risks of nausea (RR = 1.61), vomiting (RR = 2.10) and constipation (RR = 2.34), but no increase in diarrhea, serious adverse events (RR = 0.72), all-cause discontinuation (RR = 1.05) or discontinuation due to adverse events (RR = 2.14); psychiatric adverse events were infrequent and could not be pooled","limitations":"The authors state that psychiatric safety could not be established because the data were sparse and that longer trials with standardised safety reporting are needed. Only eight trials and 535 participants were pooled, heterogeneity was high for body weight and BMI, and the abstract gives no ages, no BMI values and no comparator.","plain_summary":"Eight randomized trials with 535 participants taking antipsychotics were pooled to test GLP-1 receptor agonists against the weight gain and metabolic problems these drugs cause. Body weight fell by 6.54 kg (95% CI: -9.80 to -3.29), BMI by 2.34 kg/m2, HbA1c by 0.32%, waist circumference by 5.22 cm and LDL-C by 0.16 mmol/L, while total cholesterol, triglycerides and HDL-C did not change significantly. Nausea (RR = 1.61), vomiting (RR = 2.10) and constipation (RR = 2.34) were more common, serious adverse events were not (RR = 0.72), and psychiatric safety could not be established because reports were too sparse. Results varied a lot between trials, with heterogeneity of I2 = 92% for body weight.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1232,"doi":"10.64898/2026.10.22.761061","pmid":"42996002","nct_ids":"[]","title":"Central Glucagon-Like Peptide-1 Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease","authors":"[\"Desai B\", \"Francis KL\", \"Bryan CL\", \"Connolly J\", \"Karunagaran T\", \"Mathan S\", \"Sharma K\", \"Damian V\", \"Watts CA\", \"Choi P\", \"Kadlec K\", \"Phan BA\", \"Pacheco MC\", \"Alonge KM\", \"Morton GJJ\", \"Schwartz MW\", \"Scarlett JM.\"]","journal":"preprint server","publication_date":"2026-10-24","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of obesity and type 2 diabetes (T2D). These drugs also have anti-inflammatory effects that have recently been extended to the treatment of inflammatory bowel disease (IBD). Whether the mechanism underlying this benefit involves a direct action on the intestine or instead is mediated via GLP-1Rs in the brain, however, is unknown. Based on evidence implicating the brain as the target for the anti-obesity and anti-inflammatory effects of GLP-1RAs, we sought to determine if central GLP-1R signaling is sufficient to explain its intestinal anti-inflammatory effects. To this end, we compared the efficacy of peripheral vs central administration of the GLP-1RA, semaglutide (SEMA), in diet-induced obese (DIO) mice with dextran sodium sulfate (DSS)-induced colitis. We report that compared to vehicle, both colitis severity and histopathological injury following DSS administration are reduced by peripheral administration of SEMA. We also report that this benefit is largely recapitulated by intracerebroventricular administration of SEMA at a low dose that, when administered peripherally, is below that needed to affect food intake and body weight. We conclude that in a mouse model of colitis, activation of GLP-1Rs in the brain is sufficient to explain the intestinal anti-inflammatory effect conferred by GLP-1R agonism.","url":"https://doi.org/10.64898/2026.10.22.761061","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"vehicle\", \"dose\": \"a low dose that, when administered peripherally, is below that needed to affect food intake and body weight (no numeric dose stated)\", \"route\": \"various\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"rheumatologic\"]","outcome_type":"intermediate","primary_outcome":"colitis severity and histopathological injury after DSS administration","endpoints":null,"effect_estimate":"Colitis severity and histopathological injury were reduced by peripheral semaglutide compared with vehicle, and the benefit was largely recapitulated by intracerebroventricular semaglutide at a low dose; no effect sizes, group sizes or test statistics are reported","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (diet-induced obese mice)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diet-induced obesity with DSS-induced colitis\", \"sample_size\": null, \"inclusion_exclusion\": \"diet-induced obese mice with dextran sodium sulfate-induced colitis\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: the study was done in diet-induced obese mice with dextran sodium sulfate-induced colitis, which is non-human evidence.","mediation":"possibly","mediation_notes":"No body weight, food intake or glycaemic data are reported, so under the presumption that GLP-1 effects are confounded with weight and metabolic change, mediation stays possible. The authors give the central dose as one that, peripherally, falls below the threshold needed to affect food intake and body weight, which argues for a weight-independent central mechanism but is a dose argument rather than a mediation analysis, a weight-matched comparison or a measurement taken before weight loss.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"vehicle\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI, p-value or group sizes reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY because the record is a preprint and has not been peer reviewed, which is the level the model gives anything not peer reviewed; the exception that leaves a preprint unrated applies only to a preprint holding no outcome data, and this one reports outcomes. The underlying design, an animal study in a chemically induced colitis model with no group sizes, effect sizes or statistics in the abstract, would itself sit at VERY_LOW, so the rating credits it with no more than preclinical weight.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"An animal study in a chemically induced colitis model, reported as a preprint without peer review. The abstract gives no group sizes, no effect sizes and no statistics, and the central dose is described only as low rather than quantified.","plain_summary":"In diet-induced obese mice given dextran sodium sulfate to induce colitis, researchers compared semaglutide injected into the body with semaglutide delivered directly into the brain. Both colitis severity and tissue injury were reduced by semaglutide given peripherally compared with vehicle, and the benefit was largely reproduced by a low dose given into the brain, below the amount that affects food intake and body weight when given peripherally. The authors conclude that activating GLP-1 receptors in the brain is enough to explain the anti-inflammatory effect in the gut. This is an animal study, released as a preprint without peer review, and the abstract reports no numbers of animals, effect sizes or statistics.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1191,"doi":"10.1007/s11657-026-01785-8","pmid":"42920024","nct_ids":"[]","title":"Skeletal effects of GLP-1 receptor agonist therapy in adults with overweight or obesity: a systematic review","authors":"[\"Lai CH\", \"Li YT\", \"Wu TS\", \"Wu CT\"]","journal":"Archives of osteoporosis","publication_date":"2026-10-23","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[UNLABELLED] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for weight management, yet their skeletal effects remain unclear. This systematic review of eight randomized controlled trials (n = 493) evaluating dual-energy X-ray absorptiometry (DXA)-derived bone mineral density reports findings separately for each agent, without pooling, because the trials evaluated four pharmacologically distinct agents differing markedly in weight-lowering potency. The evidence is sparse for every agent and is insufficient to establish the skeletal effects of GLP-1 RA therapy in this population. [PURPOSE] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for weight management, yet their skeletal effects remain uncertain. We systematically reviewed the randomized evidence on bone mineral density (BMD) and bone turnover markers in adults with overweight or obesity, reporting findings separately for each individual agent. [METHODS] This PRISMA 2020-compliant systematic review (INPLASY202630076) searched PubMed, Embase, Cochrane CENTRAL, and Google Scholar (January 2015 to July 2026). Eligible randomized controlled trials (RCTs) enrolled adults aged ≥18 years with mean baseline body mass index (BMI) > 25 kg/m², compared a GLP-1 RA with placebo or another antidiabetic therapy for ≥12 weeks, and reported BMD assessed by dual-energy X-ray absorptiometry (DXA). Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool and certainty of evidence using GRADE. Because the included trials evaluated pharmacologically distinct agents that differ substantially in weight-lowering potency, results were synthesized narratively and reported separately by agent; no meta-analysis was performed. [RESULTS] Eight RCTs (n = 493) were included. Three trials were at low risk of bias (Eriksson 2019; Hygum 2020; Hansen 2024) and five raised some concerns, principally regarding the randomization process and selective reporting; no agent is supported by more than one trial at low risk of bias. (Cai 2021 contributes two treatment arms assessed separately, giving nine comparisons in the risk-of-bias assessment.) Evidence was unevenly distributed across agents: semaglutide and dulaglutide were each evaluated in one trial, liraglutide in two, and exenatide in five. Five of the eight trials enrolled adults with type 2 diabetes, including all four that randomized an insulin comparator arm; three enrolled adults without diabetes, of which one was defined by obesity alone. By study-level mean baseline BMI, five trials lay in the obese range ( ≥ 30 kg/m²) and three in the overweight range (25 to <30 kg/m²). The single semaglutide trial (Hansen 2024; n = 64; low risk of bias), which produced the largest weight loss of any trial (estimated treatment difference [ETD] -6.8 kg vs placebo), reported reduced lumbar spine BMD (ETD - 0.018 g/cm², p = 0.007), reduced whole-body BMD (mean difference [MD] -0.02 g/cm²; 95% CI - 0.03 to -0.01), and increased C-terminal telopeptide (CTX; MD 166.50 pg/mL; 95% CI 66.60 to 266.40). Liraglutide was evaluated at two doses with divergent results. At the weight-management dose of 3.0 mg daily, in the only trial conducted in adults with obesity and without diabetes (Jensen 2024; ETD - 6.7 kg vs placebo), lumbar spine BMD (MD - 0.019 g/cm²; 95% CI - 0.034 to -0.004) and total hip BMD (MD - 0.013 g/cm²; 95% CI - 0.024 to -0.002) were reduced. At the diabetes dose of 1.8 mg daily (Hygum 2020; -3.8 kg), no site changed materially (lumbar spine MD 0.00 g/cm²; 95% CI - 0.01 to 0.01). Exenatide trials were inconsistent, ranging from 0.03 g/cm² (95% CI 0.02 to 0.03) at the lumbar spine (Renyuan 2015) to -0.04 g/cm² (95% CI - 0.15 to 0.07; Akyay 2023). Certainty of evidence was very low for every agent. [CONCLUSION] The randomized evidence is too sparse and too clinically heterogeneous to determine the skeletal effects of GLP-1 RA therapy in adults with overweight or obesity. Each agent has been evaluated in at most five small trials, most conducted in adults with type 2 diabetes rather than in adults with obesity alone. The two trials producing the largest weight loss, one of semaglutide and one of liraglutide 3.0 mg, both reported reduced lumbar spine and total hip BMD at closely similar magnitudes of weight loss, and the semaglutide trial additionally reported increased bone resorption. This convergence warrants dedicated evaluation rather than extrapolation across the drug class. Adequately powered, agent-specific trials with fracture endpoints are required. [PROTOCOL REGISTRATION] INPLASY202630076.","url":"https://pubmed.ncbi.nlm.nih.gov/42920024/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: Not applicable. This study is a systematic review of previously published data. Competing interests: Cheng-Hao Lai, Yu-Tzu Li, Ting-Shuan Wu, and Chia-Ta Wu declare that they have no conflict of interest.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"dulaglutide\", \"liraglutide\", \"exenatide\"]","drug_details":"{\"dose\": \"liraglutide 3.0 mg daily (weight-management dose) and 1.8 mg daily (diabetes dose); doses not stated for semaglutide, dulaglutide or exenatide\", \"comparator\": \"placebo or another antidiabetic therapy; four trials randomized an insulin comparator arm\", \"route\": null, \"treatment_duration\": \"≥12 weeks (eligibility requirement)\"}","domains":"[\"lean_mass\", \"bone\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"bone mineral density measured by dual-energy X-ray absorptiometry, and bone turnover markers","endpoints":null,"effect_estimate":"Semaglutide (Hansen 2024, n = 64, the largest weight loss at ETD - 6.8 kg vs placebo): lumbar spine BMD ETD - 0.018 g/cm², whole-body BMD MD -0.02 g/cm², C-terminal telopeptide MD 166.50 pg/mL. Liraglutide 3.0 mg (Jensen 2024): lumbar spine MD - 0.019 g/cm², total hip MD - 0.013 g/cm². Liraglutide 1.8 mg (Hygum 2020): lumbar spine MD 0.00 g/cm², no material change. Exenatide trials inconsistent, from 0.03 g/cm² to -0.04 g/cm² at the lumbar spine. Certainty of evidence very low for every agent","confidence_interval":"95% CI - 0.03 to -0.01 (whole-body BMD MD -0.02 g/cm², semaglutide trial)","p_value":"p = 0.007 (lumbar spine BMD, semaglutide trial)","sample_size":493,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 25, \"obesity_status\": \"mixed (study-level mean BMI: five trials ≥30 kg/m², three 25 to <30 kg/m²)\", \"diabetes_status\": \"mixed (five of eight trials enrolled adults with type 2 diabetes, three enrolled adults without diabetes)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"overweight or obesity, with type 2 diabetes in five of the eight trials\", \"sample_size\": 493, \"inclusion_exclusion\": \"adults ≥18 years, mean baseline BMI > 25 kg/m², GLP-1 RA vs placebo or antidiabetic therapy for ≥12 weeks, DXA bone mineral density\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the eight trials enrolled adults aged ≥18 years with study-level mean baseline BMI > 25 kg/m², five of them in adults with type 2 diabetes, and no participant ages are reported.","mediation":"possibly","mediation_notes":"The outcomes are bone mineral density and bone turnover rather than weight itself, and the review reports the weight loss in each trial alongside the bone results, noting that the two largest weight losses came with reduced lumbar spine and total hip BMD at closely similar magnitudes. That is a comparison across trials and doses, not a participant-level mediation analysis, a weight-matched comparison or a measurement taken before weight loss, so weight change cannot be separated from drug effect here.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": 493, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo or another antidiabetic therapy; four trials randomized an insulin comparator arm\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"per-trial 95% CIs reported; no pooled estimate; eight trials, n = 493; certainty of evidence very low for every agent\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: the review synthesised its eight trials narratively and performed no meta-analysis, so it contributes no new pooled estimate. Its own certainty assessment was very low for every agent, and the authors conclude that the randomized evidence is too sparse and too heterogeneous to determine skeletal effects.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The four named authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The skeletal findings are the safety signal: reduced lumbar spine and total hip BMD in the two trials with the largest weight loss and increased bone resorption (CTX) in the semaglutide trial, against no material change at the liraglutide diabetes dose; no fracture outcomes and no other adverse events reported","limitations":"The authors state that the randomized evidence is too sparse and too clinically heterogeneous to determine skeletal effects, that each agent has been evaluated in at most five small trials, mostly in adults with type 2 diabetes rather than obesity alone, and that certainty is very low for every agent. No trial reported fracture endpoints, no pooling was possible, and five of the eight trials raised risk-of-bias concerns.","plain_summary":"This systematic review collected eight randomized trials (n = 493) of GLP-1 receptor agonists in adults with overweight or obesity that measured bone mineral density by DXA scan, and reported each drug separately rather than pooling them. The single semaglutide trial (n = 64), which produced the largest weight loss, reported reduced bone density at the lumbar spine and whole body and increased bone resorption, and liraglutide at the weight-management dose of 3.0 mg daily showed similar reductions at the spine and hip; liraglutide at the 1.8 mg diabetes dose changed nothing materially, and the five exenatide trials disagreed with each other. Certainty was very low for every drug, no trial measured fractures, and the authors conclude the evidence is too sparse to determine skeletal effects.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1234,"doi":"10.64898/2026.10.21.26366084","pmid":null,"nct_ids":"[]","title":"GLP-1 Receptor Agonists (GLP-1RAs) for treatment of tobacco and alcohol dependence: a systematic review and meta-analysis of randomised controlled trials","authors":"[\"Taylor G\", \"Burke C\", \"Titheradge D\", \"Jia S\", \"Cihan B\", \"Faulkner I\", \"Williams G\", \"Abeysekera K\", \"Hickman M\", \"Thomas K.\"]","journal":"preprint server","publication_date":"2026-10-23","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Background: </h4> Glucagon-like peptide-1 receptor agonists (GLP-1RAs) might reduce tobacco and alcohol use. We synthesised evidence from randomised controlled trials (RCTs) on smoking and alcohol outcomes, including secondary outcomes reported in trials conducted for other clinical purposes. Methods We searched MEDLINE, Embase, PsycINFO, Web of Science, CENTRAL, PubMed, and registries for RCTs comparing GLP-1RAs with placebo from inception to August 18, 2026. Smoking and alcohol outcomes were synthesised using random-effects meta-analyses. We assessed risk of bias (RoB) with RoB-2, and certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.  Findings Fourteen trials involving 1149 participants were included; 13 contributed to meta-analyses. Across the 14 trials, 8 recruited participants not seeking either tobacco or alcohol treatment. The other 6 recruited treatment-seeking participants: 3 for tobacco and 3 for alcohol. Eight trials reported smoking-related outcomes, 11 reported alcohol outcomes, and 5 reported both. Follow-up ranged from 6 to 60 weeks. All 4 pooled smoking-related estimates favoured GLP-1RAs, although all 95% CIs included no difference and were compatible with increases and decreases in outcomes; e.g., smoking cessation, OR 1.39 (95% CI, 0.77 to 2.53, k=3). Restricting analyses to semaglutide trials indicated a reduction in cigarettes per day (CPD) (SMD=-0.10, 95%CI:-0.16 to -0.04; k=3). Across agents, pooled estimates favoured GLP-1RAs for days without alcohol (SMD=0.35, 95%CI: 0.12 to 0.59, k=3). Pooled estimates of semaglutide-only trials also favoured treatment for alcohol consumption (grams/day; SMD=-0.56, 95%CI:-0.82 to -0.30; k=2), craving (SMD=-0.60, 95%CI:-0.91 to -0.29; k=2), drinks per drinking day (SMD=-0.59, 95%CI:-0.86 to -0.32; k=3), drinks per calendar day (SMD=-0.48, 95%CI:-0.87 to -0.09; k=2) and heavy drinking days (SMD=-0.45, 95%CI:-0.85 to -0.06; k=3), and alcohol-free days (SMD=0.41, 95%CI:0.09 to 0.73; k=2). Two of 41 assessed results were at low RoB, 31 raised some concerns and 8 were at high risk; certainty was moderate for 1 outcome, low for 4 and very low for 8.  Interpretation GLP-1RAs may reduce alcohol consumption and CPD, with the clearest evidence for semaglutide. These findings should be contextualised by most evidence being low- to very-low-certainty. Larger trials are needed to establish clinically meaningful benefit and sustained abstinence.","url":"https://doi.org/10.64898/2026.10.21.26366084","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-06T14:50:31+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"addiction\"]","outcome_type":"intermediate","primary_outcome":"smoking outcomes, including smoking cessation and cigarettes per day, and alcohol outcomes","endpoints":null,"effect_estimate":"All 4 pooled smoking-related estimates favoured GLP-1RAs but every 95% CI included no difference (smoking cessation OR 1.39); semaglutide-only cigarettes per day SMD=-0.10; days without alcohol SMD=0.35 across agents; semaglutide-only alcohol consumption SMD=-0.56, craving SMD=-0.60, drinks per drinking day SMD=-0.59, drinks per calendar day SMD=-0.48, heavy drinking days SMD=-0.45, alcohol-free days SMD=0.41","confidence_interval":"95% CI, 0.77 to 2.53 (smoking cessation OR 1.39)","p_value":null,"sample_size":1149,"follow_up":"6 to 60 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"tobacco or alcohol use; 8 of the 14 trials recruited participants not seeking tobacco or alcohol treatment and 6 recruited treatment-seeking participants\", \"sample_size\": 1149, \"inclusion_exclusion\": \"randomized controlled trials comparing GLP-1RAs with placebo and reporting smoking or alcohol outcomes, including secondary outcomes from trials run for other clinical purposes\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: the pooled trials addressed tobacco and alcohol dependence, a condition selected for itself, with 8 of the 14 trials recruiting participants not seeking treatment, and no age, BMI or diabetes data are reported.","mediation":"possibly","mediation_notes":"The outcomes are smoking and drinking behaviour, and no weight change, HbA1c or mediation analysis is reported, so weight and metabolic change cannot be separated from the drug effect. Several of the pooled trials were run for other clinical purposes, where weight loss would be expected, but the record gives neither doses nor weight results.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1149, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"6 to 60 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"95% CIs reported for every pooled estimate, with all four smoking estimates including no difference; 2 to 3 trials per pooled estimate; risk of bias assessed with RoB-2 and certainty with GRADE\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY because the record is a preprint and has not been peer reviewed, which is the level the model gives anything not peer reviewed; the exception that leaves a preprint unrated applies only to a preprint holding no outcome data, and this one reports pooled outcomes. The evidence is also thin on its own terms: 14 small trials with 1149 participants, only 2 of 41 assessed results at low risk of bias, and the authors' own certainty low for 4 outcomes and very low for 8.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The authors say the findings should be read against most of the evidence being low to very low certainty and that larger trials are needed for clinically meaningful benefit and sustained abstinence. Of 41 assessed results only 2 were at low risk of bias, 8 of the 14 trials did not recruit participants seeking treatment, the trials are small (1149 participants in total), and the record is a preprint that has not been peer reviewed.","plain_summary":"This review pooled 14 randomized trials with 1149 participants comparing GLP-1 receptor agonists with placebo for smoking and drinking outcomes, with follow-up from 6 to 60 weeks. All four pooled smoking estimates favoured the drugs but every confidence interval included no difference (smoking cessation OR 1.39, 95% CI, 0.77 to 2.53), while days without alcohol improved (SMD=0.35) and semaglutide-only analyses favoured treatment for alcohol consumption, craving and heavy drinking days. Only 2 of 41 assessed results were at low risk of bias, and the authors rated certainty low for 4 outcomes and very low for 8. The record is a preprint and has not been peer reviewed.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1341,"doi":"10.1097/md.0000000000051306","pmid":"42937793","nct_ids":"[]","title":"Efficacy and safety of GLP-1 receptor agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH): A systematic review and meta-analysis","authors":"[\"Alfawaz M\", \"Bajamaan D\", \"Alghamdi L\", \"Alorfi Y\", \"Khared S\", \"Ameen N\", \"Alamri R\", \"Abuladel M\", \"Alshehri R\", \"Altowairqi S\"]","journal":"Medicine","publication_date":"2026-10-23","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are increasingly prevalent liver diseases closely linked to obesity, type 2 diabetes mellitus, and cardiometabolic risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve hepatic and metabolic outcomes through weight reduction, improved glycemic control, and reductions in hepatic steatosis. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of GLP-1 RAs in adults with MASLD or MASH. [METHODS] A systematic review and meta-analysis was conducted in accordance with PRISMA 2020 guidelines. PubMed, Web of Science, Scopus, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched for English-language studies published between January 2019 and December 2025. Eligible studies included adults with MASLD or MASH treated with GLP-1 RAs and reporting hepatic, metabolic, or safety outcomes. Pooled estimates were calculated using random-effects models. [RESULTS] Nine studies involving 795 participants were included. GLP-1 RA therapy was associated with significant reductions in liver fat content (mean difference [MD]: -3.17; 95% CI: -4.06 to -2.29), body weight (MD: -4.68; 95% CI: -6.88 to -2.47), alanine aminotransferase (MD: -15.17; 95% CI: -21.29 to -9.05), aspartate aminotransferase (MD: -9.89; 95% CI: -13.65 to -6.13), and HbA1c (MD: -0.78; 95% CI: -1.07 to -0.49). Adverse events were more frequent with GLP-1 RAs, particularly nausea and vomiting, while serious adverse events did not differ significantly between groups. [CONCLUSION] GLP-1 RAs are associated with meaningful improvements in hepatic steatosis, liver enzymes, body weight, and glycemic control in patients with MASLD or MASH. These findings support their potential role, particularly in patients with coexisting obesity or type 2 diabetes. However, further long-term, adequately powered trials are needed to clarify their effects on fibrosis regression, histological outcomes, and liver-related clinical events.","url":"https://pubmed.ncbi.nlm.nih.gov/42937793/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors have no funding and conflicts of interest to declare.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:40+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"liver\", \"addiction\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1137,"doi":"10.3803/enm.2026.2979","pmid":"42908410","nct_ids":"[]","title":"Transient Adipose Inflammatory Remodeling during High-Dose Semaglutide-Induced Weight Loss and Regain","authors":"[\"Seo M\", \"Julietta V\", \"Averia M\", \"Soedono S\", \"Budiono E\", \"Park HK\", \"Suh K\", \"Cho KW\"]","journal":"Endocrinology and metabolism (Seoul, Korea)","publication_date":"2026-10-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Weight loss improves obesity-associated metabolic dysfunction, yet resolution of adipose inflammation may be incomplete and can reappear during weight regain. Whether high-dose semaglutide induces sustained immunological remodeling of adipose and hepatic tissues during weight cycling remains unclear. [METHODS] Male C57BL/6 mice with diet-induced obesity were treated with semaglutide (60 nmol/kg, intraperitoneally, every 3 days) or vehicle for 3 weeks, followed by drug withdrawal under continued high-fat diet feeding. Body weight, body composition, and glucose homeostasis were assessed during treatment and after weight regain. Inflammatory changes in visceral and subcutaneous adipose tissue and liver were analyzed by flow cytometry, histology, immunofluorescence, and gene expression profiling. [RESULTS] Semaglutide induced rapid fat mass-selective weight loss with preservation of lean mass and significantly improved fasting glucose, insulin levels, insulin sensitivity, and glucose tolerance. During treatment, visceral adipose tissue exhibited marked reductions in pro-inflammatory macrophages, crown-like structures, and inflammatory gene expression, whereas subcutaneous adipose tissue was minimally affected. Following withdrawal, mice rapidly regained weight and adiposity. Visceral adipose inflammation fully reverted, with macrophage infiltration and inflammatory gene expression comparable to chronically obese controls. Hepatic steatosis and inflammatory markers similarly returned to obese levels. Despite this tissue-level reversion, fasting glycemia and insulin levels remained partially improved. [CONCLUSION] High-dose semaglutide induces robust metabolic improvement and transient suppression of visceral adipose inflammation during active treatment; however, these inflammatory changes are not sustained after withdrawal and largely revert with weight regain. In contrast, partial improvement in fasting glycemia persisted, suggesting differential durability between systemic metabolic adaptation and local inflammatory remodeling during pharmacological weight cycling.","url":"https://pubmed.ncbi.nlm.nih.gov/42908410/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:05+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"lean_mass\", \"body_composition\", \"liver\", \"immune\", \"adverse_effects\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1207,"doi":"10.1111/dom.71473","pmid":"42919108","nct_ids":"[]","title":"Sustained Versus Minimal GLP-1 Receptor Agonist Exposure and Metabolic Outcomes in Older Adults Without Diabetes","authors":"[\"Zaritsky R\", \"Elior N\", \"Razi T\", \"Sitry N\", \"Lustman A\", \"Eilat-Tsanani S\", \"Shahaf H\", \"Barzilay I\", \"Tamir-Brahms B\", \"Afek S\", \"Katz Hanein N\", \"Arbel R\", \"Shani M\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To compare changes in body mass index (BMI) categories after sustained versus minimal glucagon-like peptide-1 receptor agonist (GLP-1 RA) exposure in older adults with obesity and without diabetes. A secondary aim was to compare changes in glycated haemoglobin (HbA1c) categories among those with paired HbA1c measurements. [MATERIALS AND METHODS] Retrospective cohort study within Clalit Health Services, Israel. Adults aged ≥ 65 years without diabetes, with baseline BMI ≥ 30 kg/m2 and paired BMI measurements, were classified as minimal (1-2 dispensations) or sustained (≥ 3) exposure. The primary outcome was BMI category improvement. Secondary outcomes were relative BMI change, HbA1c category change in the paired-HbA1c subset, and incident diagnosed diabetes. BMI improvement was modelled by logistic regression adjusted for age, sex, socioeconomic status and comorbidity. [RESULTS] Of 13 387 patients (69% female), 11 121 (83%) had sustained and 2266 (17%) minimal exposure. BMI category improved in 55% of the sustained versus 30% of the minimal group (p < 0.001; median change -8% vs. -2%). Among 7392 with paired HbA1c, HbA1c improved in 34% versus 20% (sustained vs. minimal; p < 0.001), and 65% versus 37% of those with prediabetes became normoglycaemic. Diabetes diagnosis was less frequent with sustained exposure (2.5% vs. 5.3%; p < 0.001). Adjusted for measured confounders, sustained exposure was associated with BMI improvement (OR: 2.77, 95% CI: 2.51-3.06). [CONCLUSIONS] Among older adults with obesity and without diabetes, sustained versus minimal GLP-1 RA exposure was associated with greater improvement in BMI and HbA1c categories and a lower incidence of diabetes. These findings describe observed changes after treatment initiation, not a proven causal treatment effect.","url":"https://pubmed.ncbi.nlm.nih.gov/42919108/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:22+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1213,"doi":"10.1111/dom.71474","pmid":"42919104","nct_ids":"[]","title":"How Well Are We Measuring Nausea? A Narrative Review of Patient-Reported Outcome Gaps in GLP-1 Receptor Agonist Obesity Trials","authors":"[\"Oria L\", \"Darkhabani M\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Across the full spectrum of major clinical trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for obesity management, nausea consistently emerges as the most documented adverse effect, yet the methods used to capture it have received little scrutiny relative to their clinical importance. This narrative review traces how nausea was actually measured across the pivotal liraglutide (SCALE), semaglutide (STEP) and tirzepatide (SURMOUNT) obesity trial programmes, and situates those methods against the standards set out in the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) and the United States Food and Drug Administration's Patient-Focused Drug Development guidance. Across all three drug classes, nausea was ascertained through investigator-recorded, spontaneously reported adverse events coded to the Medical Dictionary for Regulatory Activities (MedDRA), a pharmacovigilance framework built for a different purpose than symptom characterization, rather than through any validated, symptom-specific patient-reported outcome instrument. This observation gains further importance when considered alongside a second, less widely recognized fact: these same trial programmes devoted substantial methodological effort to developing and implementing a rigorous, quality of life measure specifically for obesity, the Impact of Weight on Quality of Life-Lite Clinical Trials Version in addition to the Short Form-36 and EuroQol-5D. We argue that this asymmetry, more than any single mismeasurement, helps explain why real-world persistence with these agents falls so far short of what trial-reported tolerability figures would predict, and we outline what a fit-for-purpose metabolic nausea instrument would need to capture that adverse-event surveillance cannot.","url":"https://pubmed.ncbi.nlm.nih.gov/42919104/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1163,"doi":"10.1007/s13679-026-00770-z","pmid":"42905300","nct_ids":"[]","title":"Decoding the Safety Profile of GLP-1 Receptor Agonists: Facts, Myths, and Ongoing Controversies","authors":"[\"Kounatidis DC\", \"Vallianou NG\", \"Kouveletsou M\", \"Kontrafouri P\", \"Stamatopoulos V\", \"Rebelos E\", \"Diakoumopoulou E\", \"Dalamaga M\"]","journal":"Current obesity reports","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE OF REVIEW] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent one of the most significant therapeutic advances in the management of type 2 diabetes and obesity. As their indications have expanded to include cardiovascular and kidney disease, safety concerns involving multiple organ systems have received increasing attention. This narrative review examines the spectrum of adverse effects linked to GLP-1RAs and provides a clinically relevant platform for assessing their safe prescription. [RECENT FINDINGS] Gastrointestinal intolerance, modest increases in heart rate, and a modest but reproducible increase in the risk of gallbladder and biliary disease represent the most consistently supported adverse effects of GLP-1RAs. A risk of pancreatitis is also considered to exist, although some studies have challenged this association. Conversely, correlations with neuropsychiatric and dermatological disorders, diabetic retinopathy, nonarteritic anterior ischemic optic neuropathy, perioperative aspiration, sexual and reproductive disturbances, sarcopenia, and malignancy remain controversial. Most available evidence derives from pharmacovigilance databases, retrospective observational studies, and secondary analyses of randomized trials, which are limited by reporting bias, residual confounding, and inability to establish causality. Heterogeneity in study design, statistical methodology, outcome definitions, and patient populations further complicates interpretation. Although several proposed adverse effects have biologically plausible mechanisms, prospective clinical validation remains limited. Notably, recent regulatory decisions, including the Food and Drug Administration (FDA)'s removal of the suicidality warning from GLP-1RA prescribing information, reflect the evolving nature of these safety assessments. The overall benefit-risk profile of GLP-1RAs is favorable. Most emerging safety concerns should currently be regarded as hypothesis-generating signals rather than established toxicities. Individualized risk assessment and appropriate clinical monitoring remain important as ongoing and future prospective studies further define the long-term safety of this rapidly expanding therapeutic class.","url":"https://pubmed.ncbi.nlm.nih.gov/42905300/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Informed Consent: Not applicable. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare no competing interests.. Animal and Human Rights and Informed Consent: None of the authors of this article conducted any research using either human or animal subjects Institutional Review Board Statement: Not applicable.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:07+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"muscle\", \"cancer\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\", \"ophthalmologic\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1179,"doi":"10.1016/j.ijpharm.2026.127576","pmid":"42906796","nct_ids":"[]","title":"Poly(vinyl alcohol) dissolving microneedles for transdermal semaglutide delivery and anti-obesity therapy in rats","authors":"[\"Cheng X\", \"Wang F\", \"Liu H\", \"Li F\", \"Li T\", \"Liu C\"]","journal":"International journal of pharmaceutics","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide is an effective anti-obesity peptide, but repeated subcutaneous injections may reduce its acceptability for long-term therapy. We prepared semaglutide-loaded poly(vinyl alcohol) (PVA) dissolving microneedles (Sema-MNs) by sequential vacuum-assisted molding and room-temperature drying. The 15 × 15 arrays concentrated Cy5-labelled semaglutide toward the needle tips, resisted axial compression, penetrated rat skin, and partially dissolved within 5 min; skin barrier function approached baseline within 4-6 h. Sema-MNs contained 29 ± 2 μg semaglutide per patch, with an apparent delivered amount of 18 ± 2 μg (63 ± 3%; n = 3), and released more than 90% of the Sema-Cy5-associated cargo within 30 min. In high-fat-diet-induced obese rats, once-daily Sema-MN treatment for 7 days reduced food intake and body weight. Treatment also decreased adipocyte size and hepatic lipid accumulation, improved glucose tolerance and serum metabolic indices, and reduced hypothalamic neuropeptide Y immunofluorescence relative to the disease and unloaded-microneedle controls. No evident renal biochemical or major-organ histopathological abnormalities were observed during the study. These findings support the feasibility of a compositionally simple, rapid-release PVA microneedle system for transdermal semaglutide administration.","url":"https://pubmed.ncbi.nlm.nih.gov/42906796/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"kidney\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1186,"doi":"10.1017/s0033291726106412","pmid":"42904347","nct_ids":"[]","title":"Semaglutide modulates explore/exploit decision-making in major depressive disorder: A randomized clinical trial","authors":"[\"Zhang Z\", \"Chen N\", \"Wang D\", \"Gill H\", \"Badulescu S\", \"Shah H\", \"Brudner RM\", \"Di Vincenzo JD\", \"Tabassum A\", \"Llach CD\", \"Rosenblat JD\", \"McIntyre RS\", \"Sarhangian V\", \"Mansur RB\"]","journal":"Psychological medicine","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Explore/exploit decision-making is a crucial component of motivated behavior. Explore/exploit behaviors are related to disparate cognitive and reward-related functions and have been implicated in multiple neuropsychiatric conditions, including major depressive disorder (MDD). Several mediators of explore/exploit decision-making have been proposed; metabolic mechanisms have been theorized to potentially affect its underlying processes. Here, we examined the effects of a GLP-1 receptor agonist (GLP-1RA), semaglutide, on explore/exploit behavior in patients with MDD, using a four-armed restless bandit task. [METHODS] In this secondary analysis of a randomized clinical trial, 72 participants with MDD were randomized either to oral semaglutide (n = 35) or placebo (n = 37), and completed the bandit task at baseline and following 16 weeks of treatment. Explore/exploit decision-making was assessed using computational modeling of choice behavior, with a trial-by-trial reinforcement-learning model. [RESULTS] Treatment with semaglutide resulted in increased exploitation (i.e. choosing the option with the highest expected reward) (Average Treatment Effect [ATE] = 0.0242, p < 0.001), directed exploration (i.e. exploring a choice with higher uncertainty) (ATE = 0.0619, p = 0.013), and perseveration (i.e. the value-independent tendency to repeat the previous action) (ATE = 0.3017, p = 0.013). These effects were moderated by, but ultimately independent of, baseline characteristics and weight loss during the trial. [CONCLUSIONS] Treatment with semaglutide modulated explore/exploit behaviors in patients with MDD. These results highlight the role of metabolic mechanisms in decision-making processes in MDD and expand knowledge of the potential neuropsychiatric effects of GLP-1RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/42904347/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"route\": \"oral\", \"comparator\": \"placebo\", \"dose\": null, \"treatment_duration\": \"16 weeks\"}","domains":"[\"cognition\", \"addiction\", \"psychiatric\"]","outcome_type":"surrogate","primary_outcome":"explore/exploit decision-making on a four-armed restless bandit task (computational model parameters)","endpoints":null,"effect_estimate":"Semaglutide vs placebo: exploitation ATE = 0.0242 (p < 0.001); directed exploration ATE = 0.0619 (p = 0.013); perseveration ATE = 0.3017 (p = 0.013); effects moderated by, but independent of, baseline characteristics and weight loss","confidence_interval":null,"p_value":"p < 0.001 (exploitation); p = 0.013 (directed exploration and perseveration)","sample_size":72,"follow_up":"16 weeks","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"major depressive disorder\", \"sample_size\": 72, \"inclusion_exclusion\": \"participants with major depressive disorder (MDD)\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: participants were enrolled for major depressive disorder, a condition selected for itself; the abstract reports no BMI or diabetes data.","mediation":"specifically_tested","mediation_notes":"The authors report the effects were moderated by, but independent of, weight loss during the trial, which indicates a participant-level analysis that included weight change. The abstract calls it moderation rather than mediation and gives no numbers for it.","adjusted_for":"[\"body-weight change\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 72, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"16 weeks\", \"outcome_type\": \"surrogate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"no CI reported; p values reported; 72 participants\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a secondary analysis of a small randomized trial (72 participants, 16 weeks) with an exploratory computational outcome and no confidence intervals.","funding_source":"Physicians' Services Incorporated Foundation","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A small secondary analysis of a 16-week trial using a computational task measure whose clinical meaning is uncertain; no confidence intervals are reported.","plain_summary":"In a secondary analysis of a randomized trial, 72 people with major depression took oral semaglutide (35) or placebo (37) for 16 weeks and did a reward-learning computer task before and after. Semaglutide shifted three measures of how people chose between familiar and uncertain options, and the authors report these shifts did not depend on weight loss. Whether these changes help patients is not established, and the study is small.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1219,"doi":"10.1016/j.amjmed.2026.09.033","pmid":"42906844","nct_ids":"[]","title":"The Impact of Glucagon-Like Peptide-1 Receptor Agonists on Post-Anesthetic Pulmonary and Gastrointestinal Adverse Events: A Target Trial Emulation Using Multinational Database","authors":"[\"Chen SS\", \"Lin TT\", \"Chiang YL\", \"Chen CY\", \"Chen HY\", \"Hung YM\", \"Chang R\"]","journal":"The American journal of medicine","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying, raising concerns about perioperative aspiration and postoperative complications. This target trial emulation aims to evaluate the association between the use of GLP-1 RAs and the risk of postoperative pulmonary and gastrointestinal adverse events in patients undergoing general anesthesia. [METHODS] Data was utilized from the TriNetX Global Collaborative Network. The study analyzed data from January 1, 2023, to December 31, 2023. Patients aged 20 years or older who underwent general anesthesia were included. These patients were divided into two groups: those using GLP-1 RA and those who were not. Propensity score matching was used to balance baseline characteristics. The primary outcome measures were the incidence of pulmonary and gastrointestinal adverse events within one-month post-anesthesia. Hazard ratios were calculated using Cox proportional hazards regression models to estimate the risk of these adverse events associated with GLP-1 RA use. [RESULTS] A total of 21,948 patients were included after matching. Patients who used GLP-1 RAs demonstrated a significantly lower risk of pulmonary adverse events (HR 0.682 [0.496-0.938]). Secondary outcomes further revealed a reduction in the risk of postoperative respiratory failure, as well as postoperative hospitalization and emergency department revisits. However, there was a marginally increased risk of gastrointestinal adverse events in the GLP-1 RA group (HR, 1.034 [1.003-1.067]). [CONCLUSIONS] The use of GLP-1 RAs prior to general anesthesia was not associated with higher risk of pulmonary adverse events. A slight elevation in gastrointestinal risks was observed, although the signal remained modest.","url":"https://pubmed.ncbi.nlm.nih.gov/42906844/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1220,"doi":"10.1016/j.spinee.2026.10.020","pmid":"42906643","nct_ids":"[]","title":"Outcomes after Posterior Cervical Spine Surgery: A Matched Cohort Analysis and Comparison of GLP-1 Receptor Agonist Use and Bariatric Surgery in Patients with Type 2 Diabetes","authors":"[\"Rivera N\", \"Bradley T\", \"Crowell KA\", \"Goodwin CR\", \"Erickson M\"]","journal":"The spine journal : official journal of the North American Spine Society","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND CONTEXT] Obesity and diabetes can increase perioperative risk, especially in posterior cervical spine surgery. Bariatric surgery provides durable weight loss but carries surgical and nutritional risks, while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are non-surgical alternatives that may optimize weight and metabolic status preoperatively. Evidence evaluating GLP-1 therapy in spine surgery is limited. [PURPOSE] To evaluate associations between preoperative GLP-1 RA use and perioperative, short-term, and long-term complications following posterior cervical spine surgery in patients with type 2 diabetes, including comparisons to matched controls and patients with prior bariatric surgery. [STUDY DESIGN] Retrospective database analysis. [PATIENT SAMPLE] Patients with type 2 diabetes treated with metformin undergoing posterior cervical spine surgery between 2010 and 2023 were identified in the PearlDiver Mariner database. Patients were stratified into GLP-1 users, non-GLP-1 controls, and patients with prior bariatric surgery. [OUTCOME MEASURES] Physiologic measures included perioperative outcomes and postoperative complications assessed at 90 days and 2 years, including pneumonitis, surgical site infection, revision surgery, readmission, nutritional deficiency, and other medical and surgical complications. [METHODS] The PearlDiver Mariner database was queried for eligible patients. Propensity-score matching adjusted for baseline cohort differences. Outcomes included perioperative, 90-day, and 2-year complications, with BMI-stratified analyses conducted within the matched GLP-1 and control cohort. Benjamini-Hochberg false discovery rate correction was applied for multiple comparisons. [RESULTS] GLP-1 users demonstrated lower odds of perioperative complications, including pneumonitis (OR 0.57; 95% CI 0.43-0.75; p <0.001). At 90 days, GLP-1 users experienced reduced odds of surgical site infection (OR 0.72; 95% CI 0.65-0.80; p <0.001), revision surgery (OR 0.33; 95% CI 0.29-0.36; p <0.001), readmission (OR 0.82; 95% CI 0.76-0.90; p <0.001), and other complications. At 2 years, GLP-1 users had lower odds of revision surgery (OR 0.31; 95% CI 0.28-0.34; p <0.001), nutritional deficiency (OR 0.62; 95% CI 0.59-0.66; p <0.001), and other complications. Exploratory BMI-stratified analyses suggested similar directional trends across overweight and obese patients. Comparisons to prior bariatric surgery patients showed no significant differences. [CONCLUSIONS] Preoperative GLP-1 RA use was associated with reduced perioperative, short-term, and long-term complications following posterior cervical spine surgery in patients with type 2 diabetes. When compared with a matched bariatric surgery cohort, no significant differences in postoperative outcomes were observed. These findings should be interpreted in the context of potential residual confounding and support further prospective investigation of GLP-1 therapy as a strategy for preoperative metabolic optimization in posterior cervical spine surgery. [CLASSIFICATIONS] Cervical Spine, Outcomes Research, Risk Factors, Perioperative Complications.","url":"https://pubmed.ncbi.nlm.nih.gov/42906643/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration competing interest The authors have no competing interests to declare that could have influenced the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"nutrition\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1221,"doi":"10.1056/nejmoa2611477","pmid":"42904878","nct_ids":"[\"NCT05929066\", \"NCT05929079\"]","title":"Retatrutide Once Weekly for Treatment of Obstructive Sleep Apnea","authors":"[\"Grunstein RR\", \"Somers VK\", \"Azarbarzin A\", \"Malhotra A\", \"Sands SA\", \"Lucey BP\", \"Allen SE\", \"Giblin K\", \"Falcon BL\", \"Park SY\", \"Lou J\", \"Krueger K\", \"TRIUMPH-1-OSA and TRIUMPH-2-OSA Investigators\"]","journal":"The New England journal of medicine","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide, an investigational triple agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, may be useful for treating obstructive sleep apnea (OSA). [METHODS] In two phase 3, double-blind, randomized, placebo-controlled trials nested within larger basket trials of once-weekly subcutaneous retatrutide, we assigned adults with moderate-to-severe OSA and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 27, without (TRIUMPH-1-OSA) or with (TRIUMPH-2-OSA) type 2 diabetes, to receive retatrutide (4, 9, or 12 mg) or placebo. The primary end point was the change in the apnea-hypopnea index (AHI, the average number of apneas and hypopneas per hour of sleep) at 80 weeks with 9 mg and 12 mg of retatrutide. For OSA-related end points, a hybrid-treatment estimand was applied, with a hypothetical strategy used for participants who had intercurrent events suggesting treatment failure and a treatment-policy strategy used elsewhere. We also report intention-to-treat (ITT) results. [RESULTS] A total of 243 participants underwent randomization in TRIUMPH-1-OSA and 448 in TRIUMPH-2-OSA. The baseline mean AHI was 58.6 and 55.9 events per hour, respectively, and the mean body weight was 119.6 and 115.9 kg. At 80 weeks, the mean changes in the AHI (hybrid-treatment estimand) with retatrutide in TRIUMPH-1-OSA were -22.9 (4 mg), -34.3 (9 mg), and -31.7 (12 mg) events per hour, versus -9.9 with placebo (difference vs. placebo, -13.0 [95% confidence interval {CI}, -23.0 to -3.0], -24.4 [95% CI, -34.1 to -14.7], and -21.9 [95% CI, -32.2 to -11.5], respectively). The changes with retatrutide in TRIUMPH-2-OSA were -19.2 (4 mg), -24.7 (9 mg), and -25.4 (12 mg) events per hour, versus -10.3 with placebo (difference vs. placebo, -8.9 [95% CI, -15.9 to -2.0], -14.4 [95% CI, -21.6 to -7.2], and -15.1 [95% CI, -22.5 to -7.7]). For the ITT estimand, the corresponding differences from placebo were -13.2 (95% CI, -22.6 to -3.9), -24.7 (95% CI, -34.1 to -15.3), and -22.5 (95% CI, -31.9 to -13.1) in TRIUMPH-1-OSA and -8.8 (95% CI, -15.8 to -1.7), -13.9 (95% CI, -21.3 to -6.6), and -15.0 (95% CI, -22.5 to -7.4) in TRIUMPH-2-OSA. The mean percent change in body weight with retatrutide (key secondary end point) was -12.5 to -22.2% in TRIUMPH-1-OSA and -12.1 to -18.5% in TRIUMPH-2-OSA, versus -4.8% and -5.6% with placebo (treatment-regimen estimand). The most common adverse events were gastrointestinal. [CONCLUSIONS] In adults with OSA and obesity or overweight with or without type 2 diabetes, retatrutide resulted in significantly greater decreases in the AHI than placebo. (Funded by Eli Lilly; TRIUMPH-1 and -2 ClinicalTrials.gov numbers, NCT05929066 and NCT05929079.).","url":"https://pubmed.ncbi.nlm.nih.gov/42904878/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"4, 9, or 12 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\", \"treatment_duration\": null}","domains":"[\"sleep\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"change in the apnea-hypopnea index (AHI) at 80 weeks with 9 mg and 12 mg","endpoints":null,"effect_estimate":"AHI difference vs. placebo at 80 weeks (hybrid-treatment estimand): TRIUMPH-1-OSA -13.0 (4 mg), -24.4 (9 mg), -21.9 (12 mg); TRIUMPH-2-OSA -8.9, -14.4, -15.1 events per hour; ITT differences similar; body weight -12.5 to -22.2% and -12.1 to -18.5% vs. -4.8% and -5.6% with placebo","confidence_interval":"TRIUMPH-1-OSA: 9 mg 95% CI, -34.1 to -14.7; 12 mg 95% CI, -32.2 to -11.5. TRIUMPH-2-OSA: 9 mg 95% CI, -21.6 to -7.2; 12 mg 95% CI, -22.5 to -7.7 (hybrid-treatment estimand)","p_value":null,"sample_size":691,"follow_up":"80 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"overweight or obesity required (body-mass index of at least 27)\", \"diabetes_status\": \"mixed: excluded in TRIUMPH-1-OSA, required in TRIUMPH-2-OSA\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"moderate-to-severe obstructive sleep apnea\", \"sample_size\": 691, \"inclusion_exclusion\": \"adults with moderate-to-severe OSA and BMI at least 27, without (TRIUMPH-1-OSA) or with (TRIUMPH-2-OSA) type 2 diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had moderate-to-severe OSA and a BMI of at least 27 (mean body weight 119.6 and 115.9 kg); TRIUMPH-2-OSA enrolled only people with type 2 diabetes.","mediation":"likely","mediation_notes":"Likely: body weight fell by -12.5 to -22.2% (TRIUMPH-1-OSA) and -12.1 to -18.5% (TRIUMPH-2-OSA) with retatrutide, and sleep apnoea is known to improve with weight loss. The abstract reports no analysis separating the AHI effect from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 691, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"80 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: TRIUMPH-1-OSA: 9 mg 95% CI, -34.1 to -14.7; 12 mg 95% CI, -32.2 to -11.5. TRIUMPH-2-OSA: 9 mg 95% CI, -21.6 to -7.2; 12 mg 95% CI, -22.5 to -7.7 (hybrid-treatment estimand)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: two phase 3, double-blind, placebo-controlled randomized trials (243 and 448 participants) with an intermediate outcome (AHI) at 80 weeks; funded by Eli Lilly.","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The most common adverse events were gastrointestinal.","limitations":"Each OSA trial was nested in a larger basket trial of an investigational drug; all participants had overweight or obesity and lost substantial weight, so the AHI effect cannot be separated from weight loss; the primary analysis used a hybrid estimand, with ITT results alongside.","plain_summary":"Two placebo-controlled trials randomized 243 adults without diabetes and 448 with type 2 diabetes, all with moderate-to-severe obstructive sleep apnea and a BMI of at least 27, to weekly retatrutide or placebo, with results at 80 weeks. Retatrutide reduced breathing interruptions during sleep more than placebo at every dose (for 9 mg, -24.4 and -14.4 events per hour versus placebo in the two trials), while body weight fell by up to -22.2%. Much of the benefit may reflect that weight loss; side effects were mostly gastrointestinal, and the trials were funded by Eli Lilly.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1231,"doi":"10.64898/2026.10.18.26365821","pmid":null,"nct_ids":"[\"NCT06492330\"]","title":"Linafexor, a Pulsatile FXR Agonist, Augments Low-Dose Semaglutide for Weight Loss in Adults with Obesity, MASH, and Type 2 Diabetes","authors":"[\"Zhang Y\", \"Chen Y\", \"Huang S\", \"Jiang L\", \"Wang Y\", \"Ma J\", \"Deng R\", \"Du J\", \"Xia L\", \"Ma Y\", \"Wu P\", \"Zhang W\", \"Liu C\", \"Zhao G\", \"Wang G\", \"Qian M\", \"Lin H\", \"Yan F\", \"Ning G\", \"Xu HE\", \"Wang W.\"]","journal":"preprint server","publication_date":"2026-10-21","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>ABSTRACT</h4>  Glucagon-like peptide-1 (GLP-1) receptor agonists produce less weight loss in people with type 2 diabetes than without, and higher compensatory doses are limited by gastrointestinal adverse events and lean-mass loss—leaving patients with obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) inadequately treated. We tested whether linafexor, a pulsatile farnesoid X receptor (FXR) agonist, could augment the weight-loss efficacy of low-dose semaglutide in this population while preserving tolerability. In this multicenter, randomized, double-blind, placebo-controlled, phase 2 trial, 62 adults with obesity (body-mass index, 30– 45 kg/m²), treatment-naive type 2 diabetes, and MASH (MRI-PDFF ≥10%) were assigned to linafexor (4 mg orally once daily) or placebo, each with semaglutide (0.5 mg once weekly), for 16 weeks. The primary outcome was the percentage change in body weight at week 16. Adding linafexor more than doubled weight loss (−6.17% vs. −2.91%; treatment difference, −3.26%; 95% CI, −5.35 to −1.18; P=0.003), and more participants achieved at least 5% weight loss (53.3% vs. 28.1%; P=0.046). Consistent with this, combination therapy further reduced visceral adipose tissue (treatment difference, −13.85 cm²; P=0.035), the liver enzymes alanine aminotransferase and γ-glutamyl transferase, and serum bile acids, whose changes correlated with weight and liver-enzyme improvements—associations absent with monotherapy. Gastrointestinal adverse events were comparable (23.3% vs. 18.8%), with no treatment-related serious adverse events or discontinuations. Thus, in a population with blunted GLP-1 responses, adding linafexor to low-dose semaglutide enhanced weight loss and improved body composition and hepatic measures while preserving tolerability—a dose-sparing, mechanism-complementary strategy (ClinicalTrials.gov number,  NCT06492330 ).","url":"https://doi.org/10.64898/2026.10.18.26365821","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-11-11T18:56:18+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"0.5 mg once weekly\", \"treatment_duration\": \"16 weeks\", \"comparator\": \"placebo (added to semaglutide 0.5 mg once weekly in both arms)\", \"route\": null}","domains":"[\"body_composition\", \"liver\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percentage change in body weight at week 16","endpoints":null,"effect_estimate":"Linafexor plus semaglutide vs placebo plus semaglutide: weight change −6.17% vs. −2.91% (treatment difference, −3.26%; 95% CI, −5.35 to −1.18; P=0.003); at least 5% weight loss 53.3% vs. 28.1% (P=0.046); visceral adipose tissue difference −13.85 cm² (P=0.035)","confidence_interval":"95% CI, −5.35 to −1.18","p_value":"P=0.003","sample_size":62,"follow_up":"week 16","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"obesity required (body-mass index, 30– 45 kg/m²)\", \"diabetes_status\": \"type 2 diabetes required (treatment-naive)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity, type 2 diabetes and MASH\", \"sample_size\": 62, \"inclusion_exclusion\": \"obesity (BMI 30– 45 kg/m²), treatment-naive type 2 diabetes, MASH (MRI-PDFF ≥10%)\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (body-mass index 30– 45 kg/m²), treatment-naive type 2 diabetes and MASH.","mediation":"not_applicable","mediation_notes":"Not applicable for the primary outcome, which is weight change itself. The visceral-fat and liver-enzyme changes were reported alongside weight change and correlated with it; no mediation analysis is described.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 62, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (added to semaglutide 0.5 mg once weekly in both arms)\", \"follow_up_duration\": \"week 16\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, −5.35 to −1.18\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a preprint (not peer reviewed) of a small randomized, double-blind phase 2 trial with 62 participants over 16 weeks.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Gastrointestinal adverse events were comparable (23.3% vs. 18.8%), with no treatment-related serious adverse events or discontinuations","limitations":"A small, 16-week phase 2 trial reported as a preprint; both arms received semaglutide, so the randomized contrast tests linafexor rather than semaglutide itself.","plain_summary":"In 62 adults with obesity, type 2 diabetes and fatty liver disease (MASH), all taking low-dose semaglutide, this randomized trial added either linafexor or placebo for 16 weeks. Weight fell by 6.17% with the combination versus 2.91% with semaglutide plus placebo, and gastrointestinal side effects were similar (23.3% vs. 18.8%). Because everyone took semaglutide, the trial tests the add-on drug rather than semaglutide itself, and it is a preprint that has not been peer reviewed.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1310,"doi":"10.3390/diseases14100387","pmid":"42930014","nct_ids":"[]","title":"Real-World Pharmacological Patterns and Residual Cardiometabolic Risk in Patients with Type 2 Diabetes in Romania","authors":"[\"Petca BL\", \"Popovici PA\", \"Igna AD\", \"Ghitea TC\", \"Popoviciu MS\"]","journal":"Diseases (Basel, Switzerland)","publication_date":"2026-10-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Contemporary management of type 2 diabetes mellitus (T2DM) has shifted from a glucose-centered approach toward integrated cardio-renal-metabolic protection. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and intensive lipid-lowering therapies have demonstrated substantial cardiovascular and renal benefits, implementation in routine outpatient care and the burden of persistent residual risk remain insufficiently characterized in Romania. [OBJECTIVES] We aimed to evaluate routine-care pharmacological treatment patterns, identify residual cardio-renal-metabolic risk despite ongoing therapy, determine independent correlates of persistent adverse outcomes, and explore potential therapeutic gaps in adults with T2DM. [METHODS] This cross-sectional observational study included 232 unique adults with T2DM attending a specialized outpatient diabetes clinic in Romania between 1 October 2024 and 19 February 2026. One eligible outpatient record per participant was analyzed; when multiple records were available, the earliest eligible record in the exported dataset was used as the index visit. No a priori sample-size calculation was performed. Pharmacological therapies, cardiovascular and renal phenotypes, metabolic biomarkers, and clinical outcomes were extracted from routinely collected electronic medical records. Residual risk was evaluated using glycemic, lipid, renal, obesity, and blood-pressure targets. Multivariable logistic regression analyses identified independent correlates of persistent cardio-metabolic abnormalities. An exploratory cumulative residual-risk count was constructed by summing seven clinically relevant uncontrolled risk factors. [RESULTS] Biguanides were the most frequently prescribed glucose-lowering agents (53.0%), followed by SGLT2 inhibitors (44.8%), insulin (32.3% of the total cohort), GLP-1 receptor agonists (15.5%), and DPP-4 inhibitors (14.7%). Statins were prescribed to 48.7% of participants. SGLT2 inhibitor use did not differ significantly according to established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease phenotypes, whereas GLP-1 receptor agonists were prescribed more frequently in participants with obesity (22.0% vs. 7.6%, p = 0.003). Clinically important residual risk persisted across all treatment groups. Among SGLT2 inhibitor users, 57.3% had HbA1c ≥ 7%, while 27.9% remained albuminuric. Among insulin-treated participants, 84.0% had HbA1c ≥ 7%; reduced eGFR and albuminuria were also more frequent than among non-users. Despite statin therapy, 33.6% of treated participants continued to exhibit LDL cholesterol ≥ 100 mg/dL. In multivariable logistic regression, insulin therapy was associated with higher odds of HbA1c ≥ 7% (adjusted odds ratio [aOR] 7.41, 95% confidence interval [CI] 3.50-15.65), while SGLT2 inhibitor therapy was associated with lower odds of albuminuria (aOR 0.54, 95% CI 0.30-0.95). Absence of statin-containing therapy was associated with higher odds of LDL cholesterol ≥ 100 mg/dL (aOR 6.01, 95% CI 3.38-10.66). Absence of statin-containing therapy was associated with higher odds of residual LDL cholesterol ≥ 100 mg/dL (aOR 4.21, 95% CI 2.34-7.58). Seventy-two percent of participants presented at least three persistent cardio-renal-metabolic abnormalities, while 24.2% exhibited five or more. More than half of participants with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease were not receiving either an SGLT2 inhibitor or a GLP-1 receptor agonist. [CONCLUSIONS] Significant residual cardio-renal-metabolic risk persists in adults with T2DM despite use of contemporary pharmacological therapies. Disease severity markers and treatment exposure were associated with persistent adverse outcomes, but the cross-sectional design does not establish causality. The study identified potentially modifiable therapeutic gaps among patients with established cardiovascular and renal disease. Comprehensive and repeatedly reassessed cardio-renal-metabolic management, integrating pharmacological optimization with individualized risk stratification, may improve implementation of guideline-directed therapy and reduce long-term complications in routine clinical practice.","url":"https://pubmed.ncbi.nlm.nih.gov/42930014/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1141,"doi":"10.1136/bmjopen-2026-122207","pmid":"42901597","nct_ids":"[]","title":"Adverse oral effects of GLP-1 and GIP receptor agonists: a scoping review protocol","authors":"[\"Escudero Samaniego DG\", \"Falconí Tarapués MA\", \"Cañarte Vergara BT\", \"Coelho MS\", \"De Magalhães Gonzaga MF\", \"Stefani CM\", \"Gonçalves TMS\", \"De Luca Canto G\", \"Pauletto P\"]","journal":"BMJ open","publication_date":"2026-10-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[ABSTRACT]  [INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin receptor agonists such as glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) are increasingly being prescribed for type 2 diabetes and obesity due to their efficacy in glycaemic control, weight loss and cardiovascular risk reduction. Emerging pharmacovigilance data suggest potential oral adverse effects, including xerostomia, dysgeusia, oral hypoesthesia and throat discomfort. Therefore, alterations in salivary function may compromise oral homeostasis and increase susceptibility to dental caries, periodontal inflammation and mucosal irritation. Additionally, metabolic and inflammatory changes mediated by GLP-1 and GIP may indirectly affect oral tissues. However, current evidence remains limited and inconsistently reported. Further research is needed to investigate the prevalence, underlying mechanisms and clinical significance of oral manifestations associated with GLP-1RA and GLP-1/GIP dual receptor agonist medications, as well as to explore the need for individualised management strategies and more frequent monitoring for patients receiving these therapies. [METHODS AND ANALYSIS] This protocol describes the methodology for a future scoping review to be conducted in accordance with the JBI reporting guidelines. Studies addressing incretin-based medications and their implications for oral health will be eligible for inclusion in the review, with no restrictions on language or publication date. The following databases will be searched: Cochrane, LILACS, PubMed/MEDLINE, Scopus and Web of Science. Additional literature will be identified through Google Scholar and ProQuest Dissertations & Theses Global. The snowballing technique and consultation with experts in the field will be used to identify additional relevant studies. The findings will be presented through a narrative synthesis, supported by tables, graphs and maps. When data are available, exploratory comparisons will be performed according to therapeutic indication (type 2 diabetes or obesity) and pharmacological class (GLP-1RAs and GLP-1/GIP dual receptor agonists), with particular attention to tirzepatide and other incretin-based agents, to explore potential differences in reported oral manifestations. In particular, studies involving different GLP-1RA and GLP-1/GIP dual receptor agonists agents (eg, semaglutide, liraglutide and tirzepatide) may be compared to explore potential differences in reported oral manifestations. These comparisons will be conducted descriptively, considering variations in dosage, treatment duration and pharmacological class when such information is reported. [REGISTRATION DETAILS] This protocol has been registered prospectively on the Open Science Framework (DOI:10.17605/OSF.IO/NWTCS). [ETHICS AND DISSEMINATION] This scoping review protocol does not require ethics approval, as it only describes the methodological aspects of a future scoping review and uses secondary data from previously published studies. The findings of the review will be disseminated through publication in a peer-reviewed journal and presentations at scientific conferences. As this study is a protocol for a scoping review and does not involve human participants or identifiable data, ethics committee approval was not required.","url":"https://pubmed.ncbi.nlm.nih.gov/42901597/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: None declared.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:05+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1142,"doi":"10.1016/j.xcrm.2026.103115","pmid":"42901164","nct_ids":"[]","title":"Gut-derived glucagon-like peptides attenuate T cell-induced intestinal injury","authors":"[\"Koehler JA\", \"Baggio LL\", \"Cao X\", \"Shang R\", \"Yusta B\", \"Wong CK\", \"Matthews D\", \"Sandoval DA\", \"Drucker DJ\"]","journal":"Cell reports. Medicine","publication_date":"2026-10-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are produced in enteroendocrine L cells and control energy homeostasis. GLP-1 receptor (GLP-1R) activation improves glucose homeostasis and induces satiety and weight loss, whereas GLP-2 receptor (GLP-2R) signaling promotes intestinal growth and nutrient absorption. GLP-1R and GLP-2R agonism also reduce intestinal damage in preclinical studies. Here, we demonstrate that endogenous GLP-1R and GLP-2R signaling are essential for protecting the intestine from T cell-mediated enteropathy. Gut injury induced by T cell activation is increased in Glp1r-/- and Glp2r-/- mice, as well as in mice with selective loss of intestinal proglucagon gene expression (GcgGut-/-). Conversely, the GLP-2R agonist teduglutide and the GLP-1R agonist semaglutide, administered separately or together, attenuate αCD3-induced intestinal damage in GcgGut-/- mice. Collectively, these findings demonstrate distinct biological roles for endogenous GLP-1R/GLP-2R activity in immune-mediated intestinal injury and highlight the therapeutic potential of glucagon-like peptides, alone or together, for ameliorating T cell-mediated mucosal injury.","url":"https://pubmed.ncbi.nlm.nih.gov/42901164/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests D.J.D. has received consulting fees from Amgen, AstraZeneca Inc., Crinetics Pharmaceuticals Inc., Eli Lilly Inc., General Medicines, Kallyope, Metsera, Pfizer Inc., Protagonist Therapeutics, Roche, and Sanofi and speaking fees from Novo Nordisk Inc. Mt. Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc., and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker lab unrelated to the current studies. The University of Toronto, the University Health Network, and Takeda are parties to a license agreement surrounding the use of teduglutide for short bowel syndrome.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"immune\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1167,"doi":"10.1016/j.kint.2026.09.026","pmid":"42901325","nct_ids":"[\"NCT03819153\"]","title":"Safety outcomes of semaglutide by chronic kidney disease severity in the FLOW trial","authors":"[\"Tuttle KR\", \"Andersen MR\", \"Arici M\", \"Arslan EG\", \"Bellary S\", \"Idorn T\", \"Ji L\", \"Kamenov Z\", \"Kashihara N\", \"Mahaffey KW\", \"Mann JFE\", \"Perkovic V\", \"Rasmussen S\", \"Rossing P\", \"Schytz PA\", \"Sreenivasamurthy L\", \"Pratley RE\"]","journal":"Kidney international","publication_date":"2026-10-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] People with type 2 diabetes (T2D) and chronic kidney disease (CKD) often experience medication intolerance and side effects that worsen with lower estimated glomerular filtration rate (eGFR). This prespecified secondary analysis assessed the safety of semaglutide by baseline eGFR. [METHODS] FLOW (NCT03819153) was a double-blind, randomized, placebo-controlled trial testing the efficacy of subcutaneous semaglutide 1.0 mg once-weekly on a primary kidney outcome (50% or more eGFR reduction, kidney failure, or death due to kidney or cardiovascular causes) in participants with T2D and CKD. Safety data were collected selectively and included serious adverse events (SAEs), AEs leading to treatment discontinuation, and prespecified AEs of special interest (AESIs). In this descriptive assessment, systematically collected safety data were reported numerically by baseline eGFR. [RESULTS] Of 3533 participants, 1767 received semaglutide and 1766 received placebo. Fewer SAEs were reported with semaglutide than placebo across baseline eGFR subgroups (45.1% versus 50.4% in the 60 or more ml/min per 1.73 m2 subgroup, and 56.4% versus 60.4% in the under 30 ml/min per 1.73 m2 subgroup). SAEs related to infections and infestations; cardiac disorders; respiratory, thoracic and mediastinal disorders; and metabolism and nutrition disorders were generally less frequent with semaglutide than placebo, regardless of baseline eGFR. Treatment discontinuations due to AEs were higher with lower baseline eGFR across treatment groups (60 or more ml/min per 1.73 m2: semaglutide 11.2%, placebo 11.3%; under30 ml/min per 66 1.73 m2: semaglutide 18.8%, placebo 18.7%). Discontinuations specifically due to gastrointestinal AEs were reported more frequently with semaglutide (4.5%) than placebo (1.1%), regardless of baseline eGFR. Frequencies of AESI were similar between treatment groups across baseline eGFR subgroups. [CONCLUSIONS] In this safety assessment, SAEs were reported less frequently with semaglutide than placebo, with corresponding patterns observed for treatment discontinuations and AESIs. No unexpected safety concerns were identified across the spectrum of eGFR represented in the FLOW trial.","url":"https://pubmed.ncbi.nlm.nih.gov/42901325/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1.0 mg once-weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"adverse_effects\", \"nutrition\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":"safety by baseline eGFR: serious adverse events, AEs leading to discontinuation, and adverse events of special interest","endpoints":null,"effect_estimate":"SAEs fewer with semaglutide across eGFR subgroups (45.1% versus 50.4% at eGFR 60 or more; 56.4% versus 60.4% under 30); discontinuations for gastrointestinal AEs higher with semaglutide (4.5% vs 1.1%); AESI frequencies similar","confidence_interval":null,"p_value":null,"sample_size":3533,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"chronic kidney disease required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes and chronic kidney disease\", \"sample_size\": 3533, \"inclusion_exclusion\": \"type 2 diabetes and chronic kidney disease\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and chronic kidney disease.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight or HbA1c change and no analysis separating them from the safety findings (rule 6 default).","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 3533, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; 3533 participants; descriptive numerical reporting\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a prespecified secondary analysis of a large double-blind randomized trial (3533 participants), reported descriptively by subgroup without confidence intervals.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"SAEs less frequent with semaglutide than placebo across eGFR subgroups; discontinuations for gastrointestinal AEs more frequent with semaglutide (4.5% vs 1.1%); AESIs similar; no unexpected safety concerns.","limitations":"A descriptive subgroup analysis without statistical testing, in a trial where safety data were collected selectively; limited to people with type 2 diabetes and CKD.","plain_summary":"This prespecified analysis of the FLOW trial looked at side effects of weekly semaglutide versus placebo in 3533 people with type 2 diabetes and chronic kidney disease, grouped by kidney function. Serious adverse events were less common with semaglutide in every kidney-function group (for example 45.1% versus 50.4% in the 60 or more ml/min per 1.73 m2 subgroup), but stopping treatment because of gastrointestinal side effects was more common (4.5% vs 1.1%). The results are descriptive, without statistical tests.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1170,"doi":"10.1038/s41392-026-02945-5","pmid":"42897130","nct_ids":"[]","title":"Real-world renoprotective effects of polyethylene glycol-loxenatide in type 2 diabetes: a multicenter, ambispective cohort study","authors":"[\"Ye J\", \"Li J\", \"Chen Y\", \"Chen F\", \"Zhu D\", \"Zhang C\", \"Chen Q\", \"Tian Y\", \"Yang S\", \"Xu W\", \"Xie B\", \"Chen ZS\", \"Hou K\"]","journal":"Signal transduction and targeted therapy","publication_date":"2026-10-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Patients with type 2 diabetes mellitus and chronic kidney disease face persistent risks despite standard care. Polyethylene glycol-loxenatide lacks real-world renoprotective evidence in high-risk Chinese populations relative to non-incretin-based standard care. This multicenter, ambispective cohort study enrolled 3305 patients with type 2 diabetes mellitus, renal impairment, and elevated cardiovascular risk at six Chinese tertiary institutions (median follow-up 36.4 months; trial registration: ChiCTR2300073001). Data were extracted via an artificial intelligence-enhanced pipeline. Co-primary analyzes comprised multivariable-adjusted Cox regression and 1:1 propensity score matching (332 per group); pre-specified landmark analyzes at 6 and 12 months addressed immortal time bias. Polyethylene glycol-loxenatide was associated with a reduced risk of the primary kidney composite outcome in the original cohort (hazard ratio [HR], 0.49; 95% CI, 0.25-0.95; P = 0.035), which was corroborated in the propensity score matched cohort (HR, 0.44; 95% CI, 0.20-0.97; P = 0.043) and progressive across 6-month (HR, 0.40; 95% CI, 0.19-0.84) and 12-month (HR, 0.33; 95% CI, 0.14-0.75) landmarks. While a reduction in 3-point major adverse cardiovascular events was observed in the unmatched cohort (HR, 0.60; 95% CI, 0.43-0.85; P = 0.004), this association was not sustained in the matched analysis (HR, 0.92; 95% CI, 0.57-1.48; P = 0.735). In conclusion, long-term therapy was associated with an attenuated risk of major renal events. Given the null findings in the matched cohort, the cardiovascular observations are exploratory and require randomized confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42897130/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: The authors declare no competing interests. While the primary baseline study (FLYING 1) received support from Jiangsu Hansoh Pharmaceutical Group Co., Ltd., the sponsor played no role in the design, execution, analysis, or funding of this secondary extended study (FLYING 2).","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:07+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1230,"doi":"10.21203/rs.3.rs-11391047/v1","pmid":null,"nct_ids":"[]","title":"Pulmonary Aspiration and Related Outcomes Associated with Semaglutide and Tirzepatide: A Comparative Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS)","authors":"[\"Sarıca O.\"]","journal":"preprint server","publication_date":"2026-10-20","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>Background  Incretin-based therapies, including the GLP-1 receptor agonist semaglutide and the dual GIP/GLP-1 receptor co-agonist tirzepatide, delay gastric emptying, raising clinical concerns regarding pulmonary aspiration. This study evaluates serious clinical outcomes among pulmonary aspiration-related adverse event reports and characterizes dual-exposure cases. Methods  Adverse event reports associated with pulmonary aspiration and aspiration pneumonia were identified from the FDA Adverse Event Reporting System (FAERS). Reports listing both agents as suspect products were segregated into an independent co-reported cohort (n = 7). Single-agent semaglutide (n = 132) and tirzepatide (n = 79) cohorts were analyzed for demographic profiles and serious clinical outcomes (death, hospitalization, and life-threatening events). Fisher's exact tests were performed to compare outcomes between cohorts. Results  A total of 218 cases were analyzed. In the semaglutide cohort (n = 132; mean age 61.1, SD (standard deviation) 14.6 years; 48.5% female), mortality was 17.4% and hospitalization was 62.1%. In the tirzepatide cohort (n = 79; mean age 65.2, SD 15.4 years; 51.9% female), mortality was 16.5% and hospitalization was 53.2%. Mortality (p = 1.000, OR = 1.071) and hospitalization (p = 0.2477, OR = 1.445) showed no significant differences between groups. However, reports designated as life-threatening were significantly more frequent with tirzepatide compared to semaglutide (17.7% vs. 7.6%; p = 0.0417, OR = 0.381). In the co-reported cohort (n = 7), 57.1% required hospitalization, with no deaths or life-threatening events reported. Conclusion  Spontaneous reports of pulmonary aspiration associated with semaglutide and tirzepatide demonstrate similar frequencies of mortality and hospitalization, but a higher proportion of life-threatening designations in tirzepatide cases. Identifying and isolating co-reported cases prevents cross-contamination in incretin pharmacovigilance studies.</p>","url":"https://doi.org/10.21203/rs.3.rs-11391047/v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:32+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"mortality\", \"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1235,"doi":"10.64898/2026.10.18.26365823","pmid":null,"nct_ids":"[]","title":"Heart rate rises most during REM sleep after semaglutide initiation: a matched longitudinal cohort study","authors":"[\"Krongauz D\", \"Kohn S\", \"Zulti A\", \"Schlesinger Y\", \"Godneva A\", \"Talmor-Barkan Y\", \"Segal E.\"]","journal":"preprint server","publication_date":"2026-10-20","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Study Objectives.</h4>  Glucagon-like peptide-1 (GLP-1) receptor agonists raise resting heart rate. We asked whether, after semaglutide initiation, the increase is larger during rapid eye movement (REM) sleep than during non-rapid eye movement (NREM) sleep. <h4>Methods.</h4>  In the Human Phenotype Project, an Israeli cohort of generally healthy adults aged 40 to 70 years, 96 of 494 self-reported semaglutide initiators had a home sleep study (WatchPAT; sleep stages estimated from peripheral arterial tone and actigraphy) before and at least three months after starting. Each was propensity-matched 1:1 to a never-user of GLP-1 drugs measured at the same visits. We estimated the initiators’ change minus their controls’ change (difference-in-differences). The REM minus NREM contrast was designated primary after an exploratory analysis. <h4>Results.</h4>  Relative to controls (90 to 94 pairs), heart rate rose during nocturnal wake (+3.89 beats per minute [bpm], 95% confidence interval 2.35 to 5.44), NREM sleep (+4.82 bpm, 3.12 to 6.52) and REM sleep (+6.25 bpm, 4.42 to 7.91); the REM increase exceeded the NREM increase by 1.42 bpm (0.98 to 1.89). The excess persisted across matching designs and on a relative scale; the proportion of REM sleep did not change. Never-users with similar weight loss showed no REM sleep heart-rate rise (+0.40 bpm, −0.63 to 1.50). Heart-rate variability decreases disappeared after adjustment for heart rate. <h4>Conclusions.</h4>  Semaglutide initiation was associated with higher heart rate throughout sleep, most during REM sleep, unexplained by weight loss. Clinic measurements may understate this effect. Confirmation with polysomnographic staging is needed. <h4>Graphical Abstract</h4>  <h4>Statement of Significance</h4>  Glucagon-like peptide-1 receptor agonists lower body weight and cardiovascular risk but raise heart rate, an effect usually measured while patients sit awake in a clinic. Whether it differs between sleep stages has not been formally tested. After people started semaglutide, heart rate rose in every sleep stage estimated by a home sleep apnea test, most during rapid eye movement sleep; weight loss did not explain it. A higher sleeping heart rate on a wearable after starting the drug may therefore be an expected effect, not illness. Whether the rise matters for patients with heart disease, in whom rapid eye movement sleep can provoke ischemia and arrhythmia, requires prospective studies with dispensed exposure and electroencephalographic sleep staging.","url":"https://doi.org/10.64898/2026.10.18.26365823","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:32+00:00","study_design":"prospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"sleep\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1185,"doi":"10.1111/dme.70500","pmid":"42897718","nct_ids":"[]","title":"Real-world observational study evaluating metabolic and kidney outcomes in patients living with chronic kidney disease and type 2 diabetes mellitus with obesity prescribed tirzepatide","authors":"[\"Carruthers JE\", \"Ooi XY\", \"Goodall D\", \"Reed J\", \"Bedi R\", \"McGrath A\", \"Willicombe M\", \"Avari P\", \"Frankel AH\"]","journal":"Diabetic medicine : a journal of the British Diabetic Association","publication_date":"2026-10-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity and type 2 diabetes mellitus (T2DM) accelerate chronic kidney disease (CKD) progression. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has demonstrated metabolic and potential renoprotective benefits in clinical trials. There have been limited reports of the implications of prescribing tirzepatide in a real-world cohort of patients with advanced CKD. [METHODS] This observational study includes a multi-ethnic cohort of 62 adults with CKD stages 1-5 who initiated tirzepatide indicated for T2DM with concurrent obesity in a general nephrology clinic between June 2024 and October 2025. Patients were followed for a median of 21.4 weeks. Clinical outcomes including weight, glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), blood pressure, lipid profile and insulin requirements were collected. [RESULTS] Tirzepatide significantly reduced median weight (103-100 kg; p < 0.0001), HbA1c (63 [7.9%] to 54 [7.1%] mmol/mol; p = 0.002) and uACR (111-44 mg/mmol; p = 0.008), while eGFR remained stable. Significant improvements were also observed in triglycerides, total cholesterol, LDL cholesterol and total daily insulin dose. Gastrointestinal symptoms and decreased serum bicarbonate were the most common adverse events. [CONCLUSIONS] In this real-world, multi-ethnic cohort, including patients with advanced CKD, tirzepatide was associated with clinically meaningful improvements in weight, glycaemic control, albuminuria, lipid profile and insulin requirements without adversely affecting kidney function. The introduction of tirzepatide to patients with CKD should be guided by a multidisciplinary team.","url":"https://pubmed.ncbi.nlm.nih.gov/42897718/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1233,"doi":"10.64898/2026.10.12.753973","pmid":null,"nct_ids":"[]","title":"An Injectable Antisense Oligonucleotide Approach to Treat Obesity in Preclinical Models","authors":"[\"Bond ST\", \"Keating MF\", \"Liu Y\", \"Yang C\", \"Walker SM\", \"Jurrjens AW\", \"Liu KH\", \"Parslow AC\", \"Nath AP\", \"Ruiz Carmona S\", \"Inouye M\", \"Calkin AC\", \"Drew BG.\"]","journal":"preprint server","publication_date":"2026-10-19","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>ABSTRACT</h4>  Obesity leads to metabolic dysregulation and thus drives complications including type 2 diabetes, cardiovascular disease, steatotic liver disease and some cancers. Obesity is primarily driven by lifestyle factors, which impacts individuals differently depending on their genetic susceptibility. Studies on this genetic risk have provided major insights into gene networks that modulate obesity development, including incretins and their regulatory circuits. Indeed, incretin-based therapeutics (i.e. GLP1 RA) have proven to be enormously successful in promoting weight loss, but do so with several ongoing challenges including significant weight rebound upon cessation, loss of lean mass, and side effects that reduce therapeutic longevity. Thus, ongoing research is necessary to identify additional interventions that overcome or minimise these concerns. To this end, in our previous work we have identified a novel lipid regulatory protein with potential to influence lipid storage. In the current study, we use antisense oligonucleotides (ASO) to silence this protein in mouse models of diet induced obesity, and demonstrate that once weekly IP injections of ASO prevents the development of obesity, and defends against the progression of existing obesity. This is shown to be effective in multiple mouse strains fed different diets over various time frames, with gene targeting ASOs leading to reductions in fat mass, no change in lean mass, along with improvements in whole body glucose tolerance and steatotic liver disease. Additional studies demonstrate that this phenotype is likely driven by effects in adipose tissue, but not liver, and is not linked to activation of the Type 1 Interferon response, a previously implicated off target effect of ASO administration. Thus, these studies demonstrate that our injectable ASO approach in mice can successfully treat obesity in the absence of major change in lean mass, thus positioning this intervention as a therapeutic program that works alternatively to, or in conjunction with current weight loss medicines.","url":"https://doi.org/10.64898/2026.10.12.753973","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:32+00:00","study_design":"preclinical_animal","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"lean_mass\", \"body_composition\", \"cancer\", \"aging\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1396,"doi":"10.64898/2026.08.10.744052","pmid":null,"nct_ids":"[]","title":"An area postrema GLP-1R to NTS pathway dissociates semaglutide-induced satiation, nausea and reduced food motivation from satiety","authors":"[\"Jones, L.\", \"Cross, E.\", \"Song, Y.\", \"Claxton, P.\", \"Monaco, N.\", \"Yu, Y.\", \"Trapp, S.\", \"Adriaenssens, A.\", \"Brierley, D. I.\"]","journal":"biorxiv (preprint)","publication_date":"2026-10-19","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"The GLP-1-based anti-obesity drug semaglutide lowers bodyweight primarily by increasing satiation and satiety, whilst also reducing motivation to consume high calorie foods, and commonly causing nausea. The brainstem dorsal vagal complex (DVC) has been identified as a key mediator of these phenotypic components of semaglutide's anorectic effect. However, which DVC neuron populations are recruited to mediate these components and whether they are dissociable, are translationally important but unresolved questions. We addressed these in mice using metabolic and behavioural phenotyping to resolve the distinct anorectic components elicited by the acute administration of semaglutide. We combined this phenotyping approach with activity-dependent genetic labelling to identify semaglutide-recruited neuron populations ('Sema-TRAP') and chemogenetic manipulation to interrogate their contribution to these effects. Semaglutide potentiated satiation and satiety, caused behavioural proxies of nausea, and suppressed motivation to consume high-fat, high-sugar Western diet, in a largely sex-independent manner. It activated a substantial proportion of GLP-1R-expressing neurons in the brainstem area postrema (AP), but surprisingly most semaglutide-activated neurons in the nucleus tractus solitarius (NTS) did not express GLP-1R. Chemogenetic reactivation of Sema-TRAP neurons in the NTS alone was sufficient to recapitulate the effects of semaglutide on satiation, nausea, motivation for Western diet, and bodyweight. Knockdown of GLP-1R expression in the AP prior to Sema-TRAPing prevented the recruitment of Sema-TRAP NTS neurons which elicited these effects on satiation, nausea and motivation. AP GLP-1R knockdown also abolished semaglutide's effect on satiation and motivation, while effects on satiety and bodyweight were preserved. These data demonstrate that semaglutide suppresses eating via distinct behavioural mechanisms, at least some of which are mediated by dissociable circuits. GLP-1R populations outside the DVC, or distinct subpopulations within the non-GLP-1R NTS neurons recruited downstream of GLP-1RAP, may therefore represent therapeutic targets to tune GLP-1-based obesity drugs towards a better-tolerated effect profile.","url":"https://www.biorxiv.org/content/10.64898/2026.08.10.744052","source_name":"medrxiv:biorxiv","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:53:55+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1517,"doi":"10.1111/dom.71432","pmid":"42897109","nct_ids":"[]","title":"Changes in Muscle Strength Following Semaglutide Treatment in Adults: A Systematic Review With Meta-Analysis of Handgrip Strength","authors":"[\"Machado LG\", \"Siedschlag Schmidt PH\", \"Tasca Petroski G\", \"Lopes Costa GL\", \"Vieira Dos Santos Ribeiro L\", \"Ramos Da Cruz JV\", \"De Luca Canto G\", \"Hohl A\", \"Ronsoni MF\", \"van de Sande-Lee S\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To systematically review and quantitatively synthesize within-group changes in skeletal muscle strength following semaglutide treatment in adults. [MATERIALS AND METHODS] This PRISMA 2020 systematic review was registered in PROSPERO (CRD420251185935). MEDLINE, Embase, CENTRAL, LILACS and Google Scholar were searched through 20 August 2026, without language restrictions. Eligible studies included adults treated with semaglutide reporting quantitative skeletal muscle strength outcomes, including handgrip and knee extension strength. Randomized, non-randomized and uncontrolled before-after studies were included. The primary meta-analysis pooled within-group changes in handgrip strength from baseline to the longest available follow-up of semaglutide-only arms using a random-effects model. Knee extension strength was summarized descriptively. [RESULTS] Sixteen reports represented eleven studies, all assessing handgrip strength; one small randomized trial also assessed knee extension strength. Ten studies (660 semaglutide-treated participants) contributed to the primary meta-analysis of uncontrolled within-group changes, showing a nonsignificant pooled handgrip strength change (-0.16 kgf; 95% confidence interval: -1.98 to 1.65), with substantial heterogeneity (I2 = 90.8%) and a 95% prediction interval from -5.96 to 5.63 kgf. Duration-stratified and sensitivity analyses were also nonsignificant. Individual study findings were heterogeneous. Certainty was very low. [CONCLUSIONS] Available evidence is insufficient to determine whether semaglutide is associated with changes in handgrip strength because the principal synthesis was based on uncontrolled within-group changes, with very low certainty and significant heterogeneity. These findings do not establish strength preservation or a causal treatment effect. More robust comparative studies with standardized strength assessment and longer follow-up are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42897109/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T17:07:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"none: pooled uncontrolled within-group changes in semaglutide-only arms\", \"treatment_duration\": null}","domains":"[\"muscle\"]","outcome_type":"intermediate","primary_outcome":"within-group change in handgrip strength from baseline to the longest available follow-up (pooled)","endpoints":null,"effect_estimate":"pooled within-group handgrip strength change -0.16 kgf, not significant (I2 = 90.8%; 95% prediction interval -5.96 to 5.63 kgf); duration-stratified and sensitivity analyses also nonsignificant; individual study findings heterogeneous; no comparator","confidence_interval":"95% confidence interval: -1.98 to 1.65","p_value":null,"sample_size":660,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 660, \"inclusion_exclusion\": \"adults treated with semaglutide with quantitative muscle strength outcomes; randomized, non-randomized and uncontrolled before-after studies\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a meta-analysis of adults treated with semaglutide whose abstract gives no age, BMI or diabetes data for the pooled participants; there is no cached full text.","mediation":"unlikely","mediation_notes":"The pooled handgrip change was nonsignificant, so there is no effect to attribute to weight change (null-result boundary). The abstract reports no weight or HbA1c change and no mediation analysis.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 660, \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"none: pooled uncontrolled within-group changes in semaglutide-only arms\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval: -1.98 to 1.65\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: although it pools, the primary synthesis pools only uncontrolled before-after changes from semaglutide arms, with no comparator; that is pooled case-series evidence, which the model rates VERY_LOW, as it rates an uncontrolled study of treated users (IN-063). Heterogeneity was substantial (I2 = 90.8%) and the authors rate certainty very low.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The main pooled result rests on uncontrolled within-group changes with substantial heterogeneity and very low certainty, so it cannot show a treatment effect; knee extension strength came from one small trial and was summarised only descriptively.","plain_summary":"This systematic review and meta-analysis pooled handgrip strength measured before and after semaglutide in 660 treated adults from ten studies, with no untreated comparison group. Average handgrip strength did not change significantly (-0.16 kgf), but the studies disagreed widely and the authors rate the certainty very low. Because people were compared only with themselves, the result cannot show whether semaglutide preserves or reduces strength.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1298,"doi":"10.3390/ijms27209251","pmid":"42942021","nct_ids":"[]","title":"GLP-1 Receptor Agonist Therapy in Patients with Cancer: A Review of Clinical Outcomes","authors":"[\"Andronescu AC\", \"Ciumărnean L\", \"Orășan OH\", \"Cozma A\", \"Leah NV\", \"Lucaciu RL\", \"Hangan AC\", \"Procopciuc LM\"]","journal":"International journal of molecular sciences","publication_date":"2026-10-18","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the management of obesity and type 2 diabetes, including among patients with cancer. Although previous research has mainly focused on cancer incidence, their associations with clinical outcomes after cancer diagnosis remain less well characterized. Therefore, the present study aimed to evaluate the oncologic and survival outcomes associated with GLP-1 RA use in adults with an established malignancy. We performed a systematic review of comparative studies evaluating GLP-1 RA use in patients with a confirmed cancer diagnosis. PubMed, Scopus and Web of Science were searched for English-language publications from 1 January 2016 to 8 August 2026. Twenty-six retrospective cohort studies were included in the qualitative synthesis. Thirteen studies included selective GLP-1 RAs and tirzepatide within the same exposure group. Study quality was assessed using the Newcastle-Ottawa Scale. Twenty-five studies evaluated overall survival and/or all-cause mortality, while nine assessed cancer recurrence, progression, or related outcomes. Survival and mortality outcomes more often favored the exposed group (especially compared with nonuse) than not, but findings were less consistent in active-comparator analyses. Evidence for recurrence and progression was sparse and heterogeneous, and no clear signal of increased risk was observed. Because all of these were observational studies with substantial differences in populations, comparators, exposure definitions, and duration of follow-up, the survival associations do not imply causality or direct antitumor effects of GLP-1 RAs. Clinically, the preponderance of evidence does not support the use of GLP-1 RAs as cancer-directed therapy, and their use in patients with cancer should be guided by established indications such as obesity and type 2 diabetes. Potential explanations include effects on glycemic and cardiovascular risk factors, treatment selection, residual confounding, or combinations thereof. Prospective studies and randomized controlled trials with cancer-specific outcomes and longer follow-up are needed to further evaluate these associations.","url":"https://pubmed.ncbi.nlm.nih.gov/42942021/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"nonuse or active comparators\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cancer\", \"mortality\", \"metabolic\"]","outcome_type":"hard","primary_outcome":"overall survival and/or all-cause mortality, and cancer recurrence or progression","endpoints":null,"effect_estimate":"No pooled estimate: survival and mortality more often favoured GLP-1 RA use (especially vs nonuse) but less consistently vs active comparators; no clear signal of increased recurrence or progression risk","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"established cancer (malignancy)\", \"sample_size\": null, \"inclusion_exclusion\": \"comparative studies of GLP-1 RA use in patients with a confirmed cancer diagnosis; English-language, 2016 to August 2026\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: the review covers adults with established cancer, a disease selected for itself; no BMI or diabetes data for the included populations are reported.","mediation":"possibly","mediation_notes":"Possibly: no weight or HbA1c data are reported, and the authors name effects on glycaemic and cardiovascular risk factors as a possible explanation for the survival associations.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"nonuse or active comparators\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"no CI reported; qualitative synthesis only\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review of 26 retrospective cohort studies with a qualitative synthesis only (no pooled estimate).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"All included studies were retrospective cohorts with differing populations, comparators, exposure definitions and follow-up, so survival associations do not imply causality; there was no pooled estimate.","plain_summary":"This systematic review gathered 26 retrospective studies of people with cancer, comparing those who used GLP-1 drugs with non-users or users of other drugs. Survival was more often better among GLP-1 users, especially compared with non-users, but less consistently against other drugs, and there was no clear signal of higher risk of cancer recurrence or progression. Because all the studies were observational, these are associations, not proof that the drugs affect cancer.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1060,"doi":"10.1016/j.ijcard.2026.135000","pmid":"42892471","nct_ids":"[]","title":"GLP-1 receptor agonist therapy and incident atrial fibrillation in non-diabetic adults with obesity and chronic kidney disease: a propensity matched cohort study","authors":"[\"Hassan A\", \"Okorigba E\", \"Grace C\", \"Otabor E\", \"Osineye B\", \"Olayiwola O\", \"Oyeleye T\", \"Amin P\"]","journal":"International journal of cardiology","publication_date":"2026-10-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity and chronic kidney disease (CKD) are potent risk factors for atrial fibrillation (AF), yet whether GLP-1 receptor agonists (GLP-1RAs) prevent incident AF in non-diabetic adults with obesity and CKD is unexamined. We assessed whether GLP-1RA therapy reduces 1-year AF incidence in this cardiorenal phenotype. [METHODS] Using the TriNetX US Collaborative Network (66 healthcare organizations), we conducted a retrospective target trial emulation of non-diabetic adults aged 18 or older with obesity and CKD stages 3-5 diagnosed 2021-2024. Patients receiving semaglutide, liraglutide, or tirzepatide (n = 10,985) were compared with unexposed patients (n = 94,527). After propensity score matching, 7326 patients remained per cohort. The primary outcome was incident AF at 1 year; secondary outcomes included AF subtypes, ventricular tachyarrhythmias, and all-cause hospitalization. Cox models generated hazard ratios (HRs); sensitivity analyses extended follow-up to 2-3 years with landmark analyses. [RESULTS] At 1 year, GLP-1RA use was associated with significantly lower incident AF (1.63% vs. 2.62%; HR 0.655, 95% CI 0.508-0.844; p = 0.001), a 34.5% relative risk reduction. Reductions were consistent for paroxysmal (HR 0.586), persistent (HR 0.482), and longstanding persistent AF (HR 0.527; all p < 0.05); permanent AF was non-significant at 1 year. Ventricular tachyarrhythmias (HR 0.556; p = 0.002) and hospitalization (HR 0.668; p < 0.001) were also significantly reduced. Benefits persisted across 2- and 3-year follow-up and remained consistent in landmark analyses. [CONCLUSIONS] In non-diabetic adults with obesity and CKD, GLP-1RA therapy was associated with significant, durable reductions in incident AF, ventricular arrhythmias, and hospitalization. These findings are consistent with a possible cardiorenal benefit and support prioritizing this phenotype for dedicated randomized trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42892471/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest All authors had no conflict of interest to declare.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"unexposed patients\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":"hard","primary_outcome":"incident atrial fibrillation at 1 year","endpoints":null,"effect_estimate":"Incident AF at 1 year 1.63% vs. 2.62% (HR 0.655); paroxysmal HR 0.586, persistent HR 0.482, longstanding persistent HR 0.527; permanent AF non-significant at 1 year; ventricular tachyarrhythmias HR 0.556; hospitalization HR 0.668","confidence_interval":"95% CI 0.508-0.844","p_value":"p = 0.001","sample_size":14652,"follow_up":"1 year (sensitivity analyses extended follow-up to 2-3 years)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required (criterion not stated)\", \"diabetes_status\": \"excluded (non-diabetic)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD stages 3-5 required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity with CKD stages 3-5, without diabetes\", \"sample_size\": 14652, \"inclusion_exclusion\": \"non-diabetic adults aged 18 or older with obesity and CKD stages 3-5 diagnosed 2021-2024 (TriNetX)\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity and CKD stages 3-5 (diabetes excluded); mean age and BMI are not reported.","mediation":"possibly","mediation_notes":"Obesity is a stated AF risk factor, and the abstract reports no weight, blood-pressure or glycaemic change and no analysis separating weight loss from a direct drug effect; propensity score matching addresses baseline confounding only.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 14652, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"unexposed patients\", \"follow_up_duration\": \"1 year (sensitivity analyses extended follow-up to 2-3 years)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0.508-0.844\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single retrospective cohort (target trial emulation) in TriNetX records; the observational design caps the tier.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"All authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective target trial emulation in health-record data compared with unexposed patients, so residual confounding is possible; the primary outcome was at 1 year, and the authors call for dedicated randomized trials.","plain_summary":"This study used US health records (TriNetX) to compare non-diabetic adults with obesity and chronic kidney disease who took semaglutide, liraglutide or tirzepatide with similar people who did not, with 7326 matched patients per group. GLP-1 drug use was linked to less new atrial fibrillation at 1 year (1.63% vs. 2.62%; HR 0.655, 95% CI 0.508-0.844) and to fewer ventricular arrhythmias and hospitalizations, while permanent AF did not differ significantly. Because the study is observational, these are associations, not proof that the drugs prevented AF.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1038,"doi":"10.1093/ejhf/xuag313","pmid":"42886864","nct_ids":"[]","title":"GLP-1 receptor agonist treatment and cardiovascular outcomes following aortic valve replacement: a nationwide observational study","authors":"[\"Krasniqi L\", \"Hamandi M\", \"Mortensen PE\", \"Nissen H\", \"Pellikka PA\", \"Borlaug BA\", \"Gerke O\", \"Haujir A\", \"Krasniqi LO\", \"Terkelsen CJ\", \"Riber LP\", \"Dahl JS\"]","journal":"European journal of heart failure","publication_date":"2026-10-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] GLP-1 receptor agonists reduce major adverse cardiovascular events among patients with diabetes, overweight, and obesity. Whether these benefits extend to patients undergoing aortic valve replacement (AVR) for severe aortic stenosis (AS) remains unknown. Thus, we investigated the association between GLP-1 receptor agonist treatment and cardiovascular outcomes after AVR. [METHODS] Nationwide population-based cohort study including consecutive patients with severe AS undergoing TAVI or SAVR in Western Denmark between January, 2016 and April, 2022. Patients were followed until death, emigration, crossover, or end of follow up on May 12, 2026. Propensity score-matching was performed to balance confounding. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, or aortic valve reoperation. Secondary outcomes included all-cause mortality, heart failure hospitalization, aortic valve reoperation, with analyses accounting for the competing risk of death. [RESULTS] Among 5259 eligible patients undergoing AVR, 292 propensity score-matched patients were included in the final analyses. During a mean follow up of 4.8±2.4 years, GLP-1 receptor agonist treatment was associated with a lower risk of the primary composite outcome compared with controls (HR 0.69, 95%CI 0.50-0.96, p=0.029). GLP-1 receptor agonist treatment was also associated with lower risk of all-cause mortality (HR 0.66, 95%CI 0.46-0.95, p=0.025). In competing risk analyses accounting for death, lower risks were observed for heart failure hospitalization (HR 0.67, 95%CI 0.48-0.93, p=0.018), and aortic valve reoperation (HR 0.69, 95%CI 0.49-0.98, p=0.037). [CONCLUSION] Treatment with GLP-1 receptor agonists was associated with lower risk of cardiovascular outcomes including mortality following AVR among patients with severe AS.","url":"https://pubmed.ncbi.nlm.nih.gov/42886864/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"propensity score-matched controls\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"composite of all-cause mortality, heart failure hospitalization or aortic valve reoperation","endpoints":null,"effect_estimate":"Primary composite HR 0.69 (95%CI 0.50-0.96, p=0.029); all-cause mortality HR 0.66 (95%CI 0.46-0.95, p=0.025); heart failure hospitalization HR 0.67 (95%CI 0.48-0.93, p=0.018); aortic valve reoperation HR 0.69 (95%CI 0.49-0.98, p=0.037); no null outcome reported","confidence_interval":"95%CI 0.50-0.96 (primary composite)","p_value":"p=0.029 (primary composite)","sample_size":292,"follow_up":"mean 4.8±2.4 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"severe aortic stenosis required (undergoing valve replacement)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"severe aortic stenosis undergoing TAVI or SAVR\", \"sample_size\": 292, \"inclusion_exclusion\": \"consecutive patients with severe aortic stenosis undergoing TAVI or SAVR in Western Denmark, January 2016 to April 2022\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: patients were selected for severe aortic stenosis undergoing valve replacement in Western Denmark; age, BMI, obesity and diabetes status are not reported, though the background frames GLP-1 benefit in diabetes, overweight and obesity.","mediation":"possibly","mediation_notes":"The abstract reports no weight, HbA1c or blood-pressure change and no analysis separating them from a drug effect; propensity score matching balanced baseline confounding only.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 292, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"propensity score-matched controls\", \"follow_up_duration\": \"mean 4.8±2.4 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"CIs reported; 292 matched patients; event counts not stated\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single nationwide observational cohort with propensity matching and 292 analysed patients; the observational design caps the tier.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Observational registry cohort with a small matched sample (292 of 5259 eligible patients), so residual confounding and imprecision are possible; the abstract does not say why patients received GLP-1 receptor agonists.","plain_summary":"This Danish registry study looked at patients with severe aortic stenosis who had their aortic valve replaced, comparing 292 propensity-matched patients with and without GLP-1 receptor agonist treatment. Over a mean follow-up of 4.8±2.4 years, treatment was linked to a lower risk of the combined outcome of death, heart failure hospitalization or valve reoperation (HR 0.69, 95%CI 0.50-0.96) and of death alone (HR 0.66); no outcome was reported as null. Only 292 of 5259 eligible patients were matched and the study is observational, so these are associations, not proof of benefit.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1039,"doi":"10.1161/jaha.126.051982","pmid":"42885796","nct_ids":"[]","title":"Glucagon-Like Peptide-1 Receptor Agonists and Incident Cardiovascular Events and Death in Treated Serious Mental Illness, Type 2 Diabetes, and Obesity","authors":"[\"Governor SB\", \"Dávila-García DM\", \"Rivera-Segarra E\", \"Filiatreau LM\", \"Tollinchi-Natali N\", \"Essien E\", \"Altaee O\", \"Otchere P\", \"Cabassa LJ\", \"Dávila-Román VG\"]","journal":"Journal of the American Heart Association","publication_date":"2026-10-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Adults with serious mental illness (SMI), type 2 diabetes, and obesity have elevated cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have established cardiometabolic benefits in the general population, but their effects in SMI are unclear. We evaluated whether GLP-1RA use was associated with lower risks of incident myocardial infarction (MI), heart failure (HF), and all-cause death. [METHODS] This was a retrospective propensity score-matched cohort study of 218 043 adults with SMI, type 2 diabetes, obesity, and active antipsychotic or antidepressant medications in the TriNetX database (73 health care organizations). Outcomes were incident MI, HF, and all-cause death at 1 and 3 years. The primary exposure was GLP-1RA use versus nonuse; secondary analyses examined semaglutide or tirzepatide. Exploratory analyses evaluated sex, race, and sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor use. [RESULTS] GLP-1RA use was associated with lower risks of incident MI, HF, and all-cause death. Risk differences at 1 and 3 years were -0.007 and -0.010 for MI, -0.011 and -0.018 for HF, and -0.039 and -0.065 for death (all P<0.001). Semaglutide or tirzepatide use was also associated with lower risks of MI, HF, and death (all P<0.001). Findings were directionally consistent after accounting for sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor use. [CONCLUSIONS] Adults with treated SMI, type 2 diabetes, and obesity using GLP-1RAs, particularly semaglutide or tirzepatide, had significantly reduced 1- and 3-year risks of incident MI, HF, and all-cause death versus nonusers. These pooled associations should be interpreted in the context of SMI's clinical heterogeneity and the limitations of administrative case ascertainment.","url":"https://pubmed.ncbi.nlm.nih.gov/42885796/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\", \"semaglutide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"nonuse of GLP-1RAs\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"incident myocardial infarction, heart failure and all-cause death at 1 and 3 years","endpoints":null,"effect_estimate":"Risk differences at 1 and 3 years: MI -0.007 and -0.010; HF -0.011 and -0.018; death -0.039 and -0.065 (all P<0.001); semaglutide or tirzepatide also associated with lower risks; no null outcome reported","confidence_interval":null,"p_value":"all P<0.001","sample_size":218043,"follow_up":"1 and 3 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required (criterion not stated)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"serious mental illness treated with antipsychotics or antidepressants, with type 2 diabetes and obesity\", \"sample_size\": 218043, \"inclusion_exclusion\": \"adults with serious mental illness, type 2 diabetes, obesity and active antipsychotic or antidepressant medication (TriNetX)\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had serious mental illness, type 2 diabetes and obesity and were taking antipsychotics or antidepressants; age and BMI are not reported.","mediation":"possibly","mediation_notes":"All participants had obesity and type 2 diabetes, and the abstract reports no weight or HbA1c change and no mediation analysis; accounting for SGLT2 and DPP-4 inhibitor use addresses co-medication, not weight mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 218043, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"nonuse of GLP-1RAs\", \"follow_up_duration\": \"1 and 3 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; risk differences with P values; event counts not stated\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single retrospective propensity-matched TriNetX cohort; the observational design caps the tier, and no confidence intervals are given in the abstract.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective observational study in administrative records with no confidence intervals in the abstract; the authors note the clinical heterogeneity of serious mental illness and the limits of administrative case ascertainment.","plain_summary":"This study used TriNetX health records of 218,043 adults with serious mental illness, type 2 diabetes and obesity who were taking antipsychotics or antidepressants. GLP-1 receptor agonist use was linked to lower risks of heart attack, heart failure and death at 1 and 3 years (for death, risk differences of -0.039 and -0.065; all P<0.001), and semaglutide or tirzepatide showed the same pattern; no outcome was reported as null. The study is observational, so these are associations, not proof that the drugs lowered the risk.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1062,"doi":"10.1007/s00592-026-02810-5","pmid":"42886239","nct_ids":"[]","title":"GLP-1 receptor agonist use and contrast-associated acute kidney injury after contrast-enhanced CT and CT angiography in adults with type 2 diabetes and chronic kidney disease: a propensity score-matched cohort study","authors":"[\"Chang Y\", \"Chi KY\", \"Lin HM\"]","journal":"Acta diabetologica","publication_date":"2026-10-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To examine whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with contrast-associated acute kidney injury (CA-AKI) after contrast-enhanced computed tomography (CE-CT) or computed tomographic angiography (CTA) in adults with type 2 diabetes and chronic kidney disease (CKD). [METHODS] We conducted a TriNetX retrospective cohort study of adults with type 2 diabetes and CKD who underwent CE-CT or CTA from January 2020 to January 2025. GLP-1 RA use was defined by a prescription within six months before imaging. The primary outcome was a new acute kidney injury diagnosis within three days. Separate 1:1 propensity score-matched analyses were conducted for CE-CT and CTA, with eGFR-stratified and sensitivity analyses. [RESULTS] After matching, the CE-CT and CTA cohorts included 6,995 and 3,285 pairs, respectively. CA-AKI occurred in 3.8% of GLP-1 RA users versus 4.5% of non-users after CE-CT (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.71-0.99) and in 4.5% versus 6.1% after CTA (OR 0.74, 95% CI 0.59-0.92). The absolute risk differences were 0.7% points and 1.5% points, respectively. HbA1c remained imbalanced after matching. Negative-control outcomes were null, and eGFR-stratified associations were inconsistent between cohorts. [CONCLUSIONS] GLP-1 RA use was associated with a lower observed risk of CA-AKI after CE-CT and CTA in adults with type 2 diabetes and CKD. Residual HbA1c imbalance and the observational design limit causal interpretation; prospective studies using creatinine-based outcomes are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42886239/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: This study was conducted using de-identified data obtained from the TriNetX Global Collaborative Network. The study was approved by the National Cheng-Kung University Hospital institutional review board (approval number: A-ER-114-687; date: 21 February 2026). Individual patient consent was waived in accordance with applicable regulations governing secondary analysis of de-identified data. Consent to participate: The requirement for individual informed consent was waived because the study used de-identified secondary data. Clinical trial registration: Not applicable. Prior presentation: This work has not been previously presented or published as an abstract.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"non-users\", \"treatment_duration\": null}","domains":"[\"kidney\", \"metabolic\"]","outcome_type":"hard","primary_outcome":"new acute kidney injury diagnosis within three days of contrast-enhanced CT or CT angiography (CA-AKI)","endpoints":null,"effect_estimate":"CA-AKI 3.8% in users vs 4.5% in non-users after CE-CT (OR 0.84) and 4.5% vs 6.1% after CTA (OR 0.74); absolute risk differences 0.7% points and 1.5% points; negative-control outcomes null; eGFR-stratified associations inconsistent between cohorts","confidence_interval":"CE-CT: 95% CI 0.71-0.99; CTA: 95% CI 0.59-0.92","p_value":null,"sample_size":20560,"follow_up":"three days after imaging (outcome window)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD required (stage not specified)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with CKD, undergoing contrast-enhanced CT or CT angiography\", \"sample_size\": 20560, \"inclusion_exclusion\": \"adults with type 2 diabetes and CKD who underwent CE-CT or CTA from January 2020 to January 2025 (TriNetX)\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and chronic kidney disease and were having contrast imaging; age and BMI are not reported.","mediation":"possibly","mediation_notes":"HbA1c stayed imbalanced between users and non-users after matching, so glycaemic differences were not separated from a drug effect; no weight data are reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 20560, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"non-users\", \"follow_up_duration\": \"three days after imaging (outcome window)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CIs reported (CE-CT upper bound 0.99); event rates 3.8% vs 4.5% (CE-CT) and 4.5% vs 6.1% (CTA); event counts not stated; 6,995 and 3,285 matched pairs\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single retrospective TriNetX cohort with propensity matching; the observational design caps the tier.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective observational design; HbA1c remained imbalanced after matching and eGFR-stratified associations were inconsistent, and the outcome was an AKI diagnosis rather than creatinine-based, so the authors call for prospective studies using creatinine-based outcomes.","plain_summary":"This study used TriNetX health records of adults with type 2 diabetes and chronic kidney disease who had contrast CT scans, comparing people with a GLP-1 receptor agonist prescription in the six months before imaging with matched non-users. Kidney injury within three days was less common in users: 3.8% versus 4.5% after CE-CT (OR 0.84, 95% CI 0.71-0.99) and 4.5% versus 6.1% after CT angiography (OR 0.74, 95% CI 0.59-0.92). Negative-control outcomes were null, results by kidney-function level were inconsistent, and HbA1c stayed imbalanced, so this is an association, not proof of protection.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1316,"doi":"10.3390/jcm15208039","pmid":"42941552","nct_ids":"[]","title":"Urinary Stone Recurrence After Initiation of GLP-1-Based Therapy: A Romanian Retrospective Cohort Study of Clinical, Renal, and Hydration-Related Factors","authors":"[\"Danau RA\", \"Munteanu MA\", \"Mitel A\", \"Predoiu G\", \"Secareanu I\", \"Jinga V\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Glucagon-like peptide-1 receptor agonists and dual GIP/GLP-1 receptor agonists produce substantial weight loss and improve glycemic control, but their relationship with urinary stone recurrence remains incompletely characterized. We evaluated clinically and radiologically confirmed recurrent stone episodes occurring after initiation of semaglutide or tirzepatide. Methods: This retrospective single-center cohort screened 168 adults receiving semaglutide or tirzepatide. Four patients with previous bariatric surgery, 33 without at least 6 months of post-initiation clinical follow-up, and five with hyperparathyroidism were excluded, leaving 126 participants. Follow-up was calculated from GLP-1-based therapy initiation to the last documented clinical or imaging assessment. Recurrence required a stone episode documented before treatment initiation and a new symptomatic or radiologically progressive stone event after initiation. Results: The cohort included 94 semaglutide and 32 tirzepatide users. Median follow-up was 9 months [IQR 8-12]. Thirteen patients (10.3%; 95% CI 6.1-16.9%) had a recurrent episode after treatment initiation. No measured demographic, metabolic, renal, hydration-related, electrolyte, or treatment characteristic clearly differentiated patients with and without recurrence. Allopurinol use was more frequent among recurrent stone formers in an unadjusted analysis, a finding considered exploratory and likely affected by confounding by indication. Conclusions: In this single-arm cohort, 10.3% of patients had clinically and radiologically documented stone recurrence after GLP-1-based therapy initiation. The study describes post-initiation events but cannot estimate treatment-attributable risk because it lacked an untreated comparator, pre-treatment incidence-rate analysis, standardized surveillance, and complete exposure data. Larger prospective comparator studies with baseline imaging, time-to-event follow-up, complete urinary chemistry, and treatment-dose data are required.","url":"https://pubmed.ncbi.nlm.nih.gov/42941552/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:24+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1371,"doi":"10.3390/jcm15208027","pmid":"42941539","nct_ids":"[]","title":"Biliary and Pancreatic Safety of Incretin-Based Therapies in Obesity and Type 2 Diabetes: A Propensity-Matched Real-World Comparison of Tirzepatide, Semaglutide, and DPP-4 Inhibitors","authors":"[\"Ghusn W\", \"Abi-Aad SJ\", \"Hurtado MD\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"To compare the 1-year risk of biliary/pancreatic adverse events among patients with obesity and type 2 diabetes treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4i), and to directly compare tirzepatide with semaglutide. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network. Adults with obesity and type 2 diabetes without prior biliary or pancreatic disease were included. Two prespecified comparisons were performed: GLP-1RA (semaglutide or tirzepatide) versus DPP-4i, and tirzepatide versus semaglutide. The primary outcome was incident cholelithiasis at 1 year. Secondary outcomes included cholecystitis, cholangitis, acute pancreatitis, and cholecystectomy. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Results: After matching, 281,283 patients were included in each GLP-1RA and DPP-4i cohort, and 242,876 patients in each tirzepatide and semaglutide cohort. Compared with DPP-4i, GLP-1RA therapy was associated with lower risks of cholelithiasis (1.02% vs. 1.16%; HR 0.92, 95%CI 0.87-0.96), cholecystitis (HR 0.88, 95%CI 0.79-0.98), cholangitis (HR 0.46, 95%CI 0.36-0.58), acute pancreatitis (HR 0.68, 95%CI 0.61-0.76), and cholecystectomy (HR 0.51, 95%CI 0.38-0.69). In the head-to-head comparison, semaglutide was associated with higher risks of cholelithiasis (HR 1.11, 95%CI 1.05-1.18) and cholecystitis (HR 1.22, 95%CI 1.10-1.37) compared with tirzepatide, while risks of pancreatitis, cholangitis, and cholecystectomy did not differ significantly. Conclusions: In this large real-world study, GLP-1RA therapy was associated with lower risks of biliary and pancreatic events compared with DPP-4i. Tirzepatide demonstrated a modestly more favorable biliary safety profile than semaglutide, supporting the overall hepatobiliary safety of contemporary GLP-1-based therapies.","url":"https://pubmed.ncbi.nlm.nih.gov/42941539/","source_name":"pubmed","source_tier":1,"coi_statement":"Maria Daniela Hurtado Andrade has received payment for consulting from Verge Genomics, received honoraria and support for meeting attendance/travel from The Menopause Society, participated in an advisory board for Novo Nordisk, participated in an advisory board for F. Hoffmann-La Roche AG, and received research support (paid to Mayo Clinic) from the Mayo Clinic Center for Women’s Health Research, National Institutes of Health, Eli Lilly, Endogenex, and Phenomix Sciences. All other authors have no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1013,"doi":"10.1007/s10735-026-11013-9","pmid":"42878930","nct_ids":"[]","title":"Retatrutide treatment in streptozotocin-induced diabetic rats: renal inflammatory cytokines, HIF‑1α expression, and histopathological injury profile","authors":"[\"Keskin U\", \"Altın E\", \"Özatik FY\", \"Sezgin AK\", \"Gündoğdu AÇ\", \"Arı NS\", \"Kara MK\"]","journal":"Journal of molecular histology","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"This study investigated whether Retatrutide, a triple incretin agonist, attenuates early diabetes-associated renal injury in a streptozotocin-induced rat model, and whether any protective effect is mediated through modulation of inflammatory cytokines (IL-1β, TNF-α) and HIF-1α gene expression in kidney tissue. Male Sprague-Dawley rats were divided into four groups: control, STZ-induced diabetic, STZ plus Retatrutide, and Retatrutide alone. Diabetes was induced via a single intraperitoneal STZ injection; Retatrutide was administered subcutaneously for 21 days at a dose adapted from prior metabolic studies. Renal tissue underwent ELISA for interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), quantitative real-time PCR for HIF-1α expression, and semi-quantitative histopathological scoring of cortical and medullary parameters including haemorrhage, tubular dilatation, inflammatory cell infiltration, tubular vacuolisation, interstitial fibrosis, and intraluminal debris. STZ-induced rats exhibited significantly elevated cortical and medullary histopathological scores and increased renal IL-1β levels relative to controls, confirming successful early injury induction. Retatrutide did not produce statistically significant histopathological protection, although STZ plus Retatrutide animals showed consistently lower damage scores than STZ-only animals, corresponding to large standardised effects (Cliff's δ = 0.90 in the cortex and 0.85 in the medulla) that could not be confirmed under family-wise error correction. HIF-1α expression was highest in the untreated diabetic group and was significantly lower in Retatrutide-treated diabetic animals (S vs. SR, p = 0.020), whereas Retatrutide alone did not alter expression relative to controls. TNF-α did not differ significantly in any pairwise comparison; levels in Retatrutide-treated diabetic animals were nonetheless comparable to controls (g* = 0.03). Retatrutide selectively modulated HIF-1α transcriptional levels in the acute STZ model without statistically confirmed histopathological renoprotection, and without evidence of intrinsic renal toxicity. Because the acute STZ model reflects insulin-deficient rather than T2DM-like disease, the model itself is a critical limitation; chronic type 2 diabetes models, together with longer treatment durations and refined dosing regimens, are required to determine whether the observed early molecular effects translate into structural renal benefit.","url":"https://pubmed.ncbi.nlm.nih.gov/42878930/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and European Union Directive 2010/63/EU on the protection of animals used for scientific purposes. The original animal experiment was approved by the Kütahya Health Sciences University Animal Experiments Local Ethics Committee (Decision No: 2024.01.06, Date: 30.01.2024), and the renal analyses reported in the present study were approved by the same committee under a separate decision (Decision No: 2025.06.05, Date: 29.05.2025). No additional animals were used for the present study; kidney tissues were obtained from archived material of the same cohort in accordance with the 3Rs principle of reduction.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"retatrutide\"]","drug_details":"{\"route\": \"subcutaneous\", \"dose\": null, \"comparator\": \"untreated STZ-induced diabetic rats; also healthy control and retatrutide-alone groups\", \"treatment_duration\": \"21 days\"}","domains":"[\"inflammation\", \"kidney\", \"cancer\"]","outcome_type":"mixed","primary_outcome":"renal histopathological injury scores, IL-1β and TNF-α levels, and HIF-1α expression in kidney tissue","endpoints":null,"effect_estimate":"No statistically significant histopathological protection (Cliff's δ = 0.90 cortex, 0.85 medulla, not confirmed under family-wise error correction); HIF-1α expression lower with retatrutide in diabetic rats (p = 0.020); TNF-α no significant difference","confidence_interval":"not reported in abstract","p_value":"p = 0.020 (HIF-1α, S vs. SR)","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male rats only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"STZ-induced diabetic and non-diabetic groups (rat model)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"streptozotocin-induced diabetes with early renal injury (rat model)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male rats with streptozotocin-induced diabetes; non-human evidence.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight or glycaemic data, so metabolic change is not separated from a drug effect (the evidence model's default for GLP-1 effects).","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"untreated STZ-induced diabetic rats; also healthy control and retatrutide-alone groups\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; p-values and Cliff's δ effect sizes; histology effects not confirmed under family-wise error correction\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical rat study with no number of animals given in the abstract.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No evidence of intrinsic renal toxicity with retatrutide","limitations":"Rat study in an acute insulin-deficient model that the authors call a critical limitation, with 21 days of treatment and no number of animals in the abstract; longer studies in type 2 diabetes models are needed.","plain_summary":"In male rats made diabetic with streptozotocin, researchers tested 21 days of subcutaneous retatrutide on early kidney injury. Kidney HIF-1α expression was lower than in untreated diabetic rats (p = 0.020), but kidney damage scores were not significantly better after correction for multiple testing, and TNF-α did not differ significantly. The authors note that this acute model does not resemble type 2 diabetes, and animal results do not show what happens in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1042,"doi":"10.1055/a-2982-7440","pmid":"42880346","nct_ids":"[]","title":"GLP-1 Receptor Agonist Use Before Total Knee Arthroplasty is Associated With Lower Postoperative MI, DVT, and VTE Rates","authors":"[\"Yavari B\", \"Soltankhah A\", \"Eghrari N\", \"Calderon S\", \"Lederman E\", \"Shah A\"]","journal":"The journal of knee surgery","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly prescribed for glycemic control and weight management, but their association with postoperative thrombotic events after total knee arthroplasty remains unclear. We performed a retrospective cohort study using deidentified data from the TriNetX United States Collaborative Network, including adults who underwent primary total knee arthroplasty between December 1, 2006 and June 1, 2025. Patients with prior myocardial infarction, deep vein thrombosis, venous thromboembolism, or pulmonary embolism were excluded. Exposure was defined as a prescription for a GLP-1 RA within 1 year and 1 day before surgery. A 1:1 propensity score match was performed on demographics, relevant comorbidities, and medications, yielding 11,765 patients in each cohort. Outcomes were postoperative myocardial infarction, deep vein thrombosis, venous thromboembolism, and pulmonary embolism. Compared with matched controls, patients prescribed GLP-1 receptor agonists had a significantly lower risk of myocardial infarction (25/11,246 vs 47/11,171; risk ratio [RR] 0.528; 95% confidence interval [CI], 0.325 - 0.858). GLP-1 RA use was also associated with a reduced risk of deep vein thrombosis (74/11,319 vs 103/11,308; RR 0.718; 95% CI, 0.533 - 0.966) and venous thromboembolism (133/11,040 vs 172/11,027; RR 0.772; 95% CI, 0.617 - 0.967). In contrast, no statistically significant difference was observed in the incidence of pulmonary embolism between groups (49/11,352 vs 58/11,382; RR 0.847; 95% CI, 0.580 - 1.238). Overall, preoperative GLP-1 receptor agonist use was associated with a significantly lower postoperative risk of myocardial infarction, deep vein thrombosis, and venous thromboembolism following total knee arthroplasty in this large, nationally representative cohort.","url":"https://pubmed.ncbi.nlm.nih.gov/42880346/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no conflict of interest.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"propensity-matched controls\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":"hard","primary_outcome":"postoperative myocardial infarction, deep vein thrombosis, venous thromboembolism and pulmonary embolism","endpoints":null,"effect_estimate":"Myocardial infarction RR 0.528; deep vein thrombosis RR 0.718; venous thromboembolism RR 0.772; pulmonary embolism RR 0.847, not statistically significant","confidence_interval":"95% CI 0.325 - 0.858 (myocardial infarction)","p_value":null,"sample_size":23530,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"prior myocardial infarction excluded (as were prior DVT, VTE and pulmonary embolism)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"primary total knee arthroplasty\", \"sample_size\": 23530, \"inclusion_exclusion\": \"adults with primary total knee arthroplasty, December 1, 2006 to June 1, 2025; prior MI, DVT, VTE or pulmonary embolism excluded\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract gives no age, BMI or diabetes status for the knee-replacement cohorts.","mediation":"possibly","mediation_notes":"Possibly: propensity matching covered demographics, comorbidities and medications; no weight or glycaemic mediation was examined, so these are not separated from a drug effect.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 23530, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"propensity-matched controls\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI 0.325 - 0.858 (myocardial infarction)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single retrospective database cohort with propensity matching, capped at LOW; residual confounding remains possible.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective database study open to confounding by indication despite propensity matching; the abstract does not give follow-up length, dose or the reason for GLP-1 RA use.","plain_summary":"This US database study compared adults having a first total knee replacement who had a GLP-1 receptor agonist prescription in the year before surgery with matched patients who did not, with 11,765 in each group. GLP-1 use was linked to lower rates of heart attack (RR 0.528), deep vein thrombosis (RR 0.718) and venous thromboembolism (RR 0.772), but pulmonary embolism did not differ significantly (RR 0.847). These are associations from health records, not proof that the drugs caused the difference.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1064,"doi":"10.1016/j.eprac.2026.10.004","pmid":"42880590","nct_ids":"[]","title":"Clinical Feasibility of a Low-Dose Tirzepatide Strategy in Older Adults with Type 2 Diabetes: Persistence, Metabolic Benefit, and Treatment Simplification in a Real-World Cohort","authors":"[\"Kanazawa K\", \"Hayashi K\", \"Xinyi C\", \"Hijikata M\", \"Kuwabara K\"]","journal":"Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To evaluate the clinical feasibility of a low-dose tirzepatide strategy in older adults with type 2 diabetes mellitus in routine outpatient practice. [METHODS] This single-center retrospective cohort included Japanese adults who initiated tirzepatide between April 2024 and December 2025 and received a maximum observed dose of ≤5 mg/week through week 28. The primary endpoint in adults aged ≥65 years combined treatment persistence, absence of adverse event (AE)-related discontinuation, and either ≥3% weight loss or an HbA1c reduction ≥1.0 percentage point (≥11 mmol/mol). Younger adults were contextual comparators using overlap weighting. [RESULTS] Among 122 tirzepatide initiators, 107 were included in the low-dose strategy cohort, including 37 older adults. The primary endpoint was achieved by 23/37 (62.2%); 33/37 (89.2%) remained on treatment, and 2/37 (5.4%) discontinued because of AEs. Median body weight change was -3.07%, median HbA1c change was -1.0 percentage point (-11 mmol/mol), and 19/37 (51.4%) achieved HbA1c <7.0% (<53 mmol/mol). Renal, hydration, and nutritional laboratory markers remained generally stable. Overlap-weighted comparisons showed no clear age-related attenuation. [CONCLUSION] In selected older adults, low-dose tirzepatide provided modest metabolic benefit with high persistence and infrequent AE-related discontinuation.","url":"https://pubmed.ncbi.nlm.nih.gov/42880590/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"maximum observed dose of ≤5 mg/week through week 28\", \"route\": null, \"comparator\": \"no untreated comparator; younger adults used as contextual comparators with overlap weighting\", \"treatment_duration\": null}","domains":"[\"kidney\", \"metabolic\", \"adverse_effects\", \"nutrition\"]","outcome_type":"mixed","primary_outcome":"composite in adults aged ≥65 years: persistence, no AE-related discontinuation, and either ≥3% weight loss or HbA1c reduction ≥1.0 percentage point","endpoints":null,"effect_estimate":"Primary endpoint met by 23/37 (62.2%); 33/37 (89.2%) persisted; 2/37 (5.4%) stopped for AEs; median weight change -3.07%; median HbA1c change -1.0 percentage point; 19/37 (51.4%) reached HbA1c <7.0%; no clear age-related attenuation","confidence_interval":"not reported in abstract","p_value":null,"sample_size":107,"follow_up":"through week 28","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": \"≥65 years in the primary-endpoint group of 37; younger adults also in the cohort\", \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 107, \"inclusion_exclusion\": \"Japanese adults with type 2 diabetes starting tirzepatide April 2024 to December 2025 with maximum observed dose ≤5 mg/week through week 28\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes; the primary group was aged ≥65 years but BMI was not reported.","mediation":"not_applicable","mediation_notes":"The main outcomes are themselves weight and HbA1c change (with persistence), so mediation by weight loss is not a separate question; no mediation analysis was reported.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 107, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"no untreated comparator; younger adults used as contextual comparators with overlap weighting\", \"follow_up_duration\": \"through week 28\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; counts and percentages in 37 older adults\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a single-centre retrospective cohort with 37 older adults in the primary analysis and no untreated comparison group.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"2/37 (5.4%) older adults discontinued because of AEs; renal, hydration and nutritional laboratory markers remained generally stable","limitations":"Single-centre retrospective study with 37 older adults in the primary analysis, no untreated comparison group and a selected low-dose population; results are observational through week 28.","plain_summary":"This single-centre retrospective study in Japan followed adults with type 2 diabetes who took low-dose tirzepatide (107 people), focusing on 37 aged 65 or over. Among them, 23/37 (62.2%) met the combined goal of staying on treatment without stopping for side effects and reaching a weight or HbA1c target; median weight change was -3.07%, median HbA1c change was -1.0 percentage point, and 2/37 (5.4%) stopped because of side effects. There was no untreated comparison group, so these are observational findings, not proof that the drug caused the changes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1110,"doi":"10.1097/prs.0000000000013542","pmid":"42879169","nct_ids":"[]","title":"Impact of GLP-1 Agonists on Post-Operative Outcomes in Aesthetic & Body Contouring Surgery: A Systematic Review & Meta-Analysis","authors":"[\"McMahon ME\", \"Wong R\", \"Hanson RP\"]","journal":"Plastic and reconstructive surgery","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly expanded in use for weight loss, resulting in a growing population of patients presenting for aesthetic and body-contouring procedures. Despite their increasing prevalence, the effects of GLP-1 RAs on postoperative wound healing and surgical outcomes remain poorly defined. [METHODS] A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane CENTRAL were searched from database inception through May 2026. Studies comparing postoperative outcomes in patients undergoing aesthetic and/or body-contouring surgery with and without GLP-1 RA exposure were included. Primary outcomes included infection, wound dehiscence, delayed wound healing, hypertrophic scarring, seroma, hematoma, and venous thromboembolism (VTE). Random-effects meta-analyses were performed using risk ratios (RRs) with 95% confidence intervals (CIs). [RESULTS] Twelve studies comprising 29,357 patients met inclusion criteria, with 10 studies included in quantitative synthesis. In pooled observational analyses, GLP-1 RA exposure was associated with increased risk of delayed wound healing and hypertrophic scarring. Subgroup analysis comparing GLP-1 RA users with patients who had previously undergone bariatric surgery demonstrated decreased seroma rates in the GLP-1 RA group. [CONCLUSIONS] GLP-1 RA use in patients undergoing aesthetic and body-contouring surgery was associated in pooled observational analyses with increased risks of delayed wound healing and hypertrophic scarring, while GLP-1 RA use was associated with lower seroma rates in comparison with patients who have undergone bariatric surgery. As GLP-1 RA use become increasingly prevalent, further prospective studies are needed to clarify their perioperative effects and optimize patient selection and surgical outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42879169/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflict of Interest Statement: All authors declare no competing interests that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"patients without GLP-1 RA exposure; in a subgroup analysis, patients who had previously undergone bariatric surgery\", \"treatment_duration\": null}","domains":"[\"immune\", \"perioperative\"]","outcome_type":"hard","primary_outcome":"postoperative infection, wound dehiscence, delayed wound healing, hypertrophic scarring, seroma, hematoma and venous thromboembolism","endpoints":null,"effect_estimate":"Pooled observational analyses: GLP-1 RA exposure associated with increased risk of delayed wound healing and hypertrophic scarring; lower seroma rates than in patients with prior bariatric surgery (subgroup); no risk ratios, and no results for infection, dehiscence, hematoma or VTE, given in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":29357,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"undergoing aesthetic and/or body-contouring surgery\", \"sample_size\": 29357, \"inclusion_exclusion\": \"studies comparing postoperative outcomes after aesthetic and/or body-contouring surgery with and without GLP-1 RA exposure\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract does not report age, BMI or diabetes status for the 29,357 pooled surgical patients.","mediation":"possibly","mediation_notes":"Possibly: the abstract does not examine whether weight loss, reduced intake or nutritional status explains the wound-healing findings, so they are not separated from a drug effect.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 29357, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"patients without GLP-1 RA exposure; in a subgroup analysis, patients who had previously undergone bariatric surgery\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI values reported in the abstract; random-effects risk ratios with 95% CIs stated as the method\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a meta-analysis of observational studies; the abstract reports the direction of results only, with no risk ratios or confidence intervals.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Higher risk of delayed wound healing and hypertrophic scarring with GLP-1 RA exposure; lower seroma rates than in patients with prior bariatric surgery","limitations":"Pools observational analyses only; the abstract gives no effect sizes, patient characteristics or reason for GLP-1 RA use, and the authors call for prospective studies.","plain_summary":"This systematic review and meta-analysis pooled twelve studies (29,357 patients) of people having aesthetic or body-contouring surgery with and without GLP-1 receptor agonist exposure. In the pooled observational analyses, GLP-1 drug use was linked to more delayed wound healing and hypertrophic scarring, while seroma was less common than in people who had earlier had bariatric surgery. The abstract gives no effect sizes and no results for infection, wound breakdown, haematoma or blood clots, and these associations do not show cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1229,"doi":"10.1016/j.ejogrb.2026.115499","pmid":"42893679","nct_ids":"[]","title":"The effect of glucagon-like peptide-1 receptor agonists versus metformin on pregnancy rates in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized trials","authors":"[\"Kar E\", \"Yeh J\", \"Efe MA\", \"Çelik HG\", \"Bozdağ G\", \"Baştu E\"]","journal":"European journal of obstetrics, gynecology, and reproductive biology","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] PCOS-related infertility is closely linked to metabolic dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve insulin resistance and promote weight loss in women with PCOS, but their direct effect on reproductive outcomes remains uncertain. [OBJECTIVES] To evaluate whether GLP-1RA-based therapy improves pregnancy outcomes in women with PCOS. [SEARCH STRATEGY] PubMed, Scopus, and Web of Science were searched from inception to February 2026. [SELECTION CRITERIA] Randomized controlled trials comparing GLP-1RA-based therapy, alone or combined with metformin, with metformin monotherapy in women with PCOS. [DATA COLLECTION AND ANALYSIS] Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2. Dichotomous outcomes were pooled as odds ratios with 95% confidence intervals using a random-effects model. Certainty of evidence was rated with GRADE, and trial sequential analysis was performed. [MAIN RESULTS] Four reports from three randomized trials (252 participants) were included. GLP-1RA-based treatment did not significantly improve overall pregnancy (OR 1.41, 95% CI 0.81-2.45), but was associated with an increase in natural pregnancy (OR 3.10, 95% CI 1.74-5.49), with no significant effect on IVF pregnancy (OR 1.01, 95% CI 0.36-2.85). TSA supported the finding for natural pregnancy, while evidence for overall pregnancy remained underpowered. Certainty of evidence was moderate for natural pregnancy and low for the other outcomes. [CONCLUSIONS] GLP-1 receptor agonists show promising preliminary signals for improving spontaneous conception in women with PCOS, but the available evidence remains limited. Current evidence is insufficient to draw conclusions regarding IVF outcomes. Larger trials with standardized endpoints, including live birth, are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42893679/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:31+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1332,"doi":"10.3390/jcm15208008","pmid":"42941522","nct_ids":"[]","title":"Weight-Loss Magnitude, Fat Mass, and Device-Estimated Muscle Mass Loss During Obesity Pharmacotherapy","authors":"[\"Tomescu C\", \"Albai A\", \"Avram VF\", \"Timar S\", \"Cipu A\", \"Timar B\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Body-composition changes during routine obesity pharmacotherapy require cautious interpretation. Methods: This retrospective observational cohort included 59 adults with paired InBody 770 assessments: 53 receiving tirzepatide and 6 receiving semaglutide. Paired changes and relative device-estimated muscle mass loss were analyzed in all 59; component-share analyses were restricted to the 51 achieving ≥5% weight loss. Analyses used rank-based methods and exploratory robust regression. Results: Recorded treatment duration was a median of 7.0 months, and median observed weight loss was 12.11%. Median fat mass and device-estimated muscle mass losses were 9.9 and 2.3 kg, respectively. Among the 51 participants achieving ≥5% weight loss, median fat, device-estimated muscle, and residual shares were 73.95%, 14.91%, and 10.85%. Each additional five percentage points of weight loss was associated with 2.47 percentage points greater relative device-estimated muscle mass loss (95% CI, 1.89 to 3.05). The corresponding fully adjusted association with muscle share was -0.52 percentage points (95% CI, -1.66 to 0.62); this does not establish stability or equivalence. Final drug-specific dose intensity was not statistically associated with either outcome in the adjusted models. Conclusions: Weight loss observed in this selected, predominantly tirzepatide-treated cohort was mainly accounted for by estimated fat mass reduction. Larger observed weight-loss responses accompanied greater device-estimated muscle mass reductions. Muscle-share estimates were uncertain and model-dependent. The study cannot establish causal medication effects or functional consequences.","url":"https://pubmed.ncbi.nlm.nih.gov/42941522/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:29+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"muscle\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1017,"doi":"10.1016/j.ejphar.2026.179426","pmid":"42874910","nct_ids":"[]","title":"Effects of Sitagliptin Combined with GTS-21 on Improving Glycemic Control and Diabetic Nephropathy by Anti-Apoptosis in Leprdb/db Mice","authors":"[\"Tian W\", \"Wang W\", \"Tang S\", \"Su L\", \"Cooney R\", \"Tian X\", \"Meng Q\"]","journal":"European journal of pharmacology","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Activation of α7 nicotinic acetylcholine receptor (α7nAChR) by GTS-21 engages the cholinergic anti-inflammatory pathway (CAP). This study investigated adding GTS-21 to sitagliptin, a DPP-4 inhibitor used to increase endogenous GLP-1, confers additional benefit over sitagliptin monotherapy on glycemic control and diabetic nephropathy (DN) in Leprdb/db mice, focusing on anti-apoptotic mechanisms. [METHODS] Leptin receptor-deficient (Leprdb/db, 8-week-old) mice were randomized into control (saline), sitagliptin (20 mg/kg), or combination (sitagliptin 20 mg/kg + GTS-21 4 mg/kg) groups for 4 weeks. Oral glucose tolerance test (OGTT), serum creatinine (Scr), blood urea nitrogen (BUN), and IL-6 were measured. Renal histology was evaluated by H&E staining. Apoptosis was assessed by TUNEL staining and cleaved caspase-3 expression. In vitro, HK-2 cells exposed to high glucose (30 mM) were treated with liraglutide (100 nM) and/or GTS-21 (20 nM) to examine apoptosis. [RESULTS] Combination therapy significantly improved glucose tolerance at weeks 1 and 4 (AUC reduction, P=0.0366 and P=0.0435 vs control), whereas sitagliptin alone showed no effect. Both treatments reduced Scr (P=0.0002 for combination; P=0.0101 for monotherapy), but only combination therapy attenuated renal histological injury (P=0.002) and decreased IL-6 in serum and kidney (P=0.0433 and P=0.0041). Renal apoptosis was also suppressed, with reduced TUNEL-positive cells (P=0.0043) and cleaved caspase-3 (P=0.0122). In HK-2 cells, high glucose increased cleaved caspase-3 (P=0.0324), which was attenuated by liraglutide plus GTS-21 (P=0.0320). [CONCLUSIONS] Add-on GTS-21 to sitagliptin improved glycemic control and attenuated diabetic nephropathy beyond sitagliptin monotherapy in Leprdb/db mice, with reduced renal inflammation and suppressed apoptosis. These findings suggest that combined activation of GLP-1 receptor and α7nAChR signaling warrants further investigation as a renoprotective strategy in diabetic nephropathy.","url":"https://pubmed.ncbi.nlm.nih.gov/42874910/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Qinghe Meng reports was provided by SUNY Upstate Medical University. Qinghe Meng reports a relationship with SUNY Upstate Medical University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"sitagliptin\", \"liraglutide\"]","drug_details":"{\"dose\": \"sitagliptin 20 mg/kg (mice, alone or with GTS-21 4 mg/kg); liraglutide 100 nM (HK-2 cells)\", \"treatment_duration\": \"4 weeks\", \"route\": null, \"comparator\": \"control (saline); sitagliptin monotherapy\"}","domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"glycaemic control (OGTT) and diabetic nephropathy markers (serum creatinine, BUN, IL-6, renal histology, apoptosis)","endpoints":null,"effect_estimate":"Combination therapy improved glucose tolerance at weeks 1 and 4 (P=0.0366 and P=0.0435 vs control) while sitagliptin alone showed no effect; both reduced serum creatinine (P=0.0002 combination; P=0.0101 monotherapy); only the combination attenuated renal histological injury (P=0.002) and lowered IL-6.","confidence_interval":null,"p_value":"P=0.0366 and P=0.0435 (combination vs control, glucose tolerance); P=0.0002 (combination) and P=0.0101 (sitagliptin monotherapy), serum creatinine","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"diabetes required (Leprdb/db diabetic mouse model)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"diabetic nephropathy required (Leprdb/db mouse model)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diabetic nephropathy in leptin receptor-deficient (Leprdb/db) mice; high-glucose HK-2 cells\", \"sample_size\": null, \"inclusion_exclusion\": \"8-week-old Leprdb/db mice\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: diabetic (Leprdb/db) mice and high-glucose kidney cells; no human data.","mediation":"possibly","mediation_notes":"No body-weight or HbA1c data and no mediation analysis are reported; the kidney findings are not separated from the improved glucose tolerance.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"control (saline); sitagliptin monotherapy\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"P values reported; no CI reported; group sizes not stated\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: preclinical mouse and cell study.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"One author reports employment by SUNY Upstate Medical University; the other authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Mouse and cell study of 4 weeks' treatment with group sizes not stated; the GLP-1 receptor agonist was tested only in cells, and the in vivo exposure is a DPP-4 inhibitor.","plain_summary":"In diabetic mice, researchers compared saline, the DPP-4 inhibitor sitagliptin (which raises the body's own GLP-1) and sitagliptin plus GTS-21 for 4 weeks. Sitagliptin alone did not improve glucose tolerance but lowered serum creatinine; adding GTS-21 improved glucose tolerance, kidney tissue injury and inflammation markers. In kidney cells, liraglutide with GTS-21 reduced a cell-death marker. These are animal and cell results, not evidence in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1018,"doi":"10.1007/s00592-026-02812-3","pmid":"42873315","nct_ids":"[]","title":"GLP-1 receptor agonists and hair loss: adverse effect, epiphenomenon, or therapeutic paradox?","authors":"[\"Leite Júnior AC\", \"Ribeiro Junior HL\"]","journal":"Acta diabetologica","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual/triple agonists, have revolutionized the management of obesity and type 2 diabetes. However, hair loss has emerged as an adverse event in clinical practice. This review synthesizes the evidence on the prevalence, mechanistic pathways, and clinical course of hair loss associated with semaglutide, tirzepatide, and retatrutide. [METHODS] A narrative review was conducted using the PubMed/MEDLINE database. Data were integrated from clinical trials, real-world observational studies, and pharmacovigilance databases to evaluate the oncological and dermatological implications of these therapies. [RESULTS] There is a discrepancy in hair loss prevalence, ranging from 3 to 7% in controlled trials to over 70% in real-world cohorts. Telogen effluvium (TE) is the predominant phenotype, driven primarily by the magnitude and velocity of weight loss rather than drug toxicity. Newer agents like tirzepatide demonstrate stronger associations with hair shedding compared to older GLP-1 RAs. Pharmacovigilance data show inconsistent but significant signals for semaglutide and tirzepatide, with reporting odds ratios indicating a drug-associated risk. Conversely, paradoxical improvements in androgenetic alopecia and inflammatory scarring alopecias have been reported, likely mediated by metabolic normalization and anti-inflammatory effects. Female sex and significant weight reduction (> 10%) were the most robust predictors of hair loss. [CONCLUSION] Hair loss associated with incretin-based therapies is a biologically complex, threshold-dependent phenomenon reflecting systemic metabolic reprogramming. While predominantly transient and reversible, its psychological impact can compromise treatment adherence. Clinicians should provide proactive counseling, emphasizing the self-limiting nature of TE in this context while monitoring for diverse follicular responses.","url":"https://pubmed.ncbi.nlm.nih.gov/42873315/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declares that they have no conflicts of interest. All authors conceived and wrote the study.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"narrative_review","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"cancer\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"Prevalence, mechanisms and clinical course of hair loss with incretin-based therapies","endpoints":null,"effect_estimate":"Hair loss prevalence from 3 to 7% in controlled trials to over 70% in real-world cohorts; inconsistent but significant pharmacovigilance signals for semaglutide and tirzepatide; paradoxical improvements in androgenetic and scarring alopecias reported.","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a narrative review defined by drug and side effect rather than by a population; the abstract gives no age, BMI or diabetes data for the people in the studies it covers.","mediation":"likely","mediation_notes":"The authors state that telogen effluvium is driven mainly by the size and speed of weight loss rather than drug toxicity, and that weight reduction above 10% predicts hair loss; this is the reviewers' synthesis, not a mediation analysis.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a narrative review with no new primary data and no pooled estimate.","funding_source":"Conselho Nacional de Desenvolvimento Científico e Tecnológico","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Hair loss, mainly telogen effluvium, which the authors attribute chiefly to the size and speed of weight loss; pharmacovigilance reporting odds ratios indicate a drug-associated risk for semaglutide and tirzepatide; female sex and weight reduction above 10% were the strongest predictors; described as mostly transient and reversible.","limitations":"Narrative review of a single database (PubMed/MEDLINE) with no pooled estimate; prevalence figures differ widely between trials and real-world cohorts.","plain_summary":"This narrative review looks at hair loss with semaglutide, tirzepatide and retatrutide. Reported rates range from 3 to 7% in controlled trials to over 70% in real-world cohorts, and drug-safety databases show signals for semaglutide and tirzepatide. The authors say most cases are a temporary shedding driven by fast, large weight loss, with women and people losing more than 10% of body weight most affected, while some other hair conditions were reported to improve. As a narrative review of mixed sources, it cannot show that the drugs cause hair loss.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1019,"doi":"10.1177/00220345261488338","pmid":"42873199","nct_ids":"[]","title":"GLP-1 Receptor Agonists in Dentistry: Promise, Pitfalls, and Evidence Gaps","authors":"[\"Werner N\", \"Pitchika V\", \"Bumm CV\", \"Heck K\", \"Folwaczny M\", \"Schwendicke F\"]","journal":"Journal of dental research","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"GLP-1RAs (glucagon-like peptide-1 receptor agonists) have become one of the fastest-growing drug classes worldwide, with prescriptions for obesity treatment increasing by 587% from 2019 to 2024. While their metabolic and cardiovascular benefits are well established, the implications for oral health remain largely unexamined. Preclinical evidence consistently demonstrates anti-inflammatory and osteoprotective effects on periodontal and peri-implant tissues: GLP-1RAs promote osteogenic differentiation of periodontal ligament stem cells, reduce alveolar bone resorption in animal models of periodontitis, and enhance implant osseointegration in diabetic rats. However, these findings are based exclusively on in vitro and animal studies, with only a single retrospective cohort study providing limited clinical data. Conversely, several oral adverse effects have been reported based on pharmacovigilance analyses, including xerostomia, dysgeusia, and anosmia, particularly for semaglutide. Gastrointestinal side effects, particularly nausea (15% to 50%), vomiting (5% to 24%), and gastroesophageal reflux, pose a plausible but unquantified risk for tooth erosion and secondary caries. A bidirectional link between GLP-1 signaling and the oral microbiota, mediated by bacterial dipeptidyl peptidase (DPP)-4-like enzymes that degrade endogenous GLP-1, adds further complexity. Despite this breadth of potential interactions, no prospective study has used any dental outcome as an endpoint in patients receiving GLP-1RAs. This critical appraisal synthesizes the evidence across multiple dental disciplines, grades it in each domain, and identifies the gaps that demand urgent investigation.","url":"https://pubmed.ncbi.nlm.nih.gov/42873199/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"narrative_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"route\": null, \"dose\": \"various\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"bone\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"none","primary_outcome":"oral and dental health effects of GLP-1 receptor agonists (periodontal, peri-implant, oral adverse effects)","endpoints":null,"effect_estimate":"No pooled estimate. Preclinical studies show anti-inflammatory and osteoprotective effects on periodontal and peri-implant tissues; pharmacovigilance analyses report xerostomia, dysgeusia and anosmia; no prospective study has a dental endpoint.","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a narrative appraisal with no study population of its own; most of the evidence it covers comes from cell and animal studies, and no age, BMI or diabetes data are given.","mediation":"possibly","mediation_notes":"No weight, HbA1c or mediation data are reported, so any effect is presumed to be confounded with weight and metabolic change.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a narrative critical appraisal that adds no new primary data and pools nothing.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Oral adverse effects reported in pharmacovigilance analyses (xerostomia, dysgeusia, anosmia), particularly for semaglutide; nausea, vomiting and gastroesophageal reflux pose a plausible but unquantified risk of tooth erosion and secondary caries.","limitations":"A narrative appraisal with no new data. The clinical evidence it draws on is one retrospective cohort; the rest is in vitro and animal work, and no prospective study has used a dental endpoint.","plain_summary":"This is a narrative appraisal of what is known about GLP-1 receptor agonists and dental and oral health. Lab and animal studies suggest anti-inflammatory and bone-protective effects on gum and implant tissue, but clinical data come from a single retrospective cohort. Drug-safety report databases describe dry mouth, taste changes and loss of smell, and stomach side effects may pose a risk to teeth that has not been measured. No prospective study has used a dental outcome.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1022,"doi":"10.1007/s10735-026-10993-y","pmid":"42870021","nct_ids":"[]","title":"Liraglutide ameliorates obese type 2 diabetes by regulating macrophage cholesterol metabolism and H3K27ac modification to promote M2 polarization and adipocyte thermogenic activation","authors":"[\"Wang P\", \"Zhang J\", \"Zhou W\", \"Zhang N\", \"Chen Y\"]","journal":"Journal of molecular histology","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity-related type 2 diabetes mellitus (O&T2DM) has become a major global public health issue. Chronic low-grade inflammation in adipose tissue is one of its core pathological features, among which excessive infiltration of M1-type macrophages and impaired function of M2-type macrophages are key drivers of inflammation. Liraglutide, a glucagon-like peptide-1 receptor agonist, exhibits significant glucose-lowering, weight-reducing, and anti-inflammatory effects. However, the molecular mechanisms by which liraglutide regulates cholesterol metabolism and epigenetic modifications in adipose tissue macrophages remain to be fully elucidated. A high-fat diet combined with streptozotocin was used to establish an O&T2DM model in male C57BL/6 mice. After 8 weeks of intervention, metabolic phenotypes, adipose tissue macrophage polarization, and cholesterol metabolism-related indicators were assessed. Raw264.7 macrophages were cultured in vitro and stimulated with IFN-γ + LPS to induce M1 polarization. Following liraglutide pretreatment, cell polarization phenotypes, the expression of genes involved in cholesterol metabolic pathways, and histone modification levels were examined. Using shRNA gene silencing, p300 inhibitor intervention, and Acetyl-CoA supplementation experiments in combination with ChIP-qPCR, the central role of the cholesterol metabolism-epigenetic axis in macrophage polarization was elucidated. Finally, a Transwell co-culture system was employed to verify the regulatory effects of liraglutide-reprogrammed macrophages on adipocyte lipid accumulation and energy metabolism. Liraglutide significantly reduced body weight, fasting blood glucose, and HOMA-IR in O&T2DM mice, decreased visceral fat accumulation, and promoted adipose tissue browning. It also increased the proportion of M2 macrophages within adipose tissue and significantly activated the key cholesterol efflux pathway LXRα/ABCA1. In vitro experiments confirmed that liraglutide pretreatment suppressed IFN-γ + LPS-induced M1 polarization and promoted the expression of M2-type markers, upregulated the expression of ABCA1, ABCG1, PPARγ, and LXRα, and increased levels of histone H3K27ac. Mechanistic studies revealed that silencing ABCA1 or LXRα reversed the liraglutide-induced increase in H3K27ac and M2 polarization. Acetyl-CoA supplementation partially restored the macrophage polarization phenotype following ABCA1 silencing. ChIP-qPCR results showed that liraglutide significantly enhanced the enrichment of H3K27ac in the promoter regions of M2 polarization genes and cholesterol metabolism genes. Co-culture experiments demonstrated that liraglutide-reprogrammed macrophages significantly promoted adipocyte thermogenic gene expression, increased mitochondrial membrane potential-dependent staining intensity, and enhanced ATPase activity via paracrine signaling, an effect that was blocked by silencing ABCA1 or LXRα. This study demonstrates that liraglutide activates the ABCA1/LXRα-mediated cholesterol metabolism pathway, upregulates histone H3K27ac modification, and drives macrophage M2 polarization, which in turn induces adipocyte lipid accumulation and mitochondrial metabolic activation via paracrine signaling. These findings provide a new molecular mechanism for the anti-inflammatory and metabolic-improving effects of liraglutide, and also offers a potential epigenetic target for the treatment of O&T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/42870021/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declare no conflict of interest.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": \"8 weeks\"}","domains":"[\"inflammation\", \"body_composition\", \"immune\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"metabolic phenotypes, adipose tissue macrophage polarization and cholesterol metabolism-related indicators","endpoints":null,"effect_estimate":"In mice, liraglutide reduced body weight, fasting blood glucose, HOMA-IR and visceral fat, and increased M2 macrophages and LXRα/ABCA1 activation; no numeric estimates in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male mice\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (high-fat-diet obese diabetic mouse model)\", \"diabetes_status\": \"required (high-fat diet plus streptozotocin diabetes model in mice)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity-related type 2 diabetes model in mice, plus Raw264.7 macrophages in vitro\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male mice with diet- and streptozotocin-induced obese diabetes, plus cultured macrophages.","mediation":"possibly","mediation_notes":"Weight, glucose and visceral fat all fell in the mice, so the fat-tissue effects may partly reflect weight loss; the cell experiments show a direct cellular effect but are not a formal mediation analysis.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; significance stated without numbers\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical mouse and cell-culture mechanism study.","funding_source":"Anhui Provincial Department of Education natural science key project","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Mouse and cell-culture study of mechanisms with no sample size, dose or numeric results in the abstract; it does not test effects in people.","plain_summary":"In male mice made obese and diabetic, 8 weeks of liraglutide lowered body weight, fasting blood glucose, insulin resistance and visceral fat, and shifted fat-tissue immune cells toward an anti-inflammatory type. Cell experiments pointed to a cholesterol-handling and gene-regulation pathway. These are animal and laboratory findings, not evidence of effects in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1098,"doi":"10.1017/neu.2026.10097","pmid":"42870759","nct_ids":"[]","title":"Effects of glucagon-like peptide-1 (GLP-1) mono-agonists on reward processing in animal models: a systematic review","authors":"[\"Zheng YJ\", \"Au HCT\", \"Le GH\", \"Wong S\", \"Teopiz KM\", \"Kwan ATH\", \"Rosenblat JD\", \"Mansur RB\", \"Rhee TG\", \"Lo HKY\", \"McIntyre RS\"]","journal":"Acta neuropsychiatrica","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 (GLP-1), indicated in the treatment of type 2 diabetes mellitus, influences reward processing, integral to disparate mental disorders. Emerging evidence suggests that GLP-1 receptor mono-agonists (GLP-1RAs) are potential treatment strategies for select mental disorders. Herein, we systematically review preclinical research documenting how GLP-1 and GLP-1RAs may impact reward function. [METHODS] Relevant studies were identified through Web of Science, OVID (MedLINE, Embase, PsycInfo), and PubMed from database inception to June 28, 2026. Preclinical research investigating the association between GLP-1 and select GLP-1RAs and reward function was included. Reward functions assessed were food-, drug-, and sexual-related reward. [RESULTS] A total of 66 studies met inclusion and were synthesised herein. Taken together, results indicate that GLP-1 and GLP-1RAs affect measures of food-related, drug-associated, and sexual behaviours. GLP-1 administration was associated with a reduction in food intake and gross locomotor activity with respect to approaching and engaging in reward-seeking behaviours. When locally administered in selected brain regions of evaluated animal models, exenatide was associated with reduced substance use, food seeking, and sexual behaviours (p < 0.05). Similarly, liraglutide was observed to attenuate substance and food-related rewards (p < 0.05). In addition, semaglutide was demonstrated to reduce substance and sucrose intake, while dulaglutide is reported to reduce substance intake (p < 0.001). [DISCUSSION] Extant preclinical findings demonstrate a trend toward reductions in reward-associated behaviours following GLP-1RA administration. Our findings can also provide rationale and impetus for evaluating GLP-1RAs in the treatment of psychiatric disorders characterised by disturbance in hedonic function and behaviours.","url":"https://pubmed.ncbi.nlm.nih.gov/42870759/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"addiction\", \"psychiatric\"]","outcome_type":"surrogate","primary_outcome":"food-, drug- and sexual-related reward in animal models","endpoints":null,"effect_estimate":"GLP-1 and GLP-1RAs reduced food intake, substance use and reward-seeking in animals; exenatide and liraglutide effects p < 0.05; semaglutide reduced substance and sucrose intake and dulaglutide reduced substance intake (p < 0.001)","confidence_interval":"not reported in abstract","p_value":"p < 0.05 (exenatide, liraglutide); p < 0.001 (semaglutide and dulaglutide statement)","sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"animal models of food-, drug- and sexual-related reward\", \"sample_size\": null, \"inclusion_exclusion\": \"preclinical studies of GLP-1 or select GLP-1RAs and reward function\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: all included evidence comes from animal models.","mediation":"possibly","mediation_notes":"Possibly: food intake and locomotor activity also fell, so reward findings may be entangled with reduced intake or activity; no separation is reported.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"surrogate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; p-values only\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review of 66 preclinical animal studies with no pooled estimate.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A review of animal studies only, with no pooled estimates or quality assessment described in the abstract; reductions in locomotor and sexual behaviour make the findings hard to read as benefit or harm for people.","plain_summary":"This systematic review gathered 66 animal studies on how GLP-1 and GLP-1 receptor agonists affect reward-driven behaviour for food, drugs and sex. Across studies, drugs such as exenatide, liraglutide, semaglutide and dulaglutide tended to reduce food intake, substance intake and reward-seeking, but also reduced locomotor activity and sexual behaviour. These are animal findings and do not show effects in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1103,"doi":"10.1111/dom.71405","pmid":"42875725","nct_ids":"[]","title":"GLP-1 Receptor Agonist Therapy Is Associated With Lower Risk of Lower Extremity Amputation in Adults With Type 2 Diabetes and Foot Ulcer Without Coded Peripheral Arterial Disease: A Hypothesis-Generating Real-World Cohort Study","authors":"[\"Robinson H\", \"Yassin M\", \"Robinson D\", \"Eisa M\", \"Rashed WA\", \"Qawasmi F\", \"Mahamid A\", \"Murad H\", \"Khatib M\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To compare lower extremity amputation (LEA) risk in adults with Type 2 diabetes and diabetic foot ulcer (DFU) treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus other glucose-lowering therapy, and to test whether coded peripheral arterial disease (PAD) modifies this association and replicates across comparator classes. [MATERIALS AND METHODS] This new-user, active-comparator retrospective cohort study used the TriNetX Global Collaborative Network (queried 11 July 2026). Adults with Type 2 diabetes and DFU were propensity-score matched 1:1 on 22 covariates, giving 21 325 pairs for the primary comparison. Effect modification by coded PAD (ICD-10 I70.2) was examined in independently matched subgroups. Six sensitivity analyses were pre-specified: 30- and 180-day landmarks, all-cause mortality, background-therapy balancing, limb-severity adjustment and a broadened PAD definition. [RESULTS] GLP-1 RA use was associated with lower 5-year LEA risk than all non-GLP-1 RA therapy (hazard ratio [HR]: 0.60, 95% CI: 0.54-0.67). The association was confined to the no-PAD stratum (HR: 0.21, 0.13-0.33) and absent where PAD was coded (HR: 0.97, 0.78-1.20); ratio of hazard ratios 0.21 (0.13-0.36; p < 0.001). All-cause mortality was also lower (HR: 0.48, 0.45-0.50). The insulin no-PAD estimate persisted under background-therapy balancing (0.14), limb-severity adjustment (0.16) and 30- and 180-day landmarks (0.28, 0.33). Broadening the PAD definition attenuated the no-PAD association without abolishing it (HR: 0.34, 0.17-0.65). [CONCLUSIONS] In Type 2 diabetes with DFU, GLP-1 RA use was associated with lower LEA risk, surviving six pre-specified sensitivity analyses. These observational findings are hypothesis-generating and require prospective confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42875725/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"all non-GLP-1 RA glucose-lowering therapy (active comparator; insulin also examined)\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"mortality\"]","outcome_type":"hard","primary_outcome":"lower extremity amputation","endpoints":null,"effect_estimate":"5-year amputation HR 0.60; HR 0.21 with no coded PAD and 0.97 with coded PAD (no association); all-cause mortality HR 0.48","confidence_interval":"95% CI 0.54-0.67 (overall amputation HR 0.60)","p_value":"p < 0.001 (ratio of hazard ratios, PAD effect modification)","sample_size":42650,"follow_up":"5-year outcome window","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"mixed (coded peripheral arterial disease examined as an effect modifier)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with diabetic foot ulcer\", \"sample_size\": 42650, \"inclusion_exclusion\": \"new users; adults with type 2 diabetes and diabetic foot ulcer, propensity-matched 1:1 on 22 covariates\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and a diabetic foot ulcer.","mediation":"possibly","mediation_notes":"Possibly: no weight or glycaemic mediation analysis is described, so weight and glycaemic change are not separated from a drug effect (the evidence model's default); matching on 22 covariates, background-therapy balancing and limb-severity adjustment address confounding, not mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 42650, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"all non-GLP-1 RA glucose-lowering therapy (active comparator; insulin also examined)\", \"follow_up_duration\": \"5-year outcome window\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0.54-0.67 (overall amputation HR 0.60)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single retrospective database cohort, capped at LOW and described by the authors as hypothesis-generating.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Retrospective database study open to residual confounding; the authors describe the findings as hypothesis-generating, and the subgroup result relies on coded PAD diagnoses.","plain_summary":"This database study matched adults with type 2 diabetes and a diabetic foot ulcer who started GLP-1 receptor agonists with similar people starting other glucose-lowering drugs. GLP-1 use was linked to a lower 5-year amputation risk (HR 0.60, 95% CI 0.54-0.67) and lower all-cause mortality (HR 0.48); the link was seen in people without coded peripheral arterial disease (HR 0.21) but not where that disease was coded (HR 0.97). The authors call the results hypothesis-generating; they show an association, not cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1111,"doi":"10.1007/s00125-026-06892-2","pmid":"42875600","nct_ids":"[\"NCT06393348\"]","title":"Efficacy and safety of HRS-7535, a novel oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes mellitus inadequately controlled by metformin and sodium-glucose co-transporter 2 inhibitors: a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase II trial","authors":"[\"Xu M\", \"Song W\", \"Lv F\", \"Fu Y\", \"Yang L\", \"Bin X\", \"Zhang X\", \"Ye Z\", \"Zhang D\", \"Lin X\", \"Dai W\", \"Shu C\", \"Yan L\"]","journal":"Diabetologia","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS/HYPOTHESIS] This study aimed to evaluate the efficacy and safety of HRS-7535, an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1RA), in Chinese participants with type 2 diabetes mellitus inadequately managed by metformin and sodium-glucose co-transporter 2 inhibitors (SGLT2i). [METHODS] This multicentre, randomised, double-blind, placebo-controlled, Phase II study included participants aged 18-75 years with type 2 diabetes, HbA1c 58-97 mmol/mol (7.5-11.0%) and BMI 20.0-35.0 kg/m2 and on stable-dose metformin and sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy for ≥8 weeks prior to screening. Participants were assigned in a 1:1:1 ratio to receive HRS-7535 30 mg, HRS-7535 60 mg or visually matching placebo tablets once daily using a stratified block randomisation method, with treatment assignments concealed until study completion. The primary endpoint was the change in HbA1c from baseline to week 16. Secondary efficacy outcomes included the proportions of participants achieving HbA1c targets of <53 mmol/mol (7.0%) and ≤48 mmol/mol (6.5%), and changes from baseline in fasting body weight to week 16. [RESULTS] A total of 155 participants with a mean baseline HbA1c of 69 mmol/mol (8.5%) were randomly assigned to HRS-7535 30 mg (n=51), HRS-7535 60 mg (n=53) or placebo (n=51). At week 16, the least‑squares mean differences in HbA1c from baseline for the HRS-7535 30 mg, HRS-7535 60 mg and placebo groups were -16 mmol/mol (95% CI -19, -14) (-1.5% [95% CI -1.7, -1.3]), -20 mmol/mol (95% CI -22, -17) (-1.8% [95% CI -2.0, -1.6]) and -4 mmol/mol (95% CI -7, -2) (-0.4% [95% CI -0.6, -0.2]), respectively (p<0.0001 for both HRS-7535 doses vs placebo). The proportions of participants achieving HbA1c <53 mmol/mol (7.0%) were 51.0% in the HRS‑7535 30 mg group, 66.0% in the HRS‑7535 60 mg group, and 9.8% in the placebo group; the corresponding proportions for HbA1c ≤48 mmol/mol (6.5%) were 35.3%, 37.7% and 3.9%, respectively. Body weight loss was -2.4% in the HRS-7535 60 mg group vs -0.7% in the placebo group. Most treatment-emergent adverse events (TEAEs) were mild to moderate, and gastrointestinal adverse events were the most common. No severe hypoglycaemia was reported. The only TEAE that led to treatment discontinuation occurred in the placebo group. [CONCLUSIONS/INTERPRETATION] Treatment with HRS-7535 resulted in significant improvements in glycaemic management in participants with type 2 diabetes, and the drug exhibited a favourable safety profile. To address a significant clinical data void, this research focused on the addition of HRS‑7535 to the background regimen of metformin and SGLT2i for glycaemic management in participants with type 2 diabetes. Trial registration ClinicalTrials.gov NCT06393348. Funding This study was funded by Jiangsu Hengrui Pharmaceuticals.","url":"https://pubmed.ncbi.nlm.nih.gov/42875600/","source_name":"pubmed","source_tier":1,"coi_statement":"Acknowledgements: Medical writing assistance was provided by J. Du (medical writer at Jiangsu Hengrui Pharmaceuticals) according to good publication practice guidelines. We thank clinical trial participants and their caregivers, without whom this work would not have been possible. Preliminary results were presented in part at the EASD 61st Annual Meeting, Vienna, Austria, 15–19 September 2025. Data availability: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and electronic supplementary material [ESM]), will be made available to researchers who provide a methodologically sound proposal. The study protocol, statistical analysis plan and informed consent form will also be available. Data will be available starting from 6 months and ending 5 years after article publication. Proposals should be directed to the corresponding author, and a data access agreement will be required before data release. Data requests are subject to approval by the trial sponsor (Jiangsu Hengrui Pharmaceuticals). Funding: The study was sponsored by Jiangsu Hengrui Pharmaceuticals. The trial was jointly designed by the principal investigator and the sponsor. Both the authors and the sponsor were involved in data collection, analysis and interpretation. They also ensured the accuracy and completeness of the data, contributed to the writing of the report, and participated in the decision to submit the findings for publication. Authors’ relationships and activities: LYan, MX, WS, FL, YF, LYang, XB and XZ report having received consulting and speaker fees from Jiangsu Hengrui Pharmaceuticals Co. Ltd. ZY, DZ, XL, WD and CS are employees of Jiangsu Hengrui Pharmaceuticals Co. Ltd. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: LYan contributed to the study design. MX and WS provided medical oversight during the trial. FL, YF, LYang, XB and XZ were the clinical research scientists. ZY and DZ provided methodological guidance. CS was responsible for the pharmacokinetic analyses. XL and WD were responsible for the statistical analyses. MX wrote the first draft with medical writing support. All authors participated in interpretation of the data and critical review of the manuscript, had full access to the data, and approved this manuscript for submission for publication. LYan is the guarantor of this work, and, as such, takes responsibility for the integrity of the data and the accuracy of the data analysis.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"hrs-7535\"]","drug_details":"{\"dose\": \"30 mg or 60 mg once daily\", \"comparator\": \"placebo (on background metformin and SGLT2 inhibitor therapy)\", \"route\": \"oral\", \"treatment_duration\": \"to week 16\"}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"biomarker","primary_outcome":"change in HbA1c from baseline to week 16","endpoints":null,"effect_estimate":"HbA1c change at week 16: -16 mmol/mol (-1.5%) with 30 mg and -20 mmol/mol (-1.8%) with 60 mg versus -4 mmol/mol (-0.4%) with placebo (p<0.0001 for both doses); HbA1c <53 mmol/mol reached by 51.0%, 66.0% and 9.8%; body weight -2.4% (60 mg) vs -0.7% (placebo)","confidence_interval":"Change from baseline in each group: 30 mg 95% CI -19, -14 mmol/mol (-1.7, -1.3%); 60 mg 95% CI -22, -17 mmol/mol (-2.0, -1.6%); placebo 95% CI -7, -2 mmol/mol (-0.6, -0.2%)","p_value":"p<0.0001 for both HRS-7535 doses vs placebo","sample_size":155,"follow_up":"to week 16","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": \"18-75 years (eligibility)\", \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 20.0, \"obesity_status\": \"mixed (BMI 20.0-35.0 kg/m2 eligible; obesity not required)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes inadequately controlled on metformin and SGLT2 inhibitors\", \"sample_size\": 155, \"inclusion_exclusion\": \"aged 18-75 years, type 2 diabetes, HbA1c 58-97 mmol/mol (7.5-11.0%), BMI 20.0-35.0 kg/m2, stable metformin plus SGLT2 inhibitor for ≥8 weeks\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 155 participants had type 2 diabetes inadequately controlled on metformin and SGLT2 inhibitors; eligibility allowed BMI 20.0-35.0 kg/m2 and ages 18-75.","mediation":"not_applicable","mediation_notes":"The primary outcome is HbA1c change itself; weight change (-2.4% vs -0.7%) was a secondary outcome and no mediation analysis was reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 155, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (on background metformin and SGLT2 inhibitor therapy)\", \"follow_up_duration\": \"to week 16\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: Change from baseline in each group: 30 mg 95% CI -19, -14 mmol/mol (-1.7, -1.3%); 60 mg 95% CI -22, -17 mmol/mol (-2.0, -1.6%); placebo 95% CI -7, -2 mmol/mol (-0.6, -0.2%)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a 155-person Phase II randomised double-blind trial to week 16 whose primary endpoint is a glycaemic biomarker.","funding_source":"Jiangsu Hengrui Pharmaceuticals","industry_funded":"yes","manufacturer":"Jiangsu Hengrui Pharmaceuticals (named as trial sponsor)","author_conflicts":"Some authors report consulting and speaker fees from Jiangsu Hengrui Pharmaceuticals, and others are its employees.","sponsor_role":"Sponsor co-designed the trial and took part in data collection, analysis, interpretation, writing and the decision to submit; medical writing support came from a sponsor employee.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Jiangsu Hengrui Pharmaceuticals","adverse_events":"Most TEAEs mild to moderate, gastrointestinal events most common; no severe hypoglycaemia; the only TEAE leading to discontinuation was in the placebo group","limitations":"A Phase II trial of 155 Chinese participants to week 16 with a glycaemic biomarker primary endpoint, sponsored and co-designed by the manufacturer; it cannot show long-term or clinical outcomes.","plain_summary":"This randomised, double-blind trial gave 155 Chinese adults with type 2 diabetes, already on metformin and an SGLT2 inhibitor, the experimental oral GLP-1 drug HRS-7535 (30 mg or 60 mg) or placebo once daily. At week 16, HbA1c fell by 1.5% and 1.8% with the two doses versus 0.4% with placebo, and body weight fell by 2.4% at 60 mg versus 0.7% with placebo. Side effects were mostly mild to moderate and gastrointestinal, with no severe hypoglycaemia; the drug maker funded and co-designed the trial, and some authors are its employees.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1112,"doi":"10.1007/s00592-026-02809-y","pmid":"42873314","nct_ids":"[]","title":"Risk of recurrent acute pancreatitis with GLP-1 receptor agonists after prior pancreatitis: a systematic review","authors":"[\"Voltani DL\", \"Pinto FG\", \"Holland S\"]","journal":"Acta diabetologica","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for patients with type 2 diabetes (T2D) and obesity. However, their safety in patients with prior pancreatitis remains uncertain. This systematic review aims to evaluate the risk of recurrent acute pancreatitis (RAP) associated with GLP-1 RA therapy. [METHODS] We systematically searched for studies evaluating the safety of GLP-1 receptor agonists in adults with type 2 diabetes mellitus (T2DM) or obesity and a history of acute pancreatitis. The primary outcome was recurrent acute pancreatitis. We included studies of adults with prior acute pancreatitis treated with GLP-1 receptor agonists for type 2 diabetes, obesity, or related metabolic conditions. Studies without recurrent acute pancreatitis outcomes, pediatric populations, overlapping cohorts, insufficient data, or non-original publications were excluded. [RESULTS] We included four studies comprising 10,624 patients, of whom 5,427 (51.0%) received GLP-1 receptor agonists. Two studies provided comparative data (5,224 GLP-1 RA users; 5,197 controls). GLP-1 receptor agonist use was associated with lower odds of recurrent acute pancreatitis than placebo (OR 0.26, 95% CI 0.05-1.32) and lower risk than SGLT2 inhibitor use (OR 0.57, 95% CI 0.52-0.64). Two additional studies provided recurrence rates among GLP-1 RA users with prior pancreatitis, reporting rates of 9.9% (95% CI 5.8%-16.3%) and 11.9% (95% CI 5.1%-25.8%). [CONCLUSION] Across the four included studies, GLP-1 receptor agonist use was not associated with an increase in RAP among patients with a prior history of acute pancreatitis. However, comparative evidence was limited to two studies, warranting cautious interpretation of these findings.","url":"https://pubmed.ncbi.nlm.nih.gov/42873314/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: Ethical approval was not required because this study is a systematic review of previously published studies and did not involve human participants or identifiable patient data. Disclosures: All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo and SGLT2 inhibitors (two comparative studies)\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"recurrent acute pancreatitis","endpoints":null,"effect_estimate":"Versus placebo OR 0.26 (CI includes no effect); versus SGLT2 inhibitors OR 0.57; recurrence rates among GLP-1 RA users 9.9% and 11.9% in two non-comparative studies; no increase in recurrent pancreatitis","confidence_interval":"95% CI 0.05-1.32 (vs placebo); 95% CI 0.52-0.64 (vs SGLT2 inhibitors)","p_value":null,"sample_size":10624,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (type 2 diabetes or obesity)\", \"diabetes_status\": \"mixed (type 2 diabetes or obesity)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"prior acute pancreatitis\", \"sample_size\": 10624, \"inclusion_exclusion\": \"adults with prior acute pancreatitis treated with GLP-1 RAs for type 2 diabetes, obesity or related conditions; studies without recurrent pancreatitis outcomes, pediatric populations, overlapping cohorts, insufficient data or non-original publications excluded\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes or obesity and a history of acute pancreatitis.","mediation":"unlikely","mediation_notes":"A safety question with no raised risk found; the abstract reports no weight or glycaemic analysis.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": 10624, \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"placebo and SGLT2 inhibitors (two comparative studies)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CIs reported; comparative evidence from two studies (5,224 GLP-1 RA users; 5,197 controls); wide CI versus placebo\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a small systematic review in which only two studies gave comparative data and the included study designs are not stated.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests and report no relationships that could be construed as a conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"GLP-1 RA use was not associated with an increase in recurrent acute pancreatitis after prior pancreatitis; recurrence rates 9.9% and 11.9% among users in two studies","limitations":"Only four studies, with comparative evidence from two, and the included study designs are not stated in the abstract; the authors urge cautious interpretation.","plain_summary":"This systematic review gathered four studies of 10,624 adults with type 2 diabetes or obesity who had previously had acute pancreatitis; 5,427 (51.0%) used GLP-1 receptor agonists. GLP-1 drug use was not linked to more repeat pancreatitis: odds were lower than with SGLT2 inhibitors (OR 0.57), the comparison with placebo (OR 0.26, 95% CI 0.05-1.32) was too imprecise to be conclusive, and two other studies reported recurrence in 9.9% and 11.9% of users. Only two studies compared groups and their designs are not given in the abstract, so the authors urge caution.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1237,"doi":"10.64898/2026.10.13.26365377","pmid":null,"nct_ids":"[]","title":"Do drugs proposed to protect or harm joints change serious osteoarthritis events? A meta-analysis of adverse event tables from 881 randomized trials","authors":"[\"Xu, Z.\", \"Pan, M.\", \"Cheng, J.\", \"Chen, X.\", \"Luo, J.\", \"Guo, X.\", \"Zhu, X.\"]","journal":"medrxiv (preprint)","publication_date":"2026-10-14","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"ObjectivesObservational studies report large, conflicting associations between common drugs and hip or knee replacement. We tested them in the serious adverse event (SAE) tables of randomized trials on ClinicalTrials.gov.\n\nMethodsWe included randomized drug trials with [&ge;]500 participants. A language model classified arms from summaries without outcome counts (masked by instruction only). We pooled osteoarthritis-related SAEs by drug class as Mantel-Haenszel risk ratios (RRs). Because the plan followed a preliminary analysis of 72 trials, we report estimates rather than tests, checked by positive and negative controls and calibration.\n\nResultsThe 881 placebo- or usual-care-controlled trials included 1.75 million participants and 9,408 osteoarthritis-related SAEs. The tables reproduced CANTOSs own canakinumab effect (RR 0.57, 95% CI 0.39 to 0.82), the anti-nerve growth factor excess (2.31, 1.82 to 2.92) and two of three modest effects specified before extraction: gallbladder disease with glucagon-like peptide-1 receptor agonists (GLP-1RAs; 1.36, 1.22 to 1.51) and ketoacidosis with sodium- glucose cotransporter-2 (SGLT2) inhibitors (1.96, 1.48 to 2.60). In the same trials, osteoarthritis-related SAEs did not differ detectably with GLP-1RAs (0.97, 0.86 to 1.10; calibrated 0.87, 0.54 to 1.41) or SGLT2 inhibitors (0.96, 0.82 to 1.12; calibrated 0.86, 0.53 to 1.40). Other proposed drugs gave imprecise estimates. Post hoc, 8 of 21 published observational estimates differed from randomized ones, in both directions (3 to 6 after calibration).\n\nConclusionsOver about two years, GLP-1RAs and SGLT2 inhibitors had no detectable effect on osteoarthritis-related SAEs in trials that detected their known effects. Slow or modest structural effects remain possible.\n\nKey messagesWhat is already known on this topic O_LIObservational studies associate glucose-lowering drugs, bisphosphonates and warfarin with large and conflicting changes in the risk of hip or knee replacement; randomized evidence is limited to a few exploratory analyses of single trials.\nC_LI\n\nWhat this study adds O_LIGLP-1 receptor agonists and SGLT2 inhibitors had no detectable effect on serious osteoarthritis events over about two years, in randomized trials whose adverse-event tables detected these drugs known effects.\nC_LI\n\nHow this study might affect research, practice or policy O_LITrial registries can test osteoarthritis repurposing signals for large, short-term effects before dedicated trials are funded; slow structural effects still need such trials.\nC_LI","url":"https://www.medrxiv.org/content/10.64898/2026.10.13.26365377","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo or usual care\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"osteoarthritis\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"osteoarthritis-related serious adverse events","endpoints":null,"effect_estimate":"Osteoarthritis-related SAEs with GLP-1RAs RR 0.97 (0.86 to 1.10; calibrated 0.87, 0.54 to 1.41), no detectable difference; positive control: gallbladder disease with GLP-1RAs RR 1.36 (1.22 to 1.51)","confidence_interval":"0.86 to 1.10 (calibrated 0.54 to 1.41)","p_value":null,"sample_size":null,"follow_up":"about two years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": \"randomized drug trials with at least 500 participants on ClinicalTrials.gov, placebo- or usual-care-controlled\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract reports no age, BMI or diabetes data for the populations of the 881 pooled trials.","mediation":"unlikely","mediation_notes":"Unlikely: the main GLP-1RA result for osteoarthritis-related serious events is null.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo or usual care\", \"follow_up_duration\": \"about two years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 0.86 to 1.10 (calibrated 0.54 to 1.41)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a medRxiv preprint (not peer reviewed) pooling serious adverse event tables from randomized trials.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Gallbladder disease was raised with GLP-1RAs (RR 1.36, 1.22 to 1.51), a known effect used as a positive control; osteoarthritis-related SAEs did not differ detectably.","limitations":"Arms were classified by a language model and masking was by instruction only; adverse-event tables capture only serious events over about two years, so slow or modest structural effects remain possible. Not peer reviewed.","plain_summary":"This preprint pooled serious adverse event tables from 881 placebo- or usual-care-controlled randomized drug trials on ClinicalTrials.gov to test whether common drugs change serious osteoarthritis events. Over about two years, GLP-1 drugs showed no detectable effect on these events (risk ratio 0.97, 0.86 to 1.10), while the same tables picked up their known raised risk of gallbladder disease (1.36, 1.22 to 1.51). Slow or modest effects on joints remain possible, and the work has not been peer reviewed.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1420,"doi":"10.5152/archrheumatol.2026.26556","pmid":"42969449","nct_ids":"[]","title":"Relationship Between Osteoarthritis and Metabolic Diseases: A Bibliometric and Visual Analysis","authors":"[\"Weng Y\", \"Wu J\", \"Xie S\", \"Zhang Y\"]","journal":"Archives of rheumatology","publication_date":"2026-10-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/AIMS] To map global research on osteoarthritis (OA) and metabolic diseases, separately examining individual metabolic diseases and metabolic syndrome (MetS), and identify gaps and emerging frontiers. [MATERIALS AND METHODS] Web of Science Core Collection publications (2009-2025) were retrieved on February 22, 2026. Co-authorship and keyword co-occurrence networks, Louvain clustering (modularity and silhouette evaluation), burst detection, and keyword-cluster visualization were performed. Betweenness centrality assessed country collaboration. Chord diagrams and temporal streamgraphs mapped pairwise disease co-study patterns and trajectories. GLP-1 receptor agonist (GLP-1RA) trends were assessed using 24 predefined terms. [RESULTS] We included 10,217 articles from 1582 journals by 38,665 authors. Annual output rose 4.4-fold between 2009 and 2025. The United States (33.4%), China (15.0%), and the United Kingdom (9.3%) were the leading contributors. Ten major themes were identified: progression, arthroplasty, physical activity, inflammation, prevalence, Mendelian randomization, meta-analysis, knee OA, body mass index, and hip. Obesity and type 2 diabetes were the most frequently co-studied conditions. Obesity showed the strongest sustained growth, whereas nonalcoholic fatty liver disease (NAFLD) received limited attention. Inflammation and risk were the strongest burst terms. OA-related GLP-1RA publications increased 9.7-fold after 2021. [CONCLUSION] OA-metabolic disease research is expanding rapidly. NAFLD, hyperuricemia, and MetS remain underexplored, while GLP-1RA is a major emerging frontier.","url":"https://pubmed.ncbi.nlm.nih.gov/42969449/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:06+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"osteoarthritis\", \"liver\", \"addiction\", \"metabolic\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1023,"doi":"10.1210/clinem/dgag284","pmid":"42867450","nct_ids":"[]","title":"Effects of tirzepatide (GIP/GLP-1 dual receptor agonist) on cardiorenal biomarkers and functional capacity in heart failure: a systematic review and meta-analysis","authors":"[\"Eisa N\", \"Khoury M\"]","journal":"The Journal of clinical endocrinology and metabolism","publication_date":"2026-10-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated clinical benefits in heart failure with preserved ejection fraction (HFpEF) and obesity. However, its effects on cardiorenal biomarkers and functional capacity have not been comprehensively synthesized. We hypothesized that tirzepatide produces significant reductions in cardiorenal biomarkers and improvements in functional capacity compared to placebo or standard of care. [METHODS] This systematic review and meta-analysis (PROSPERO: CRD42026137255) searched PubMed, Embase, CENTRAL, Web of Science, and Scopus from inception to April 17, 2026, without restrictions. Randomized controlled trials and prospective observational studies reporting NT-proBNP, high-sensitivity C-reactive protein (hsCRP), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), 6-minute walk test (6 MWT), or renal outcomes with tirzepatide vs placebo or standard of care were included. Data were pooled using random-effects models with Hartung-Knapp-Sidik-Jonkman adjustment. [RESULTS] Seven studies (5 RCTs, 2 observational; 5406 participants) were included. Tirzepatide significantly reduced hsCRP by 34.3% (95% CI: -38.4% to -30.1%; P < .0001; I2 = 0.0%; 6 studies) and NT-proBNP by 17.6% (95% CI: -26.7% to -8.5%; P = .0001; I2 = 58.1%; 3 studies). In the SUMMIT trial, KCCQ-CSS improved by 5.1 points (P < .001) and 6 MWT by 15.8 m (P = .004). Single-trial data demonstrated estimated glomerular filtration rate (eGFR) preservation (+2.90 mL/min/1.73 m2/year; 95% CI: 0.94 to 4.86) and urine albumin-to-creatinine ratio reduction (-25.0%; 95% CI: -36.0% to -13.0%). [CONCLUSION] Tirzepatide produces consistent anti-inflammatory effects and significant natriuretic peptide reductions, supported by moderate Grading of Recommendations Assessment, Development and Evaluation certainty. Evidence for functional and renal outcomes remains limited to single-trial analyses and should be considered hypothesis-generating pending larger dedicated heart failure trials. [PROSPERO REGISTRATION] CRD42026137255.","url":"https://pubmed.ncbi.nlm.nih.gov/42867450/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo or standard of care\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\"]","outcome_type":"mixed","primary_outcome":"cardiorenal biomarkers (NT-proBNP, hsCRP), functional capacity (KCCQ-CSS, 6-minute walk) and renal outcomes in heart failure","endpoints":null,"effect_estimate":"Pooled: hsCRP -34.3% (95% CI -38.4% to -30.1%; 6 studies); NT-proBNP -17.6% (95% CI -26.7% to -8.5%; 3 studies). Single trial (SUMMIT): KCCQ-CSS +5.1 points, 6 MWT +15.8 m; eGFR +2.90 mL/min/1.73 m2/year; UACR -25.0%.","confidence_interval":"95% CI: -38.4% to -30.1% (hsCRP); NT-proBNP 95% CI: -26.7% to -8.5%","p_value":"P < .0001 (hsCRP); P = .0001 (NT-proBNP)","sample_size":5406,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"heart failure required (review scope)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure\", \"sample_size\": 5406, \"inclusion_exclusion\": \"RCTs and prospective observational studies of tirzepatide vs placebo or standard of care reporting the listed biomarker, functional or renal outcomes\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: a review scoped to people with heart failure, a condition the target population does not have, and framed around heart failure with obesity; no age, BMI or diabetes data are given for the pooled participants.","mediation":"possibly","mediation_notes":"No weight change, HbA1c or mediation analysis is reported; the biomarker, symptom and walking-distance changes are not separated from tirzepatide's weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 5406, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo or standard of care\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -38.4% to -30.1% (hsCRP); NT-proBNP 95% CI: -26.7% to -8.5%\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis pooling 5 RCTs and 2 observational studies on mainly biomarker outcomes, with heterogeneity for NT-proBNP (I2 = 58.1%) and functional and renal results from single trials.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Biomarker-led meta-analysis mixing RCTs and observational studies, with moderate heterogeneity for NT-proBNP; functional and renal results come from single trials and are hypothesis-generating.","plain_summary":"This meta-analysis pooled seven studies (5 randomised trials and 2 observational studies; 5406 participants) of tirzepatide in heart failure. Compared with placebo or standard care, tirzepatide lowered the inflammation marker hsCRP by 34.3% and the heart-strain marker NT-proBNP by 17.6%. Gains in symptom scores, walking distance and kidney measures came from single trials only, and weight loss was not separated from these effects.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1068,"doi":"10.1016/j.mce.2026.112931","pmid":"42869327","nct_ids":"[]","title":"Endothelial AGGF1 contributes to glomerular barrier dysfunction via TNFSF12/FN14-Src-VE-cadherin signaling in diabetic kidney disease","authors":"[\"Zhang M\", \"Cheng Y\", \"Wu S\", \"Li G\", \"Tian L\", \"Sun S\", \"Miao Y\", \"Deng X\", \"Meng Z\", \"Sun B\", \"Chen L\"]","journal":"Molecular and cellular endocrinology","publication_date":"2026-10-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Disruption of the glomerular filtration barrier (GFB) is a key feature of diabetic kidney disease (DKD), but the underlying mechanisms remain incompletely understood. We investigated the role of angiogenic factor 1 (AGGF1) in glomerular endothelial barrier dysfunction in DKD. AGGF1 expression was examined in kidney samples from patients with DKD and in db/db mice. We also used endothelial cell-specific Aggf1 knockout mice and in vitro endothelial cell experiments to assess the effects of AGGF1 on vascular leakage and endothelial junctions. AGGF1 expression was increased in kidneys from patients with DKD and db/db mice. Endothelial Aggf1 deletion reduced vascular leakage in diabetic mice. Mechanistically, AGGF1 promoted Src-dependent VE-cadherin phosphorylation and dissociation of the VE-cadherin/β-catenin complex. Semaglutide treatment was associated with reduced renal AGGF1 expression and improved endothelial barrier-related outcomes in db/db mice. In vitro, AGGF1 overexpression attenuated the beneficial effect of semaglutide on endothelial junctional proteins under high-glucose conditions. Together, these findings identify endothelial AGGF1 as a contributor to GFB dysfunction in DKD and suggest that it may be a potential therapeutic target.","url":"https://pubmed.ncbi.nlm.nih.gov/42869327/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"kidney\"]","outcome_type":"biomarker","primary_outcome":"role of AGGF1 in glomerular endothelial barrier dysfunction in diabetic kidney disease","endpoints":null,"effect_estimate":"Semaglutide was associated with reduced renal AGGF1 expression and improved endothelial barrier-related outcomes in db/db mice; AGGF1 overexpression blunted semaglutide's effect on junctional proteins in high-glucose cells. No numbers reported.","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"diabetes required (db/db mice; kidney samples from patients with diabetic kidney disease; type not stated)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"diabetic kidney disease required (db/db mice; patient kidney samples)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diabetic kidney disease (patient kidney samples; db/db mice)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: semaglutide was studied only in diabetic db/db mice and cultured cells.","mediation":"possibly","mediation_notes":"No body-weight, glucose or mediation data are reported for the semaglutide-treated mice, so weight and metabolic change are not separated from the kidney findings.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical mouse and cell study in which the semaglutide result is a secondary finding.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no known competing financial interests or personal relationships.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Mechanistic mouse and cell study; the semaglutide finding is secondary, unquantified in the abstract, and has no stated dose or group size.","plain_summary":"This lab study looked at a protein called AGGF1 in kidney damage from diabetes, using patient kidney samples, diabetic mice and cells. In diabetic mice, semaglutide was associated with lower AGGF1 levels and better function of the kidney's filtering barrier, and raising AGGF1 in cells weakened semaglutide's effect. No numbers are given for the semaglutide results, and this is animal and cell evidence, not evidence in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1069,"doi":"10.1111/dom.71441","pmid":"42865317","nct_ids":"[\"NCT07309094\"]","title":"The Effects of GLP-1RA-Based and SGLT2 Inhibitor Therapy on Perirenal Adipose Tissue in CKD Patients","authors":"[\"Checa-Ros A\", \"Arias-Mutis O\", \"Okojie OJ\", \"Salvador P\", \"D'Marco L\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Perirenal adipose tissue (PRAT) surrounds the kidney and may contribute to chronic kidney disease (CKD) progression. SGLT2 inhibitors have been associated with reductions in this depot, but PRAT has not been quantified under GLP-1RA-based therapy in CKD. We assessed ultrasound-measured PRAT thickness under both treatments and whether changes tracked weight loss. [MATERIALS AND METHODS] Adults with CKD Stages 1-4 in the prospective ADIPO-CKD inception cohort underwent ultrasound at baseline and at the 8-month visit. PRAT thickness was the mean of right and left measurements; epicardial adipose tissue and body composition were also assessed. Patients received neither drug class (reference), SGLT2i or GLP-1RA-based therapy. Follow-up PRAT was analysed by covariance analysis adjusted for baseline. [RESULTS] Of 277 patients, 80 had paired studies (32 reference, 24 SGLT2i, 24 GLP-1RA-based; body weight 46-122 kg). PRAT was unchanged in the reference group (+0.035 cm, p = 0.376) and decreased with SGLT2i (-0.273 cm, -20.4%, p = 0.0006) and GLP-1RA-based therapy (-0.463 cm, -36.2%, p < 0.0001). Adjusted differences versus reference were -0.227 cm (95% CI -0.417 to -0.036) and -0.433 cm (-0.622 to -0.244); under multiple imputations, -0.218 cm (-0.482 to +0.046) and -0.421 cm (-0.693 to -0.149). GLP-1RA-based therapy reduced body weight, fat mass and visceral fat area; SGLT2i only body weight, modestly. PRAT change correlated with none. [CONCLUSIONS] In CKD, both drug classes were associated with lower follow-up PRAT, not explained by measured body-composition change. Under multiple imputations, both estimates were essentially unchanged, though the SGLT2i interval included no difference. PRAT may represent a candidate depot-specific target. [TRIAL REGISTRATION] ClinicalTrials.gov identifier: NCT07309094 (ADIPO-CKD).","url":"https://pubmed.ncbi.nlm.nih.gov/42865317/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"prospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"reference group receiving neither drug class; SGLT2 inhibitors\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"kidney\", \"body_composition\"]","outcome_type":"biomarker","primary_outcome":"Change in ultrasound-measured perirenal adipose tissue (PRAT) thickness","endpoints":null,"effect_estimate":"GLP-1RA-based therapy versus reference: adjusted difference -0.433 cm (-0.622 to -0.244); under multiple imputations -0.421 cm (-0.693 to -0.149). Within-group PRAT change -0.463 cm (-36.2%, p < 0.0001) with GLP-1RA-based therapy and +0.035 cm (p = 0.376) in the reference group. SGLT2i versus reference -0.227 cm (95% CI -0.417 to -0.036); -0.218 cm (-0.482 to +0.046) under multiple imputations.","confidence_interval":"-0.622 to -0.244 cm (adjusted difference versus reference, GLP-1RA-based therapy; level not stated for this interval)","p_value":"p < 0.0001 (within-group change, GLP-1RA-based therapy); no p value given for the between-group difference","sample_size":80,"follow_up":"8 months","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD required (Stages 1-4)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Chronic kidney disease, Stages 1-4\", \"sample_size\": 80, \"inclusion_exclusion\": \"adults with CKD stages 1-4 in the ADIPO-CKD cohort with paired ultrasound studies; body weight 46-122 kg\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: adults with CKD Stages 1-4; the abstract reports no BMI or diabetes status (only a body-weight range of 46-122 kg) and no age.","mediation":"possibly","mediation_notes":"GLP-1RA-based therapy lowered body weight, fat mass and visceral fat area. The authors report that PRAT change correlated with none of these and conclude the fall was not explained by measured body-composition change, but a correlation of changes is not a formal mediation analysis or a weight-matched comparison, so weight and metabolic change are not excluded as contributors.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Prospective cohort\", \"sample_size\": 80, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"reference group receiving neither drug class; SGLT2 inhibitors\", \"follow_up_duration\": \"8 months\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: -0.622 to -0.244 cm (adjusted difference versus reference, GLP-1RA-based therapy; level not stated for this interval)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single small prospective observational cohort (24 patients on GLP-1RA-based therapy) with an imaging-biomarker outcome.","funding_source":"CEU San Pablo Foundation","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Small, non-randomised observational cohort (80 of 277 patients had paired scans, 24 on GLP-1RA-based therapy) with an imaging-biomarker outcome; under multiple imputation the SGLT2i interval included no difference.","plain_summary":"In a prospective cohort of adults with chronic kidney disease, 80 had kidney ultrasound at baseline and at an 8-month visit. GLP-1 receptor agonist-based therapy was associated with a thinner layer of fat around the kidneys than in patients on neither drug class (adjusted difference -0.433 cm), and SGLT2 inhibitors with a smaller difference whose interval included no difference under multiple imputation. The change did not correlate with weight or fat loss. This is a small observational study of a fat-depot measure, so it shows an association, not a clinical benefit.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1114,"doi":"10.1007/s00405-026-10708-9","pmid":"42867646","nct_ids":"[]","title":"Audiovestibular adverse event reporting profiles of GLP-1 receptor agonists: A case-case pharmacovigilance study using FDA AEMS data","authors":"[\"Wang X\", \"Du D\", \"Liu R\", \"Zheng H\"]","journal":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","publication_date":"2026-10-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] To characterize and compare audiovestibular adverse-event reporting patterns among glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the US Food and Drug Administration Adverse Event Monitoring System (AEMS). [METHODS] We performed a retrospective case-level analysis of AEMS reports through 2026 Q1. Reports naming exenatide, liraglutide, dulaglutide, lixisenatide, or semaglutide as the primary suspect and containing at least one prespecified audiovestibular MedDRA preferred term were deduplicated by case. Among adequately represented agents, phenotype composition was compared using chi-square testing, and case-case comparative reporting odds ratios (cRORs) were calculated for six common preferred terms with Benjamini-Hochberg correction. Time to onset (TTO) was summarized descriptively. [RESULTS] We identified 1,950 unique reports: exenatide 576, liraglutide 192, dulaglutide 622, lixisenatide 1, and semaglutide 559. Hypoacusis (46.9%), vertigo (27.7%), tinnitus (12.7%), and deafness (7.9%) were most frequent. Phenotype composition differed across the four adequately represented agents (chi-square = 78.12, P < 0.001; Cramer V = 0.142). Dulaglutide reports were enriched for hypoacusis (cROR 3.06, 95% CI 2.51-3.74), whereas liraglutide and semaglutide reports were enriched for vertigo and tinnitus. Median TTO was 3 days (IQR 0-35), but valid dates were available for only 19.3% of reports. [CONCLUSION] Individual GLP-1 RAs showed distinct audiovestibular reporting compositions. These findings are hypothesis-generating and do not establish incidence, comparative safety, or causality.","url":"https://pubmed.ncbi.nlm.nih.gov/42867646/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval: Not applicable. This study used deidentified, publicly available spontaneous-report data and involved no direct interaction with human participants. Consent for publication: Not applicable. Consent to participate: Not applicable. Competing interests: The authors have no relevant financial or non-financial interests to disclose.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"pharmacovigilance","drugs":"[\"exenatide\", \"liraglutide\", \"dulaglutide\", \"lixisenatide\", \"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"other GLP-1 receptor agonists (case-case comparison)\", \"treatment_duration\": null}","domains":"[\"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"Audiovestibular adverse-event reporting patterns across GLP-1 RAs","endpoints":null,"effect_estimate":"Phenotype composition differed across agents (chi-square = 78.12, P < 0.001); dulaglutide reports enriched for hypoacusis (cROR 3.06, 95% CI 2.51-3.74); liraglutide and semaglutide reports enriched for vertigo and tinnitus.","confidence_interval":"95% CI 2.51-3.74","p_value":"P < 0.001","sample_size":1950,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"spontaneous FDA adverse-event reports naming a GLP-1 receptor agonist as primary suspect with an audiovestibular term\", \"sample_size\": 1950, \"inclusion_exclusion\": \"reports with a GLP-1 RA as primary suspect and at least one prespecified audiovestibular term, deduplicated by case\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: spontaneous adverse-event reports with no age, BMI or diabetes data in the abstract.","mediation":"possibly","mediation_notes":"No weight, HbA1c or mediation data are reported, so a drug effect cannot be separated from weight or metabolic change.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": 1950, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"other GLP-1 receptor agonists (case-case comparison)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI 2.51-3.74\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a pharmacovigilance analysis of spontaneous reports, which the authors call hypothesis-generating.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors report no relevant financial or non-financial interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Most frequent reported terms: hypoacusis (46.9%), vertigo (27.7%), tinnitus (12.7%), deafness (7.9%); median time to onset 3 days (IQR 0-35), with valid dates for only 19.3% of reports.","limitations":"Spontaneous reports with no denominator, so no incidence, comparative safety or causality; onset dates were valid for only a minority of reports.","plain_summary":"This study looked at 1,950 FDA adverse-event reports of hearing or balance problems naming a GLP-1 receptor agonist. The most common reported problems were reduced hearing (46.9%), vertigo (27.7%), tinnitus (12.7%) and deafness (7.9%), and the mix differed by drug, with dulaglutide reports more often about reduced hearing. Report databases cannot show how often these problems occur or whether the drugs cause them, as the authors note.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1126,"doi":"10.64898/2026.10.09.26365158","pmid":null,"nct_ids":"[]","title":"Real-World Twelve-Month Weight Loss Outcomes in a Comprehensive Obesity Care Program Utilizing Individualized Nutrition Therapy and Incretin-Based Obesity Medications","authors":"[\"Athinarayanan, S.\", \"Zoller, A. R.\", \"Bergethon, K. E.\", \"Goss, A. M.\", \"Gower, B. A.\"]","journal":"medrxiv (preprint)","publication_date":"2026-10-13","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"BackgroundIncretin-based obesity medications (IOMs) produce substantial weight loss, but the incremental benefit of structured nutritional therapy when integrated with pharmacotherapy remains unclear.\n\nObjectivesTo compare 12-month weight-loss outcomes between individualized carbohydrate-reduced nutritional therapy combined with IOMs (VINT+IOM) and IOM-based care without structured nutritional therapy (IOM only).\n\nMethodsThis retrospective cohort study evaluated 4,269 adults enrolled in a comprehensive telemedicine obesity care program (VINT+IOM, n=1,658; IOM only, n=2,611). Both pathways included clinician-guided medication management and behavioral coaching. The primary analysis focused on GLP-1-naive participants receiving a single medication ingredient (semaglutide or tirzepatide). Adjusted weight changes were estimated using longitudinal linear mixed-effects models. Additional analyses evaluated weight-loss responders, prior GLP-1 exposure, and medication utilization.\n\nResultsAmong GLP-1-naive semaglutide users, adjusted 12-month weight loss was greater with VINT+IOM than IOM only (30.7 vs. 24.1 lb; P=0.01), with corresponding observed weight loss of 13.3% versus 11.1%. Among tirzepatide users, adjusted weight loss was 45.9 versus 34.4 lb (P=0.003), with observed reductions of 19.7% versus 15.6%, respectively. Weight-loss responder rates consistently favored VINT+IOM. In the overall cohort (GLP-1 naive, prior users and all other treatment trajectories), adjusted weight loss was 29.4 versus 21.5 lb (P<0.001), with observed reductions of 12.7% versus 9.6%. Greater weight loss with VINT+IOM was also observed among participants with prior GLP-1 exposure. Weight loss continued between 6 and 12 months in both pathways. Medication coverage was high, with approximately 80% of participants achieving proportion of days covered [&ge;]80% in both pathways.\n\nConclusionsIntegrating individualized carbohydrate-reduced nutritional therapy with IOM-based care was associated with greater 12-month weight loss than IOM-based care without structured nutritional therapy. These real-world findings support further evaluation of individualized nutritional approaches as an adjunct to incretin-based obesity pharmacotherapy.","url":"https://www.medrxiv.org/content/10.64898/2026.10.09.26365158","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"IOM-based care without structured nutritional therapy (IOM only); both arms received incretin-based medication\", \"treatment_duration\": null}","domains":"[\"nutrition\"]","outcome_type":"intermediate","primary_outcome":"12-month weight loss, VINT+IOM versus IOM only","endpoints":null,"effect_estimate":"Adjusted 12-month weight loss with VINT+IOM versus IOM only: GLP-1-naive semaglutide users 30.7 vs. 24.1 lb (P=0.01); tirzepatide users 45.9 versus 34.4 lb (P=0.003); overall cohort 29.4 versus 21.5 lb (P<0.001). Both arms received incretin medication, so the contrast is nutrition therapy, not the drug.","confidence_interval":null,"p_value":"P=0.01 (semaglutide); P=0.003 (tirzepatide); P<0.001 (overall)","sample_size":4269,"follow_up":"12 months","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Adults enrolled in a telemedicine obesity care program\", \"sample_size\": 4269, \"inclusion_exclusion\": \"primary analysis: GLP-1-naive adults on a single medication ingredient (semaglutide or tirzepatide)\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: adults enrolled in a telemedicine obesity care program; the abstract reports no BMI, age or diabetes status.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is weight loss itself.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 4269, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"IOM-based care without structured nutritional therapy (IOM only); both arms received incretin-based medication\", \"follow_up_duration\": \"12 months\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"P values reported; no CI reported; 4,269 adults\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a medRxiv preprint, not peer reviewed; as a single retrospective cohort it would otherwise be capped at LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Preprint, not peer reviewed; retrospective comparison of non-randomised care pathways within one program, open to confounding; no BMI, age or diabetes data in the abstract.","plain_summary":"This retrospective study, a preprint that has not been peer reviewed, looked back at 4,269 adults in a telemedicine obesity program taking semaglutide or tirzepatide, with or without individualised carbohydrate-reduced nutrition therapy. Adding nutrition therapy was associated with more weight loss at 12 months (for semaglutide users 30.7 vs 24.1 lb; for tirzepatide users 45.9 vs 34.4 lb). Everyone took the drugs, so the study does not compare the drugs with no drug, and as an observational study it shows an association, not cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1347,"doi":"10.3390/jcm15207876","pmid":"42941393","nct_ids":"[]","title":"Body Weight Changes and Exploratory Metabolic Outcomes During Semaglutide and Tirzepatide Treatment: A Real-World Longitudinal Cohort Study from Türkiye","authors":"[\"Çokiçli E\", \"Kayır M\", \"Abbasoğlu AR\", \"Ozkan Sonay H\", \"Utku İK\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Comparative real-world evidence on early body-weight changes during semaglutide and tirzepatide treatment remains limited, particularly in populations with unequal and irregularly timed follow-up. To compare longitudinal percentage changes in body weight between adults initiating semaglutide and those initiating tirzepatide and to describe changes in anthropometric measures, weight-loss responses, and exploratory metabolic outcomes. Methods: This retrospective, single-center, real-world longitudinal cohort study included adults aged ≥18 years initiating semaglutide or tirzepatide for weight management, with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with a weight-related comorbidity. Patients with type 2 diabetes and concomitant obesity were eligible. Participants were naïve to incretin-based therapy; pregnancy, previous bariatric surgery, and active malignancy were exclusion criteria. Anthropometric and laboratory data were extracted from clinical records. Percentage body-weight change over days 1-230 was analyzed using a linear mixed-effects model incorporating exact follow-up time and adjusting for age, sex, baseline BMI, and diabetes status. Scheduled-visit and sensitivity analyses were also performed. Results: The cohort included 184 patients: 94 (51.1%) receiving semaglutide and 90 (48.9%) receiving tirzepatide. Overall, mean age was 41.7 ± 12.0 years, baseline weight was 97.0 ± 17.9 kg, and 139 patients (75.5%) were female. The longitudinal analysis included 345 measurements from 148 patients (80.4%). The treatment-by-time interaction was significant (p = 0.002). Adjusted weight changes with semaglutide versus tirzepatide were -3.39% versus -4.44% at month 1 (p = 0.116), -8.38% versus -11.52% at month 3 (p < 0.001), and -14.40% versus -15.06% at month 6 (p = 0.699). Sensitivity analyses yielded consistent findings. Only four tirzepatide-treated patients had measurements within the month 6 visit window; therefore, the month 6 estimate for this group relied primarily on the model and requires cautious interpretation. Conclusions: Both semaglutide and tirzepatide were associated with early reductions in body weight. Tirzepatide was associated with larger model-adjusted weight loss at month 3 (between-group difference, -3.14 percentage points; 95% CI, -4.55 to -1.74; p < 0.001), whereas no statistically significant between-group difference was observed at month 1 (p = 0.116). Only four tirzepatide-treated patients had measurements within the month 6 visit window, limiting the reliability of this comparison. Longer-term comparisons require cohorts with more balanced follow-up and more observations at later time points.","url":"https://pubmed.ncbi.nlm.nih.gov/42941393/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:42+00:00","study_design":"prospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cancer\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1071,"doi":"10.1016/j.clnesp.2026.105169","pmid":"42863671","nct_ids":"[]","title":"Characterizing the adverse event profile of semaglutide: A comprehensive U.S. food and drug administration adverse event reporting system-based pharmacovigilance study","authors":"[\"Thawkar SA\", \"Singare SR\", \"Sakle NS\"]","journal":"Clinical nutrition ESPEN","publication_date":"2026-10-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide, a glucagon-like peptide-1 receptor agonist, is increasingly used for the management of type 2 diabetes mellitus and obesity. Given its expanding clinical use, a comprehensive evaluation of its safety profile using real-world data is warranted. This study aimed to characterize adverse event signals associated with semaglutide using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). [METHODS] Adverse event reports associated with semaglutide were extracted from the FAERS database from 2004 Q1 to 2025 Q3. After data extraction and screening, cases in which semaglutide was recorded as the primary suspected drug were included. Adverse events were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) at the preferred term (PT) and system organ class (SOC) levels. Signal detection was performed using disproportionality methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), relative reporting ratio (RRR), and empirical Bayes geometric mean (EBGM). [RESULTS] A total of 43,754 reports were identified. Gastrointestinal disorders were the most frequently reported system organ class, with nausea (n = 5637; 12.88%), vomiting (n = 4097; 9.36%), diarrhoea (n = 3276; 7.49%) and constipation (n = 2257; 5.16%) being the most frequently reported adverse events. Impaired gastric emptying (n = 2200; 5.03%) showed a markedly elevated reporting signal. Significant signals were also observed for metabolic and nutritional events, including decreased appetite (n = 2221; 5.08%), dehydration (n = 1231; 2.81%) and diabetic ketoacidosis. Notably, high disproportionality signals were detected for weight loss poor and optic ischaemic neuropathy. Additional signals involved psychiatric, renal and hepatobiliary systems. The consistency of findings across multiple statistical methods, including empirical Bayes geometric mean, supports the robustness of the detected signals. [CONCLUSION] Semaglutide is primarily associated with gastrointestinal and metabolic adverse events consistent with its pharmacological effects; however, several less common but potentially important safety signals were identified. These findings highlight the need for continued pharmacovigilance and careful clinical monitoring in real-world use.","url":"https://pubmed.ncbi.nlm.nih.gov/42863671/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests All authors have declared no conflicts of interest.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"kidney\", \"adverse_effects\", \"nutrition\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"mixed","primary_outcome":"Adverse event reporting signals for semaglutide in FAERS (disproportionality)","endpoints":null,"effect_estimate":"Gastrointestinal events most often reported (nausea n = 5637; 12.88%, vomiting n = 4097; 9.36%); signals for impaired gastric emptying, decreased appetite, dehydration, diabetic ketoacidosis, weight loss poor and optic ischaemic neuropathy; no ROR or PRR values given in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":43754,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 43754, \"inclusion_exclusion\": \"FAERS reports 2004 Q1 to 2025 Q3 with semaglutide as the primary suspected drug\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: spontaneous FAERS reports; the abstract gives no age, BMI or diabetes data for the reported cases.","mediation":"possibly","mediation_notes":"Possibly: no weight or glycaemic data are reported, so the evidence model's default applies. Some signals (decreased appetite, dehydration, weight loss poor) may relate to reduced intake, but this was not examined.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": 43754, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"disproportionality statistics (ROR, PRR, RRR, EBGM); no CI reported in abstract; 43,754 reports\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a pharmacovigilance disproportionality analysis of spontaneous reports, with no incidence denominator and no comparator group.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"All authors declared no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Reporting signals mainly gastrointestinal (nausea, vomiting, diarrhoea, constipation, impaired gastric emptying) and metabolic (decreased appetite, dehydration, diabetic ketoacidosis), with high signals for weight loss poor and optic ischaemic neuropathy and further signals in psychiatric, renal and hepatobiliary systems.","limitations":"Spontaneous-report disproportionality analysis: signals show reporting imbalance, not incidence or causation; no denominator of treated people, no population data and no comparator group are reported. The authors do not list limitations in the abstract.","plain_summary":"This study searched the US FDA's spontaneous adverse event reporting database for reports naming semaglutide as the main suspected drug, finding 43,754 reports. Stomach and bowel problems such as nausea, vomiting, diarrhoea and constipation were reported most, and the analysis flagged reporting signals for slowed stomach emptying, dehydration, diabetic ketoacidosis and a type of optic nerve damage. Reporting signals show that an event is reported more often than expected with the drug; they do not show how often it happens or that the drug causes it.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1090,"doi":"10.1002/jpr3.70246","pmid":"42865987","nct_ids":"[]","title":"Tirzepatide use in adolescents with metabolic dysfunction-associated steatotic liver disease (MASLD): A case series","authors":"[\"Perumpail BJ\", \"Tou A\", \"Panganiban J\"]","journal":"JPGN reports","publication_date":"2026-10-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Pediatric obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence has risen markedly over the past decade. Due to transition delays and workforce shortages, pediatric specialists often manage patients into young adulthood, and thus familiarity with adult pharmacotherapies for MASLD is essential. Currently, Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is approved for adults with metabolic dysfunction-associated steatohepatitis (MASH) and F2-F3 fibrosis; however, dual and triple agonists are being evaluated. Tirzepatide, a dual agonist that targets gastric inhibitory peptide (GIP) and the GLP-1 receptor, has demonstrated superior weight reduction to Semaglutide (-20.2% vs. -13.7%) with a more favorable gastrointestinal adverse effect profile. Adult literature has demonstrated its effectiveness in MASH resolution, and pediatric data suggest it is safe in younger populations. Currently, there are no pediatric/adolescent studies exploring the use of Tirzepatide in MASLD. We present our experience using Tirzepatide in two adolescent patients with obesity and MASLD.","url":"https://pubmed.ncbi.nlm.nih.gov/42865987/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"case_series","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"not reported in abstract\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"liver\", \"gastrointestinal\"]","outcome_type":"none","primary_outcome":"not reported in abstract","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":null,"p_value":null,"sample_size":2,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity in both patients (entry criterion not stated)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD)\", \"sample_size\": 2, \"inclusion_exclusion\": \"adolescents with obesity and MASLD\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: two adolescents, both with obesity and MASLD.","mediation":"possibly","mediation_notes":"No weight, liver-fat or glycaemic results are reported for the two patients, so weight and metabolic change cannot be separated from any effect.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Case series\", \"sample_size\": 2, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; two patients\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a case series of two patients with no comparator.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Two patients, no comparator, and no results in the abstract.","plain_summary":"This report describes two adolescents with obesity and fatty liver disease (MASLD) treated with tirzepatide. The abstract gives no results for these patients; the weight-loss figures it mentions come from earlier adult studies. With two patients and no comparison group, it cannot show whether the drug helped.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1267,"doi":"10.3390/genes17101266","pmid":"42938381","nct_ids":"[]","title":"Signature Definition Shapes Associations Between Exenatide-Related Transcriptional Programs and Macrophage Senescence Scores in Colorectal Cancer","authors":"[\"Song Y\", \"Tayier A\", \"Peng Y\", \"Li T\", \"Xu L\", \"Zhong M\", \"Yu C\", \"Ma H\"]","journal":"Genes","publication_date":"2026-10-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Treatment-derived expression signatures are often applied to untreated tumor cohorts, although their biological meaning may depend on signature construction and cellular composition. We examined the relationship between an exenatide-derived signature and senescence-associated macrophage expression in colorectal cancer. Methods: Archived pan-cancer and patient-level results were examined alongside a reconstruction from public mouse bulk RNA sequencing and colorectal single-cell matrices. Exenatide signatures were re-derived with tissue and batch adjustment, within-mouse correlation, and one-to-one orthologue mapping. Shared-gene removal, stricter macrophage annotation, expression-matched random signatures, virtual perturbation summaries, and three murine treatment comparisons assessed interpretation and robustness. Results: The original signature was associated with SenMayo in stomach, colon, and rectal tumor analyses. Reconstruction retained 209,207 colorectal cells and 4316 tumor macrophages, with 17 patients eligible for tumor-level analysis. Removing CXCR2 and IL1B from both signatures preserved a positive association (Spearman ρ = 0.804; adjusted β = 1.526; p = 0.00219). The corresponding mean expression association exceeded most expression-matched random signatures (empirical p = 0.006). Associations persisted with a blocked log-expression derivation but were absent with a blocked voom-derived signature using one-to-one orthologues (ρ = 0.056; p = 0.620). Archived virtual IL1B deletion and overexpression predicted opposing shifts after multiplicity adjustment. Treatment-macrophage fold-change correlations remained small (ρ = -0.038 to 0.046), with heterogeneous enrichment. The association was attenuated after adjustment for either inflammatory score-it remained statistically detectable after TNFα/NF-κB adjustment (β = 0.672, 95% CI 0.307-1.037) and was less precisely estimated after broader inflammatory response adjustment (β = 0.383, 95% CI -0.031-0.797). Conclusions: The original exenatide-derived signature was associated with SenMayo scores in colorectal tumor macrophages after removal of shared genes. This association overlapped with inflammatory expression and varied with signature derivation. Dependence on signature derivation limits its interpretation as a pharmacological response marker. These findings support investigation of inflammatory macrophage states without establishing drug-induced senescence.","url":"https://pubmed.ncbi.nlm.nih.gov/42938381/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:19+00:00","study_design":"preclinical_animal","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"cancer\", \"aging\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1337,"doi":"10.3390/genes17101258","pmid":"42938374","nct_ids":"[]","title":"Hypoglycemic Agent Targets and Susceptibility to Lower Respiratory Infection: A Pharmacogenomic Mendelian Randomization Study","authors":"[\"Yao T\", \"Wu N\", \"Ma Y\", \"Wang Z\", \"Liu B\", \"Lu M\", \"Wu Z\", \"Shen N\"]","journal":"Genes","publication_date":"2026-10-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Patients with type 2 diabetes face heightened risks of lower respiratory tract infections, but whether distinct glucose-lowering drug targets differentially alter pulmonary susceptibility remains unclear. We investigated how genetically proxied perturbations of major antidiabetic targets relate to respiratory infection and sepsis risks. Methods: Using two-sample drug-target Mendelian randomization, we examined genetic instruments proxying six antidiabetic pathways: insulin (INSR), sulfonylureas (KCNJ11/ABCC8), thiazolidinediones (PPARG), GLP-1 receptor agonists (GLP1R), SGLT2 inhibitors (SLC5A2), and metformin (GPD1, GPD2, PRKAG2). Associations were calibrated to standardized glycemic decrements and tested across 13 respiratory infection and sepsis GWAS outcomes. Analyses incorporated functional-variant comparisons, a type 2 diabetes positive control, and linkage disequilibrium adjustment. Results: Genetically proxied glucose lowering through PPARG showed consistent nominal associations with increased respiratory infection risk. Per 0.1 mmol/L lower glucose, the primary proxy and Pro12Ala functional variant were associated with higher odds of influenza and pneumonia (odds ratio [OR] 1.53, 95% CI 1.16-2.02, p = 0.003; and OR 1.53, 95% CI 1.13-2.06, p = 0.006) and other acute lower respiratory infections (OR 1.78, 95% CI 1.14-2.77, p = 0.011; and OR 1.87, 95% CI 1.16-3.01, p = 0.010). PPARG primary and functional proxies agreed in direction for 10/13 outcomes, whereas potassium-channel proxies agreed for only 3/13. Other targets showed distinct, heterogeneous patterns. Crucially, all signals were nominal and none survived false discovery rate correction (q ≥ 0.05). Conclusions: Genetically proxied glucose-lowering pathways exhibit divergent associations with respiratory infection susceptibility. While findings do not support class-wide causal risks, the repeated PPARG pattern highlights target-specific pulmonary immune mechanisms warranting functional and clinical investigation.","url":"https://pubmed.ncbi.nlm.nih.gov/42938374/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:38+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1348,"doi":"10.3390/jcm15207834","pmid":"42941350","nct_ids":"[]","title":"Semaglutide, Other GLP-1 Receptor Agonists, and Papillary Thyroid Carcinoma: A Narrative Review of Risk, Progression, and Mechanisms","authors":"[\"Barseghyan L\", \"Munir I\", \"Chrysafide S\", \"Simental AA\", \"Khan S\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is widely prescribed for type 2 diabetes and obesity. Rodent studies showed thyroid C-cell tumors, prompting a boxed warning for medullary thyroid carcinoma (MTC); whether this extends to papillary thyroid carcinoma (PTC), a follicular-cell-derived tumor, is uncertain. This narrative review examines semaglutide and other GLP-1RAs in relation to PTC, distinguishing semaglutide-specific from class-level evidence, and PTC from differentiated thyroid cancer (DTC), MTC, and thyroid cancer overall. Most human studies evaluated GLP-1RAs as a class and reported thyroid cancer overall; semaglutide-specific and PTC-specific estimates are scarce. Pooled trials and national cohorts mostly showed no statistically significant increase in thyroid cancer, although three separate meta-analyses of randomized trials each reported a statistically significant increase in overall thyroid cancer, and case-control and spontaneous-reporting studies reported signals vulnerable to detection bias and confounding. In a matched cohort of 1072 patients with DTC, GLP-1RA exposure (median 16 months) was not significantly associated with progression over 69 months. Receptor-expression findings were inconsistent, and preclinical data did not show proliferative effects. The cohort and progression findings indicate no statistically detectable increase within the available sample sizes, exposure durations, and event numbers; they do not establish oncological safety. Semaglutide-specific, histology-resolved studies with longer exposure are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42941350/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:42+00:00","study_design":"case_control","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cancer\", \"adverse_effects\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":905,"doi":"10.1016/j.bcp.2026.118534","pmid":"42858820","nct_ids":"[]","title":"A GLP-1/apelin dual receptor agonist shows neuroprotective effects in the MPTP mouse model of Parkinson's disease","authors":"[\"Xu A\", \"Wei Y\", \"Liu E\", \"Tong W\", \"Lu A\", \"Zhang F\", \"Flatt P\", \"Gault V\", \"Irwin N\", \"Hölscher C\", \"Zhang Z\"]","journal":"Biochemical pharmacology","publication_date":"2026-10-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Parkinson's disease (PD) is a chronic disorder with no disease-modifying treatment available. The glucagon-like peptide-1 (GLP-1) class of drugs is on the market to treat diabetes and obesity. GLP-1 drugs have also shown neuroprotective effects in animal models and clinical trials in PD patients. Apelin (APJ) is an adipokine peptide hormone with neuroprotective actions in preclinical studies. Here, we test the effects of a rationally designed bifunctional peptide, namely ELA (exendin-4-linker-apelin), in the MPTP mouse model of PD. The single GLP-1 receptor agonist liraglutide was used as a comparator. Motor activity was improved by both drugs (open field, pole test, Rotarod), and the inflammation response was reduced (activation of microglia and astrocytes, pro-inflammatory cytokine levels). In addition, synapse numbers were improved in the striatum (Golgi strain, TEM), expression of synapse-associated proteins was enhanced, alongside reduced expression of genes that increase mitochondrial fission. Mitochondrial fusion gene expressions (Opa1, Mfn2, Drp1) and mitochondrial morphology were also normalized (TEM). ELA was superior to liraglutide in some, but not all, parameters measured. The results suggest that the rational design of bifunctional peptides targeting both GLP-1 and APJ pathways-with optimized pharmacokinetics and enhanced blood-brain barrier (BBB) permeability-merits further investigation as a strategy for developing more effective treatments for PD.","url":"https://pubmed.ncbi.nlm.nih.gov/42858820/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors do not declare any conflicts of interest. Figures were created with BioRender software, (https://www.biorender.com/).","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"exendin-4-linker-apelin (ela)\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"liraglutide\", \"treatment_duration\": null}","domains":"[\"inflammation\", \"parkinsons\", \"neuroinflammation\"]","outcome_type":"mixed","primary_outcome":"Motor activity, neuroinflammation, synapse and mitochondrial measures in MPTP mice","endpoints":null,"effect_estimate":"Both ELA and liraglutide improved motor activity and reduced glial activation and pro-inflammatory cytokines, improved striatal synapse numbers and normalised mitochondrial measures; ELA was superior to liraglutide in some but not all parameters; no numbers in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MPTP mouse model of Parkinson's disease\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: mouse MPTP model of Parkinson's disease, non-human evidence.","mediation":"possibly","mediation_notes":"Possibly: no body-weight or glucose data are reported for the mice; the evidence model's default is possibly, animal studies included.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"not reported in abstract\", \"blinding\": \"not stated\", \"comparator\": \"liraglutide\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI, p values or group sizes reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical animal study.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Mouse toxin model of Parkinson's disease; results in animals do not establish effects in people, and the abstract gives no group sizes or effect sizes.","plain_summary":"In mice given a toxin that mimics Parkinson's disease, researchers tested a new combined GLP-1/apelin peptide (ELA) against the GLP-1 drug liraglutide. Both drugs improved movement tests, reduced brain inflammation and improved synapse and mitochondrial measures; the new peptide did better than liraglutide on some measures but not others. These are animal results and do not show effects in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":931,"doi":"10.1210/clinem/dgag423","pmid":"42857939","nct_ids":"[]","title":"Preconception incretin therapy reduces pregnancy and cardiometabolic outcomes in polycystic ovary syndrome","authors":"[\"Henney AE\", \"Holmes PJ\", \"Riley D\", \"Heague M\", \"Hapangama DK\", \"Alam U\", \"Cuthbertson DJ\"]","journal":"The Journal of clinical endocrinology and metabolism","publication_date":"2026-10-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Polycystic ovary syndrome (PCOS), now polyendocrine metabolic ovarian syndrome (PMOS), is associated with reproductive and cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists (RAs) improve obesity-related outcomes, but their impact on pregnancy outcomes in PMOS remains unclear. [METHODS] We conducted a target trial emulation using the TriNetX global federated health research network. Women ≥18 years with PCOS/PMOS receiving pre-conception GLP-1/dual GLP-1/GIP RA therapy (liraglutide, semaglutide or tirzepatide) were compared with metformin. Propensity score matching (1:1) accounted for demographics, anthropometrics, comorbidities and medications. The primary outcome was a composite of adverse pregnancy outcomes (hypertensive, glycaemic, placental, delivery, labour, foetal growth, preterm and early pregnancy complications) over two years. Individual pregnancy endpoints, major adverse cardiovascular events (MACE) and type 2 diabetes (T2D) were exploratory secondary outcomes. Cox regression generated hazard ratios (HRs) and 95% confidence intervals (CIs). [RESULTS] After matching, 48,126 patients were included per group. Pre-conception GLP-1/GIP RA use was associated with lower risk of the composite pregnancy outcome (HR 0.38; 95% CI 0.34-0.41). Exploratory analyses also demonstrated lower risks of individual pregnancy endpoints, MACE (HR 0.88; 95% CI 0.81-0.95) and T2D (HR 0.31; 95% CI 0.30-0.33). Associations varied across some sensitivity analyses. [CONCLUSION] Pre-conception GLP-1/GIP RA use in women with PCOS/PMOS was associated with lower risks of adverse pregnancy outcomes and cardiometabolic disease compared with metformin, consistent with potential benefits of pre-conception metabolic optimisation. This study cannot evaluate in-pregnancy safety or efficacy, and these findings do not support GLP-1/GIP RA use during gestation.","url":"https://pubmed.ncbi.nlm.nih.gov/42857939/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"liraglutide\", \"semaglutide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"metformin\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"other_emerging\"]","outcome_type":"hard","primary_outcome":"Composite of adverse pregnancy outcomes over two years","endpoints":null,"effect_estimate":"Composite adverse pregnancy outcome HR 0.38; exploratory MACE HR 0.88 and type 2 diabetes HR 0.31; associations varied across some sensitivity analyses","confidence_interval":"95% CI 0.34-0.41","p_value":null,"sample_size":96252,"follow_up":"over two years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"women only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"polycystic ovary syndrome (PCOS/PMOS)\", \"sample_size\": 96252, \"inclusion_exclusion\": \"women ≥18 with PCOS/PMOS on pre-conception GLP-1/GIP RA or metformin; 1:1 propensity matching\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: women aged 18 or older with PCOS/PMOS, which the authors describe as a metabolic-endocrine syndrome the target group does not have; BMI, diabetes status and age distribution are not reported.","mediation":"possibly","mediation_notes":"Possibly: no weight or glycaemic change is reported, and the authors frame the result as pre-conception metabolic optimisation; matching on baseline anthropometrics addresses confounding, not mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 96252, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"metformin\", \"follow_up_duration\": \"over two years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported; event counts not reported in abstract; 48,126 patients per group after matching\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational target trial emulation in health-record data, capped at LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Observational target-trial emulation in health-record data, open to residual confounding; associations varied across sensitivity analyses and the study cannot assess safety or efficacy during pregnancy.","plain_summary":"Using a large health-record network, this study compared women aged 18 or older with polycystic ovary syndrome who took liraglutide, semaglutide or tirzepatide before conception with matched women taking metformin, 48,126 per group. GLP-1 drug use was linked to a lower risk of a combined measure of pregnancy complications (HR 0.38), and in exploratory analyses to lower risks of major cardiovascular events and type 2 diabetes, though results varied in some sensitivity analyses. This is an observational association, not proof of cause, and it says nothing about using these drugs during pregnancy.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1096,"doi":"10.1016/j.addbeh.2026.108878","pmid":"42880142","nct_ids":"[]","title":"Exploring semaglutide for alcohol use disorder: A review of clinical efficacy and neurobiological mechanisms","authors":"[\"Nittur A\", \"Belzar A\", \"Rai C\"]","journal":"Addictive behaviors","publication_date":"2026-10-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To examine emerging clinical evidence, real-world data, and neurobiological mechanisms supporting the repurposing of semaglutide as a novel treatment for alcohol use disorder (AUD) METHODS: Of records identified, articles were selected based on clinical relevance to AUD outcomes and mechanisms of action. Included studies ranged from hypothesis-generating designs to confirmatory randomized controlled trials in non-treatment-seeking individuals and patients diagnosed with AUD, with several cohorts enriched for comorbid obesity. [RESULTS] Randomized controlled trials demonstrated that once-weekly semaglutide significantly reduced alcohol cravings and drinks per drinking day, even in non-treatment-seeking populations. Large-scale cohort studies showed a reduction in AUD-related hospitalizations for patients on semaglutide compared to non-users. Dual agonists like tirzepatide also showed significant reductions in binge drinking odds and AUDIT scores, with reductions in alcohol craving and consumption appearing most pronounced among individuals with comorbid obesity or metabolic disease. Mechanistically, preclinical and early human data indicate GLP-1 receptor activity in the VTA and nucleus accumbens modulates mesolimbic reward circuitry to attenuate dopamine-mediated reinforcement, alongside indirect behavioral and satiety effects. [CONCLUSIONS] GLP-1 receptor agonists show early promise in reducing alcohol craving and consumption, particularly in individuals with comorbid metabolic disease. No GLP-1 receptor agonist currently carries FDA approval for alcohol use disorder, and all discussed clinical applications still remain investigational. Definitive randomized trials in AUD-only populations are still needed. Current evidence remains limited by small sample sizes, brief follow-up periods, self-reported outcomes, and potential confounding from weight loss.","url":"https://pubmed.ncbi.nlm.nih.gov/42880142/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"narrative_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"non-users (cohort studies); comparator in the randomised trials not stated\", \"treatment_duration\": null}","domains":"[\"addiction\"]","outcome_type":"mixed","primary_outcome":"alcohol craving, consumption and AUD-related hospitalisation","endpoints":null,"effect_estimate":"Included RCTs reported reduced alcohol craving and drinks per drinking day with semaglutide; cohort studies linked semaglutide to fewer AUD-related hospitalisations; tirzepatide linked to lower binge-drinking odds and AUDIT scores; no numeric estimates in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (several cohorts enriched for comorbid obesity)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"alcohol use disorder, including non-treatment-seeking individuals\", \"sample_size\": null, \"inclusion_exclusion\": \"studies chosen for clinical relevance to AUD outcomes and mechanisms\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: the review covers people selected for alcohol use disorder rather than for obesity or diabetes, with several included cohorts enriched for obesity; age, BMI and diabetes status are not given.","mediation":"possibly","mediation_notes":"Possibly: the authors themselves list potential confounding from weight loss and note effects seemed strongest in people with obesity or metabolic disease; no separation of weight effects is reported.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"non-users (cohort studies); comparator in the randomised trials not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"no CI or pooled estimate reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a narrative review with no pooled estimate and no new primary data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no known competing financial interests or personal relationships.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The authors note small samples, brief follow-up, self-reported outcomes and possible confounding by weight loss, and that trials in AUD-only populations are still needed; non-systematic study selection.","plain_summary":"This narrative review gathered trials, real-world studies and laboratory work on semaglutide and alcohol use disorder. The authors report that trials found less craving and fewer drinks per drinking day with semaglutide, that cohort studies linked it to fewer alcohol-related hospital stays, and that effects looked strongest in people with obesity or metabolic disease. They stress that the evidence is early, based on small and short studies, possibly confounded by weight loss, and that no GLP-1 drug is approved for this use.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1295,"doi":"10.3390/ph19101607","pmid":"42943304","nct_ids":"[]","title":"SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus: A Propensity Score-Matched Cohort Study Comparing Adherence and Persistence with Specific Reference to Cardiovascular Disease","authors":"[\"González-González MA\", \"Pedrosa-Naudín MA\", \"Fernández-Lázaro D\", \"Díaz Planelles I\", \"Álvarez FJ\", \"Gutiérrez-Abejón E\"]","journal":"Pharmaceuticals (Basel, Switzerland)","publication_date":"2026-10-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Poor adherence and persistence to sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a critical issue in the treatment of type 2 diabetes mellitus (T2DM), especially in patients with cardiovascular disease (CVD). We aimed to compare adherence and persistence to these drugs in routine care. Methods: A retrospective propensity score-matched (PSM) cohort study was conducted using pharmacy claims data. Patients aged 40 years or older with T2DM initiating SGLT-2is or GLP-1 RAs from 1 January 2019 to 31 December 2024 were included. Adherence was measured using the Medication Possession Ratio (MPR), and persistence was defined as the time to discontinuation (gap ≥ 60 days between refills). Results: At the 1-year follow-up, the SGLT-2i cohort showed significantly higher adherence compared to the GLP-1 RA cohort (86.66% vs. 76.53%; OR = 2.02) and higher persistence (71.48% vs. 66.52% at 12 months; HR = 0.83). The main factors associated with lack of persistency were newly diagnosed T2DM (HR = 1.25) and insulin use (HR = 1.32). In the CVD subgroup, the differences in favor of the SGLT-2i cohort were more pronounced for adherence (89.57% vs. 78.12%; OR = 2.44) and persistence (73.9% vs. 63.59%; HR = 0.66). Conclusions: In real-world clinical practice, adherence and persistence rates were higher in patients on SGLT-2is compared to those on GLP-1 RAs, particularly in the CVD subgroup. Our findings suggest that the new strategies are necessary to improve adherence and persistence to these medications, particularly in patients with CVD.","url":"https://pubmed.ncbi.nlm.nih.gov/42943304/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:21+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":911,"doi":"10.1097/md.0000000000051019","pmid":"42854065","nct_ids":"[]","title":"Short-term clinical efficacy and recorded adverse events of semaglutide combined with dapagliflozin in patients with type 2 diabetes mellitus and chronic kidney disease","authors":"[\"Gong C\", \"Luo Q\", \"Li Q\"]","journal":"Medicine","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 2 diabetes mellitus (T2DM) complicated by chronic kidney disease (CKD) is associated with persistent hyperglycemia, progressive renal impairment, systemic inflammation, and an increased risk of adverse clinical outcomes. Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have shown metabolic and cardiorenal benefits, but clinical evidence regarding their combined use in patients with T2DM and CKD remains limited. This retrospective observational study included 126 patients with T2DM complicated by CKD who were treated at our hospital between March 2023 and July 2024. Patients were identified through a review of electronic medical records and the application of predefined eligibility criteria. Treatment groups reflected the actual regimen documented in the medical record rather than random allocation. The final analytic cohort comprised 42 patients in each group; the equal group size reflected the eligible records with complete baseline and 8-week follow-up data available in each treatment category during the study period rather than a prospective 1:1:1 enrollment target. The treatment duration was 8 weeks. Glycemic indices, renal function-related parameters, inflammatory markers, clinical response, and recorded adverse events were compared among the 3 groups. After 8 weeks of treatment, fasting plasma glucose, 2-hour postprandial plasma glucose, hemoglobin A1c, blood urea nitrogen, serum creatinine, 24-hour urinary protein, erythrocyte sedimentation rate, interleukin-6, and high-sensitivity C-reactive protein were significantly reduced in all 3 groups compared with baseline. The combination group showed greater short-term reductions in glycemic indices, renal function-related parameters, and inflammatory markers than either monotherapy group. The overall clinical response rate was significantly higher in the combination group than in the dapagliflozin or semaglutide group. In patients with T2DM complicated by CKD, semaglutide combined with dapagliflozin was associated with greater short-term improvements in glycemic control, inflammatory markers, and renal function-related indicators, as well as a higher exploratory clinical response rate, than either monotherapy. No increase in recorded adverse events was detected during 8 weeks of treatment. Because of the retrospective design, modest sample size, and short observation period, these findings should not be interpreted as demonstrating definitive long-term renal benefit or equivalent long-term safety. Further large-scale prospective studies with standardized renal outcomes are required.","url":"https://pubmed.ncbi.nlm.nih.gov/42854065/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors have no funding and conflicts of interest to declare.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"dapagliflozin alone and semaglutide alone (combination group vs each monotherapy)\", \"dose\": null, \"route\": null, \"treatment_duration\": \"8 weeks\"}","domains":"[\"inflammation\", \"kidney\", \"metabolic\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":"Glycaemic indices, renal function-related parameters, inflammatory markers, clinical response and recorded adverse events over 8 weeks","endpoints":null,"effect_estimate":"All 3 groups improved from baseline; the semaglutide plus dapagliflozin group had greater reductions in glycaemic, renal and inflammatory markers and a higher clinical response rate than either monotherapy; no numeric values in abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":126,"follow_up":"8 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"chronic kidney disease required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with chronic kidney disease\", \"sample_size\": 126, \"inclusion_exclusion\": \"T2DM with CKD treated at one hospital March 2023 to July 2024 with complete baseline and 8-week data\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 126 patients had type 2 diabetes with chronic kidney disease; BMI not reported.","mediation":"possibly","mediation_notes":"Possibly: HbA1c and glucose fell alongside the renal and inflammatory markers, and no analysis separated glycaemic improvement from the other effects; weight was not reported.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 126, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"dapagliflozin alone and semaglutide alone (combination group vs each monotherapy)\", \"follow_up_duration\": \"8 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"No confidence intervals or p values in abstract; 42 patients per group\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a small single-hospital retrospective cohort (42 per group, 8 weeks, laboratory outcomes, no events).","funding_source":"no funding declared","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No increase in recorded adverse events detected during 8 weeks","limitations":"The authors cite the retrospective design, modest sample and short observation period; single hospital, non-random treatment allocation and laboratory outcomes only.","plain_summary":"This retrospective study at one hospital compared 126 people with type 2 diabetes and kidney disease who had received semaglutide, dapagliflozin or both for 8 weeks, 42 per group. The combination was linked to larger short-term falls in blood sugar, kidney-function and inflammation markers and a higher response rate than either drug alone, with no increase in recorded side effects. The design is observational and short, and the authors say it does not show long-term kidney benefit.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":930,"doi":"10.1016/j.jacadv.2026.103311","pmid":"42858539","nct_ids":"[]","title":"Cardiovascular Risk in SELECT-Eligible MI Patients With Overweight or Obesity: The Western Denmark Heart Registry","authors":"[\"Hansen MK\", \"Olesen KKW\", \"Gyldenkerne C\", \"Stødkilde-Jørgensen N\", \"Andersen MH\", \"Sattar N\", \"Maeng M\"]","journal":"JACC. Advances","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] In the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial, treatment with semaglutide reduced the risk of major adverse cardiovascular events (MACE) in patients with cardiovascular disease, overweight or obesity, and no diabetes. [OBJECTIVES] The purpose of this study was to estimate cardiovascular risk in first-time myocardial infarction (MI) patients meeting the SELECT-eligibility criteria and the preventive potential for treatment with semaglutide. [METHODS] We conducted an observational cohort study applying the SELECT trial's inclusion and exclusion criteria to patients with first-time MI recorded between 2010 and 2021 in the Western Denmark Heart Registry. Five-year incidence of second MI, MACE, and all-cause death was estimated for SELECT-eligible patients with a body mass index (BMI) ≥27 kg/m2. In an assumption-dependent scenario analysis the preventive potential for semaglutide was estimated as the postponement of MACE incidence. [RESULTS] In 21,777 first-time MI patients without diabetes, 10,768 patients were SELECT-eligible with BMI ≥27 kg/m2. Median age at first-time MI was 65 years for the SELECT-eligible MI patients and 69 years for normal-weight (BMI 20-26 kg/m2) comparisons. Five-year incidence of second MI (n = 544), MACE (n = 975), and all-cause death (n = 914) was 5.9% (95% CI: 5.4%-6.4%), 10.7% (95% CI: 10.1%-11.4%), and 10.3% (95% CI: 9.7%-11.0%) in SELECT-eligible MI patients, respectively. Among these, treatment with semaglutide was estimated to postpone a 5% MACE incidence by 12 months. [CONCLUSIONS] In SELECT-eligible first-time MI patients with overweight or obesity and no diabetes, the cardiovascular risk was substantial with 1 in 10 having a MACE event within 5 years after first-time MI. Based on the SELECT trial results, semaglutide may markedly postpone MACE incidence in these patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42858539/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding support and author disclosures The study is part of a larger project funded by an institutional research grant from the Novo Nordisk Foundation (grant number NNF22OC0074083). Dr Olesen is supported by a research grant from the Danish Cardiovascular Academy funded by the Danish Heart Association and Novo Nordisk. Dr Andersen is a minor shareholder in Novo Nordisk and supported by a research grant from the Danish Cardiovascular Academy (grant number, PhD2023001-HF) funded by the Danish Heart Foundation and the Novo Nordisk Foundation. Dr Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Menarini-Ricerche, Metsera, Novartis, Novo Nordisk, Pfizer, and Roche; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche outside the submitted work. Dr Maeng is supported by a grant from the Novo Nordisk Foundation (grant number NNF22OC0074083); has received lecture and/or advisory board fees from Novo Nordisk; has received research grants from Philips, Bayer, and Novo Nordisk; has ongoing institutional research contracts with Janssen, Novo Nordisk, Philips, and ResoTher; and has minor shareholder equity positions in Eli Lilly and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"none observed: no patient received semaglutide; its effect was projected from SELECT trial results; normal-weight MI patients were a descriptive comparison\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"five-year incidence of second MI, MACE and all-cause death","endpoints":null,"effect_estimate":"Five-year incidence 5.9% second MI, 10.7% MACE and 10.3% all-cause death in SELECT-eligible patients; semaglutide estimated (scenario, not observed) to postpone a 5% MACE incidence by 12 months","confidence_interval":"95% CI: 10.1%-11.4% (five-year MACE incidence)","p_value":null,"sample_size":10768,"follow_up":"five-year incidence","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"overweight or obesity required (BMI ≥27)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"required (first-time myocardial infarction)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"first-time myocardial infarction with overweight or obesity and no diabetes\", \"sample_size\": 10768, \"inclusion_exclusion\": \"first-time MI 2010-2021, no diabetes, SELECT criteria, BMI ≥27 kg/m2\", \"healthy_volunteers\": false, \"normal_weight_included\": true, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all had overweight or obesity (BMI ≥27) and a first myocardial infarction, without diabetes; median age 65.","mediation":"possibly","mediation_notes":"Possibly: no one in the cohort was treated, and the projected semaglutide effect is borrowed from SELECT, where weight loss was not separated from the drug effect; no weight or glycaemic data are reported.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 10768, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"none observed: no patient received semaglutide; its effect was projected from SELECT trial results; normal-weight MI patients were a descriptive comparison\", \"follow_up_duration\": \"five-year incidence\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CIs reported for incidence (e.g. MACE 95% CI: 10.1%-11.4%); 975 MACE events\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: the registry data describe cardiovascular risk but contain no observed GLP-1 outcome; the semaglutide estimate is an assumption-dependent projection.","funding_source":"Novo Nordisk Foundation institutional research grant (part of a larger project)","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Several authors report Novo Nordisk Foundation or Novo Nordisk-funded grants, Novo Nordisk shareholdings, and fees from Novo Nordisk, Eli Lilly and other companies; the rest report none.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk (shareholdings, lecture and advisory fees, research grants)","adverse_events":"not reported in abstract","limitations":"Registry cohort with no semaglutide exposure; the semaglutide benefit is an assumption-dependent projection from SELECT, not an observed result; single registry.","plain_summary":"This Danish registry study looked at 10,768 people without diabetes who had a first heart attack and would have qualified for the SELECT semaglutide trial because of overweight or obesity. Within five years, 10.7% had a major cardiovascular event and 10.3% died. Nobody in the study was given semaglutide: the authors' estimate that it could delay such events by about 12 months is a projection from the SELECT trial, not an observed result.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":974,"doi":"10.1016/j.disamonth.2026.102231","pmid":"42855378","nct_ids":"[]","title":"Status Of GLP-1 drugs and their application in treating substance use disorders: A systematic review","authors":"[\"Inban P\", \"Agrawal A\", \"Rushika K\", \"Tariq H\", \"Thai A\", \"Kudaiarov D\", \"Prajjwal P\", \"John J\"]","journal":"Disease-a-month : DM","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/OBJECTIVE] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have an exciting future potential beyond metabolic disorders. This review gauges their effectiveness, safety, and clinical role in the management of substance use disorders in diverse populations. [METHODS] A PRISMA-guided systematic review searched PubMed, Scopus, WoS, CENTRAL and PsycINFO up to March 2026; 1641 records were identified, 11 included; screening, extracting and evaluating the efficacy, safety, and bias of the studies. [RESULTS] 11 studies were selected out of 1641 records. Reduced substance-related outcomes were always observed with GLP-1RAs. In alcohol use disorder (AUD), there was a decrease in the risk of hospitalization (aHR 0.640.72), and reduced incident AUD (OR 0.260.71), but randomized controlled trials (RCTs) provided contradictory outcomes (p = 0.37; 29% reduction, p = 0.04). Semaglutide reduced the risk of tobacco use disorder (HR 0.68; 95% CI 0.630.74). There was a great decrease in the risk of opioid overdose (HR 0.32-0.58). The incidence (HR 0.86), mortality (HR 0.50), and suicidal ideation were less in composite substance use disorder (SUD) outcomes (HR 0.75). Weight reduction was consistent (-2.9 kg; ≥16 kg in 37.5%), with HbA1c improvements (-0.25%). RCTs were found to be low-bias and the observational studies were moderate-bias. The safety profiles were positive, and there were no patterns of increasing serious adverse events (SAEs). [CONCLUSION] GLP-1RAs have good potential protective properties against SUD especially in observational research with good safety. However, robust randomized trials are needed to confirm causality and clinical applicability.","url":"https://pubmed.ncbi.nlm.nih.gov/42855378/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflict of interest The Author(s) declare(s) that there is no conflict of interest","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": \"various\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"addiction\", \"mortality\", \"metabolic\", \"adverse_effects\", \"psychiatric\"]","outcome_type":"mixed","primary_outcome":"substance use disorder outcomes (alcohol, tobacco, opioid and composite SUD)","endpoints":null,"effect_estimate":"Observational studies linked GLP-1RAs to lower AUD hospitalisation and incident AUD, tobacco use disorder (HR 0.68) and opioid overdose (HR 0.32-0.58); RCTs in AUD were contradictory (p = 0.37; 29% reduction, p = 0.04); no pooled estimate","confidence_interval":"95% CI 0.630.74 (tobacco use disorder, as printed)","p_value":"p = 0.37; p = 0.04 (RCTs in AUD)","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"substance use disorders (alcohol, tobacco, opioid)\", \"sample_size\": null, \"inclusion_exclusion\": \"11 studies included of 1641 records identified; studies of GLP-1RAs and substance use outcomes\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: systematic review of 11 studies in “diverse populations”; age, BMI and diabetes status are not reported.","mediation":"possibly","mediation_notes":"Possibly: weight loss and HbA1c improvement were reported alongside the substance-use results, and the abstract reports no analysis separating them.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"one CI reported (tobacco use disorder); no pooled estimate\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review with a study-by-study synthesis and no pooled estimate.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Safety profiles reported as positive, with no patterns of increasing serious adverse events","limitations":"Most benefit comes from observational studies rated moderate risk of bias, the RCTs disagreed, only 11 studies were included and no pooled estimate is given; the authors call for robust randomised trials.","plain_summary":"This systematic review included 11 studies of GLP-1 receptor agonists and substance use disorders. Observational studies linked the drugs to lower risks of alcohol-related hospital stays, tobacco use disorder and opioid overdose, but the randomised trials in alcohol use disorder gave conflicting results, one not statistically significant. Participants also lost weight, and the authors say robust randomised trials are needed before the link can be treated as cause and effect.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1125,"doi":"10.20944/preprints202610.0695.v1","pmid":null,"nct_ids":"[]","title":"<span data-teams=\"true\">A GPCR-Signaling Addiction Hub in the Murine Nucleus Accumbens and Its Partial Restitution by a GLP-1 Receptor Agonist: A Retrospective Transcriptomic Analysis","authors":"[\"Baik R\", \"Collette J\", \"Cruz NJ\", \"Nesta AV\", \"Narayan P.\"]","journal":"preprint server","publication_date":"2026-10-09","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Substance use disorders, including opioid use disorder, cocaine use disorder, alcohol use disorder, and behavioral disorders including food addiction, represent immense global health and economic burdens. Although initiated by distinct pharmacological mechanisms, these conditions converge on shared reward and compulsive neural circuitry within the mesocorticolimbic system, particularly the nucleus accumbens (NAc). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), developed for metabolic indications, have recently demonstrated activity in suppressing craving across multiple substance classes. We tested the hypothesis that there exists a shared transcriptomic hub across OUD, CUD, AUD, and FA that is restituted by GLP-1 RA. We conducted a retrospective transcriptomic analysis of publicly available bulk RNA-seq data from the murine NAc across these addictions, alongside an addiction-naive GLP-1 RA treatment model. At the individual gene level, cross-addiction overlap was not observed. Submitting top-ranked transcripts per condition to gene list enrichment and functional annotation analyses revealed shared upregulation of G-protein coupled receptor (GPCR) signaling with GLP-1 RA administration exhibiting a discordant, restitutive transcriptional signature. These findings demonstrate that in the murine NAc, diverse addictive substances converge on NAc GPCR overactivation with restitution of signaling, at least, in part, by a GLP-1 RA.","url":"https://doi.org/10.20944/preprints202610.0695.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"addiction\"]","outcome_type":"biomarker","primary_outcome":"Shared nucleus accumbens transcriptomic signature across addictions and its restitution by a GLP-1 RA","endpoints":null,"effect_estimate":"No cross-addiction overlap at the individual gene level; enrichment analysis showed shared upregulation of GPCR signalling across addictions, with GLP-1 RA administration showing a discordant, restitutive signature; no numbers in the abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"mouse models of opioid, cocaine and alcohol use disorder and food addiction, plus an addiction-naive GLP-1 RA model\", \"sample_size\": null, \"inclusion_exclusion\": \"publicly available bulk RNA-seq datasets from mouse nucleus accumbens\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: transcriptomic data from mouse nucleus accumbens, non-human evidence.","mediation":"possibly","mediation_notes":"Possibly: no weight or glycaemic data are reported for the GLP-1 RA-treated mice; the evidence model's default applies, animal studies included.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI, p values or sample counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a preprint, not peer reviewed; as a preclinical analysis it would otherwise be VERY_LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Preprint re-analysis of public mouse RNA-seq datasets; the GLP-1 RA data come from addiction-naive animals, so reversal of the addiction signature is inferred across separate datasets rather than tested, and gene expression is not a behavioural or clinical outcome.","plain_summary":"This preprint re-analysed publicly available gene-expression data from a reward area of the mouse brain across models of opioid, cocaine, alcohol and food addiction, and from mice given a GLP-1 receptor agonist without any addiction. No single genes overlapped across the addictions, but a shared rise in a family of cell-signalling pathways was found, and the GLP-1 drug data showed an opposite pattern. Because the drug was not tested in addicted animals and these are mouse data, it does not show that GLP-1 drugs treat addiction.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1301,"doi":"10.3390/metabo16100757","pmid":"42941232","nct_ids":"[]","title":"Weight Regain After Discontinuation of GLP-1 and GIP/GLP-1 Receptor Agonists: A Systematic Review","authors":"[\"Marchetti M\", \"Campisano G\", \"Paragliola RM\", \"Francomano D\", \"Cipolloni V\", \"Conforti A\"]","journal":"Metabolites","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Weight regain and loss of cardiometabolic benefit commonly follow the withdrawal of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists, yet maintenance strategies are incompletely characterized. [METHODS] We conducted a systematic review reported according to PRISMA 2020 of primary studies in adults with overweight or obesity, with or without type 2 diabetes. PubMed/MEDLINE, Europe PMC and ClinicalTrials.gov were searched from inception to September 2026, supplemented by backward/forward citation searching and cross-checking of recent systematic reviews. Eligible reports quantified weight or cardiometabolic outcomes at least 12 weeks after planned or unplanned treatment cessation, or tested a post-cessation maintenance strategy. Randomized reports were assessed with RoB 2 and non-randomized reports with ROBINS-I. Owing to incompatible estimands, follow-up schedules, cointerventions and overlapping trial families, results were synthesized narratively without a new pooled estimate. [RESULTS] Eighteen reports representing 16 study families were included. Randomized withdrawal trials showed renewed weight gain after treatment cessation: +6.9% over 48 weeks after switching from semaglutide to placebo in STEP 4, and +14.0% over 52 weeks after switching from tirzepatide to placebo in SURMOUNT-4. In the STEP 1 extension, participants regained 11.6 percentage points over one year, approximately two-thirds of their prior loss, while several cardiometabolic measures moved toward baseline. Real-world estimates were smaller and more variable because discontinuation was often inferred from prescriptions, follow-up weights were missing, and many patients restarted or switched therapy. Cardiometabolic rebound was associated with the degree of weight regain, but clinical cardiovascular events were not evaluated. Evidence for maintenance strategies was sparse: one randomized post-treatment study supported supervised exercise, with the exercise-plus-liraglutide group retaining an additional 5.1 kg of weight loss one year after both interventions ended compared with liraglutide alone; a small pilot supported sitagliptin plus metformin after liraglutide in polycystic ovary syndrome. No eligible controlled trial isolated a specific diet after cessation. [CONCLUSIONS] Weight regain is frequent after stopping GLP-1-based therapy, although magnitude varies by drug, design, follow-up and subsequent treatment. Structured exercise may help reduce regain and preserve lean mass, but evidence for dietary, behavioral, tapering or pharmacologic transition strategies remains limited. Discontinuation should therefore be planned as part of chronic obesity care, with explicit monitoring and shared decision-making, rather than presented as a predictable short course.","url":"https://pubmed.ncbi.nlm.nih.gov/42941232/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\", \"gip/glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"switch to placebo after treatment (randomized withdrawal trials); otherwise treatment cessation without a stated comparator\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"lean_mass\", \"adverse_effects\", \"endocrine\", \"discontinuation\", \"other_emerging\"]","outcome_type":"intermediate","primary_outcome":"weight and cardiometabolic outcomes after stopping GLP-1-based therapy","endpoints":null,"effect_estimate":"No pooled estimate. Weight regain of +6.9% over 48 weeks after switching semaglutide to placebo (STEP 4) and +14.0% over 52 weeks after switching tirzepatide to placebo (SURMOUNT-4); 11.6 percentage points regained over one year in the STEP 1 extension; exercise plus liraglutide retained an additional 5.1 kg one year after both interventions ended.","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (overweight or obesity)\", \"diabetes_status\": \"mixed (with or without type 2 diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"overweight or obesity, after stopping GLP-1-based therapy\", \"sample_size\": null, \"inclusion_exclusion\": \"primary studies in adults with overweight or obesity reporting weight or cardiometabolic outcomes at least 12 weeks after cessation, or testing a maintenance strategy\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review covers adults with overweight or obesity, with or without type 2 diabetes; no mean age or BMI is given.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is weight regain itself. The authors report that cardiometabolic rebound tracked the degree of weight regain, which is a correlation, not a mediation analysis.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"switch to placebo after treatment (randomized withdrawal trials); otherwise treatment cessation without a stated comparator\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; narrative synthesis without a pooled estimate\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Systematic review with a narrative synthesis and no new pooled estimate: NOT_RATED.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"No pooled estimate because of incompatible estimands and overlapping trials; real-world data inferred discontinuation from prescriptions with missing follow-up weights; clinical cardiovascular events were not evaluated and maintenance-strategy evidence was sparse.","plain_summary":"This systematic review gathered eighteen reports from 16 study families on adults with overweight or obesity who stopped GLP-1 or GIP/GLP-1 drugs, and did not pool them. In randomized withdrawal trials, people switched to placebo regained weight: +6.9% over 48 weeks after semaglutide (STEP 4) and +14.0% over 52 weeks after tirzepatide (SURMOUNT-4). Real-world estimates were smaller and more variable, clinical cardiovascular events were not evaluated, and evidence on ways to prevent regain was sparse, with one trial favouring supervised exercise.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1323,"doi":"10.3390/nu18203312","pmid":"42942883","nct_ids":"[]","title":"Impact of GLP-1 Receptor Agonists on Cognitive Performance in Adults at Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","authors":"[\"Abbatecola AM\", \"Migliara G\", \"D'Agostino F\", \"Veronese N\", \"Giuliani A\", \"Caponnetto S\", \"Corbi G\", \"Signoriello E\", \"Incalzi RA\", \"Paolisso G\"]","journal":"Nutrients","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Type 2 diabetes, a widely recognized risk factor of Alzheimer's disease (AD), is mainly due to the role played by insulin resistance on neuronal degeneration. Mild Cognitive Impairment (MCI) also significantly increases the risk of developing AD by approximately 40%. Epidemiological studies have demonstrated correlations between glucagon-like peptide-1 agonists (GLP-1RAs) on reducing the risk of AD. We synthesize current data from randomized controlled trials (RCTs) to summarize the effects of GLP-1RA treatment in adults with Type 2 diabetes or with MCI on cognitive performance. Methods: We searched databases from inception to 1 January 2026 investigating effects of GLP-1RA(s) on cognition. PubMed, Web of Science and Scopus databases were explored following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We selected only RCTs in adults investigating GLP-1RA(s) on cognitive performance. Results: Overall mean age was 64.5 yrs with an average follow-up period of 28.4 months. A total of 13,711 participants from five RCTs were included. Following a source-data audit, four randomized controlled trials contributed analytically compatible data to at least one cognitive domain. Cognitive domains were analyzed separately using Hedges' g. Random-effects models used restricted maximum likelihood (REML) estimation with Knapp-Hartung inference when at least two compatible studies contributed. For global cognition, three studies yielded g = 0.014 (95% CI: -0.061 to 0.088; p = 0.515; I2 = 0%). For attention, two studies yielded g = 0.072 (95% CI: -2.164 to 2.308; p = 0.753; I2 = 31.1%). For delayed memory, executive function, and verbal function, only one compatible study was available per domain; these were therefore reported as single-study estimates rather than pooled effects. A sensitivity analysis excluding the dominant Cukierman trial yielded an imprecise and non-significant effect estimate for global cognition (g = -0.205, 95% CI: -2.678 to 2.269) indicating that the robustness of the pooled result could not be established. Conclusions: Current randomized evidence is insufficient to establish a consistent beneficial effect of GLP-1RA(s) on cognitive function in adults at risk of AD. The available findings should be considered exploratory and hypothesis-generating because few analytically compatible trials were available within each cognitive domain.","url":"https://pubmed.ncbi.nlm.nih.gov/42942883/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest. ","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cognition\", \"alzheimers\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":"cognitive performance by domain (global cognition, attention, delayed memory, executive and verbal function)","endpoints":null,"effect_estimate":"Global cognition g = 0.014 (3 studies, not significant); attention g = 0.072 (2 studies, not significant); sensitivity analysis without the Cukierman trial g = -0.205 (imprecise, not significant)","confidence_interval":"95% CI: -0.061 to 0.088 (global cognition)","p_value":"p = 0.515 (global cognition)","sample_size":13711,"follow_up":"average follow-up period of 28.4 months","direction":"null","population":"{\"mean_age\": 64.5, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"mixed (type 2 diabetes or mild cognitive impairment)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes or mild cognitive impairment (at risk of Alzheimer's disease)\", \"sample_size\": 13711, \"inclusion_exclusion\": \"RCTs in adults investigating GLP-1RAs on cognitive performance\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: participants had type 2 diabetes or mild cognitive impairment (mean age 64.5 yrs); type 2 diabetes, which the target group lacks, decides (IN-063).","mediation":"unlikely","mediation_notes":"Unlikely: the pooled cognition results are null.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 13711, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"average follow-up period of 28.4 months\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -0.061 to 0.088 (global cognition)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis of randomized trials (13,711 participants from five trials, four contributing data) with a null pooled result, limited by few compatible trials per cognitive domain and dependence on one dominant trial.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Few analytically compatible trials per cognitive domain, so most domains rest on one or two studies and the pooled global-cognition result depends on one dominant trial.","plain_summary":"This meta-analysis pooled randomized trials of GLP-1 drugs in 13,711 adults with type 2 diabetes or mild cognitive impairment, average age 64.5 years, followed for an average of 28.4 months. GLP-1 drugs showed no detectable effect on global cognition (g = 0.014, 95% CI: -0.061 to 0.088) or attention, and the result rested heavily on one large trial. The authors call the evidence insufficient and exploratory.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1338,"doi":"10.3390/medsci14060652","pmid":"42930571","nct_ids":"[]","title":"Cutaneous Adverse Events Associated with Semaglutide, Liraglutide and Tirzepatide: A Systematic Review","authors":"[\"Gupta AK\", \"Teasell EM\", \"Magalhães RF\", \"Mirmirani P\", \"Piguet V\"]","journal":"Medical sciences (Basel, Switzerland)","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/OBJECTIVES] Incretin-based therapies, including glucagon like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs, are increasingly prescribed for obesity, leading to greater recognition of associated dermatological adverse events (AEs). We aimed to characterize the spectrum, frequency, and clinical characteristics of cutaneous AEs reported with semaglutide, liraglutide and tirzepatide, focusing on these agents because of their established use in both weight management and diabetes mellitus. [METHODS] A systematic literature search was conducted in MEDLINE (via PubMed), Embase, and Web of Science. Search terms combined skin-related manifestations (e.g., skin, dermatologic, injection-site reactions, pruritus, rash, hypersensitivity, dysesthesia, vasculitis) with GLP-1 RA and GIP/GLP-1 RAs (semaglutide, tirzepatide, liraglutide). Clinical trials, observational studies, pharmacovigilance studies, and case reports reporting skin-related AEs associated with semaglutide, liraglutide and tirzepatide were included. [RESULTS] One hundred and one studies were included (32 randomized controlled trials, 6 retrospective cohort/cross-sectional studies, 20 pharmacovigilance studies, and 43 case series/reports). Cutaneous AEs ranged from generally common but mild reactions to rare but potentially severe immune-mediated disorders. Injection-site reactions, including erythema, pruritus, and hemorrhage, were reported most frequently with tirzepatide (2-7%), then liraglutide, and less commonly with semaglutide, with evidence of dose dependence. Dysesthesia was most strongly associated with semaglutide, occurring in approximately 5% of patients at standard doses and up to 20% with high-dose formulations indicated for weight management, with events frequently occurring during dose escalation. Uncommon reactions reported in association with GLP-1 or GIP/GLP-1 RA use included angioedema, hypersensitivity reactions, autoimmune blistering diseases, drug eruptions, vasculitis, and severe cutaneous reactions. [CONCLUSIONS] Although most cutaneous AEs associated with GLP-1 and GIP/GLP-1 RAs are mild and manageable, clinically relevant drug-specific differences exist. The recognition of common and uncommon skin manifestations may facilitate earlier diagnosis, support treatment adherence, and reduce the adverse outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42930571/","source_name":"pubmed","source_tier":1,"coi_statement":"A.K.G., E.M.T. and R.F.M. declare no conflicts of interest. V.P. has received grants from AbbVie, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Incyte, Janssen, LEO Pharma, L’Oréal, Novartis, Organon, Pfizer, Sandoz and Sanofi; received payment or honoraria for speaking engagement from Sanofi; participated on an advisory board for LEO Pharma, Novartis, Sanofi, Union Therapeutics, Abbvie and UCB; and received equipment donation from L’Oréal. PM is affiliated with the Permanente Medical Group (a general hospital in California, USA; no conflicts of interest); reports research grants from Amgen, Sun Pharmaceuticals, Eli Lilly, Incyte, Pfizer, and Priovant; has served on the board of directors and medical advisory board for the American Hair Research Society, National Alopecia Areata Foundation, and Scarring Alopecia Foundation; and is a consultant for Veradermics, Priovant, Sanofi, L’Oreal, and Unilever. The sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Author Paradi Mirmirani was employed by the company The Permanente Medical Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cognition\", \"rheumatologic\", \"immune\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":"spectrum, frequency and clinical characteristics of cutaneous adverse events","endpoints":null,"effect_estimate":"No pooled estimate: injection-site reactions most frequent with tirzepatide (2-7%); dysesthesia approximately 5% with semaglutide at standard doses and up to 20% with high-dose formulations","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": \"clinical trials, observational, pharmacovigilance studies and case reports reporting skin-related AEs with semaglutide, liraglutide or tirzepatide\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a review whose included populations are not described beyond the drugs' use for weight management and diabetes.","mediation":"possibly","mediation_notes":"Possibly by the no-data default (IN-062): the abstract reports no weight or HbA1c data; for injection-site and immune-mediated skin reactions weight mediation seems implausible, and dysesthesia occurred mainly during dose escalation.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI reported; narrative synthesis of one hundred and one studies\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review of one hundred and one studies (trials, cohorts, pharmacovigilance and case reports) with no pooled estimate.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Three authors declare no conflicts; two report grants, honoraria, advisory or consulting relationships with many companies, including Eli Lilly, Sanofi, Novartis, Pfizer and AbbVie.","sponsor_role":"The sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"Injection-site reactions most frequent with tirzepatide (2-7%), then liraglutide, less with semaglutide; dysesthesia approximately 5% with semaglutide at standard doses, up to 20% at high doses; rare angioedema, hypersensitivity, blistering disease, vasculitis and severe cutaneous reactions.","limitations":"A narrative systematic review with no pooled estimate, mixing trials with pharmacovigilance and case reports, so frequencies are not comparable across sources.","plain_summary":"This systematic review collected one hundred and one studies, from randomized trials to case reports, describing skin side effects of semaglutide, liraglutide and tirzepatide. Injection-site reactions were most often reported with tirzepatide (2-7%), and a burning or tingling skin sensation (dysesthesia) with semaglutide, in about 5% at standard doses and up to 20% at high-dose formulations. Rare but serious reactions were also reported; most skin effects were mild, and no pooled estimate or comparison with untreated people was made.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1372,"doi":"10.3390/jcm15207797","pmid":"42941312","nct_ids":"[]","title":"Real-World Effectiveness, Documented Adverse Events, and Treatment Adherence of Semaglutide and Liraglutide in Omani Patients: A Retrospective Observational Study","authors":"[\"Al-Himali N\", \"Al-Habsi H\", \"Al Mushrafi A\", \"Al Shidi A\", \"Abbas A\", \"Al Kindi A\", \"Syed H\", \"Mohammadi I\", \"Al Subhi A\", \"Al Kiyumi MH\"]","journal":"Journal of clinical medicine","publication_date":"2026-10-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in obesity and type 2 diabetes mellitus (T2DM), but comparative real-world evidence from the Middle East remains limited. We compared the effectiveness, documented adverse events, adherence and persistence of once-weekly semaglutide and once-daily liraglutide in Omani adults. Methods: Retrospective cohort study of adults treated with semaglutide or liraglutide at Sultan Qaboos University Hospital between January 2024 and December 2025. The primary outcome was change in body mass index (BMI) at 3 and 6 months; change in body weight, percentage total body weight loss and the proportions achieving at least 5% and at least 10% weight loss. Because treatment indication and exposure differed markedly between groups, the primary comparison used propensity-score overlap weighting with additional covariate adjustment, implemented in a design-based general linear model. A mixed model for repeated measures supported the primary analysis and handled missing visits under a missing-at-random assumption, with a delta-adjusted pattern-mixture analysis used to test departures from that assumption. Persistence was analysed with Kaplan-Meier estimation and Cox regression adjusted for baseline covariates only. Secondary outcomes were corrected for multiplicity using the Benjamini-Hochberg procedure. Analyses are labelled throughout as primary, prespecified secondary, or post hoc exploratory. No patient received semaglutide 2.4 mg weekly, the dose licenced for chronic weight management, due to unavailability during the study period. Results: Of 287 treatment records supplied, 257 unique patients were analysed (liraglutide n = 135; semaglutide n = 122). Semaglutide was associated with a greater reduction in BMI than liraglutide at 3 months (adjusted difference -0.60 kg/m2, 95% CI -1.12 to -0.07; p = 0.026) and at 6 months (-1.42 kg/m2, 95% CI -2.60 to -0.24; p = 0.019). In clinical units, the adjusted difference in body weight was -1.70 kg at 3 months (95% CI -3.10 to -0.29; p = 0.018) and -3.66 kg at 6 months (95% CI -6.72 to -0.60; p = 0.020). At 6 months, 56.5% of semaglutide-treated and 24.7% of liraglutide-treated patients had lost at least 5% of body weight (p < 0.001), and 30.4% versus 4.9% had lost at least 10% (p < 0.001). The mixed model gave the same conclusion (group-by-time interaction p < 0.001). No statistically detectable difference in glycated hemoglobin HbA1c change was observed at either time point (p = 0.132 and p = 0.158; interaction p = 0.360). Of eight secondary cardiometabolic outcomes, only total cholesterol at 3 months remained significant after correction for multiplicity (adjusted p = 0.024). Documented adverse events were infrequent and did not differ between groups (12.6% versus 8.2%, p = 0.251). Hypoglycaemia occurred in seven liraglutide-treated and one semaglutide-treated patient (p = 0.069 by exact test) and was not significant after weighting and adjustment for background insulin or sulfonylurea use (p = 0.345). Crude discontinuation was 48.9% with liraglutide versus 9.0% with semaglutide, but median exposure was 17 versus 6 months. After accounting for time at risk, no difference in persistence was statistically apparent (log-rank p = 0.328; adjusted hazard ratio for semaglutide 1.60, 95% CI 0.61 to 4.19). Documented adherence was higher with semaglutide (95.9% versus 83.7%, p = 0.001). Conclusions: In this cohort, semaglutide was associated with a modestly greater reduction in BMI and body weight than liraglutide, and with a higher proportion of patients achieving clinically meaningful weight loss. Glycaemic and most cardiometabolic comparisons were inconclusive once confounding, multiplicity and limited precision were accounted for, and the large apparent difference in discontinuation was no longer statistically apparent after allowing for unequal time at risk. These findings are associative. They describe the drugs as prescribed in one health-care setting, at doses that are not pharmacologically equivalent, and should not be read as evidence of comparative causal superiority.","url":"https://pubmed.ncbi.nlm.nih.gov/42941312/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":915,"doi":"10.1016/j.ejphar.2026.179418","pmid":"42849688","nct_ids":"[]","title":"Tirzepatide alleviates hepatic steatosis and inflammation in MASLD partly through suppression of macrophage Dectin-1/Syk/NF-κB signaling","authors":"[\"He Y\", \"Ma T\", \"Xing H\", \"Cao X\", \"Song F\", \"Pan Y\", \"Ren L\"]","journal":"European journal of pharmacology","publication_date":"2026-10-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Metabolic stress, hepatic lipid accumulation, and macrophage-associated sterile inflammation are closely involved in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Tirzepatide improves metabolic outcomes, but its effects on macrophage inflammatory signaling in MASLD remain unclear. This study investigated the protective effects of tirzepatide against high-fat, high-fructose diet (HFHFD)-induced MASLD and examined the potential involvement of macrophage Dectin-1/spleen tyrosine kinase (Syk)/nuclear factor-κB (NF-κB) signaling. After 7 weeks of HFHFD feeding to establish the MASLD model, male C57BL/6J mice received tirzepatide (10 nmol/kg, subcutaneously, every 3 days) for an additional 7 weeks. Biochemical assays, histology, hepatic RNA sequencing (RNA-seq), RT-qPCR, Western blotting, and immunofluorescence were performed. Palmitic acid (PA)-stimulated RAW264.7 cells, siRNA-mediated Dectin-1 knockdown, and a RAW264.7 cell-derived conditioned medium-based macrophage-hepatocyte indirect interaction model were used for mechanistic validation. Tirzepatide treatment improved HFHFD-induced metabolic dysfunction, liver injury, hepatic steatosis, and inflammatory responses in mice. RNA-seq revealed enrichment of C-type lectin receptor and NF-κB signaling pathways, while HFHFD-induced Clec7a upregulation was reversed by tirzepatide. Tirzepatide reduced hepatic macrophage accumulation, Dectin-1 expression, and Syk/p65 phosphorylation. In PA-stimulated RAW264.7 cells, tirzepatide suppressed pro-inflammatory cytokine expression and secretion and inhibited Dectin-1/Syk/NF-κB activation. Conditioned medium from tirzepatide-treated RAW264.7 cells attenuated lipid accumulation and abnormalities in lipid metabolism- and inflammation-related gene expression in HepG2 cells. Dectin-1 knockdown itself attenuated PA-induced inflammatory responses and was associated with a reduced additional response to tirzepatide. These findings suggest that tirzepatide alleviates HFHFD-induced MASLD, with suppression of macrophage Dectin-1/Syk/NF-κB signaling potentially contributing to these effects.","url":"https://pubmed.ncbi.nlm.nih.gov/42849688/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":"{\"route\": \"subcutaneous\", \"dose\": \"10 nmol/kg every 3 days\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": \"7 weeks\"}","domains":"[\"inflammation\", \"liver\", \"immune\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"diet-induced hepatic steatosis and inflammation (MASLD) in mice, and the role of macrophage Dectin-1/Syk/NF-κB signalling","endpoints":null,"effect_estimate":"Tirzepatide improved diet-induced metabolic dysfunction, liver injury, hepatic steatosis and inflammation in mice and reduced Dectin-1/Syk/NF-κB signalling; Dectin-1 knockdown itself reduced inflammation and left a smaller additional response to tirzepatide; no numbers reported","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male mice only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"high-fat, high-fructose diet-induced MASLD (mouse model)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male mice on a high-fat, high-fructose diet and macrophage and liver cell lines; no human participants.","mediation":"possibly","mediation_notes":"Tirzepatide improved metabolic dysfunction in the mice, and the abstract reports no weight data or analysis separating the liver effect from metabolic change; the Dectin-1 knockdown tests a signalling pathway, not weight loss.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; no p values or group sizes reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: preclinical mouse and cell-line study.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no known competing financial interests or personal relationships that could have influenced the work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Preclinical mouse and cell-line study with no group sizes or numerical results in the abstract; the authors say the macrophage signalling pathway only potentially contributes to the effect.","plain_summary":"In male mice with fatty liver disease brought on by a high-fat, high-fructose diet, 7 weeks of tirzepatide improved liver fat, liver injury and inflammation, and lowered a macrophage inflammatory pathway (Dectin-1/Syk/NF-κB); cell experiments supported the same pathway. The abstract gives no group sizes or numerical results. This is animal and cell work and does not show the same effect in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1073,"doi":"10.23876/j.krcp.26.147","pmid":"42860337","nct_ids":"[]","title":"Combined empagliflozin and liraglutide therapy protects against tacrolimus-induced pancreatic and renal injury associated with oxidative stress reduction","authors":"[\"Na DH\", \"Fang X\", \"Lee H\", \"Eum SH\", \"Ko EJ\", \"Yoon HE\", \"Shin YJ\", \"Lim SW\", \"Chung BH\"]","journal":"Kidney research and clinical practice","publication_date":"2026-10-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in type 2 diabetes mellitus for glycemic control and organ protection. This study investigated whether the combined use of empagliflozin (EMPA) and liraglutide (LIRA) could protect against pancreatic and renal damage caused by tacrolimus (TAC). [METHODS] Male Sprague-Dawley rats received TAC for 4 weeks, either alone, or in combination with EMPA, LIRA, or both. Metabolic, histologic, and molecular parameters were assessed in vivo and in vitro. TAC caused hyperglycemia, reduced creatinine clearance, pancreatic β-cell loss, renal tubulointerstitial fibrosis, and increased oxidative stress and apoptosis. [RESULTS] Either EMPA or LIRA alone partially attenuated these changes, whereas their combination provided enhanced protection- improving kidney function, preserving islet integrity, and reducing fibrosis and cell death. In the kidney and pancreas, dual therapy restored antiapoptotic and antioxidant signaling while suppressing profibrotic pathways, thereby mitigating oxidative stress and injury. Cell-based experiments further confirmed that EMPA plus LIRA enhanced cell viability and reduced reactive oxygen species generation in TAC-injured HK-2 and INS-1 cells. [CONCLUSION] These findings indicate that combined SGLT2i and GLP-1RA therapy confers additive metabolic protection associated with attenuation of oxidative stress in tacrolimus-induced pancreatic and renal damage in this preclinical model, warranting further investigation of its potential as an adjunct strategy for posttransplant diabetes mellitus and nephrotoxicity.","url":"https://pubmed.ncbi.nlm.nih.gov/42860337/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":"{\"treatment_duration\": \"4 weeks\", \"dose\": null, \"route\": null, \"comparator\": \"tacrolimus alone (empagliflozin alone and liraglutide plus empagliflozin were the other arms)\"}","domains":"[\"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"protection against tacrolimus-induced pancreatic and renal injury","endpoints":null,"effect_estimate":"Liraglutide or empagliflozin alone partially attenuated tacrolimus-induced injury; the combination gave enhanced protection (better kidney function, preserved islets, less fibrosis and cell death); no numbers reported","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male rats only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract (tacrolimus caused hyperglycaemia in the rats)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"tacrolimus-induced pancreatic and renal injury (rat model)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male rats with tacrolimus-induced injury and kidney and pancreatic cell lines; no human participants.","mediation":"possibly","mediation_notes":"No weight, HbA1c or mediation analysis is reported; tacrolimus raised blood glucose and the treatments gave metabolic protection, so organ protection is not separated from glycaemic improvement.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"tacrolimus alone (empagliflozin alone and liraglutide plus empagliflozin were the other arms)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; no p values or group sizes reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: preclinical rat and cell-line study with no group sizes or statistics in the abstract.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Preclinical rat and cell-line study with no group sizes or numerical results in the abstract; the main exposure combines liraglutide with an SGLT2 inhibitor, so only the liraglutide-alone arm isolates its effect, and the authors call for further investigation.","plain_summary":"In male rats given the transplant drug tacrolimus for 4 weeks, liraglutide alone partly reduced the damage to the pancreas and kidneys, and liraglutide combined with empagliflozin protected more; cell experiments pointed the same way. The abstract gives no group sizes or numerical results. This is animal and cell work and does not show the same effect in people.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1109,"doi":"10.3390/healthcare14193355","pmid":"42881794","nct_ids":"[]","title":"Real-World Anthropometric Outcomes, Safety, and Use Patterns of GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Obesity and Glucose Metabolism Disorder: A Nationwide Multicentre Community Pharmacy Study","authors":"[\"Vergniory-Trueba O\", \"Treceño-Lobato C\"]","journal":"Healthcare (Basel, Switzerland)","publication_date":"2026-10-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although randomized clinical trials have demonstrated substantial weight loss and metabolic benefits with incretin-based therapies, real-world evidence is needed to characterize anthropometric outcomes, safety, prescribing patterns, and treatment use under routine clinical conditions. [OBJECTIVES] The objective of this study was to characterize real-world anthropometric outcomes, safety, and use patterns of GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists in patients with obesity or glucose metabolism disorder receiving treatment through Spanish community pharmacies. [METHODS] A nationwide multicentre cross-sectional study with retrospective data collection was conducted between January and April 2026 across community pharmacies in Spain. Adult patients receiving GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists were consecutively enrolled and classified according to therapeutic indication (obesity or glucose metabolism disorder). Changes in body weight and body mass index (BMI) were assessed using paired-sample t-tests, while multivariable linear regression explored independent determinants of weight loss. Crude safety signals were initially evaluated using exploratory crude safety association analysis based on Odds Ratios (ORs). Subsequently, multivariable logistic regression was performed to identify independent predictors of suspected digestive adverse drug reactions after adjustment for demographic characteristics, treatment-related variables, lifestyle factors, and concomitant glucose-lowering therapies. Baseline body weight was retrospectively reported by participants and was not independently verified against clinical records or other objective sources, whereas current body weight was measured by the pharmacist at the study visit. [RESULTS] A total of 531 patients were included (52.2% with obesity; 47.8% were classified in the glucose metabolism disorder (GMD) cohort, comprising 200 patients with type 2 diabetes mellitus and 54 with prediabetes/fasting glucose disturbance; the mean age was 56.5 ± 12.5 years; and 66.7% were women). The mean observed reduction in body weight from treatment initiation to the study assessment was 12.17 ± 10.64 kg, corresponding to an 11.71% ± 9.40% reduction relative to retrospectively reported baseline weight. Overall, 73.9% and 54.1% of participants achieved ≥5% and ≥10% weight loss, respectively. No statistically significant unadjusted difference in relative weight loss was detected across treatment groups; however, equivalence was not formally assessed. Gastrointestinal suspected adverse drug reactions were the most frequently reported safety outcomes. Exploratory crude analyses showed nominal associations between Wegovy® and nausea/vomiting and between Mounjaro® and constipation, as well as between concomitant insulin and dizziness and SGLT2 inhibitor therapy and urinary disorders; however, none of these associations remained statistically significant after Benjamini-Hochberg correction for multiple testing. In the exploratory multivariable linear regression model, treatment duration, treatment agent, dietary adherence, light physical activity, and age showed statistically significant adjusted associations with observed percentage weight loss. In the multivariable logistic regression model, increasing age was the only variable significantly associated with lower odds of reported suspected digestive adverse drug reactions (adjusted OR = 0.97 per year; 95% CI 0.96-0.99; p = 0.003). [CONCLUSIONS] Observed percentage weight loss varied across treatment groups, although between-treatment comparisons should be interpreted cautiously because of differences in treatment duration, therapeutic indication, sample size, and dose exposure. Given the retrospective ascertainment of baseline weight and the cross-sectional design, these findings should be interpreted as real-world estimates of observed weight change rather than causal estimates of treatment effectiveness. Reported suspected adverse drug reactions were common, particularly gastrointestinal events. Although several nominal associations were observed in exploratory crude analyses, none remained statistically significant after correction for multiple testing. These findings support the importance of individualized monitoring in community pharmacy settings. These findings provide a rationale for the prospective development and evaluation of a standardized pharmacy-led dispensing and follow-up protocol to support patient safety and treatment adherence.","url":"https://pubmed.ncbi.nlm.nih.gov/42881794/","source_name":"pubmed","source_tier":1,"coi_statement":"O.V.-T. and C.T.-L. are members of the Board of Directors of the Pharmaceutical Care Spain Foundation. C.T.-L. is also an employee of the Universidad Europea Miguel de Cervantes. The authors declare no other personal circumstances or interests that may be perceived as influencing the representation or interpretation of reported research results. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"unknown","drugs":"[\"glp-1 receptor agonists\", \"dual gip/glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"none (within-patient change from treatment initiation; treatment groups compared with each other)\", \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"Change in body weight and BMI, with safety (suspected adverse drug reactions) and use patterns","endpoints":null,"effect_estimate":"Mean body weight reduction 12.17 ± 10.64 kg (11.71% ± 9.40%); 73.9% reached ≥5% and 54.1% ≥10% weight loss; no unadjusted difference in relative weight loss across treatment groups; digestive reactions lower with increasing age (adjusted OR = 0.97 per year)","confidence_interval":"not reported in abstract","p_value":null,"sample_size":531,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": \"56.5 ± 12.5 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"66.7% women\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (52.2% with obesity)\", \"diabetes_status\": \"mixed (200 with type 2 diabetes mellitus and 54 with prediabetes/fasting glucose disturbance)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity or glucose metabolism disorder\", \"sample_size\": 531, \"inclusion_exclusion\": \"adults receiving GLP-1 or dual GIP/GLP-1 receptor agonists at Spanish community pharmacies, consecutively enrolled\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were treated for obesity (52.2%) or a glucose metabolism disorder, including 200 with type 2 diabetes; mean age 56.5.","mediation":"not_applicable","mediation_notes":"Not applicable: the main outcome is body weight itself.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": 531, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"none (within-patient change from treatment initiation; treatment groups compared with each other)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"SDs and one adjusted OR with CI (95% CI 0.96-0.99); no CI for the weight change; baseline weight self-reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: an uncontrolled cross-sectional study of treated users with self-reported baseline weight, closest to a case series.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Suspected gastrointestinal adverse reactions were most common; nominal crude associations (Wegovy with nausea/vomiting, Mounjaro with constipation) did not survive multiple-testing correction; older age was linked to lower odds of digestive reactions (adjusted OR = 0.97 per year).","limitations":"Baseline weight self-reported and unverified; cross-sectional design with no untreated comparator; treatment groups differ in duration, indication, size and dose, so the findings are not causal estimates.","plain_summary":"This study surveyed 531 adults collecting GLP-1 or dual GIP/GLP-1 drugs at Spanish community pharmacies for obesity or blood-sugar disorders (mean age 56.5, 66.7% women). Compared with the starting weight people recalled, they had lost on average 12.17 kg, and weight loss did not differ significantly between drugs in unadjusted analysis. Stomach and bowel side effects were the most common, and no drug-specific side-effect link held after correcting for multiple tests. With no untreated comparison group and self-reported starting weights, this describes observed change rather than proving the drugs' effect.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":960,"doi":"10.1111/dom.71402","pmid":"42842950","nct_ids":"[]","title":"Kidney Outcomes With GLP-1 Receptor Agonists and Tirzepatide Versus Finerenone in Type 2 Diabetes and Chronic Kidney Disease: A Real-World Cohort Study","authors":"[\"Sehtman-Shachar DR\", \"Fishkin A\", \"Leibowitz G\", \"Mosenzon O\", \"Schechter M\", \"Aharon-Hananel G\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To compare kidney outcomes after GLP-1 receptor agonists (RA) or tirzepatide (GLP-1/GIP RAs) versus finerenone initiation in adults with Type 2 diabetes (T2D) and moderate chronic kidney disease (CKD). [METHODS] In a retrospective TriNetX global network study (July 2021-November 2025), adults with T2D and CKD stages 3-4 initiating GLP-1/GIP RAs or finerenone were 1:1 propensity-score matched and followed ≤ 2.5 years. The primary endpoint was a composite of ESKD, Stage 5 CKD, or dialysis initiation. Secondary analyses compared annual total (0-2.5 years) and chronic (0.5-2.5 years) estimated glomerular filtration rate (eGFR) slopes. Sensitivity analyses included positive/negative controls, extended follow-up, and stratification by age, sex, baseline kidney function, glycated haemoglobin A1c, BMI, specific GLP-1/GIP RA, and baseline medications. [RESULTS] Among 4554 individuals (43.3% women, mean age 70.7 years, mean eGFR 39.4 mL/min/1.73 m2), the primary endpoint occurred in 110 (4.8%) GLP-1/GIP RAs and 136 (6.0%) finerenone initiators (hazard ratio: 0.71 [95% CI: 0.55-0.91]; 2.5-year absolute risk difference: -1.14% [-2.45 to 0.17]). Between-group differences in total and chronic eGFR slope with GLP-1/GIP RA versus finerenone were 1.04 mL/min/1.73 m2/year [95% CI: 0.32 to 1.75] and -0.08 mL/min/1.73 m2/year [95% CI, -1.27 to 1.12], respectively. Sensitivity analyses were consistent. Baseline albuminuria data were missing for most participants. [CONCLUSIONS] In a real-world cohort, GLP-1/GIP RAs versus finerenone initiation was associated with a lower relative hazard of adverse kidney outcomes, without evidence of a difference in absolute risk. This was accompanied by total, but not chronic, eGFR slope mitigation. Residual confounding from under-sampled albuminuria is possible, and findings should be interpreted within this specific matched population.","url":"https://pubmed.ncbi.nlm.nih.gov/42842950/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"finerenone\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"kidney\"]","outcome_type":"mixed","primary_outcome":"composite of ESKD, Stage 5 CKD, or dialysis initiation","endpoints":null,"effect_estimate":"Kidney composite HR 0.71 for GLP-1/GIP RAs versus finerenone (110 vs 136 events); 2.5-year absolute risk difference -1.14%, CI crossing zero; total eGFR slope difference 1.04 mL/min/1.73 m2/year; chronic slope difference -0.08, CI crossing zero","confidence_interval":"95% CI: 0.55-0.91 (hazard ratio)","p_value":null,"sample_size":4554,"follow_up":"≤ 2.5 years","direction":"mixed","population":"{\"mean_age\": \"70.7 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"43.3% women\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"CKD stages 3-4 required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with CKD stages 3-4 (moderate chronic kidney disease)\", \"sample_size\": 4554, \"inclusion_exclusion\": \"adults with T2D and CKD stages 3-4 initiating GLP-1/GIP RAs or finerenone, 1:1 propensity-score matched\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and CKD stages 3-4 (mean age 70.7 years); BMI is not reported.","mediation":"possibly","mediation_notes":"No weight or HbA1c change and no mediation analysis are reported; stratifying by baseline HbA1c and BMI tests effect modification and does not separate weight or glycaemic effects.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 4554, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"finerenone\", \"follow_up_duration\": \"≤ 2.5 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: 0.55-0.91 (hazard ratio)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single retrospective propensity-matched cohort with an active comparator; a single observational study is capped at LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Observational propensity-matched cohort with an active comparator from a different drug class; baseline albuminuria was missing for most participants, so residual confounding is possible, and the authors say findings apply to this matched population.","plain_summary":"In a TriNetX health-record study of 4554 matched adults with type 2 diabetes and moderate chronic kidney disease (mean age 70.7 years), starting a GLP-1 drug or tirzepatide rather than finerenone was linked to a lower relative risk of kidney failure, stage 5 disease or dialysis (110 vs 136 events; hazard ratio 0.71). The absolute risk difference was not significant, and the chronic eGFR slope did not differ, though the total slope favoured the GLP-1 group. This is observational, and missing albuminuria data leave room for confounding.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":970,"doi":"10.1111/jop.70191","pmid":"42843413","nct_ids":"[]","title":"Adverse Oral and Salivary Effects Associated With Glucagon-Like Peptide-1 Receptor Agonists: Clinical Insights","authors":"[\"Gilligan G\", \"Garola F\", \"Wagner VP\", \"Martins MD\"]","journal":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","publication_date":"2026-10-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The expanding use of glucagon-like peptide-1 receptor agonists and the dual incretin agonist tirzepatide for Type 2 diabetes mellitus and obesity has drawn attention to potential oral and salivary adverse effects. This short communication summarizes the available evidence, discusses potential mechanisms, and highlights implications for oral medicine practice. [METHODS] A narrative synthesis of published case reports, pharmacovigilance findings, and indirect experimental evidence was undertaken to discuss reported manifestations, biological plausibility, and existing knowledge gaps. [RESULTS] Reported manifestations include xerostomia, hyposalivation, dysgeusia, oral mucosal discomfort, burning sensations, and throat-related symptoms. Proposed mechanisms include modulation of cyclic adenosine monophosphate-dependent signaling in salivary acinar cells, altered autonomic regulation of salivary secretion, and dehydration secondary to gastrointestinal adverse events. Reduced salivary protection combined with gastric acid exposure from reflux or vomiting may increase susceptibility to dental erosion, although a direct association with these therapies has not been established. Sporadic immune-mediated mucocutaneous reactions and facial soft-tissue changes associated with rapid weight loss have also been described. Evidence remains limited and largely indirect. [CONCLUSION] Potential oral and salivary adverse effects warrant clinical awareness, careful medication history-taking, assessment of salivary function, and individualized preventive care. Systematic reporting and focused clinical and experimental studies are needed to clarify causality, frequency, and underlying mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42843413/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"narrative_review","drugs":"[\"glp-1 receptor agonists\", \"tirzepatide\"]","drug_details":"{\"dose\": \"various\", \"route\": \"various\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"immune\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"none","primary_outcome":"oral and salivary adverse effects reported with GLP-1 receptor agonists and tirzepatide","endpoints":null,"effect_estimate":"No quantitative result; reported manifestations are listed (xerostomia, hyposalivation, dysgeusia and others), and a direct association with dental erosion has not been established","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (review scope: drug use for type 2 diabetes and obesity)\", \"diabetes_status\": \"mixed (review scope: drug use for type 2 diabetes and obesity)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes mellitus and obesity (indications for the drugs, review scope)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review covers GLP-1 drug use for type 2 diabetes and obesity, conditions the target group does not have.","mediation":"possibly","mediation_notes":"No weight or glycaemic data are reported; the review attributes some oral effects to dehydration after gastrointestinal effects and some facial changes to rapid weight loss, without separating mechanisms.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; no quantitative data\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: narrative short communication with no new primary outcome data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Reported xerostomia, hyposalivation, dysgeusia, oral mucosal discomfort, burning sensations and throat-related symptoms; possible susceptibility to dental erosion, with no direct association established; evidence limited and largely indirect","limitations":"Narrative short communication drawing on case reports, pharmacovigilance and indirect experimental evidence; the authors say evidence is limited and largely indirect and that causality and frequency remain to be clarified.","plain_summary":"This short narrative review gathers case reports, adverse-event reporting findings and indirect experimental evidence on mouth and saliva problems with GLP-1 drugs and tirzepatide. Reported problems include dry mouth, reduced saliva, altered taste and mouth or throat discomfort; a direct link to dental erosion has not been established. The authors say the evidence is limited and largely indirect, so how often these effects occur and whether the drugs cause them is not known.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":971,"doi":"10.1007/s12020-026-04808-z","pmid":"42842067","nct_ids":"[]","title":"GLP-1R expression and dermatological diseases: a mendelian randomization and real-world study","authors":"[\"Duan X\", \"Liu W\", \"Ma J\", \"Sun B\"]","journal":"Endocrine","publication_date":"2026-10-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Although glucagon-like peptide-1 receptor (GLP-1R) is widely expressed in multiple tissues and organs including skin and subcutaneous tissue, with diverse physiological roles in metabolism and immunity, the potential causal association between GLP-1R expression and dermatological diseases remains unclear. [METHODS] Available cis-expression quantitative trait loci (cis-eQTLs) were selected as genetic instruments for GLP-1R expression. A two-sample Mendelian randomization (MR) analysis was employed to assess the potential causal association between GLP-1R expression and dermatological diseases. Subsequently, a two-step mediation MR analysis was conducted to explore the mediators between GLP-1R expression and dermatological diseases. Finally, a real-world pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) database was conducted to provide supplementary real-world evidence. [RESULTS] Our study revealed distinct associations between GLP-1R expression and dermatological diseases. Specifically, GLP-1R expression was significantly associated with a reduced risk of bullous pemphigoid (OR = 0.47, 95% CI = 0.31-0.72, P < 0.001), as well as an increased risk of psoriasis (OR = 1.19, 95% CI = 1.08-1.32, P < 0.001) and urticaria (OR = 1.41, 95% CI = 1.23-1.61, P < 0.001). Further mediation MR analysis suggested that the immune cell phenotype HLA-DR on B cells might mediate the causal association between GLP-1R expression and bullous pemphigoid, with an estimated mediation proportion of 35.7% (P = 0.003). Other immune cells including Monocytic Myeloid-Derived Suppressor Cells Absolute Count, HLA-DR on CD14 + CD16- monocytes, and HLA-DR on CD14 + monocytes were also identified as potential mediators, with estimated mediation proportions of 23.6% (P = 0.010), 13% (P = 0.024), and 12.7% (P = 0.036), respectively. In the complementary FAERS analysis, consistently, GLP-1RAs reports showed a lower reporting signal for bullous pemphigoid than sodium-glucose cotransporter 2 inhibitors (SGLT2is) reports. [CONCLUSION] Our findings suggest that GLP-1R expression is associated with a reduced risk of bullous pemphigoid, which may be partly mediated by specific immune cell phenotypes.","url":"https://pubmed.ncbi.nlm.nih.gov/42842067/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval: Clinical trial number: not applicable. Competing interests: The authors declare no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"mendelian_randomization","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"route\": null, \"dose\": \"various\", \"comparator\": \"MR: genetically proxied higher versus lower GLP-1R expression (no drug comparator); FAERS: SGLT2 inhibitor reports\", \"treatment_duration\": null}","domains":"[\"rheumatologic\", \"immune\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"risk of dermatological diseases (bullous pemphigoid, psoriasis, urticaria) by genetically proxied GLP-1R expression","endpoints":null,"effect_estimate":"Genetically proxied GLP-1R expression was linked to lower bullous pemphigoid risk (OR 0.47) and higher psoriasis (OR 1.19) and urticaria (OR 1.41) risk; FAERS GLP-1RA reports showed a lower bullous pemphigoid reporting signal than SGLT2 inhibitor reports","confidence_interval":"95% CI = 0.31-0.72 (bullous pemphigoid)","p_value":"P < 0.001","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the genetic-association and FAERS populations are not described in the abstract; no age, BMI or diabetes data are given.","mediation":"possibly","mediation_notes":"A two-step mediation MR attributed part of the bullous pemphigoid association to immune-cell phenotypes (largest 35.7%); weight and glycaemic mediation was not examined and no weight or HbA1c data are reported.","adjusted_for":"[\"other\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Mendelian randomization\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"MR: genetically proxied higher versus lower GLP-1R expression (no drug comparator); FAERS: SGLT2 inhibitor reports\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI = 0.31-0.72 (bullous pemphigoid)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single Mendelian randomization study, capped at LOW, with a supplementary FAERS pharmacovigilance analysis that would be VERY_LOW on its own.","funding_source":"National Natural Science Foundation of China; Natural Science Foundation of Hunan Province; Scientific Research Project of Hunan Provincial Health Commission; Talent Project established by Chinese Pharmaceutical Association Hospital Pharmacy Department; China International Medical Foundation; Medical Research Project of Hunan Medical Association: Clinical Pharmacy Research Program Funded Project","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Genetically higher GLP-1R expression was linked to higher risk of psoriasis (OR 1.19) and urticaria (OR 1.41); FAERS showed a lower bullous pemphigoid reporting signal for GLP-1RAs than for SGLT2 inhibitors","limitations":"The main exposure is genetically proxied GLP-1 receptor expression, not drug use, and the drug data come from a spontaneous-report database with no denominator; populations and sample sizes are not given in the abstract.","plain_summary":"Using genetic variants that change GLP-1 receptor expression, this Mendelian randomization study linked higher expression to a lower risk of bullous pemphigoid (OR 0.47) but a higher risk of psoriasis (OR 1.19) and urticaria (OR 1.41). A check of the FDA adverse-event reporting database found a lower bullous pemphigoid reporting signal for GLP-1 drugs than for SGLT2 inhibitors. Gene expression is not the same as taking the drug, and these are associations, not proof of cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":975,"doi":"10.1111/dom.71377","pmid":"42844025","nct_ids":"[]","title":"Association of GLP1-Receptor Agonist Use With Frailty and Falls in Adults With Type 2 Diabetes","authors":"[\"Zhang S\", \"Lingvay I\", \"Mansi I\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To evaluate the association of initiating glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors (as active comparator) with frailty progression and falls and whether associations differed by baseline frailty. [RESEARCH DESIGN AND METHODS] Five propensity score-matched retrospective cohorts using Veterans Health data (years 2006-2021), utilizing new-user, active-comparator design. The five matched cohorts were at progressive degrees of frailty at baseline and included adults with diabetes and 3 years of baseline data who initiated study medications with at least 90 days of therapy. [MAIN OUTCOMES AND MEASURES] Primary outcome was absolute change in Frailty Index from baseline to follow-up. Secondary outcomes were increase in the frailty index and fall rate during follow-up. Outcomes were assessed in an as-treated framework. [RESULTS] The main matched cohort included 73 592 pairs. Over a mean follow-up of approximately 27 months, glucagon-like peptide-1 receptor agonists initiation was associated with less worsening in frailty index (regression coefficient: -0.0010; 95% CI: -0.0018 to -0.0002; p = 0.011), lower odds of frailty index progression (OR: 0.97; 95% CI: 0.95-0.99; p = 0.003), and a lower fall rate (incidence rate ratio: 0.87; 95% CI: 0.84-0.91; p < 0.001) compared to dipeptidyl peptidase-4 inhibitor initiation. Findings were generally consistent across the other four matched cohorts, with attenuation in the matched cohort with severe frailty at baseline. [CONCLUSIONS] Initiation of glucagon-like peptide-1 receptor agonist was associated with slightly less frailty progression and fewer falls compared with dipeptidyl peptidase-4 inhibitor initiation, but estimates were attenuated in severe frailty.","url":"https://pubmed.ncbi.nlm.nih.gov/42844025/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"dipeptidyl peptidase-4 inhibitors (active comparator)\", \"treatment_duration\": null}","domains":"[\"aging\"]","outcome_type":"mixed","primary_outcome":"absolute change in Frailty Index from baseline to follow-up","endpoints":null,"effect_estimate":"GLP-1 receptor agonist initiation was linked to less frailty index worsening (regression coefficient -0.0010), lower odds of frailty index progression (OR 0.97) and a lower fall rate (IRR 0.87) than DPP-4 inhibitor initiation; estimates were attenuated in the severe-frailty cohort","confidence_interval":"95% CI: -0.0018 to -0.0002 (frailty index change)","p_value":"p = 0.011","sample_size":147184,"follow_up":"mean approximately 27 months","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes (Veterans Health data), at graded levels of baseline frailty\", \"sample_size\": 147184, \"inclusion_exclusion\": \"adults with diabetes, 3 years of baseline data, new users with at least 90 days of therapy\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants were veterans with type 2 diabetes; age and BMI are not reported in the abstract.","mediation":"possibly","mediation_notes":"No weight or HbA1c change or mediation analysis is reported; propensity matching addresses confounding, not mediation, so the frailty and falls association is presumed confounded with weight and glycaemic change.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 147184, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"dipeptidyl peptidase-4 inhibitors (active comparator)\", \"follow_up_duration\": \"mean approximately 27 months\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -0.0018 to -0.0002 (frailty index change)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: single retrospective new-user, active-comparator cohort; a single observational study is capped at LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Observational propensity-matched as-treated cohort of veterans with diabetes, open to residual confounding; associations were small and attenuated in severe frailty.","plain_summary":"In US veterans with type 2 diabetes (main matched cohort of 73 592 pairs), starting a GLP-1 receptor agonist rather than a DPP-4 inhibitor was linked to slightly less worsening of frailty and fewer falls over a mean of about 27 months (fall rate ratio 0.87). The association was weaker in people who were already severely frail. This is an observational study, so it shows an association, not that the drugs prevented frailty or falls.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":981,"doi":"10.1111/dom.71354","pmid":"42839752","nct_ids":"[]","title":"Efficacy and Safety of Chemically Synthesized Semaglutide Injection (HD1916) for the Treatment of Obesity: A Multicenter, Randomized, Phase III Trial","authors":"[\"Gao L\", \"Ma Y\", \"Zhang Q\", \"Li J\", \"Guo L\", \"Zhang L\", \"Jin H\", \"Wang Y\", \"Jiang C\", \"He W\", \"Quan T\", \"Zhang X\", \"Cao M\", \"Gu W\", \"Ji L\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To evaluate whether HD1916, a chemically synthesised semaglutide, is therapeutically equivalent to the reference product semaglutide (Wegovy) in body weight reduction among Chinese adults with obesity without diabetes. [MATERIALS AND METHODS] This multicenter, randomised, open-label, active-controlled Phase III trial was conducted at 30 centers in China. Adults aged 18-75 years with obesity (BMI ≥ 28 kg/m2) and without diabetes were randomised 1:1 to receive once-weekly subcutaneous HD1916 or semaglutide for 44 weeks. The primary endpoint was the percentage change in body weight from baseline to week 44. Equivalence was established if the 95% confidence interval (CI) of the between-group difference was within the prespecified margin of ±4.16%. Key secondary endpoints included the proportions of participants achieving ≥ 5% and ≥ 10% weight loss and change in waist circumference. [RESULTS] A total of 462 participants were randomised (231 per group). At week 44, mean body weight decreased by 13.1% with HD1916 and 14.4% with semaglutide. The estimated treatment difference was 1.35% (95% CI, -0.02 to 2.72), which fell within the equivalence margin, confirming therapeutic equivalence. Proportions of participants achieving ≥ 5% weight loss (87.8% vs. 90.5%) and ≥ 10% weight loss (68.7% vs. 73.6%), as well as reductions in waist circumference, were comparable between groups. Any-grade treatment-emergent adverse events occurred in 86.5% and 89.2% of participants in the HD1916 and semaglutide groups, respectively; most were Grade 1-2. [CONCLUSIONS] HD1916 demonstrated equivalent body weight reductions to the reference product semaglutide (Wegovy), with a comparable safety profile.","url":"https://pubmed.ncbi.nlm.nih.gov/42839752/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:43:47+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"route\": \"subcutaneous\", \"treatment_duration\": \"44 weeks\", \"dose\": null, \"comparator\": \"reference product semaglutide (Wegovy)\"}","domains":"[\"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"percentage change in body weight from baseline to week 44","endpoints":null,"effect_estimate":"Mean body weight fell 13.1% with HD1916 and 14.4% with reference semaglutide; treatment difference 1.35%, within the ±4.16% equivalence margin; ≥ 5% weight loss 87.8% vs. 90.5% and ≥ 10% weight loss 68.7% vs. 73.6%, comparable","confidence_interval":"95% CI, -0.02 to 2.72","p_value":null,"sample_size":462,"follow_up":"44 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": \"18-75 years\", \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 28, \"obesity_status\": \"obesity required (BMI ≥ 28 kg/m2)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity\", \"sample_size\": 462, \"inclusion_exclusion\": \"Chinese adults aged 18-75 years with obesity (BMI ≥ 28 kg/m2) and without diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (BMI ≥ 28 kg/m2) without diabetes and were Chinese adults aged 18-75 years; mean age and BMI are not reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is body weight change itself.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 462, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"reference product semaglutide (Wegovy)\", \"follow_up_duration\": \"44 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CI reported for the between-group difference against a ±4.16% equivalence margin; 462 randomised\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: open-label randomised phase III trial of 462 people with an intermediate outcome (body weight) over 44 weeks; both arms received semaglutide, so there is no placebo contrast.","funding_source":"CSPC Baike (Shandong) Biopharmaceutical Co., Ltd","industry_funded":"yes","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Any-grade treatment-emergent adverse events in 86.5% (HD1916) and 89.2% (reference semaglutide); most were Grade 1-2","limitations":"Open-label equivalence trial comparing two semaglutide products, so it shows no effect against placebo or no treatment; weight is an intermediate outcome, follow-up was 44 weeks and all participants were Chinese adults with obesity.","plain_summary":"In an open-label randomised trial of 462 Chinese adults with obesity and without diabetes, a chemically synthesised semaglutide (HD1916) was compared with the reference product semaglutide (Wegovy) for 44 weeks. Weight fell 13.1% with HD1916 and 14.4% with the reference product, a difference within the prespecified equivalence margin, and side effects were similar (86.5% and 89.2% had any adverse event, mostly Grade 1-2). The trial tests whether two semaglutide products are equivalent, not whether semaglutide works better than no treatment.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":759,"doi":"10.1073/pnas.2618845123","pmid":"42789307","nct_ids":"[]","title":"An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss","authors":"[\"Thorne AK\", \"Waldeck NJ\", \"Rose JP\", \"Stachowski MJ\", \"Guak H\", \"Keeble AR\", \"Kuusik B\", \"Simon E\", \"Marcheva B\", \"Mastroni JV\", \"Zhu P\", \"Chong LW\", \"Kobayashi Y\", \"Conley NJ\", \"Cohen AB\", \"Omura Y\", \"Omura C\", \"Song W\", \"Wellems M\", \"Ramsey KM\", \"Barish GD\", \"Beutler LR\", \"Gupta RK\", \"Peek CB\", \"McNally EM\", \"Hepler C\", \"Perelis M\", \"Bass J\"]","journal":"Proceedings of the National Academy of Sciences of the United States of America","publication_date":"2026-10-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Current obesity therapies reduce weight but often fail to preserve lean mass or sustain metabolic benefit. Glucagon-like peptide-1 receptor agonists (GLP-1RA) improve obesity-associated metabolic disease, but weight loss is often accompanied by reduced energy expenditure, loss of lean mass, and rapid fat-predominant regain after treatment discontinuation. We hypothesized that pharmacologic activation of adipose thermogenesis could specifically target fat loss, complement appetite suppression by increasing energy expenditure, and improve the metabolic quality of weight loss. Guided by our finding that diet-induced thermogenesis is mediated by a zinc finger protein 423 (ZFP423)-controlled pathway, we developed adipose-directed antisense oligonucleotides (ASOs) targeting ZFP423, a transcriptional repressor of brown and beige adipocyte identity. In lean and diet-induced obese mice, weekly Zfp423 ASO treatment induced white adipose beiging, increased body temperature and oxygen consumption, and improved glucose homeostasis, insulin sensitivity, lipid metabolism, mitochondrial respiration, and hepatic steatosis. When combined with the GLP1-RA semaglutide, Zfp423 ASO produced greater weight and fat loss than either monotherapy while preserving lean mass and improving metabolic outcomes. These findings identify Zfp423 as an RNA therapeutic target and support adipose thermogenesis as a complementary strategy for metabolically healthier obesity treatment.","url":"https://pubmed.ncbi.nlm.nih.gov/42789307/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests statement:E.M.M. is a member of the board of directors for Novartis and serves as a scientific advisory board member for PepGen. M.P. and L.W.C. are employees of Ionis Pharmaceuticals. M.W. is the president of Phenome Technologies. The remaining authors declare no competing interests. A provisional patent application has been filed by Northwestern University related to the methods described in this manuscript involving ZFP423-targeting antisense oligonucleotides (ASOs). A.K.T. and J.B. are listed as inventors. Ionis Pharmaceuticals holds patents on ASO chemistry and design.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"semaglutide alone and Zfp423 ASO alone (either monotherapy)\", \"treatment_duration\": null}","domains":"[\"lean_mass\", \"body_composition\", \"liver\", \"metabolic\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"weight and fat loss, lean-mass preservation and metabolic outcomes with semaglutide plus Zfp423 ASO versus either alone","endpoints":null,"effect_estimate":"Zfp423 ASO plus semaglutide gave greater weight and fat loss than either monotherapy while preserving lean mass and improving metabolic outcomes; no numbers reported","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (lean and diet-induced obese mice)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diet-induced obesity (mice)\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: lean and diet-induced obese mice; no human data.","mediation":"not_applicable","mediation_notes":"Not applicable: the main outcomes are weight and fat loss with lean-mass preservation, which is body composition itself.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"semaglutide alone and Zfp423 ASO alone (either monotherapy)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; group sizes not given\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a preclinical mouse study with no animal numbers or statistics in the abstract.","funding_source":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); HHS | NIH | National Institute on Aging (NIA); HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM); American Diabetes Association (ADA); HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI); U.S. Department of Veterans Affairs (VA); HHS | NIH | National Center for Advancing Translational Sciences (NCATS); HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS); HHS | NIH | National Human Genome Research Institute (NHGRI); HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Two authors are Ionis Pharmaceuticals employees and one sits on the Novartis board; Northwestern University has filed a provisional patent on the Zfp423 ASOs, with two authors listed as inventors.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Mouse-only study with no animal numbers or statistics in the abstract; the combination comparison mainly tests the add-on ASO, and two authors are employees of the company holding patents on ASO chemistry.","plain_summary":"In lean and diet-induced obese mice, an experimental RNA drug (Zfp423 ASO) that switches on fat-burning tissue was tested alone and with semaglutide. The combination produced more weight and fat loss than either drug alone while keeping lean mass. This is animal evidence only, and the abstract gives no numbers.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":947,"doi":"10.1016/j.ahj.2026.107626","pmid":"42838477","nct_ids":"[\"NCT05669755\"]","title":"Design and baseline characteristics of the CagriSema cardiovascular outcomes trial (REDEFINE 3)","authors":"[\"Cavender MA\", \"Jastreboff AM\", \"Cheng AYY\", \"Davies MJ\", \"Donaldson L\", \"Gerlach LO\", \"Gylvin SH\", \"Jacobsen JB\", \"Marx N\", \"Osorto Contreras CK\", \"Le Roux CW\", \"Lincoff AM\"]","journal":"American heart journal","publication_date":"2026-10-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Cagrilintide-semaglutide (CagriSema) is a fixed-dose combination of the amylin receptor agonist cagrilintide and the glucagon-like peptide-1 receptor agonist semaglutide administered subcutaneously once weekly. CagriSema has demonstrated significant weight reduction and improved glycemic control in participants with excess adiposity and type 2 diabetes (T2D). [METHODS] REDEFINE 3 is a double-blind, randomized, placebo-controlled trial involving participants with established cardiovascular disease (CVD) and body mass index (BMI) ≥25.0 kg/m2 with/without T2D randomized to CagriSema 2.4 mg/2.4 mg or placebo, plus standard of care. The safety objective is to confirm noninferiority of CagriSema compared with placebo on cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE-3). The efficacy objective is to confirm the superiority of CagriSema compared with placebo on cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or revascularization (MACE-4). [RESULTS] Between 1/2023-12/2024, 7076 adults at 575 sites in 24 countries were randomized. Mean age at baseline was 66 years. BMI ≥30 kg/m2 was present in 76% of participants (n=5370). In participants with T2D (n=4348, 61%), the mean duration of T2D was 12 years and mean glycated hemoglobin was 7.7%. Most participants had a prior myocardial infarction (n=4369, 62%). Prior stroke (n=1311, 19%) and peripheral arterial disease (n=769, 11%) were less common, and 617 participants (9%) had more than one qualifying CVD criteria. [CONCLUSION] The REDEFINE 3 trial will provide evidence regarding the cardiovascular safety and efficacy of CagriSema, a novel fixed-dose combination therapy that could improve cardiovascular outcomes in a broad population of people with established CVD and excess adiposity. [TRIAL REGISTRATION] The REDEFINE 3 trial is registered at ClinicalTrials.gov (NCT05669755).","url":"https://pubmed.ncbi.nlm.nih.gov/42838477/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew A. Cavender, Ania M. Jastreboff, Alice Y.Y. Cheng, Melanie J. Davies, Lucienne Donaldson, Lars-Ole Gerlach, Silas Hinsch Gylvin, Jacob Bonde Jacobsen, Nikolaus Marx, Cynthia Karenina Osorto Contreras, Carel W. Le Roux, A. Michael Lincoff reports financial support was provided by Novo Nordisk A S. Matthew A. Cavender reports a relationship with Amgen, Boehringer Ingelheim, Cleerly, Janssen, Novo Nordisk, Novartis, Silence Therapeutics, Massachusetts General Hospital PCORI that includes: non-financial support. Matthew A. Cavender reports a relationship with AbbVie, AOP Pharmaceuticals, Corcept, Faraday Pharma, New Amsterdam Pharma, Novo Nordisk that includes: consulting or advisory. Ania M. Jastreboff reports a relationship with Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Rhythm Pharmaceuticals that includes: employment. Ania M. Jastreboff reports a relationship with Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth Flyte, Metsera, Novo Nordisk, Pfizer, Regeneron, Roche Genentech, Scholar Rock, Structure Therapeutics, Syntis Bio, Viking Therapeutics, WW International, Zealand Pharmaceuticals that includes: consulting or advisory. Ania M. Jastreboff reports a relationship with State 4 Therapeutics that includes: employment. Alice Y.Y. Cheng reports a relationship with Abbott, Amgen, Aspen, Astra Zeneca, Bausch, Bayer, Biomea, Boehringer Ingelheim, Dexcom, Eisai, Eli Lilly, GSK, Insulet, HLS Therapeutics, Medtronic, Merck, MSD, Novo Nordisk, Pfizer, Sandoz, Sanofi, Vertex that includes: consulting or advisory and speaking and lecture fees. Alice Y.Y. Cheng reports a relationship with Abbott, Aspen, Bausch, Bayer, Biomea, BioSyent, Boehringer Ingelheim, Caliway Biopharmaceuticals, Dexcom, Eisai, Eli Lilly, Gan & Lee, Insulet, HLS Therapeutics, Merck, MSD, Novo Nordisk, Sandoz, Sanofi, Vertex that includes: consulting or advisory and speaking and lecture fees. Melanie J. Davies reports a relationship with Eli Lilly, Novo Nordisk and Sanofi that includes: consulting or advisory and speaking and lecture fees. Melanie J. Davies reports a relationship with Kailera that includes: consulting or advisory. Melanie J. Davies reports a relationship with AbbVie, Amgen, AstraZeneca, Biomea Fusion, Carmot Roche, Daewoong Pharmaceutical, EktaH, GSK, Innovent Bio, Regeneron, Sanofi and Zealand Pharma that includes: consulting or advisory. Melanie J. Davies reports a relationship with AstraZeneca, Boehringer Ingelheim and Zuellig Pharma that includes: speaking and lecture fees. Melanie J. Davies reports a relationship with AstraZeneca, Boehringer Ingelheim and Novo Nordisk that includes: funding grants. Lucienne Donaldson reports a relationship with Novo Nordisk A S that includes: employment and equity or stocks. Lars-Ole Gerlach reports a relationship with Novo Nordisk A S that includes: employment and equity or stocks. Silas Hinsch Gylvin reports a relationship with Novo Nordisk A S that includes: employment and equity or stocks. Jacob Bonde Jacobsen reports a relationship with Novo Nordisk A S that includes: employment and equity or stocks. Cynthia Karenina Osorto Contreras reports a relationship with Novo Nordisk A S that includes: employment and equity or stocks. Nikolaus Marx reports a relationship with Deutsche Forschungsgemeinschaft German Research Foundation, TRR 219, Project-ID 322900939 M03, M05 that includes: funding grants and non-financial support. Nikolaus Marx reports a relationship with Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, Novo Nordisk that includes: speaking and lecture fees. Nikolaus Marx reports a relationship with Boehringer Ingelheim that includes: funding grants. Nikolaus Marx reports a relationship with Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Novo Nordisk that includes: consulting or advisory. Nikolaus Marx reports a relationship with Boehringer Ingelheim and Novo Nordisk that includes: employment. Carel W. le Roux reports a relationship with EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board that includes: funding grants. Carel W. le Roux reports a relationship with Novo Nordisk, Roche, Herbalife, Morphic Medical, Eli Lilly, Johnson & Johnson, Gila, Irish Life Health, Boehringer Ingelheim, Currax, Zealand Pharma, Keyron, AstraZeneca, Arrowhead Pharma, Amgen, AbbVie, Metsera, Nymble, Olympus, and Rhythm Pharma that includes: consulting or advisory and speaking and lecture fees. Carel W. le Roux reports a relationship with with Irish Society for Nutrition and Metabolism that includes: board membership. Carel W. le Roux reports a relationship with Metsera and Nymble that includes: consulting or advisory and equity or stocks. Carel W. le Roux reports a relationship with My Best Weight clinic and Beyond BMI clinic that includes: employment and equity or stocks. A. Michael Lincoff reports a relationship with AbbVie, AstraZeneca, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, and Novartis that includes: funding grants. A. Michael Lincoff reports a relationship with Akebia Therapeutics, Alnylam Pharmaceuticals, Ardelyx, Canary Cure, Eli Lilly and Company, Entity, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, and ReCor Medical that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"cagrilintide-semaglutide\"]","drug_details":"{\"dose\": \"CagriSema 2.4 mg/2.4 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo, plus standard of care\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"body_composition\", \"metabolic\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"MACE-3 noninferiority (safety) and MACE-4 superiority (efficacy) versus placebo; this paper reports design and baseline only","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":"not reported in abstract","p_value":null,"sample_size":7076,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": \"66 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 25.0, \"obesity_status\": \"overweight or obesity required (BMI ≥25.0 kg/m2); BMI ≥30 kg/m2 in 76%\", \"diabetes_status\": \"mixed (with or without type 2 diabetes; 61% with T2D)\", \"cvd_status\": \"established cardiovascular disease required\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"established cardiovascular disease with excess adiposity (BMI ≥25.0 kg/m2)\", \"sample_size\": 7076, \"inclusion_exclusion\": \"established CVD and BMI ≥25.0 kg/m2, with or without T2D\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had established cardiovascular disease and BMI ≥25.0 kg/m2; 76% had BMI ≥30 kg/m2 and 61% had type 2 diabetes; mean age 66 years.","mediation":"not_applicable","mediation_notes":"Not applicable: a design and baseline report with no outcome yet, so there is no result whose mediation could be judged.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 7076, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo, plus standard of care\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no outcome results; baseline characteristics only\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a design and baseline-characteristics report of a randomized trial, with no outcome data for CagriSema yet.","funding_source":"Novo Nordisk A S (financial support, as reported in the competing-interests declaration)","industry_funded":"yes","manufacturer":"Novo Nordisk A S","author_conflicts":"Several authors are Novo Nordisk employees with stock, and others report consulting, speaking, grant or employment relationships with Novo Nordisk, Eli Lilly and many other companies.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk A S (five authors report employment and equity or stocks).","adverse_events":"not reported in abstract","limitations":"A design and baseline report with no outcome results yet, so no conclusion on cardiovascular safety or efficacy can be drawn; the population had established cardiovascular disease and excess weight, not normal weight.","plain_summary":"This paper describes the design and starting characteristics of REDEFINE 3, a double-blind randomized trial of weekly CagriSema (cagrilintide plus semaglutide) against placebo in 7076 adults with established cardiovascular disease and BMI of at least 25.0. Mean age was 66 years, 76% had BMI of 30 or more, and 61% had type 2 diabetes. It reports no results on heart attacks, strokes or deaths yet.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":982,"doi":"10.1007/s11325-026-03826-5","pmid":"42837024","nct_ids":"[]","title":"GLP-1 receptor agonists for obstructive sleep apnea: a meta-analysis of randomized controlled trials","authors":"[\"Carvalhal G\", \"Mora MMR\", \"Peralta-Jiménez GA\", \"Ayasa L\", \"Barrera V\", \"Advani K\", \"Aljazeeri J\"]","journal":"Sleep & breathing = Schlaf & Atmung","publication_date":"2026-10-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Weight reduction is recommended in all overweight and obese patients with obstructive sleep apnea (OSA). Glucagon-like peptide-1 (GLP-1) receptor agonists-based therapies have demonstrated clinical benefits in reducing weight and could potentially improve OSA outcomes. We aim to analyze the efficacy and safety of GLP-1 receptor agonists-based therapies in patients with moderate-to-severe OSA. [METHODS] We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared GLP-1 receptor agonists-based therapies versus control in adults with moderate-to-severe OSA. We systematically searched electronic databases and registries up to February 10, 2025. Outcomes assessed included apnea-hypopnea index (AHI), body weight, oxygen desaturation index (ODI), minimum oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), and adverse events. [RESULTS] A total of 6 RCTs involving 1,069 participants were included, four evaluating liraglutide and two tirzepatide. Compared with control, GLP-1 receptor agonist-based therapies reduced AHI by - 9.99 events/hour (95% CI, - 16.47 to - 3.50; p < 0.01; I2 = 87%) and body weight by - 9.68 kg (95% CI, - 15.84 to - 3.51; p < 0.01; I2 = 98%). These therapies also reduced SBP by -4.77 mmHg (95% CI, -7.04 to -2.51; p < 0.01), and DBP by -1.41 mmHg (95% CI, -2.71 to -0.11; p = 0.03). No significant differences were observed in ODI or minimum oxygen saturation. GLP-1 receptor agonists-based therapies did not increase the risk of adverse events. [CONCLUSION] GLP-1 receptor agonist-based therapies reduced AHI and body weight in the populations studied. Substantial heterogeneity limits interpretation of the pooled effect magnitude. These findings support their potential role within comprehensive OSA management but do not establish them as substitutes for CPAP. [REGISTRY] International Prospective Register of Systematic Reviews; No.: CRD42024564018; URL: https://www.crd.york.ac.uk/prospero/ .","url":"https://pubmed.ncbi.nlm.nih.gov/42837024/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval: This systematic review and meta-analysis did not require ethical approval as it utilized publicly available data from previously published studies. Disclosure of potential conflicts of interest: Nothing to declare. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Conference presentation: The abstract of preliminary results of this study was presented as a poster presentation at the 2025 International Conference and Annual Meeting of The American Thoracic Society (ATS 2025) in San Francisco, May 2025. Prospective registration: This study was registered in the PROSPERO database (registration number: CRD42024564018).","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"control\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"sleep\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"apnea-hypopnea index (AHI); body weight, ODI, minimum oxygen saturation, blood pressure and adverse events also assessed","endpoints":null,"effect_estimate":"Versus control, AHI fell by 9.99 events/hour and body weight by 9.68 kg; SBP fell by 4.77 mmHg and DBP by 1.41 mmHg; no significant difference in ODI or minimum oxygen saturation; adverse events not increased","confidence_interval":"95% CI, - 16.47 to - 3.50 (AHI)","p_value":"p < 0.01 (AHI)","sample_size":1069,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"moderate-to-severe obstructive sleep apnea\", \"sample_size\": 1069, \"inclusion_exclusion\": \"RCTs of GLP-1 receptor agonist-based therapies versus control in adults with moderate-to-severe OSA\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the review is scoped to adults with moderate-to-severe obstructive sleep apnoea, a condition the target group does not have, and is framed around weight reduction in overweight and obese patients; participant BMI, age and diabetes status are not reported.","mediation":"likely","mediation_notes":"Likely: pooled body weight fell by 9.68 kg alongside the AHI reduction, sleep apnoea is an outcome weight loss is known to improve, and the abstract reports no analysis separating the two.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1069, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"control\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, - 16.47 to - 3.50 (AHI)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis pooling 6 randomized trials (1,069 participants) on an intermediate outcome, limited by substantial heterogeneity (I2 = 87% for AHI) and the small number of trials.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declare no financial or non-financial conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"GLP-1 receptor agonist-based therapies did not increase the risk of adverse events","limitations":"The authors note substantial heterogeneity that limits interpretation of the pooled effect size; only six trials of two drugs were pooled, and the findings do not establish the drugs as substitutes for CPAP.","plain_summary":"This meta-analysis pooled 6 randomized trials (1,069 adults with moderate-to-severe obstructive sleep apnoea) of liraglutide or tirzepatide against control. The drugs lowered the apnoea-hypopnoea index by 9.99 events per hour and body weight by 9.68 kg, and lowered blood pressure, but oxygen desaturation index and minimum oxygen saturation did not differ. Adverse events were not increased, and the results varied widely between trials.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":991,"doi":"10.20944/preprints202610.0314.v1","pmid":null,"nct_ids":"[]","title":"GLP-1 Receptor Agonists and Dual GIP/GLP-1 and Reduction in Major Cardiovascular Events: A Systematic Review and Network Meta-Analysis","authors":"[\"Campos García FJ\", \"Laviada Molina H\", \"Álvarez Becerra AP\", \"Acevedo Menéndez MI\", \"Ortiz Castellanos CJ\", \"Rivera Lavalle JS.\"]","journal":"preprint server","publication_date":"2026-10-06","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Background: </h4> Type 2 diabetes is a cause of cardiovascular morbidity and mortality. Although gluca-gon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists improve cardiovascular outcomes, their comparative effects across the class re-main uncertain because direct head-to-head evidence is limited. <h4>Objective:</h4> To compare these agents for major adverse cardiovascular events (MACE) and establish a treatment hierarchy. <h4>Methods:</h4> This systematic review and network meta-analysis will include parallel-group randomized controlled trials with at least 52 weeks of follow-up involving adults with type 2 diabetes. Eligible trials will compare a GLP-1 receptor agonist or tirzepatide with placebo, standard care, another eligible in-cretin therapy, or, as connector nodes, an SGLT2 inhibitor or basal insulin. The primary outcome is time to first three-point MACE, comprising cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. MEDLINE, Cochrane CENTRAL, Web of Science, ClinicalTrials.gov, and WHO ICTRP, will be searched without date or language restrictions. Study selection and data extraction will involve human verification, and risk of bias will be assessed using RoB 2. A frequentist ran-dom-effects network meta-analysis will estimate hazard ratios, using placebo as the reference, and rank treatments with P-scores. Transitivity, heterogeneity, and inconsistency will be evaluated through prespecified effect modifiers, node-splitting, and design-by-treatment interaction methods. Confidence in network estimates will be assessed with CINeMA, alongside GRADE for pairwise comparisons. Ethics and dissemination: Ethical approval is unnecessary because only published data will be used. Results, datasets, search strategies, and analytic code will be disseminated through publications, presentations, bilingual summaries, and open repositories.","url":"https://doi.org/10.20944/preprints202610.0314.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo, standard care, another eligible incretin therapy, or an SGLT2 inhibitor or basal insulin as connector nodes\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"time to first three-point MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke)","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": null, \"inclusion_exclusion\": \"parallel-group randomized controlled trials with at least 52 weeks of follow-up in adults with type 2 diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the planned review covers trials in adults with type 2 diabetes, which the target group does not have.","mediation":"possibly","mediation_notes":"No results and no weight, HbA1c or mediation analysis are described; any future cardiovascular effect would be presumed confounded with weight and glycaemic change unless separated.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"placebo, standard care, another eligible incretin therapy, or an SGLT2 inhibitor or basal insulin as connector nodes\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; protocol with no results\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"NOT_RATED: protocol for a systematic review and network meta-analysis with no pooled estimate and no outcome data; it is also a preprint, not peer reviewed.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Protocol for a planned network meta-analysis with no results; posted as a preprint, not peer reviewed.","plain_summary":"This is a protocol, not a result: a planned network meta-analysis of randomised trials lasting at least 52 weeks in adults with type 2 diabetes, comparing GLP-1 drugs and tirzepatide for major cardiovascular events (cardiovascular death, heart attack and stroke). It reports no findings yet and has been posted as a preprint, not peer reviewed.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":995,"doi":"10.64898/2026.10.04.26364715","pmid":"42926858","nct_ids":"[]","title":"Post-Initiation Care Patterns and Weight Loss With Semaglutide and Tirzepatide for Obesity in Clinical Practice","authors":"[\"Yang, H.\", \"Kim, C.\", \"Ross, J. S.\", \"Huang, C.\", \"Choi, K.\", \"Kang, B.\", \"Arun, A.\", \"Tang, H.\", \"Chen, Y.\", \"Xu, H.\", \"Sharifi, M.\", \"Li, Z.\", \"Krumholz, H.\", \"Lu, Y.\"]","journal":"medrxiv (preprint)","publication_date":"2026-10-06","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"BackgroundRandomized trials show substantial weight loss with semaglutide and tirzepatide under structured care, but little is known about whether patients in routine practice continue therapy, reach a maintenance dose, and have their weight measured.\n\nObjectivesTo describe the first year after initiation of semaglutide or tirzepatide for obesity, including care patterns, maintenance-dose attainment, weight documentation, and total body weight loss (TBWL).\n\nMethodsThis retrospective cohort study used Epic Cosmos, an electronic health record network of >350 US health systems, to identify adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024. Outcomes over 12 months included prescribing persistence, discontinuation, switching, add-on therapy, and reinitiation; attainment of Food and Drug Administration (FDA)-labeled maintenance doses; availability of follow-up weight; and TBWL across progressively restricted populations.\n\nResultsAmong 743,153 adults (60.1% semaglutide; mean age, 48.5 years; 72.5% female), 12-month prescribing persistence was 29.9% for semaglutide and 35.9% for tirzepatide. FDA-labeled maintenance-dose attainment was 28.3% and 55.0%, respectively, and only 8.8% and 16.4% remained prescribing persistent at a maintenance dose with a recorded weight at 12 months. About half of initiators lacked a 12-month weight. Among all initiators, [&ge;]5% TBWL was documented in 25.6% (semaglutide) and 30.4% (tirzepatide), rising to 51.9% and 61.9% among those with recorded weight, 66.1% and 79.5% among those also prescribing persistent, and 82.9% and 87.3% among those further at a maintenance dose.\n\nConclusionsIn routine practice, most patients initiating semaglutide or tirzepatide did not remain on therapy, reach a maintenance dose, and have weight documented through the first year. Documented weight loss was greatest among those completing each step of care, suggesting continuation, dose escalation, and monitoring as targets for improvement.\n\nCENTRAL ILLUSTRATIONCare Cascade and Weight-Loss Outcomes Among Semaglutide and Tirzepatide Initiators, Standardized to 100 Initiators.\n\nNumbers are per 100 initiators and were rounded so that categories at each step sum to the preceding step. At the 12-month dose step, prescribed dose was missing for 1 per 100 semaglutide initiators and <1 per 100 tirzepatide initiators.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/26364715v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@18db7ceorg.highwire.dtl.DTLVardef@11e3c55org.highwire.dtl.DTLVardef@b1b14org.highwire.dtl.DTLVardef@11ef262_HPS_FORMAT_FIGEXP  M_FIG C_FIG","url":"https://www.medrxiv.org/content/10.64898/2026.10.04.26364715","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"first-year care patterns (prescribing persistence, maintenance-dose attainment, weight documentation) and total body weight loss","endpoints":null,"effect_estimate":"12-month prescribing persistence 29.9% (semaglutide) and 35.9% (tirzepatide); maintenance-dose attainment 28.3% and 55.0%; 5% or greater weight loss documented in 25.6% and 30.4% of all initiators, 51.9% and 61.9% of those with a recorded weight, and 82.9% and 87.3% of those also persistent and at a maintenance dose","confidence_interval":null,"p_value":null,"sample_size":743153,"follow_up":"12 months","direction":"unclear","population":"{\"mean_age\": \"48.5 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"72.5% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required (no BMI threshold given)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity\", \"sample_size\": 743153, \"inclusion_exclusion\": \"adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (without diabetes); mean age 48.5 years, 72.5% female.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcomes are weight loss and care patterns.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 743153, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"12 months\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; descriptive percentages in 743,153 adults\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: preprint, not peer reviewed; a descriptive observational cohort with no comparator.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Preprint, not peer reviewed; descriptive retrospective health-record cohort with no comparator, and about half of initiators lacked a 12-month weight, so weight-loss figures in the restricted groups are selected.","plain_summary":"This preprint describes 743,153 US adults with obesity and without diabetes (mean age 48.5 years) who started semaglutide or tirzepatide in 2024, using health-record data. Most did not stay on treatment for a year: 29.9% and 35.9% were still prescribed the drug at 12 months, and about half had no recorded 12-month weight. Weight loss of at least 5% was recorded in 25.6% (semaglutide) and 30.4% (tirzepatide) of all starters, more often in those who stayed on a maintenance dose; with no comparison group, this is a description, not a treatment effect.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":953,"doi":"10.1093/eurheartj/ehag732","pmid":"42830666","nct_ids":"[]","title":"Semaglutide, independent of weight loss, attenuates cardiac and hepatic remodelling in experimental heart failure with preserved ejection fraction","authors":"[\"Elbatreek MH\", \"Li Z\", \"Yu X\", \"Gehred ND\", \"Gromova T\", \"Chen J\", \"Huerta M\", \"Muraoka N\", \"Jensen MB\", \"Kartha V\", \"Carrico C\", \"Allerton TD\", \"Zhang X\", \"Yang HR\", \"Bowdish ME\", \"Shah SJ\", \"Woulfe KC\", \"McKinsey TA\", \"Yoo E\", \"Polhemus DJ\", \"Vondriska TM\", \"Lefer DJ\", \"Goodchild TT\"]","journal":"European heart journal","publication_date":"2026-10-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Heart failure with preserved ejection fraction (HFpEF) remains a significant therapeutic challenge. While GLP-1 receptor agonists (GLP-1RAs) show clinical promise, it remains unknown if their benefits are driven solely by weight loss or involve weight loss-independent mechanisms. We investigated the weight loss-independent effects of semaglutide in two preclinical models of cardiometabolic HFpEF: the ZSF1 Obese rat and the Göttingen HFpEF minipig. [METHODS] Male ZSF1 Obese rats (n = 12/group) and female Göttingen minipigs with 'two-hit' induced HFpEF (early intervention: n = 5/group; delayed intervention: n = 4/group) were treated with semaglutide at doses empirically determined to be non-weight-loss inducing. Comprehensive assessments included invasive hemodynamic (LVEDP, PCWP), echocardiography, and histological quantification of fibrosis and lipid burden. Delayed intervention utilized Cardiac MRI to quantify subcutaneous and ectopic fat depots. In rats, advanced multi-omics (NULISA plasma proteomics, single-cell RNA sequencing and tissue proteomics) were utilized to explore molecular mechanisms. [RESULTS] In ZSF1 Obese rats, semaglutide significantly improved diastolic function (reducing LVEDP by ∼60%) and attenuated cardiac hypertrophy (by ∼30%), interstitial fibrosis, and cardiac lipid deposition in the absence of a significant weight loss. These functional benefits were conserved in the minipig HFpEF model, where treatment attenuated cardiac hypertrophy, left ventricular E/e', normalized pulmonary capillary wedge pressure (PCWP) and reversed advanced hepatic bridging fibrosis. Delayed intervention in established HFpEF minipigs reversed diastolic dysfunction and significantly reduced ectopic lipid depots (intramyocardial, epicardial, and hepatic fat) without affecting subcutaneous fat or total body weight. Mechanistically, multi-omics analyses in the rat heart revealed that these benefits were driven by suppression of pro-fibrotic and hypertrophic signals and up-regulation of branched-chain amino acid (BCAA) catabolism and fatty acid oxidation pathways in cardiomyocytes. [CONCLUSIONS] Semaglutide attenuates cardiac and hepatic remodelling in preclinical models of obesity-associated cardiometabolic HFpEF in the absence of profound weight loss. The conservation of these effects across male rodents and female swine supports their translational relevance, while future studies are needed to define dose equivalence and confirm GLP-1 receptor engagement in cardiac and hepatic tissues. These findings support further mechanistic investigation of weight loss-independent GLP-1 receptor agonist signalling in this HFpEF phenotype.","url":"https://pubmed.ncbi.nlm.nih.gov/42830666/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"route\": null, \"dose\": \"doses empirically determined to be non-weight-loss inducing\", \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"liver\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":"cardiac and hepatic remodelling (diastolic function, hypertrophy, fibrosis, ectopic fat)","endpoints":null,"effect_estimate":"In ZSF1 Obese rats semaglutide reduced LVEDP by ∼60% and cardiac hypertrophy by ∼30% without significant weight loss; in minipigs it attenuated hypertrophy, normalized PCWP and reversed hepatic bridging fibrosis","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male rats; female minipigs\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (obesity-associated HFpEF models)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"experimental heart failure with preserved ejection fraction required (animal)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"experimentally induced HFpEF in ZSF1 Obese rats and 'two-hit' Göttingen minipigs\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male ZSF1 Obese rats and female Göttingen minipigs with induced HFpEF; no human data.","mediation":"specifically_tested","mediation_notes":"Specifically tested: semaglutide was given at doses chosen not to induce weight loss, and the benefits occurred without significant weight loss or change in total body weight, so weight loss is separated by design; glycaemic change is not reported in the abstract.","adjusted_for":"[\"body-weight change\"]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; 12 rats per group, 4 to 5 minipigs per group\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: preclinical rat and minipig studies with 4 to 12 animals per group.","funding_source":"NIH; NHLBI NIH HHS; American Heart Association Predoctoral Fellowship; NIH HHS; American Heart Association Collaborative Sciences Award","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Small animal studies (4 to 12 animals per group) in obesity-associated HFpEF models; the authors say dose equivalence and cardiac and hepatic GLP-1 receptor engagement still need to be confirmed.","plain_summary":"In obese rats and minipigs with an experimental form of heart failure with preserved ejection fraction, semaglutide was given at doses chosen not to cause weight loss. It improved heart filling pressure (LVEDP down by ∼60% in rats), reduced heart thickening (by ∼30% in rats) and scarring, and reversed liver scarring in minipigs without changing total body weight. This is animal evidence only.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":958,"doi":"10.4088/jcp.26m16392","pmid":"42848524","nct_ids":"[]","title":"GLP-1 Receptor Agonists and Risk of Kidney Replacement Therapy and Health Care Utilization in Bipolar Disorder With Chronic Kidney Disease","authors":"[\"Singh B\", \"Gonzalez Suarez ML\", \"Ali HM\", \"Baweja R\"]","journal":"The Journal of clinical psychiatry","publication_date":"2026-10-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Objective: To examine whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with reduced risk of kidney replacement therapy (KRT) and health care utilization (HCU) compared with active comparators in adults with bipolar disorder (BD) and chronic kidney disease (CKD; stage ≤3). Methods: Using TriNetX, we conducted a real-world, new-user active-comparator cohort study among adults with BD+CKD initiating GLP-1 RA or dipeptidyl peptidase-4 (DPP-4) inhibitor therapy (primary comparator), with a secondary analysis versus renin-angiotensin-aldosterone system (RAAS) inhibitor users. Propensity score matching (PSM) balanced baseline characteristics. Cox proportional hazards regression estimated adjusted hazard ratios (aHR) for KRT and HCU over 5-year follow-up. Subgroup analyses examined effect modification by sex, race, ethnicity, obesity, and psychotropic medication use. Results: Compared with DPP-4 inhibitor use, GLP-1 RA use was associated with lower observed risk of KRT (aHR 0.56, 95% CI 0.50-0.64) and HCU (aHR 0.74, 95% CI 0.71-0.78). Following PSM (n=3,908 per group), 5-year KRT-free survival was 87.93% versus 84.63% (P<.001); HCU-free survival did not differ significantly (P=.89). Versus RAAS inhibitors, GLP-1 RA use was similarly associated with lower observed risk of KRT (aHR 0.66) and HCU (aHR 0.62); after PSM (n=2,539 per group), KRT-free survival was higher (94.68% vs. 89.77%; P<.001), while HCU-free survival did not differ significantly (P=.15). Benefits were consistent across sex, race, and obesity status and across psychotropic subgroups, including lithium. Conclusions: GLP-1 RA use was associated with lower observed risk of KRT and HCU compared with DPP-4 inhibitors, corroborated for KRT in a secondary comparison against RAAS inhibitors. These exploratory findings warrant further investigation, including prospective studies, to evaluate whether this association reflects a causal effect.","url":"https://pubmed.ncbi.nlm.nih.gov/42848524/","source_name":"pubmed","source_tier":1,"coi_statement":"Financial Disclosures: Dr Singh has received research grant support from Mayo Clinic, the National Network of Depression Centers, Breakthrough Discoveries for Thriving with Bipolar Disorder and NIH. He is a KL2 Mentored Career Development Program scholar, supported by CTSA Grant Number KL2TR002379 from the NCATS. Dr Singh has received honoraria (to Mayo Clinic) from Elsevier for editing a Clinical Overview on Treatment-Resistant Depression. Dr Gonzalez Suarez has served on the advisory board for Alexion and has participated as principal investigator/enrollment site for AstraZeneca. Dr Baweja has received grant funding from Cardinal Health Foundation (Children’s Hospital Association and Zero Suicide Initiative), and research funding from Supernus. Dr Ali reports no relevant disclosures.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"DPP-4 inhibitors (primary); renin-angiotensin-aldosterone system (RAAS) inhibitors (secondary)\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"kidney\", \"mortality\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"kidney replacement therapy (KRT) and health care utilization (HCU)","endpoints":null,"effect_estimate":"Versus DPP-4 inhibitors: KRT aHR 0.56 and HCU aHR 0.74; after PSM, 5-year KRT-free survival 87.93% vs 84.63% but HCU-free survival did not differ (P=.89). Versus RAAS inhibitors: KRT aHR 0.66 and HCU aHR 0.62; after PSM, KRT-free survival 94.68% vs 89.77% but HCU-free survival did not differ (P=.15)","confidence_interval":"KRT aHR 0.56, 95% CI 0.50-0.64; HCU aHR 0.74, 95% CI 0.71-0.78","p_value":"KRT-free survival P<.001; HCU-free survival P=.89 (versus DPP-4 inhibitors after matching)","sample_size":7816,"follow_up":"5-year follow-up","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (obesity examined as a subgroup)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"chronic kidney disease (stage ≤3) required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"bipolar disorder with chronic kidney disease (stage ≤3)\", \"sample_size\": 7816, \"inclusion_exclusion\": \"adults with bipolar disorder and CKD stage ≤3 who were new users of a GLP-1 RA, DPP-4 inhibitor or RAAS inhibitor\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: adults with bipolar disorder and chronic kidney disease (stage ≤3), a kidney disease the target group does not have; BMI, age and diabetes status are not reported in the abstract.","mediation":"possibly","mediation_notes":"Possibly: the abstract reports no weight, HbA1c or mediation analysis; propensity matching balances baseline traits but does not separate a drug effect from weight or glycaemic change, and the obesity subgroup tests effect modification, not mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 7816, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"DPP-4 inhibitors (primary); renin-angiotensin-aldosterone system (RAAS) inhibitors (secondary)\", \"follow_up_duration\": \"5-year follow-up\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"aHRs with 95% CIs for the DPP-4 comparison; 3,908 per group after matching; no event counts reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single retrospective database cohort with propensity matching; the observational design caps it at LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"One author reports academic, foundation and NIH grant support and editing honoraria from Elsevier, another advisory work for Alexion and site-investigator work for AstraZeneca, and another foundation grant funding and research funding from Supernus; one reports none.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A retrospective database cohort with propensity matching, so residual confounding remains; the authors call the findings exploratory and say prospective studies are needed to test whether the association is causal.","plain_summary":"This retrospective database study compared adults with bipolar disorder and chronic kidney disease who started a GLP-1 drug with matched people starting a DPP-4 inhibitor (3,908 per group) over 5 years. GLP-1 drug use was linked to a lower risk of needing kidney replacement therapy (aHR 0.56), but survival free of health care use did not differ after matching. Because it is observational, it shows an association, not that the drugs caused the difference.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":983,"doi":"10.1038/s41591-026-04713-y","pmid":"42834229","nct_ids":"[\"NCT06589765\"]","title":"Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial","authors":"[\"Guo L\", \"Yu D\", \"Xu Y\", \"Tang G\", \"Peng L\", \"Meng C\", \"Zhao M\", \"Hu W\", \"Huang D\", \"Zeng C\", \"Yu L\", \"Wu G\", \"Zhang L\", \"Gao Y\", \"Zhong T\", \"Ye Z\", \"OUTSTAND-2 Investigator Group\"]","journal":"Nature medicine","publication_date":"2026-10-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety versus dapagliflozin in OUTSTAND-2, a phase 3, multicenter, randomized, double-blind, double-dummy, active-comparator-controlled trial conducted at 98 sites in China. We randomized 810 adults (mean hemoglobin A1C (HbA1c) 8.60%, median diabetes duration 5.0 years, 35.7% women) to safiglipron 30 mg (n = 202), safiglipron 60 mg (n = 203), safiglipron 90 mg (n = 203) or dapagliflozin 10 mg (n = 202) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, treatment differences versus dapagliflozin in change from baseline in HbA1c at week 32 under the primary non-inferiority estimand were -0.30% (95% confidence interval (CI): -0.51 to -0.09), -0.22% (-0.44 to -0.01) and -0.40% (-0.62 to -0.19) for safiglipron 30 mg, 60 mg and 90 mg, respectively, establishing non-inferiority for all three doses (all P < 0.0001; non-inferiority margin 0.4%). Under the treatment policy estimand, 90 mg met the prespecified statistical criterion for superiority (difference -0.25%; 95% CI: -0.45 to -0.05; one-sided P = 0.0067), whereas 60 mg did not (P = 0.0789), after which fixed-sequence testing stopped. HbA1c target attainment rates with safiglipron versus dapagliflozin were 54.9-63.5% versus 36.5% for HbA1c <7.0% and 38.9-48.6% versus 16.1% for HbA1c ≤6.5%. Mean body weight changes were -2.35%, -3.55%, -4.17% and -3.60% for safiglipron 30 mg, safiglipron 60 mg, safiglipron 90 mg and dapagliflozin, respectively. Fasting plasma glucose, seven-point self-monitored blood glucose profiles, waist circumference, HOMA-β, HOMA-IR and changes in treatment satisfaction showed varying degrees of improvement from baseline with both safiglipron and dapagliflozin. Rescue therapy was used by 0.5-1.5% versus 0% of participants, respectively. Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to treatment discontinuation in 4.0%, 4.0%, 3.9% and 1.5% of participants, respectively. Safiglipron provides an effective oral treatment option for adults with type 2 diabetes inadequately controlled with metformin. ClinicalTrials.gov identifier: NCT06589765 .","url":"https://pubmed.ncbi.nlm.nih.gov/42834229/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: Y.X., G.T., L.P., T.Z. and Z.Y. were employees of Jiangsu Hengrui Pharmaceuticals at the time of the study. L.P., Y.X. and Z.Y. declare a patent pending relating to safiglipron. The other authors declare no competing interests.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"safiglipron\"]","drug_details":"{\"dose\": \"safiglipron 30 mg, 60 mg or 90 mg\", \"comparator\": \"dapagliflozin 10 mg\", \"treatment_duration\": \"32 weeks, followed by a 20-week active-treatment extension\", \"route\": \"oral\"}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"biomarker","primary_outcome":"change from baseline in HbA1c at week 32 (non-inferiority versus dapagliflozin)","endpoints":null,"effect_estimate":"HbA1c differences versus dapagliflozin -0.30%, -0.22% and -0.40% for 30, 60 and 90 mg (non-inferior for all); superiority met for 90 mg (-0.25%) but not 60 mg (P = 0.0789); weight change -2.35%, -3.55%, -4.17% versus -3.60% with dapagliflozin","confidence_interval":"95% CI: -0.51 to -0.09 (30 mg), -0.44 to -0.01 (60 mg), -0.62 to -0.19 (90 mg)","p_value":"all P < 0.0001 for non-inferiority; 90 mg superiority one-sided P = 0.0067; 60 mg P = 0.0789","sample_size":810,"follow_up":"week 32 (primary endpoint), followed by a 20-week active-treatment extension","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"35.7% women\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required (inadequately controlled with metformin)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes inadequately controlled with metformin\", \"sample_size\": 810, \"inclusion_exclusion\": \"adults with type 2 diabetes inadequately controlled with metformin, at 98 sites in China\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes inadequately controlled with metformin (mean HbA1c 8.60%); age and BMI are not reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the primary outcome is HbA1c change, which is glycaemic control itself; body weight fell in all arms (-2.35% to -4.17% with safiglipron, -3.60% with dapagliflozin).","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 810, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"dapagliflozin 10 mg\", \"follow_up_duration\": \"week 32 (primary endpoint), followed by a 20-week active-treatment extension\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -0.51 to -0.09 (30 mg), -0.44 to -0.01 (60 mg), -0.62 to -0.19 (90 mg)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: an 810-participant double-blind phase 3 randomized trial with an active comparator; held below HIGH because the primary endpoint is a 32-week glycaemic measure, not a clinical event.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Five authors were Jiangsu Hengrui Pharmaceuticals employees at the time of the study, and three declare a patent pending relating to safiglipron.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Jiangsu Hengrui Pharmaceuticals (five employees; three with a patent pending relating to safiglipron).","adverse_events":"Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to discontinuation in 4.0%, 4.0%, 3.9% versus 1.5% with dapagliflozin; rescue therapy 0.5-1.5% versus 0%","limitations":"Conducted only in China against an active comparator rather than placebo, with a 32-week glycaemic primary endpoint; superiority was shown for the 90 mg dose only, after which fixed-sequence testing stopped, and several authors were employees of the developer.","plain_summary":"This double-blind randomized trial in China gave 810 adults with type 2 diabetes on metformin one of three doses of oral safiglipron or dapagliflozin for 32 weeks. All three doses lowered HbA1c at least as well as dapagliflozin and the 90 mg dose did better, but the 60 mg dose did not reach superiority. Weight loss was similar to or smaller than with dapagliflozin, and gut side effects and stopping for side effects were more common with safiglipron.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":985,"doi":"10.47717/turkjsurg.2026.2026-4-35","pmid":"42830623","nct_ids":"[]","title":"Effects of GLP-1 receptor agonists on aesthetic surgery practice: A contemporary review","authors":"[\"Ersan M\", \"Özturhan O\"]","journal":"Turkish journal of surgery","publication_date":"2026-10-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become increasingly relevant to aesthetic surgery because of the significant weight loss they provide in the treatment of type 2 diabetes mellitus and obesity. While these agents expand the pool of surgical candidates, they also raise new clinical questions related to rapid or substantial weight loss, including soft tissue volume loss, skin laxity, nutritional deficiencies, perioperative safety concerns, and the durability of aesthetic surgical outcomes. This contemporary narrative review evaluated the current implications of GLP-1 RAs in aesthetic plastic surgery practice. A targeted PubMed/MEDLINE search covering January 2015 through August 2026 was supplemented by manual reference screening. Retrospective cohorts, database analyses, prospective observational studies, systematic reviews, survey studies, case reports, and selected guidance or opinion articles were evaluated. Current literature indicates increasing demand for facial aesthetic, breast aesthetic, and body contouring procedures among patients using GLP-1 RAs. The facial volume loss and skin laxity popularly described as \"Ozempic face\" more plausibly reflect rapid or substantial weight loss than a proven drug-specific facial effect. Although the breast surgery literature remains limited, upper-pole volume loss, ptosis, reduced soft tissue support, and healing problems along high-tension closure lines are noteworthy. Outcomes in body contouring surgery are heterogeneous: While some studies report comparable complication rates, others emphasize delayed wound healing, wound dehiscence, altered scar behavior, or nutrition-related risks. Surgical timing, weight stabilization, nutritional balance, and individualized perioperative aspiration-risk assessment are key areas of evaluation. GLP-1 RA use should be considered neither an absolute advantage nor an automatic contraindication in aesthetic surgery. Direct pharmacologic effects often cannot be separated from the consequences of weight loss or baseline metabolic risk. Surgical decision-making should be individualized based on weight stability, metabolic optimization, nutritional status, history of bariatric surgery, psychological adaptation, and procedure-specific risks. Current evidence is promising but heterogeneous, and prospective studies are needed to clarify long-term aesthetic outcomes and procedure-specific risks.","url":"https://pubmed.ncbi.nlm.nih.gov/42830623/","source_name":"pubmed","source_tier":1,"coi_statement":"No conflict of interest was declared by the authors.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"narrative_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"adverse_effects\", \"nutrition\", \"perioperative\"]","outcome_type":"none","primary_outcome":"implications of GLP-1 RA use for aesthetic surgery (soft-tissue changes, wound healing, perioperative safety)","endpoints":null,"effect_estimate":"No pooled estimate; body contouring outcomes are heterogeneous, with some studies reporting comparable complication rates and others delayed wound healing and dehiscence","confidence_interval":"not reported in abstract","p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"aesthetic surgery patients using GLP-1 RAs\", \"sample_size\": null, \"inclusion_exclusion\": \"PubMed/MEDLINE literature January 2015 to August 2026 on GLP-1 RAs and aesthetic surgery\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: a review scoped to people using GLP-1 RAs for type 2 diabetes and obesity who seek aesthetic surgery, conditions the target group does not have; no participant data are reported.","mediation":"possibly","mediation_notes":"Possibly: the authors say direct drug effects often cannot be separated from the consequences of weight loss or baseline metabolic risk, and they judge that facial volume loss more plausibly reflects rapid weight loss than a drug-specific effect; no analysis separates the two.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no pooled estimate or CI reported\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a narrative review with no new primary outcome data and no pooled estimate.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"The authors declared no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Body-contouring studies differ: some report comparable complication rates, others delayed wound healing, wound dehiscence, altered scarring or nutrition-related risks; perioperative aspiration risk needs assessment.","limitations":"A targeted narrative review, not a systematic one, of heterogeneous mostly observational and case-level literature; the authors say drug effects often cannot be separated from weight loss and that prospective studies are needed.","plain_summary":"This narrative review looked at how GLP-1 drugs affect cosmetic surgery, drawing on a targeted literature search from 2015 to 2026. It concludes that facial volume loss and loose skin more likely reflect fast weight loss than a direct drug effect, and that body-contouring results are mixed, with some studies finding similar complication rates and others more wound-healing problems. It reports no pooled numbers.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1194,"doi":"10.1021/acs.molpharmaceut.6c00590","pmid":"42906168","nct_ids":"[]","title":"A Dicyanocobinamide Conjugate of the GLP-1R Agonist Exendin-4 Improves Glucose Homeostasis in Tumor-Bearing Rats without Exacerbating Anorexia and Weight Loss","authors":"[\"Cham N\", \"Pataro AM\", \"Liles A\", \"Choi GK\", \"Fischer SL\", \"Ramadan SA\", \"Gao SX\", \"Doebley SA\", \"Chepurny OG\", \"Holz GG\", \"Hayes MR\", \"De Jonghe BC\", \"Doyle RP\", \"Borner T\"]","journal":"Molecular pharmaceutics","publication_date":"2026-10-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Cancer anorexia-cachexia syndrome (CACS) is a prevalent and debilitating complication of malignancy, characterized by reduced food intake, loss of skeletal muscle mass, and severe metabolic dysfunction. Insulin resistance and impaired glucose tolerance are prominent features of CACS and contribute to worsened prognosis, yet treatment options that improve metabolic regulation without exacerbating anorexia are limited. Although GLP-1 receptor (GLP-1R) agonists effectively enhance glucose control, their centrally mediated anorectic and aversive effects limit their use in cancer patients. To address this limitation, we developed a peripherally restricted GLP-1R agonist by conjugating exendin-4 (Ex4) to dicyanocobinamide (Cbi), a vitamin B12-derived corrin ring with minimal blood-brain barrier penetration. Here, we evaluate Cbi-Ex4 in vitro and across healthy and tumor-bearing rodent models. Cbi-Ex4 retained GLP-1R agonism and improved glucose tolerance without inducing anorexia, weight loss, or malaise, in contrast to native Ex4. These findings support peripheralized GLP-1R agonism as a promising strategy to improve metabolic dysfunction in cancer without worsening malaise and cachexia.","url":"https://pubmed.ncbi.nlm.nih.gov/42906168/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:13+00:00","study_design":"preclinical_animal","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"muscle\", \"cancer\", \"metabolic\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":805,"doi":"10.1111/jdv.70769","pmid":"42828450","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor agonists in hidradenitis suppurativa: A nationwide cohort study","authors":"[\"Nielsen VW\", \"Holgersen N\", \"Pedersen NH\", \"Brogaard E\", \"Andersen YMF\", \"Egeberg A\", \"Thyssen JP\", \"Thomsen SF\"]","journal":"Journal of the European Academy of Dermatology and Venereology : JEADV","publication_date":"2026-10-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Hidradenitis suppurativa (HS) is associated with obesity, metabolic dysfunction and increased healthcare utilization. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated anti-inflammatory effects and reduction in HS symptoms, but real-world patterns of GLP-1RA use in HS remain limited. [OBJECTIVES] To investigate GLP-1RA use and comorbidity burden among patients with HS compared to matched psoriasis patients and background controls, including changes in healthcare utilization and treatment patterns following GLP-1RA initiation. [METHODS] In this nationwide Danish register-based cohort study, adult patients with HS and age- and sex-matched patients with psoriasis and background controls were included from 1 January 2000 to 31 December 2022. Comorbidities were assessed at the date of HS diagnosis (index date) and at GLP-1RA initiation. Healthcare utilization, surgical procedures and medication use were examined during the 2 years before and after GLP-1RA initiation among patients with HS receiving continuous GLP-1RA treatment and matched HS non-users. [RESULTS] A total of 12,581 patients with HS, 9824 patients with psoriasis, and 12,581 controls were included. During follow-up, 8.2% of patients with HS initiated GLP-1RA treatment, compared with 5.7% of psoriasis patients and 3.2% of controls. Mean time to GLP-1RA initiation was shorter among patients with HS (8.88 years) than psoriasis patients (10.1 years; p < 0.001) and controls (10.2 years; p < 0.001). Cardiometabolic and psychiatric comorbidities increased from index date to treatment initiation across all groups. Following GLP-1RA initiation, lower rates of surgical procedures and systemic medication use were observed. [CONCLUSIONS] Patients with HS demonstrated earlier and more frequent use of GLP-1RA compared with psoriasis patients and controls, with decreased use of HS-specific treatments and surgical procedures following GLP-1RA initiation. Comparable declines were observed among matched non-initiators.","url":"https://pubmed.ncbi.nlm.nih.gov/42828450/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"rheumatologic\", \"psychiatric\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":865,"doi":"10.1016/j.molmet.2026.102452","pmid":"42829171","nct_ids":"[\"NCT04641312\"]","title":"Nisotirostide (LY3457263), a novel NPY2 receptor agonist for type 2 diabetes and obesity: From discovery to clinical proof of concept","authors":"[\"Briere DA\", \"Leohr JK\", \"Linnebjerg H\", \"Muppidi A\", \"Antonellis M\", \"Antonellis P\", \"Suter TM\", \"Smith LaBell E\", \"Lopes D\", \"Dogra M\", \"Coskun T\", \"Alsina-Fernandez J\", \"Mather KJ\"]","journal":"Molecular metabolism","publication_date":"2026-10-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/OBJECTIVE] Nisotirostide is a novel selective NPY2 receptor agonist under development as adjunctive therapy for people with type 2 diabetes (T2D) on glucagon-like peptide-1 receptor agonists (GLP-1 RA). [METHODS] Nisotirostide binding affinity and potency were determined against human NPY2 receptor. Effects of nisotirostide on body weight, food intake, body composition, glucose, and insulin were evaluated in mouse models. A Phase 1 study in healthy participants and participants with T2D on 1.5 mg once-weekly dose of dulaglutide evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics, following a single subcutaneous dose of nisotirostide ranging from 0.025 to 1 mg. [RESULTS] Nisotirostide potently and selectively activated NPY2 receptor signaling in vitro. In mice, nisotirostide reduced body weight by up to 12% as monotherapy and up to 31% when combined with GLP-1 RA, demonstrating synergism. Nisotirostide-treated mice showed improved glucose control, independent of weight loss. In Phase 1 clinical study (N=65), PK of nisotirostide supported a once-weekly dosing regimen. A 1 mg dose of nisotirostide in monotherapy reduced mean body weight by 0.75 kg versus placebo (ns); when added to dulaglutide, up to 2.58 kg reduction was observed versus dulaglutide alone (p<0.05). Gastrointestinal adverse events, such as nausea and vomiting, were the most commonly reported with nisotirostide; these were dose-dependent and mild-to-moderate in severity. [CONCLUSION] Nisotirostide demonstrated potent, selective NPY2R agonism with a PK profile supporting once-weekly dosing. Preclinical metabolic benefits, including weight-independent glucose improvements, translated clinically, and a manageable tolerability profile supports further development as adjunctive GLP-1 RA therapy for T2D and obesity. [GOV NUMBER] NCT04641312.","url":"https://pubmed.ncbi.nlm.nih.gov/42829171/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest Daniel A Briere, Jennifer K Leohr, Helle Linnebjerg, Avinash Muppidi, Meghan Antonellis, Patrick Antonellis, Todd M Suter, Elizabeth Smith LaBell, Daniel Lopes, Mridula Dogra, Tamer Coskun, Jorge Alsina-Fernandez, and Kieren James Mather are employees and stockholders of Eli Lilly and Company, Indianapolis, USA.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"preclinical_animal","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"body_composition\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":874,"doi":"10.1016/j.ejphar.2026.179387","pmid":"42826814","nct_ids":"[]","title":"Tirzepatide attenuates cardiac microvascular injury and ferroptosis-related lipid peroxidation in diabetic mice: endothelial responses in the context of partial PRKN silencing","authors":"[\"Lu G\", \"Wang X\", \"Zhuang H\", \"Wang X\", \"Zhou X\", \"Zhao G\"]","journal":"European journal of pharmacology","publication_date":"2026-10-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Diabetic metabolic stress damages the cardiac microvasculature. We evaluated tirzepatide-associated cardiac and endothelial effects, including endpoint patterns after partial silencing of parkin RBR E3 ubiquitin protein ligase (PRKN) and lipidated microtubule-associated protein 1 light chain 3 beta (LC3B-II) accumulation during lysosomal blockade. [METHODS] Male C57BL/6J mice received a normal diet, a high-fat diet (HFD), or HFD/streptozotocin (STZ); HFD and HFD/STZ cohorts received tirzepatide or vehicle for 8 weeks. Metabolic, cardiac, microvascular, lipid-peroxidation, iron, and protein endpoints were assessed; ultrastructure was evaluated descriptively. Human cardiac microvascular endothelial cells (HCMECs) underwent high glucose/palmitic acid (HG/PA), PRKN-silencing, and bafilomycin A1 (BafA1) experiments. [RESULTS] In HFD/STZ mice, tirzepatide improved selected glycemic and lipid measures and attenuated ventricular dilation, systolic dysfunction, myocardial fibrosis, and microvascular injury. Myocardial 4-hydroxynonenal, malondialdehyde, and ferrous iron were lower, and mitochondrial quality-control and ferroptosis-related protein profiles shifted toward control levels. In HG/PA-exposed HCMECs, tirzepatide increased the JC-1 aggregate/monomer ratio, decreased 4-hydroxynonenal and acyl-CoA synthetase long-chain family member 4, and increased glutathione peroxidase 4 and ferritin heavy chain 1. Among tirzepatide-treated cultures, endpoints were less favorable with partial PRKN silencing than with control small interfering RNA, although treatment-associated differences remained within the PRKN-silenced background. BafA1 increased LC3B-II in control and HG/PA + tirzepatide cultures; the increase under HG/PA alone was not significant. [CONCLUSIONS] Tirzepatide was associated with less cardiac microvascular injury and ferroptosis-related lipid peroxidation. PRKN-silencing status was associated with endothelial endpoint patterns after tirzepatide treatment; effect modification and requirement were not established. Receptor dependence, mitophagic flux, and independence from systemic metabolic improvement remain unresolved.","url":"https://pubmed.ncbi.nlm.nih.gov/42826814/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gang Zhao reports financial support was provided by Natural Science Foundation of Shandong Province. Xiaoting Wang reports financial support was provided by Shandong First Medical University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:31+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1192,"doi":"10.1021/acs.jproteome.6c00404","pmid":"42918120","nct_ids":"[]","title":"Semaglutide and Tirzepatide Suppress Hepatic Fatty Acid Uptake and Fatty Acid β-Oxidation in High-Fat Diet-Induced Obesity Mice","authors":"[\"Patel D\", \"Ewida H\", \"Tareq S\", \"Aziz MT\", \"Chelikani PK\", \"Bickel U\", \"Ahmed MS\"]","journal":"Journal of proteome research","publication_date":"2026-10-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists show high efficacy in treating obesity and metabolic dysfunction-associated liver diseases, conditions that collectively represent one of the most challenging One Health crises of our time. However, their hepatic molecular mechanisms remain poorly understood. This study defined targeted hepatic proteomic signatures associated semaglutide (GLP-1 agonist) and tirzepatide (dual GLP-1/GIP) in diet-induced obese (DIO) male C57BL/6J mice using an liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted-proteomics approach and validated using western blotting. After 18 weeks of high-fat diet (HFD), obese mice received once-daily subcutaneous semaglutide (10 nmol/kg), tirzepatide (3 nmol/kg), or vehicle for 4 weeks. Tirzepatide produced greater systemic efficacy (24.6% body weight and 30.3% fat mass reduction, preserved lean mass, improved glucose homeostasis), yet both drugs yielded overlapping targeted hepatic proteomic signatures despite different receptor pharmacology. Both drugs significantly downregulated CD36 and CPT1A fatty acid importers for β-oxidation without altering lipogenic enzymes (FASN, ACC1, ACLY, ACSS2) or glucose-handling proteins (PDH, GLUT2). These findings suggest a substrate limitation over enhanced β-oxidation or broad lipogenesis-suppression, suggesting GLP-1 receptor activation is sufficient for the core liver response and GIP co-agonism mainly augments extrahepatic effects. From a One Health proteomics perspective, CD36/CPT1A anchored targeted proteomic signature provides a mechanistically informed benchmark for evaluating novel GLP-1 and non-GLP-1 investigational therapeutics.","url":"https://pubmed.ncbi.nlm.nih.gov/42918120/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:13+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"lean_mass\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":810,"doi":"10.1038/s41591-026-04674-2","pmid":"42823485","nct_ids":"[\"NCT04865770\"]","title":"Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial","authors":"[\"Tuttle KR\", \"Bjornstad P\", \"Smith C\", \"Pruijm M\", \"McCown PJ\", \"Hodgin JB\", \"Cherney DZI\", \"Belmar N\", \"Chacko MM\", \"Das V\", \"Gunnarsson TP\", \"Idorn T\", \"Schytz PA\", \"Zaratiegui A\", \"Kretzler M\"]","journal":"Nature medicine","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The GLP-1 receptor agonist semaglutide preserves kidney function in people with type 2 diabetes and chronic kidney disease, but the underlying mechanisms are unclear. Here we report a 52-week randomized trial of subcutaneous semaglutide 1 mg once weekly versus placebo (n = 106 (n = 25 women, n = 81 men)) in participants with type 2 diabetes and chronic kidney disease. To identify kidney-specific mechanisms of action for semaglutide, we performed integrated multiparametric magnetic resonance imaging of the kidney and biopsy for histology (n = 33), alongside single-nucleus (n = 22) and spatial transcriptomics (n = 13) on paired samples with before- and after-treatment measurements. Coprimary magnetic resonance imaging outcomes (oxygenation by R2*, global perfusion and tissue inflammation by T1 mapping) were not significantly altered by semaglutide versus placebo treatment. Secondary outcomes revealed that semaglutide treatment, as compared to placebo, was associated with a significantly reduced renal artery resistive index and stabilization of the apparent diffusion coefficient, indicating prevention of fibrosis progression. Moreover, secondary transcriptomic outcomes revealed pronounced effects of semaglutide on glomerular endothelial cells, consistent with the results of spatial analyses indicating reduced numbers of immune cells in the proximity of these endothelial cells. The results from this trial indicate that mechanisms of kidney protection by semaglutide may include reduced vascular resistance, prevention of fibrosis and improved underlying molecular programs promoting endothelial cell health. ClinicalTrials.gov identifier: NCT04865770 .","url":"https://pubmed.ncbi.nlm.nih.gov/42823485/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: K.R.T. is supported by United States federal research grants from the NIDDK NHLBI, NCATS, NIMHD and the NIH Director’s Office as well as the CDC. She has also received investigator-initiated grant support from Travere, Bayer, Otsuka, Doris Duke Charitable Foundation, Benaroya Research Institute and Breakthrough T1D (formerly the Juvenile Diabetes Research Foundation). She reports consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Glaxo Smith Kline, Novo Nordisk, Bayer, ProKidney, Alnylam, Otsuka and Roche as well as speaker fees from Novo Nordisk, Bayer, Boehringer Ingelheim, AstraZeneca and Travere. Additionally, she reports being chair of data safety monitoring boards for the National Institute of Diabetes and Digestive and Kidney Disease and George Clinical Institute and member of the data safety monitoring board for AstraZeneca. She reports leadership roles as chair for the Diabetic Kidney Disease Collaborative and chair for Kidney Week 2025 Program Committee, both for the American Society of Nephrology. P.B. declares grants and contracts through the University of Washington and Seattle Children’s Research Institute from the National Institutes of Health (NIH) and Breakthrough T1D. P.B. declares serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Sidera Bio, Merck, Novo Nordisk, Roche and Horizon Pharma. P.B. also serves or has served on the advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly Novo Nordisk, Sanofi, Sidera Bio, Roche and XORTX. P.B. serves as DMC Chair for Bayer. P.B. reports grant funding from AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Merck and Amgen/Horizon Pharma. M.P. declares he is member of advisory boards at Vifor, GSK, Boehringer Ingelheim, Baxter, Novo Nordisk and Bayer, has been a speaker for AstraZeneca, Astellas, Vifor, Baxter and Braun and has received investigator-initiated grant support from Nephrospec. J.B.H. declares he is a consultant at Sygnamap. D.Z.I.C. declares honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, Biobridge, Vantage, Altimmune and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo Nordisk and Bayer. N.B. is an employee of and owns shares in Novo Nordisk. M.M.C. is an employee of and owns shares in Novo Nordisk. V.D. is an employee of and owns shares in Novo Nordisk. T.I. is a former employee of and owns shares in Novo Nordisk. T.P.G. is an employee of and owns shares in Novo Nordisk. P.A.S. is an employee of and owns shares in Novo Nordisk. A.Z. is an employee of and owns shares in Novo Nordisk. M.K. declares grants and contracts through the University of Michigan from the National Institutes of Health (NIH) and Novo Nordisk in support of this work and outside of this work from Chan Zuckerberg Initiative, AstraZeneca, Apellis, Bayer, Eli Lilly, Boehringer Ingelheim, European Union Innovative Medicine Initiative, Certa Therapeutics, RenalytixAI, Regeneron, Sanofi, Dimerix, Travere and Vera Therapeutics. M.K. has received consulting fees through the University of Michigan from Novo Nordisk, Alexion, Novartis, Roche Diagnostics and Vera Therapeutics. In addition, M.K. has a patent PCT/EP2014/073413 ‘Biomarkers and methods for progression prediction for chronic kidney disease’ licensed.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\", \"treatment_duration\": \"52 weeks\"}","domains":"[\"inflammation\", \"kidney\", \"immune\"]","outcome_type":"biomarker","primary_outcome":"coprimary MRI outcomes: kidney oxygenation (R2*), global perfusion and tissue inflammation (T1 mapping)","endpoints":null,"effect_estimate":"Coprimary MRI outcomes not significantly altered vs placebo; secondary outcomes: reduced renal artery resistive index and stabilized apparent diffusion coefficient, plus transcriptomic effects on glomerular endothelial cells. No numbers given.","confidence_interval":null,"p_value":null,"sample_size":106,"follow_up":"52 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"25 women, 81 men\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"chronic kidney disease required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with chronic kidney disease\", \"sample_size\": 106, \"inclusion_exclusion\": \"type 2 diabetes and chronic kidney disease\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and chronic kidney disease; no BMI or age is reported.","mediation":"possibly","mediation_notes":"Possibly: no weight, HbA1c or mediation analysis is reported, so the secondary vascular and fibrosis signals are not separated from weight or glycaemic change. The coprimary result was null, which on its own would point to unlikely.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 106, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; 106 participants, biopsy in 33\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Randomized trial of 106 participants with imaging, histology and transcriptomic outcomes only (coprimary null): LOW.","funding_source":"NIH and Novo Nordisk grants and contracts to one author (M.K.) through the University of Michigan in support of this work (conflicts statement); no funding statement in the abstract and no PubMed grants","industry_funded":"partial","manufacturer":"not stated in source","author_conflicts":"Seven authors are current or former Novo Nordisk employees and shareholders, and others report consulting, advisory, speaker or grant ties with Novo Nordisk and many other companies.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"not reported in abstract","limitations":"Mechanistic trial of 106 people whose coprimary imaging outcomes were null; tissue analyses were in small subsets (33 biopsies, 22 and 13 for transcriptomics), and the positive findings are secondary.","plain_summary":"This 52-week randomized trial gave subcutaneous semaglutide 1 mg once weekly or placebo to 106 people with type 2 diabetes and chronic kidney disease, and studied their kidneys with imaging and biopsies. The coprimary imaging measures of oxygenation, perfusion and inflammation were not significantly altered compared with placebo. Secondary outcomes linked semaglutide to a lower renal artery resistive index and a stable diffusion measure suggesting less fibrosis progression, but these are imaging and tissue markers, not kidney failure or death.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":813,"doi":"10.1111/dom.71387","pmid":"42823075","nct_ids":"[]","title":"Nephroprotective Effects of the Dual GCGR/GLP-1R Agonist Survodutide in Hypertension-Accelerated Diabetic Kidney Disease","authors":"[\"Hamilton A\", \"Thisted L\", \"Ougaard M\", \"Hahn M\", \"Andersen K\", \"Perens J\", \"Augustin R\", \"Bajrami B\", \"Rist W\", \"Christensen M\", \"Hansen HH\", \"Klein T\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Survodutide is a novel long-acting dual glucagon (GCGR)/glucagon-like peptide-1 (GLP-1R) receptor agonist currently in phase-3 clinical development for the treatment of people living with obesity and metabolic dysfunction-associated steatohepatitis. Emerging evidence suggests impaired renal GCGR function in chronic kidney disease (CKD), including diabetic kidney disease (DKD). This study aimed to characterize the effects of survodutide in a translational mouse model of advanced DKD, induced by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) diabetic db/db mice. [MATERIALS AND METHODS] Female obese and diabetic db/db C57BKS mice received a single intravenous dose of ReninAAV 1 week prior to UNx. Three weeks post-UNx, db/db UNx-ReninAAV mice were administered (s.c., q.d.) vehicle or survodutide (7.5 nmol/kg) for 10 weeks. Endpoints included blood/urine biochemistry, histological markers of glomerulosclerosis, tubular injury and inflammation, as well as quantitative 3D whole-pancreas and whole-kidney imaging. [RESULTS] Compared to vehicle controls, survodutide reduced body weight, hyperglycemia, and HbA1c levels concurrent with improved hyperinsulinemia and β-cell islet volume distribution. Notably, survodutide promoted substantial benefits on advanced albuminuria, severe glomerulosclerosis, kidney hypertrophy and inflammation. 3D whole-kidney imaging revealed that survodutide significantly reduced kidney and glomerular hypertrophy while increasing glomerular density and improving glomerular sphericity. Survodutide reduced liver weight and plasma amino acid levels, including alanine, confirming hepatic glucagon receptor activation. [CONCLUSIONS] Survodutide markedly improved metabolic and renal outcomes in the db/db UNx-ReninAAV mouse model of advanced DKD, supporting further investigation into therapeutic options of survodutide in chronic kidney diseases.","url":"https://pubmed.ncbi.nlm.nih.gov/42823075/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"preclinical_animal","drugs":"[\"survodutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":836,"doi":"10.1093/ejhf/xuag301","pmid":"42817848","nct_ids":"[]","title":"Pharmacological treatment strategies to prevent heart failure across the cardiovascular-kidney-metabolic spectrum: an EJHF Expert Consensus Statement","authors":"[\"Inciardi RM\", \"Abdin A\", \"Abdelhamid M\", \"Ambrosio G\", \"Böhm M\", \"Cannata A\", \"Chioncel O\", \"Cosentino F\", \"Esteban-Fernandez A\", \"Elsanhoury A\", \"Girerd N\", \"Jhund PS\", \"Lindberg F\", \"Van Linthout S\", \"Lombardi CM\", \"Neuen BL\", \"Ostrominski JW\", \"Stolfo D\", \"Vaduganathan M\", \"Solomon SD\", \"Mullens W\", \"Metra M\", \"Savarese G\"]","journal":"European journal of heart failure","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Heart failure (HF) remains a major cause of morbidity, mortality, and increased healthcare costs worldwide, and is recognized as the result of progressive cardiovascular-kidney-metabolic (CKM) syndrome. Obesity, type 2 diabetes, chronic kidney disease, hypertension, and atherosclerotic cardiovascular disease frequently coexist and interact through shared pathophysiological mechanisms that promote HF onset, especially with preserved ejection fraction (HFpEF). This European Journal of Heart Failure (EJHF) Expert Consensus Statement synthesizes contemporary evidence supporting pharmacological strategies to prevent HF across the CKM spectrum. Foundational therapies, including renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and incretin-based agents, demonstrate complementary benefits in reducing HF events, cardiovascular death, and chronic kidney disease (CKD) progression in high-risk populations. Early, parallel initiation of these therapies may modify disease trajectory and attenuate progression from at-risk and pre-HF stages to overt clinical HF. This document further emphasizes the need for an up-front, accelerated implementation strategy supported by structured monitoring, multidisciplinary CKM care pathways, and proactive management of laboratory abnormalities. Overcoming barriers such as clinical inertia, safety misperceptions, polypharmacy, cost constraints, and inequities in access is essential to translate evidence into population-level impact. Harmonization of prevention frameworks across cardiology, nephrology, endocrinology, and primary care societies is urgently required. Integrated, cross-disciplinary implementation of evidence-based CKM management offers a realistic opportunity to reduce incident HF and mitigate its growing global burden.","url":"https://pubmed.ncbi.nlm.nih.gov/42817848/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:20+00:00","study_design":"guideline","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":885,"doi":"10.1136/bmjopen-2026-120507","pmid":"42823110","nct_ids":"[]","title":"Tirzepatide safety in EudraVigilance: descriptive and disproportionality analysis of preferred terms related to suboptimal treatment outcomes and drug-use-related issues","authors":"[\"Popa Ilie IR\", \"Ghibu S\", \"Butuca A\", \"Dobrea CM\", \"Frum A\", \"Stoicescu L\", \"Homorodean C\", \"Gligor FG\", \"Morgovan C\"]","journal":"BMJ open","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] As obesity and diabetes are on the verge of an alarming growth, so is the use of tirzepatide, a novel dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) and currently the most effective weight loss-drug. This research aimed to identify reporting patterns related to suboptimal therapeutic outcomes and tirzepatide-related drug-use issues, mining the EudraVigilance (EV). [DESIGN] Retrospective pharmacovigilance study using descriptive and disproportionality analyses of reports retrieved from the EV database. [SETTINGS] Analysis of individual case safety reports involving tirzepatide in comparison with other GLP-1 RAs in the overall dataset (healthcare professionals (HP) and non-HP reports combined) and in the HP group. [OUTCOME MEASURES] Reporting ORs (RORs) with 95% CIs for selected Preferred Terms (PT) related to drug-use issues. [RESULTS] Among all analysed PTs, the most frequently reported were 'Off-label use' (n=1521), 'Drug ineffective' (n=425) and 'Off-label use device' (n=99). PTs in HP reports showed lower reporting odds compared with non-HP reports. In the overall dataset, reports involving tirzepatide showed lower reporting odds of the PT 'Drug ineffective' than those involving liraglutide (ROR 0.61, 95% CI 0.54 to 0.70), dulaglutide (ROR 0.72, 95% CI 0.63 to 0.82), exenatide (ROR 0.78, 95% CI 0.67 to 0.92) and semaglutide (ROR 0.81, 95% CI 0.72 to 0.91). However, in HP reports, no difference in reporting odds was observed between tirzepatide and semaglutide. A different pattern was observed for 'off-label use' in the full dataset, with higher reporting odds for tirzepatide vs lixisenatide, dulaglutide and liraglutide, but lower reporting odds vs semaglutide (ROR 0.52, 95% CI 0.49 to 0.55). In contrast, a higher reporting odd for the PT 'off-label use of device' was observed for tirzepatide versus semaglutide (ROR 43.47, 95% CI 16.00 to 118.13) in the overall reports; however, this finding should be interpreted with caution given the wide CI. [CONCLUSIONS] This study complements existing evidence from clinical trials and current clinical practice.","url":"https://pubmed.ncbi.nlm.nih.gov/42823110/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: None declared.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:41+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":887,"doi":"10.1056/nejmoa2607219","pmid":"42820639","nct_ids":"[\"NCT06066528\"]","title":"Survodutide Once Weekly in Adults with Obesity and Type 2 Diabetes","authors":"[\"Wharton S\", \"le Roux CW\", \"Startseva E\", \"Kloer IM\", \"Alhussein A\", \"Hussain SA\", \"Unseld A\", \"Bozkurt B\", \"Ard JD\", \"Bays HE\", \"Bogdański P\", \"Butt JH\", \"Ekinci EI\", \"Jastreboff AM\", \"Ji L\", \"Schou M\", \"Tinahones FJ\", \"Kokkinos AD\", \"Merkely B\", \"Ogawa W\", \"Pedersen SD\", \"Pietiläinen KH\", \"Quinn D\", \"Sattar N\", \"Seufert J\", \"Stenlöf K\", \"van Beek AP\", \"Vangoitsenhoven R\", \"Brueckmann M\", \"Younes R\", \"Kaplan LM\", \"SYNCHRONIZE-2 Investigators\"]","journal":"The New England journal of medicine","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] For persons living with both type 2 diabetes and obesity, weight management may be the most effective therapy for type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists have potent weight-reducing effects, and other mechanisms may confer additional benefits. Survodutide is an investigational glucagon receptor-GLP-1 receptor dual agonist with potential weight-reducing and metabolic benefits. [METHODS] In this multinational, double-blind, phase 3 trial involving adults with type 2 diabetes and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 or more, we randomly assigned participants in a 1:1:1 ratio to receive once-weekly subcutaneous survodutide (3.6 mg or 6.0 mg) or placebo. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. [RESULTS] Among 752 participants (250 in the 3.6-mg survodutide group, 251 in the 6.0-mg survodutide group, and 251 in the placebo group), the mean age at baseline was 55.7 years, and the mean BMI was 36.5; 49.3% were men. The mean weight change at week 76 according to the treatment-regimen estimand (which assessed effects regardless of whether the trial regimen was discontinued or interrupted or whether other antiobesity therapies were used) was -8.2% (95% confidence interval [CI], -9.2 to -7.2) in the 3.6-mg group, -9.8% (95% CI, -10.8 to -8.8) in the 6.0-mg group, and -3.9% (95% CI, -4.9 to -2.9) in the placebo group; weight reduction of at least 5% occurred in 57.6%, 64.5%, and 35.1% of the participants, respectively (P<0.001 for all comparisons with placebo). The mean change in the glycated hemoglobin level (from a baseline level of 7.4%) was -0.9 percentage points in the 3.6-mg group, -0.8 percentage points in the 6.0-mg group, and -0.2 percentage points in the placebo group. The most common adverse events were gastrointestinal (generally mild to moderate and transient), which occurred in 182 participants (72.8%) in the 3.6-mg group, 195 (77.7%) in the 6.0-mg group, and 97 (38.6%) in the placebo group. [CONCLUSIONS] In adults with obesity and type 2 diabetes, survodutide at a weekly dose of 3.6 mg or 6.0 mg resulted in significantly greater weight reduction than placebo. (Funded by Boehringer Ingelheim; SYNCHRONIZE-2 ClinicalTrials.gov number, NCT06066528.).","url":"https://pubmed.ncbi.nlm.nih.gov/42820639/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"survodutide\"]","drug_details":"{\"dose\": \"3.6 mg or 6.0 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\", \"treatment_duration\": \"76 weeks\"}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76","endpoints":null,"effect_estimate":"Weight change at week 76: -8.2% (3.6 mg) and -9.8% (6.0 mg) vs -3.9% placebo; at least 5% weight reduction in 57.6%, 64.5% and 35.1%; glycated hemoglobin -0.9 and -0.8 vs -0.2 percentage points.","confidence_interval":"95% CI: -9.2 to -7.2 (3.6 mg); -10.8 to -8.8 (6.0 mg); -4.9 to -2.9 (placebo)","p_value":"P<0.001 for all comparisons with placebo","sample_size":752,"follow_up":"week 76","direction":"benefit","population":"{\"mean_age\": 55.7, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"49.3% men\", \"bmi_mean\": 36.5, \"bmi_min\": 27, \"obesity_status\": \"obesity or overweight required (BMI 27 or more)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with obesity or overweight\", \"sample_size\": 752, \"inclusion_exclusion\": \"adults with type 2 diabetes and BMI of 27 or more\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and a BMI of 27 or more (mean BMI 36.5); mean age 55.7 years.","mediation":"not_applicable","mediation_notes":"Not applicable: the primary outcomes are weight change, and the HbA1c change is glycaemic.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 752, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"week 76\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported; 752 participants\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large double-blind phase 3 RCT (752 participants) with intermediate weight outcomes rather than hard clinical outcomes: MODERATE.","funding_source":"Boehringer Ingelheim","industry_funded":"yes","manufacturer":"Boehringer Ingelheim","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Gastrointestinal events (generally mild to moderate and transient) in 182 (72.8%) at 3.6 mg, 195 (77.7%) at 6.0 mg and 97 (38.6%) on placebo","limitations":"The abstract states no limitations; outcomes are weight and glycaemic measures over 76 weeks with no clinical events, in a manufacturer-funded trial.","plain_summary":"In this double-blind phase 3 trial, 752 adults with type 2 diabetes and a BMI of 27 or more (mean age 55.7 years, mean BMI 36.5) received weekly survodutide 3.6 mg or 6.0 mg or placebo. At week 76, weight changed by -8.2% and -9.8% with survodutide versus -3.9% with placebo, and glycated hemoglobin changed by -0.9 and -0.8 percentage points versus -0.2. Gastrointestinal adverse events were more common with survodutide (72.8% and 77.7% versus 38.6%), and the trial measured weight and glucose, not clinical events.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1003,"doi":"10.3390/nu18193246","pmid":"42884697","nct_ids":"[]","title":"Effects of Blueberry and Collard Greens Dietary Intervention on Metabolic and Inflammatory Biomarkers in Zucker Obese Rats","authors":"[\"Yeboah JA\", \"Bradford CN\", \"Dawkins NL\"]","journal":"Nutrients","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Obesity is a global health challenge associated with metabolic and inflammatory health outcomes. Dietary interventions such as phytochemical-rich foods may offer a sustainable and cost-effective approach to improving health outcomes associated with obesity. This study evaluated the effects of diets containing 4% blueberry powder and extracts, and 4% collard greens powder and extracts, and a combination of 2% blueberry and 2% collard greens on metabolic and inflammatory biomarkers in obese Zucker rats. Methods: Fifty-six male rats were randomly assigned to seven treatment groups (n = 8), including five diet treatment groups, an AIN- 93 control group, and an Ozempic® (semaglutide)-treated group. Body weight, feed intake, plasma glucose, lipid profile, and inflammatory biomarkers were assessed following an 8-week dietary intervention. Results: A high mortality rate was observed in the Ozempic® (semaglutide)-treated group, with five out of eight rats dying during the third week of intervention. The semaglutide-treated group showed the greatest reductions in fasting plasma glucose concentrations. Diets supplemented with blueberry and collard greens significantly increased HDL cholesterol and reduced LDL cholesterol concentrations compared with the control group, while also improving selected inflammatory biomarkers. The collard green extract group had the lowest IL-6 concentration (34.65 ± 3.90 pg/mL) compared with the control group (339.57 ± 185.65 pg/mL) (p < 0.05). Conclusions: Overall, blueberries and collard greens consumption improved dyslipidemia and inflammation in obese Zucker rats. These preliminary findings suggest that phytochemical-rich fruits and vegetables may provide a cost-effective dietary strategy for improving metabolic and inflammatory outcomes associated with obesity.","url":"https://pubmed.ncbi.nlm.nih.gov/42884697/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"AIN-93 control diet (also blueberry and collard green diets)\", \"dose\": null, \"route\": null, \"treatment_duration\": \"8 weeks\"}","domains":"[\"inflammation\", \"mortality\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"body weight, feed intake, plasma glucose, lipid profile and inflammatory biomarkers","endpoints":null,"effect_estimate":"Semaglutide group: five out of eight rats died during the third week of intervention; it showed the greatest reductions in fasting plasma glucose (no numeric glucose estimate given for semaglutide).","confidence_interval":null,"p_value":null,"sample_size":56,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male rats only\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (obese Zucker rats)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity (Zucker obese rats)\", \"sample_size\": 56, \"inclusion_exclusion\": \"male obese Zucker rats\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"VERY_INDIRECT: male obese Zucker rats; non-human evidence.","mediation":"possibly","mediation_notes":"Body weight was measured but no semaglutide weight result is reported, so the glucose fall cannot be separated from weight or intake change; default possibly, which applies to animal studies too.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": 56, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"AIN-93 control diet (also blueberry and collard green diets)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"no CI reported; n = 8 per group, five of eight semaglutide rats died\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Preclinical animal study: VERY_LOW.","funding_source":"United States Department of Agriculture; Center for Excellence for Nutrition, Health, Wellness,","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"High mortality in the semaglutide group: five of eight rats died during the third week","limitations":"Animal study with 8 rats per group over 8 weeks; semaglutide served as a comparison arm in a diet study, and most of that arm died, leaving little semaglutide data.","plain_summary":"In this 8-week study, fifty-six male obese Zucker rats were randomly assigned to blueberry or collard green diets, a control diet, or Ozempic (semaglutide), which served as a comparison arm. The semaglutide group showed the greatest reductions in fasting plasma glucose, but five out of eight rats in that group died during the third week. The fruit and vegetable diets improved cholesterol and some inflammatory markers. Results in rats do not show what happens in people.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1120,"doi":"10.4103/aca.aca_307_25","pmid":"42862661","nct_ids":"[]","title":"GLP-1 Receptor Agonists and Insulin Versus Insulin for Perioperative Glycemic Control in Patients with Type 2 Diabetes Undergoing Cardiac Surgery: A Systematic Review","authors":"[\"Hassan D\", \"Shakeel R\", \"Qaisi W\", \"Ahmed SR\", \"Taj J\", \"Adi M\", \"Ahmed AY\", \"Abuzahra A\", \"Sajid EU\", \"Khan HA\", \"Basit T\", \"Iqbal J\", \"Hussain A\"]","journal":"Annals of cardiac anaesthesia","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Perioperative hyperglycemia is common in patients with type 2 diabetes undergoing cardiac surgery and is linked to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer glucose-dependent insulinotropic effects and potential cardiac benefits, but their perioperative role remains uncertain. This review evaluated the efficacy and safety of GLP-1 RA therapy as an adjunct to insulin in this setting. Three electronic databases (PubMed, Cochrane, and Google Scholar) were searched for relevant articles up to October 2025. The primary endpoint was blood glucose levels during the perioperative period, while secondary endpoints included hypoglycemia incidence, total insulin requirement, time in target glucose range, and postoperative complications. Three randomized controlled trials (RCTs) including 168 patients with type 2 diabetes undergoing cardiac surgery were assessed. Perioperative use of liraglutide (subcutaneously in doses of 0.6-1.8 mg/day) was associated with preliminary evidence of improved glycemic control across preoperative, intraoperative, and early postoperative periods, including lower glucose levels, reduced glycemic variability, and fewer insulin adjustments, with a low incidence of hypoglycemia. However, heterogeneity in dosing, timing, and monitoring protocols across studies limits direct comparisons. Mild gastrointestinal adverse events, such as nausea and vomiting, were more frequent with liraglutide. One study reported exploratory immunometabolic effects in adipose tissue. Preliminary evidence from these heterogeneous studies suggests that adding liraglutide to insulin may improve perioperative glycemic control compared to insulin or placebo in patients with type 2 diabetes undergoing cardiac surgery. However, findings are limited by the small number of studies, methodological variability, and lack of long-term outcomes, necessitating larger, standardized trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42862661/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"systematic_review","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"0.6-1.8 mg/day\", \"route\": \"subcutaneous\", \"comparator\": \"insulin alone or placebo\", \"treatment_duration\": \"perioperative period (length not stated)\"}","domains":"[\"cardiovascular\", \"body_composition\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":"biomarker","primary_outcome":"blood glucose levels during the perioperative period","endpoints":null,"effect_estimate":"No pooled numeric estimate reported. Liraglutide was associated with lower glucose levels, reduced glycemic variability and fewer insulin adjustments, with a low incidence of hypoglycemia; mild gastrointestinal adverse events were more frequent.","confidence_interval":null,"p_value":null,"sample_size":168,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes undergoing cardiac surgery\", \"sample_size\": 168, \"inclusion_exclusion\": \"RCTs of GLP-1 RA plus insulin in type 2 diabetes undergoing cardiac surgery\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 168 patients had type 2 diabetes and were undergoing cardiac surgery; no BMI or age is given.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is perioperative blood glucose control.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": 168, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"insulin alone or placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no pooled estimate or CI reported; three trials, 168 patients\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Systematic review of three small randomized trials with no pooled estimate reported: NOT_RATED.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Mild gastrointestinal adverse events (nausea, vomiting) more frequent with liraglutide; low incidence of hypoglycemia.","limitations":"Only three small, heterogeneous trials with varied dosing, timing and monitoring, no long-term outcomes and no pooled estimate.","plain_summary":"This systematic review described three randomized trials with 168 people with type 2 diabetes having cardiac surgery, without reporting a pooled estimate. Adding liraglutide to insulin was linked to lower glucose levels, less glycemic variability and fewer insulin adjustments, with a low incidence of hypoglycemia, but mild nausea and vomiting were more frequent. The authors call the evidence preliminary: the studies were few and varied, and none reported long-term outcomes.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1314,"doi":"10.1001/jamanetworkopen.2026.40781","pmid":"42944687","nct_ids":"[]","title":"GLP-1 RA Prescribing in Patients With Type 2 Diabetes and Cancer","authors":"[\"Hu X\", \"Jiang C\", \"Han X\", \"Zhang L\", \"Li P\", \"Pasquel FJ\", \"Meisel JL\", \"Vo JB\", \"Varghese JS\", \"Shao H\", \"Graetz I\"]","journal":"JAMA network open","publication_date":"2026-10-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes, yet little is known about its utilization patterns in patients with cancer history, given limited oncology-specific guidance. [OBJECTIVE] To evaluate trends and factors associated with GLP-1 RA use among Medicare beneficiaries with type 2 diabetes, comparing those with and without cancer history. [DESIGN, SETTING, AND PARTICIPANTS] This retrospective cohort study used Surveillance, Epidemiology, and End Results-Medicare linked data to identify patients diagnosed with 7 common cancers in 2010 to 2021 and preexisting type 2 diabetes before cancer diagnosis. A noncancer cohort with type 2 diabetes was identified from a 5% random sample of Medicare beneficiaries and matched 1:1 to patients with cancer based on sociodemographic characteristics; controls were assigned a pseudo-index date corresponding to their matched patient's cancer diagnosis date. Beneficiaries were followed up annually until death or December 31, 2022, for TM or December 31, 2021, for MA. Data were analyzed from December 2025 to July 2026. [EXPOSURES] Diagnosis of 1 of 7 common cancers. [MAIN OUTCOMES AND MEASURES] Any GLP-1 RA use. Proportions of beneficiaries with any GLP-1 RA use annually were stratified by traditional Medicare (TM) and Medicare Advantage (MA). Multivariable logistic regression examined (1) differences in GLP-1RA use between cancer and noncancer cohorts with and without adjusting for sociodemographic characteristics and comorbidities and diabetes-related complications; (2) cancer-specific factors associated with GLP-1RA use among the cancer cohort after 2018. [RESULTS] A total of 373 278 Medicare beneficiaries (mean [SD] age, 76.1 [6.6] years; 188 746 [50.6%] female) with cancer and diabetes and 373 278 noncancer controls (153 358 unique beneficiaries) were included. GLP-1 RA use increased from 85 beneficiaries (0.5%) to 9083 beneficiaries (8.2%) and from 138 beneficiaries (0.9%) to 9300 beneficiaries (6.2%) in the cancer and noncancer cohorts, respectively, from 2010 to 2022 under TM; a similar increase was observed under MA. Despite higher unadjusted GLP-1 RA use among the cancer cohort than the noncancer cohort (probability difference, TM: 1.19 [95% CI, 0.94 to 1.44] percentage points [pp]; P < .001; MA: 0.45 [95% CI, 0.21 to 0.68] pp, P < .001), adjusted analysis showed no significant differences in GLP-1 RA use under TM (adjusted probability difference, 0.16 [95% CI, -0.10 to 0.41,] pp; P = .22) and lower use among cancer cohort under MA (-0.52 [95% CI, -0.76 to -0.28] pp; P < .001). Complications or comorbidities, including obesity (adjusted probability difference, TM: 3.35 [95% CI, 3.10 to 3.61] pp; P < .001; MA: 2.42 [95% CI, 2.19 to 2.64] pp; P < .001), dyslipidemia (adjusted probability difference, TM: 2.26 [95% CI, 2.03 to 2.50] pp; P < .001; MA: 1.80 [95% CI, 1.57 to 2.03] pp; P < .001), neuropathy (adjusted probability difference: TM: 3.91 [95% CI, 3.64 to 4.19] pp; P < .001; MA: 3.17 [95% CI, 2.94 to 3.41] pp; P < .001), retinopathy (adjusted probability difference, TM: 2.02 [95% CI, 1.78 to 2.27] pp; P < .001; MA: 1.84 [95% CI, 1.63 to 2.06] pp; P < .001), and chronic kidney disease (adjusted probability difference, TM: 2.01 [95% CI, 1.76 to 2.26] pp; P < .001; MA: 1.63 [95% CI, 1.40 to 1.85] pp; P < .001) were associated with greater likelihood of GLP-1RA use. Within the cancer cohort, breast (adjusted probability difference, TM: 1.05 [95% CI, 0.43 to 1.66] pp; P = .001; MA: 0.89 [95% CI, 0.37 to 1.41] pp; P = .001), gynecologic (adjusted probability difference, MA: 1.13 [95% CI, 0.45 to 1.81] pp; P = .001), and prostate (adjusted probability difference, TM: 1.30 [95% CI, 0.72 to 1.88] pp; P < .001; MA: 1.07 [95% CI, 0.56 to 1.58] pp; P < .001) cancers were associated with higher GLP-1 RA use than colorectal cancer, while pancreatic cancer was associated with lower GLP-1 RA use (adjusted probability difference, TM: -2.55 [95% CI, -3.17 to -1.93] pp; P < .001; MA: -1.64 [95% CI, -2.23 to -1.05] pp; P < .001). [CONCLUSIONS AND RELEVANCE] In this retrospective study of Medicare beneficiaries with type 2 diabetes, GLP-1 RA use increased substantially and primarily was associated with metabolic risk profile, with limited associations with cancer status. Variation across cancer types and stages suggests oncologic context may influence prescribing.","url":"https://pubmed.ncbi.nlm.nih.gov/42944687/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:24+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"cancer\", \"metabolic\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":50,"doi":"10.1111/dom.71106","pmid":"42449480","nct_ids":"[]","title":"Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-Analysis","authors":"[\"Kanbay M\", \"Shah E\", \"AlShiab R\", \"Ozbek L\", \"Ay S\", \"Rustamov A\", \"Covic A\", \"Mallamaci F\", \"Zoccali C\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM), but their effects on inflammatory and oxidative biomarkers are not fully defined. [MATERIALS AND METHODS] We searched PubMed, Ovid MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to 19 February 2026 for randomised controlled trials (RCTs) in adults with T2DM comparing a GLP-1RA or dual GIP/GLP-1 agonist with placebo or active therapy, and reporting C-reactive protein (CRP or high-sensitivity CRP [hs-CRP]), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), malondialdehyde (MDA) or adiponectin. Random-effects meta-analyses were conducted using standardised mean differences (SMDs). [RESULTS] Forty-one RCTs were included. GLP-1RAs significantly reduced CRP/hs-CRP (27 studies, 1991 participants; SMD -0.37, 95% CI -0.59 to -0.14) and MDA (3 studies, 272 participants; SMD -0.98, 95% CI -1.65 to -0.30), and increased adiponectin (16 studies, 1327 participants; SMD 0.30, 95% CI 0.13 to 0.46). Pooled effects on IL-6 (17 studies, 1068 participants; SMD -0.14, 95% CI -0.37 to 0.10), TNF-α (16 studies, 1164 participants; SMD -0.25, 95% CI -0.61 to 0.12) and MCP-1 (7 studies, 450 participants; SMD -0.27, 95% CI -0.58 to 0.03) were not statistically significant, although MCP-1 decreased in sensitivity analyses. Across biomarkers, heterogeneity was moderate to high. Two tirzepatide RCTs (562 participants) showed a significant reduction in IL-6 (SMD -0.28, 95% CI -0.47 to -0.09) and a non-significant trend towards lower CRP/hs-CRP. [CONCLUSIONS] In adults with T2DM, incretin-based therapies consistently lower CRP/hs-CRP, reduce oxidative stress (MDA) and increase adiponectin, while effects on IL-6 and TNF-α are more variable. These data support a selective anti-inflammatory and metabolic regulatory profile of GLP-1-based therapy, but heterogeneity and limited data for some biomarkers warrant cautious interpretation and further mechanistic studies. [TRIAL REGISTRATION] PROSPERO number: CRD420261321430.","url":"https://pubmed.ncbi.nlm.nih.gov/42449480/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo or active therapy\"}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"CRP/hs-CRP, IL-6, TNF-alpha, MCP-1, MDA, adiponectin in RCTs in type 2 diabetes","endpoints":null,"effect_estimate":"CRP SMD -0.37 (27 studies); adiponectin +0.30; MDA -0.98; IL-6 and TNF-alpha not significant; tirzepatide IL-6 SMD -0.28","confidence_interval":"-0.59 to -0.14 (CRP)","p_value":null,"sample_size":1991,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes (all trials)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1991, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes trials; biomarkers only; heterogeneity moderate to high.","mediation":"possibly","mediation_notes":"Trials in diabetes with concurrent weight and glycaemic change; meta-analysis did not adjust for weight loss.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1991, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo or active therapy\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"41 RCTs\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -0.59 to -0.14 (CRP)\", \"risk_of_bias\": \"high heterogeneity; small trials; biomarker outcomes\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"overall\": \"Low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"one critical flaw: item 13 — risk-of-bias results are not brought into the interpretation of the pooled estimates\", \"items\": \"A: 9 Yes / 3 Partial Yes / 4 No; B: 10 Yes / 2 Partial Yes / 4 No; one item differs (item 2: Partial Yes vs Yes — both non-flaws, rating unaffected; recorded in the inbox)\", \"source\": \"full text (PMC HTML), 2026-09-13; supersedes the abstract-only assessment\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"label\": \"AI: two passes agreed\"}, \"included_trials\": [\"[21] Ahmad 2021 (LYDIA trial)\", \"[22] Ahmadi 2019 (MDI-Liraglutide Study 5)\", \"[23] Bouchi 2017\", \"[24] Bunck 2010\", \"[25] Caruso 2025\", \"[26] Derosa 2010 (exenatide vs glibenclamide)\", \"[27] Derosa 2012 (exenatide plus metformin)\", \"[28] Dutour 2016\", \"[29] Fan 2013\", \"[30] Forst 2012\", \"[31] Gurkan 2014\", \"[32] Jensen 2021 (LIRAFLAME trial)\", \"[33] Kang 2021\", \"[34] Lambadiari 2018\", \"[35] Lambadiari 2021 (yields pairwise comparisons \\\"Lambadiari 2021a\\\"/\\\"2021b\\\" vs insulin and empagliflozin)\", \"[36] Li 2019\", \"[37] Liang 2013\", \"[38] Lin 2015\", \"[39] Liu 2019\", \"[40] Pastel 2017\", \"[41] Quan 2017\", \"[42] Ripa 2021\", \"[43] Rosenstock 2025 (orforglipron)\", \"[44] Sathyanarayana 2011\", \"[45] Savvidou 2016\", \"[46] Shao 2024\", \"[47] Shi 2017\", \"[48] Suzuki 2014\", \"[49] Takeshita 2015\", \"[50] Wang J. 2019\", \"[51] Wang Q. 2020\", \"[52] Wu 2011\", \"[53] Xie 2022\", \"[54] Yan 2019 (yields pairwise comparisons \\\"Yan 2019a\\\"/\\\"2019b\\\" vs sitagliptin and insulin glargine)\", \"[55] Yao 2020\", \"[56] Ying 2023\", \"[57] Zhang W.-q. 2018\", \"[58] Zhang J. 2020\", \"[59] FLAT-SUGAR Trial Investigators 2016 (\\\"Investigators TF-ST\\\")\", \"[60] Sattar 2024 (SURMOUNT-1 and SURMOUNT-2 post-hoc, tirzepatide)\", \"[61] Wilson 2022 (tirzepatide post hoc)\"]}","evidence_rationale":"Meta-analysis of small RCTs with biomarker endpoints and high heterogeneity.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Authors declare no conflicts.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Risk-of-bias judgments (RoB 2, Table S2) are reported but not carried into the interpretation of results; registry/grey-literature search absent and English-only limit unjustified (item 4 Partial Yes).","plain_summary":"Pooling 41 randomized trials in people with type 2 diabetes, GLP-1 drugs modestly lowered CRP and raised adiponectin, but did not consistently change IL-6 or TNF-alpha, and MCP-1 was not significantly changed. In two tirzepatide trials IL-6 fell but CRP showed only a non-significant trend. Biomarkers only, in diabetes, with much variation between trials.","methodological_notes":"AMSTAR 2 from full text 2026-09-13, two passes: Low confidence (critical flaw at item 13). All 41 included RCTs listed from the text (40 of 41 author-year tokens machine-verified; the FLAT-SUGAR group-author entry verified by its reference entry). Included-trial list recorded to prevent double-counting: none of this review's trials may be separately graded in an outcome body that also uses its pooled estimate.","reviewed_by":null,"reviewed_at":null},{"id":112,"doi":"10.1016/j.jdiacomp.2026.109397","pmid":"42679726","nct_ids":"[]","title":"Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial","authors":"[\"Gullaksen S\", \"Vernstrøm L\", \"Sørensen SS\", \"Funck KL\", \"Poulsen PL\", \"Laugesen E\"]","journal":"Journal of diabetes and its complications","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. [METHODS] This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. [RESULTS] RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). [CONCLUSION] Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.","url":"https://pubmed.ncbi.nlm.nih.gov/42679726/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Esben Laugesen reports financial support was provided by Novo Nordisk Foundation. Soeren Gullaksen reports financial support was provided by Danish Medical Association Research Fund. Liv Vernstroem reports financial support was provided by Aarhus University. Steffen Skovgaard Soerensen reports financial support was provided by Independent Research Fund Denmark. Per Loegstrup Poulsen reports financial support was provided by Novo Nordisk Foundation. Per Loegstrup Poulsen reports a relationship with AstraZeneca that includes: board membership and funding grants. Per Loegstrup Poulsen reports a relationship with Bayer AG that includes: board membership. Per Loegstrup Poulsen reports a relationship with Novo Nordisk that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo (also empagliflozin alone and semaglutide plus empagliflozin arms)\", \"dose\": null, \"route\": null, \"treatment_duration\": \"32-week\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"markers of endothelial function: reactive hyperaemic index (RHI) and cell adhesion molecules (E-Selectin, ICAM-1, P-Selectin, VCAM-1)","endpoints":null,"effect_estimate":"Semaglutide vs placebo: RHI 0.11, 95%CI [-0.04;0.24], p = 0.16 (not significant; significant only vs baseline, 0.11, 95%CI [0.008;0.21]); E-Selectin -9 (p < 0.01); VCAM-1 increased by 12.3 (p = 0.01); P-Selectin and ICAM-1 not significantly affected","confidence_interval":"95%CI [-0.04;0.24] (RHI, semaglutide versus placebo)","p_value":"p = 0.16 (RHI, semaglutide versus placebo)","sample_size":120,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 50, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 120, \"inclusion_exclusion\": \"type 2 diabetes; age ≥ 50\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and were aged ≥ 50; BMI is not reported in the abstract.","mediation":"possibly","mediation_notes":"No weight, HbA1c or mediation data are reported for the semaglutide group, so the biomarker changes are not separated from weight and glycaemic change (possibly, by default).","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 120, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo (also empagliflozin alone and semaglutide plus empagliflozin arms)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95%CI [-0.04;0.24] (RHI, semaglutide versus placebo)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a post hoc analysis of a small randomized trial (one hundred and twenty participants across four arms) with biomarker outcomes only and mixed results.","funding_source":"Not stated as study funding; the competing-interest declaration reports financial support to authors from the Novo Nordisk Foundation, Danish Medical Association Research Fund, Aarhus University and Independent Research Fund Denmark","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Several authors report financial support from the Novo Nordisk Foundation and academic or public funds; one author reports board membership with AstraZeneca, Bayer AG and Novo Nordisk and funding grants from AstraZeneca; other authors declare no known competing interests","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk (one author, board membership)","adverse_events":"not reported in abstract","limitations":"A post hoc analysis of a small trial (one hundred and twenty participants across four arms) with biomarker outcomes; the authors attribute the null result versus placebo to limited power; all participants had type 2 diabetes; dose and blinding not stated in the abstract.","plain_summary":"This post hoc analysis of a 32-week randomized trial in one hundred and twenty people with type 2 diabetes aged ≥ 50 compared semaglutide, empagliflozin, both, or placebo on markers of blood-vessel lining function. Compared with placebo, semaglutide lowered E-Selectin but raised VCAM-1, its effect on the reactive hyperaemic index was not significant (0.11, 95%CI [-0.04;0.24]), and P-Selectin and ICAM-1 did not change. The authors attribute the null result versus placebo to limited power.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":203,"doi":"10.1002/osp4.70188","pmid":"42707648","nct_ids":"[]","title":"A Systematic Review and Meta-Analysis of Malnutrition and Metabolic Failure in High-Potency Incretin Therapy","authors":"[\"Ampofo E\", \"Apprey C\", \"Amoako M\", \"Turkson FD\"]","journal":"Obesity science & practice","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] High-potency incretin therapy achieved substantial weight loss, but the extreme energy deficits it induced may obscure the underlying nutritional deterioration. This meta-analysis synthesized data from 19 randomized trials across the SURMOUNT, STEP, SCALE, and OASIS programs to quantify the nutritional and body composition consequences of these agents in adults with obesity. [METHODS] This systematic review and meta-analysis followed PRISMA 2020 guidelines. Risk of bias was assessed using the Cochrane RoB2 tool, and certainty of evidence was rated using the GRADE approach. Continuous outcomes were pooled using mean differences within a random-effects model. [RESULTS] Daily energy intake declined by 24.00%-39.20% across drug classes, with model-estimated daily deficits reaching 1200 kcal. Tirzepatide 15 mg was associated with a mean fat-free mass (FFM) reduction of 1.60 kg, representing 2.80% of body weight. Investigator-reported malnutrition occurred in only 0.12% of participants. Objective laboratory screening identified low total lymphocyte counts below 910 per microliter in 2.90% of active-therapy participants, nearly double the 1.77% in placebo arms, indicating that standard adverse event reporting underestimates true nutritional risk. Pancreatic lipase increased by a mean of 31% in the SCALE program, representing a secondary metabolic signal. [CONCLUSIONS] Given these findings, a Tiered Stepped-Care Algorithm is proposed, mandating baseline screening of albumin and total lymphocyte count, periodic monitoring at weeks 12, 24, and 52, and defined intervention thresholds to prevent sarcopenia and frailty, particularly in adults aged 65 years and older.","url":"https://pubmed.ncbi.nlm.nih.gov/42707648/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no direct financial conflicts concerning this systematic review. While the 19 analyzed trials were primarily industry‐funded by Eli Lilly or Novo Nordisk, this independent synthesis received no corporate support.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"muscle\", \"lean_mass\", \"body_composition\", \"aging\", \"adverse_effects\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":254,"doi":"10.1002/osp4.70189","pmid":"42683049","nct_ids":"[]","title":"Patient-Reported Continuity of GLP-1 Receptor Agonist Therapy","authors":"[\"Chen Y\", \"Piantek G\", \"Zhang X\", \"Feng Y\", \"Yan C\", \"Samuels JM\", \"Rosenbloom ST\", \"Yu D\", \"Novak LL\", \"Srivastava G\"]","journal":"Obesity science & practice","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Use of GLP-1 receptor agonists is associated with significant weight loss in many individuals. Discontinuation is associated with weight regain. Patients' experience with this is not well characterized. This study describes the patient experience of continuity of care. [METHODS] A cross-sectional electronic survey was administered to adults identified from an academic medical center's electronic health records as having at least one GLP-1 RA prescription in the preceding 6 years and a subsequent prescription gap of greater than 90 days. The 87-item instrument spanned six domains: care settings, comorbidity and treatment context, continuity, discontinuity, dietitian/lifestyle support, and digital-feature preferences. Primary outcomes were item-level frequencies. Exploratory composites included a 7-item Continuity-of-Care Index (CCI) and a 5-item Discontinuity Index (DIS), each rescaled 0-100; subgroup comparisons used Kruskal-Wallis, Mann-Whitney, and chi-square tests, with multiple-imputation sensitivity analyses. [RESULTS] Of 4890 invitations, 261 adults completed the survey (5.3%); 143 (54.8%) reported current use of a prescription weight-management medication and 159 (60.9%) reported prior-authorization requirements. Among them, 79 (49.7%) either waited more than 7 days or were never approved. Continuity strengths included knowing whom to contact about medications (76.2%) and timely team responses (70.7%); the weakest items were cross-clinic coordination (54.1%) and visibility into required next steps (52.2%). The CCI (mean 69.5 [SD 22.7]; α = 0.90; n = 242) varied by most-visited clinic (Kruskal-Wallis p < 0.001), highest at the weight-management clinic (median 82.1) and lower at primary care (60.7). Among current medication users, 32.4% reported a ≥ 14-day medication gap. The most desired digital features were all-in-one tracking of refills, prior authorization, and appointments (89.5%) and real-time prior-authorization status (87.2%). [CONCLUSIONS] Patients described obesity-care disruptions primarily as process failures, including prior authorization delay, out-of-pocket cost, pharmacy stock-outs and dispensing delays, and fragmented cross-clinic coordination. They prioritized transparent, workflow-oriented navigation.","url":"https://pubmed.ncbi.nlm.nih.gov/42683049/","source_name":"pubmed","source_tier":1,"coi_statement":"G.S. declares advisory fees from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Quest Diagnostics, and Madrigal. Y.C., G.P., X.Z., Y.F., C.Y., J.M.S., T.R., D.Y., L.L.N. declare no conflicts of interests relevant to this work.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"adverse_effects\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":262,"doi":"10.1111/cob.70111","pmid":"42670242","nct_ids":"[]","title":"Comparative Efficacy of Tirzepatide Versus Semaglutide for Weight Loss in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis of Head-to-Head Studies","authors":"[\"Paccola GP\", \"de Oliveira RF\", \"Mochetti MM\", \"Razera FPM\", \"Vecchi R\", \"Montanher RCP\"]","journal":"Clinical obesity","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"This systematic review and meta-analysis aimed to compare the efficacy and safety of tirzepatide versus semaglutide for weight reduction in adults with overweight or obesity. We included randomised controlled trials and observational studies comparing tirzepatide and semaglutide with ≥ 24 weeks of follow-up. The primary outcome was percentage weight change from baseline. Secondary outcomes included absolute weight change, weight-loss thresholds, HbA1c and safety outcomes. Ten studies including 41 381 participants were analysed. Tirzepatide was associated with greater percentage weight reduction than semaglutide (MD -4.28 percentage points; 95% CI -5.28 to -3.28; p < 0.00001) and greater absolute weight loss (MD -4.43 kg; 95% CI -5.56 to -3.30; p < 0.00001). Tirzepatide was also associated with a higher likelihood of achieving ≥ 10%, ≥ 15% and ≥ 20% weight loss, with no difference at ≥ 5%. HbA1c reduction was greater with tirzepatide (MD -0.29%; p = 0.0002). Subgroup analyses by study design and type 2 diabetes status yielded consistent findings. There was no significant difference in treatment discontinuation due to adverse events (RR 1.28; p = 0.54), whereas serious adverse events were more frequent with tirzepatide (RR 1.83; p = 0.007). Overall and gastrointestinal adverse events were similar between groups. Tirzepatide was associated with greater weight reduction, greater glycaemic benefit and a higher likelihood of achieving weight-loss thresholds than semaglutide, but with a higher risk of serious adverse events.","url":"https://pubmed.ncbi.nlm.nih.gov/42670242/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"semaglutide\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percentage weight change from baseline","endpoints":null,"effect_estimate":"Tirzepatide vs semaglutide: percentage weight change MD -4.28 percentage points; absolute weight MD -4.43 kg; HbA1c MD -0.29%; higher likelihood of ≥ 10%, ≥ 15% and ≥ 20% weight loss, no difference at ≥ 5%; serious adverse events RR 1.83; discontinuation for adverse events RR 1.28, not significant","confidence_interval":"95% CI -5.28 to -3.28 (percentage weight change)","p_value":"p < 0.00001","sample_size":41381,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight or obesity required (adults with overweight or obesity)\", \"diabetes_status\": \"mixed\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"overweight or obesity\", \"sample_size\": 41381, \"inclusion_exclusion\": \"adults with overweight or obesity; randomised controlled trials and observational studies comparing tirzepatide and semaglutide with ≥ 24 weeks of follow-up\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: everyone studied had overweight or obesity, and the pooled studies included people with type 2 diabetes; no age or BMI data in the abstract.","mediation":"not_applicable","mediation_notes":"Not applicable: the primary outcome is weight change itself, and HbA1c is a glycaemic outcome.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 41381, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"semaglutide\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -5.28 to -3.28 (percentage weight change)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a meta-analysis with pooled estimates, weakened by mixing observational studies with randomised trials, and an intermediate primary outcome (weight change).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Serious adverse events more frequent with tirzepatide (RR 1.83; p = 0.007); no significant difference in discontinuation due to adverse events (RR 1.28; p = 0.54); overall and gastrointestinal adverse events similar","limitations":"Pools randomised controlled trials with observational studies, so part of the comparison is open to confounding; the abstract reports no heterogeneity or risk-of-bias results; everyone studied had overweight or obesity; abstract only.","plain_summary":"This review pooled ten head-to-head studies with 41 381 participants, both randomised trials and observational studies, comparing tirzepatide with semaglutide in adults with overweight or obesity. Tirzepatide was associated with more weight loss (MD -4.28 percentage points) and a larger HbA1c fall (MD -0.29%), but there was no difference in reaching ≥ 5% weight loss. Serious adverse events were more frequent with tirzepatide (RR 1.83), while stopping treatment for adverse events did not differ significantly. Part of the evidence is observational, so those results show associations rather than proof of cause.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":375,"doi":"10.1007/s12664-025-01856-7","pmid":"41066034","nct_ids":"[\"NCT05442450\"]","title":"Oral semaglutide for weight loss and liver fibrosis in overweight and obesity: A randomized controlled trial","authors":"[\"Katrevula A\", \"Kalapala R\", \"Agrawal S\", \"Jagtap N\", \"Chhabra P\", \"Kulkarni AV\", \"Merugu C\", \"Katukuri GR\", \"Duvvur NR\"]","journal":"Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND OBJECTIVES] Obesity is a leading risk factor for fatty liver disease and weight loss has been shown to improve liver parameters. This study evaluates the efficacy of oral semaglutide for weight loss in individuals with overweight or obesity, excluding those with diabetes mellitus. [METHODS] A randomized, open-label, controlled trial was conducted at the Asian Institute of Gastroenterology, Hyderabad, from June 2022 to December 2023. Adults (≥ 18 years) with a body mass index (BMI) ≥ 30 or ≥ 27 with comorbidities (pre-diabetes, hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease) were randomized into two groups. Both groups received counselling on a reduced-calorie diet and increased physical activity. Group 1 also received oral semaglutide, starting at 3 mg/day and titrated to 14 mg/day over two to four weeks. The objectives were to assess the effects of semaglutide on weight loss, non-invasive markers of liver fibrosis and cardiometabolic parameters. (ClinicalTrials.gov ID: NCT05442450). [RESULTS] Total 116 participants (58 per group) completed the study. At 28 weeks, the mean percentage weight reduction was -10.47% (SD 5.3) in the Semaglutide group vs. -2.4% (SD 4.5) in the control group (p < 0.001). Semaglutide treatment significantly improved alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) levels, along with reductions in the aspartate aminotransferase to platelet ratio index (APRI) score, liver fat content and liver stiffness. However, NFS (NAFLD fibrosis score) and FIB-4 (fibrosis-4 index) did not show significant reductions. Improvements in BMI, waist circumference, HbA1c, fasting insulin and C-reactive protein (CRP) were significantly greater with semaglutide (p < 0.001). Total fat mass decreased by 7.3 kg vs. 1.74 kg (p < 0.0001) in controls, while visceral fat ratings dropped by 3.67 vs. 0.6 (p < 0.0001). [CONCLUSIONS] In adults with overweight or obesity without diabetes, oral semaglutide, combined with dietary and lifestyle modifications, led to significant and clinically meaningful weight loss and metabolic improvements compared to lifestyle modifications alone.","url":"https://pubmed.ncbi.nlm.nih.gov/41066034/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: AK, RK, SA, NJ, PC, AVK, CM, GRK and NRD declare no conflict of interest. Ethics statement: The study was performed conforming to the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights, and the authors followed the policy concerning informed consent as shown on Springer.com. Patient Consent: Informed written consent for the publication of study data was obtained from all participants. Clinical trial registry number: ClinicalTrials.gov Identifier: NCT05442450. IRB approval: This study was approved by the Institutional Review Board of AIG Hospitals (IRB No: AIG/IEC-BH&R 27/05.2022–03, Approval Date: 28th May 2022). Disclaimer: The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers are responsible for the results/findings and content of this article.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"sleep\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":630,"doi":"10.1111/cob.70112","pmid":"42733128","nct_ids":"[]","title":"Weight Reduction Heterogenicity and Mediators of GLP-1RAs and Dual Agonists for Individuals With Obesity: A Meta-Analysis","authors":"[\"Lu D\", \"Li N\", \"Yuan Z\", \"Gao Y\"]","journal":"Clinical obesity","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual agonists have become pivotal options for obesity, but marked weight loss heterogeneity remains poorly understood. This meta-regression analysis aimed to identify factors influencing this heterogeneity. We searched Medline, Embase, The Cochrane Library, and Web of Science up to February 1, 2026, enrolling 32 eligible trials (40 408 participants) following PRISMA guidelines. Meta-regression and subgroup analyses were performed using R software. Pooled analysis showed that GLP-1RAs and dual agonists achieved a weighted mean weight reduction of 9.36% (95% CI 7.92%-10.80%), with high interstudy heterogeneity (I2 = 99.6%, p < 0.001). Subgroup analyses revealed that GLP-1/GIP dual agonists (tirzepatide) and longer treatment duration (≥ 72 weeks) yielded superior weight-lowering effects. Meta-regression demonstrated that baseline anxiety/depression was positively associated with weight loss efficacy (β = 2.44, p < 0.001, R2 = 81.34%). Comorbid Type 2 diabetes mellitus (T2DM), obstructive sleep apnea (OSA) and metabolic dysfunction-associated fatty liver disease (MAFLD) were negatively correlated with treatment response (all p < 0.05). Emotional state and metabolic comorbidities including T2DM, OSA and MAFLD are important influencing factors of the interindividual differences of weight loss efficacy of GLP-1RAs and dual agonists, providing evidence for personalized obesity management.","url":"https://pubmed.ncbi.nlm.nih.gov/42733128/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"liver\", \"sleep\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"percent weight reduction and factors explaining its heterogeneity","endpoints":null,"effect_estimate":"Weighted mean weight reduction 9.36% (95% CI 7.92%-10.80%) with I2 = 99.6%, comparator not stated; greater with tirzepatide and with treatment of 72 weeks or more; baseline anxiety/depression positively associated with weight loss (β = 2.44); comorbid T2DM, OSA and MAFLD negatively correlated with response.","confidence_interval":"95% CI 7.92%-10.80%","p_value":"p < 0.001 (heterogeneity)","sample_size":40408,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (individuals with obesity)\", \"diabetes_status\": \"mixed (type 2 diabetes as a comorbidity subgroup)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity\", \"sample_size\": 40408, \"inclusion_exclusion\": \"trials of GLP-1RAs and dual agonists in individuals with obesity\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all included trials enrolled individuals with obesity, some with type 2 diabetes; no age or BMI is given.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcome is weight reduction. The 'mediators' in the title are between-trial moderators from meta-regression, not a mediation analysis.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 40408, \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 7.92%-10.80%\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Pooling meta-analysis of 32 trials with I2 = 99.6%: MODERATE (meta-analysis with heterogeneity).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Extreme heterogeneity across trials, and the moderator findings come from between-trial meta-regression, which cannot show individual-level causes; no comparator is stated for the pooled weight change.","plain_summary":"This meta-analysis pooled 32 trials with 40 408 participants with obesity and found a weighted mean weight reduction of 9.36% on GLP-1 drugs and dual agonists, with very high heterogeneity between trials; the abstract does not say what the reduction was compared with. Weight loss was greater with tirzepatide and with treatment of 72 weeks or more. Trials with more baseline anxiety or depression showed more weight loss, while comorbid type 2 diabetes, sleep apnea and fatty liver disease were linked to smaller responses; these are between-trial associations, not causes.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":688,"doi":"10.1016/j.xkme.2026.101476","pmid":"42787930","nct_ids":"[]","title":"Real-world Evidence for Improvements in Inflammation and Anemia Biomarkers After the Initiation of GLP-1RA in Patients Receiving Hemodialysis","authors":"[\"Lama S\", \"Chaudhuri S\", \"Blankenship D\", \"Ban AN\", \"Usvyat L\", \"Pecoits-Filho R\", \"Hippen BE\"]","journal":"Kidney medicine","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[RATIONALE & OBJECTIVE] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for diabetes and obesity but have not been studied in patients with kidney failure with replacement therapy receiving hemodialysis in prospective trials. GLP-1RAs may influence inflammatory pathways relevant to anemia, although their effects in hemodialysis patients remain unclear. [STUDY DESIGN] Retrospective matched cohort study. [SETTING & PARTICIPANTS] Data were derived from a large US dialysis provider (Fresenius Kidney Care). We identified 2,468 adult patients who initiated GLP-1RA therapy between January 1, 2023, and November 1, 2024, and matched 1:1 to nonusers using propensity scores based on demographic characteristics, comorbidities, and baseline laboratory values. [EXPOSURE] Initiation of GLP-1RA therapy. [OUTCOMES] Longitudinal changes over 12 months in inflammatory markers (neutrophil-to-lymphocyte ratio, white blood cell count, and albumin level) and anemia parameters (hemoglobin level, ferritin level, transferrin saturation value, erythropoiesis-stimulating agent (ESA) dose, and erythropoietin resistance index). [ANALYTICAL APPROACH] Linear mixed models were used to compare longitudinal trajectories between matched groups. [RESULTS] Compared with matched controls, GLP-1RA users demonstrated reductions in systemic inflammation, characterized by lower neutrophil-to-lymphocyte ratio (3.97 vs 4.64, with a mean difference of -0.67 [95% CI, -0.89 to -0.45]) and white blood cell counts at 12 months, alongside greater improvements in serum albumin level (3.92 vs 3.86 g/dL, with a mean difference of 0.06 [95% CI, 0.04-0.08]). Although hemoglobin levels remained comparable between groups (10.9 vs 10.84 g/dL, with a mean difference of 0.06 [95% CI, -0.004 to 0.12]), GLP-1RA users had lower cumulative ESA exposure (1,881.9 vs 2,005.8 μg; mean difference of -123.9 μg, [95% CI, -201.7 to -46.1] μg) and a modestly reduced rate of erythropoietin resistance index compared with nonusers. Additionally, iron stores (ferritin level and transferrin saturation value) were consistently higher in the GLP-1RA group. [CONCLUSIONS] In patients receiving maintenance hemodialysis, GLP-1RA agonist use was associated with reductions in inflammatory markers and lower ESA requirements; however, as an observational study, causality cannot be inferred. These findings suggest GLP-1RAs may have potential benefits in managing inflammation and inflammation-mediated anemia in kidney failure.","url":"https://pubmed.ncbi.nlm.nih.gov/42787930/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":733,"doi":"10.1002/joa3.70455","pmid":"42774613","nct_ids":"[]","title":"Glucagon-Like Peptide-1 Agonists and the Incidence of Atrial Fibrillation in Obese Patients With Heart Failure With Preserved Ejection Fraction and No Diabetes","authors":"[\"Rassam F\", \"Lopez EK\", \"Sass S\", \"Srikulmontri T\", \"Isaacs E\", \"Malin J\", \"Wattanachayakul P\", \"Afolabi-Brown O\"]","journal":"Journal of arrhythmia","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular risk in obesity, but their effect on atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF) remains unclear. [METHODS] We analyzed TriNetX data comparing obese, non-diabetic HFpEF patients treated with GLP-1 RAs (n = 478) with untreated patients (n = 6887). Propensity matching yielded 470 patients per cohort. [RESULTS] GLP-1 RA therapy was not associated with reduced AF incidence (HR 0.86; 95% CI, 0.53-1.39; p = 0.543) but was associated with lower mortality (HR 0.42; 95% CI, 0.23-0.75; p = 0.003). [CONCLUSIONS] GLP-1 RAs may not reduce AF incidence in obese, HFpEF patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42774613/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":844,"doi":"10.1212/nxg.0000000000200425","pmid":"42812740","nct_ids":"[]","title":"Genetic Insights Into Protective Effects of GLP-1 Receptor Agonists on Stroke and Alzheimer Disease Across Ancestries","authors":"[\"Caro-Châtelier I\", \"Sargurupremraj M\", \"Yang C\", \"Akinleye C\", \"Trégouët DA\", \"Akinyemi RO\", \"Shigemizu D\", \"Coker M\", \"Akinyemi JO\", \"Tiwari HK\", \"Chasman DI\", \"Ovbiagele B\", \"Chabriat H\", \"Mooser V\", \"Couffinhal T\", \"Mishra A\", \"Cruchaga C\", \"Reitz C\", \"Kunkle B\", \"Kamatani Y\", \"Owolabi MO\", \"Mohammedi K\", \"Debette S\"]","journal":"Neurology. Genetics","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND OBJECTIVES] Stroke and dementia are leading causes of death and disability worldwide, requiring enhanced preventive strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA), widely used for type 2 diabetes (T2D) and obesity, have demonstrated pleiotropic effects, including cardiovascular benefits, with mounting evidence also suggesting potential beneficial effects on brain health. The objective of this study was to investigate the genetically proxied effect of GLP-1RA on stroke, Alzheimer disease (AD), and related endophenotypes, in a cross-ancestry setting. [METHODS] We conducted a 2-sample Mendelian randomization (MR) study using both a locus-based and a protein quantitative trait loci (pQTL)-based approach. The study leveraged summary statistics from large-scale genome-wide association studies (GWAS). These GWAS comprised participants of European, East-Asian, and African ancestry with and without T2D, stroke, and AD, and with measurements of fasting glucose, glycated hemoglobin, stroke, and AD endophenotypes. Sample size ranged from 3,026 to 1,812,017 individuals. Genetically proxied GLP-1RA exposure was instrumented using independent T2D-associated variants (p < 5 × 10-8) within GLP1R (locus-based MR) and pQTLs for circulating GLP-1R protein levels (pQTL-based MR). Instruments were validated for effects on glycemic traits and GLP1R gene expression. Primary outcomes were stroke (any, ischemic, cardioembolic, small vessel, large artery, and intracerebral hemorrhage) and AD. Secondary analyses included etiologic factors and endophenotypes of stroke and AD: heart failure, atrial fibrillation, MRI markers (white matter hyperintensity volume, perivascular space burden, and hippocampal volume), and CSF biomarkers (beta-amyloid, tau). Outcomes were stratified by ancestry and meta-analyzed. [RESULTS] In Europeans, locus-based MR indicated significant protective associations of GLP-1RA with any stroke and ischemic stroke (p FDR < 0.05) and nominally (p < 0.05) with AD. Cross-ancestry meta-analyses strengthened protective effects of GLP-1RA on any stroke (OR, 0.75; 95% CI 0.63-0.89), ischemic stroke (0.72; 0.56-0.91), cardioembolic stroke (0.55; 0.35-0.86), and AD (0.51; 0.31-0.83), all with p FDR < 0.05. pQTL-based MR analyses suggested protective effects of genetically proxied GLP-1RA on atrial fibrillation (p FDR < 0.05) and, nominally (p < 0.05), on hippocampal perivascular space burden and CSF β-amyloid levels. [DISCUSSION] GLP-1RAs may confer protective effects against stroke (especially ischemic and cardioembolic) and AD risk, across ancestries. These findings warrant further investigation in experimental models and clinical trials to confirm benefits on brain health and understand underlying mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42812740/","source_name":"pubmed","source_tier":1,"coi_statement":"C. Cruchaga is a member of the scientific advisory board of Circular Genomics; owns stocks and is on the scientific advisory board of ADmit and Alamar; consults for Sanofi, NovoNordisk, and Owkin; and has received research support from GSK, Danaher, and EISAI. K. Mohammedi reports consulting fees from Novo Nordisk, Boehringer-Ingelheim, and Sanofi; honoraria for lectures, presentations, or speaker bureaus from Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Sanofi, Abbott, and Bayer; and participation on advisory boards from Novo Nordisk, Sanofi, AstraZeneca, Boehringer-Ingelheim, Lifescan, and Amarin. The other authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"dementia\", \"alzheimers\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":863,"doi":"10.1002/alz.71888","pmid":"42805933","nct_ids":"[]","title":"GLP-1R agonist semaglutide protects human forebrain organoids from cholesterol-induced neurotoxicity","authors":"[\"Yu F\", \"Xu J\", \"Hou Y\", \"Zheng H\", \"Guo L\", \"Khutsishvili D\", \"Hai C\", \"Xu W\", \"Chen B\", \"Wang Z\", \"Ma S\"]","journal":"Alzheimer's & dementia : the journal of the Alzheimer's Association","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Dysregulated cholesterol metabolism represents a critical metabolic stressor in the central nervous system, contributing to neuronal injury across multiple neurological conditions, including Alzheimer's disease (AD). While glucagon-like peptide-1 receptor (GLP-1R) agonists show neuroprotective potential, their capacity to directly mitigate cholesterol-induced metabolic stress in human neural cells remains to be established. [METHODS] Here, we modeled metabolic stress using human induced pluripotent stem cell-derived forebrain organoids exposed to cholesterol overload. The protective effects of the GLP-1R agonist semaglutide were characterized by integrating bulk/single-cell transcriptomics, calcium imaging, and biochemical assays. Furthermore, clinical translatability was supported by mapping organoid expression signatures against human post mortem neurodegenerative brain datasets. [RESULTS] Cholesterol overload induced cellular stress and transcriptomic alterations that partially overlapped with AD-associated signatures. Semaglutide protected neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engaged the cyclic adenosine 3',5'-monophosphate-protein kinase A and phosphoinositide 3 kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, consistent with reduced lipid droplet accumulation and oxidative stress. Intercellularly, single-cell analysis indicated partial preservation of disrupted cellular communication, including the neurotrophic midkine signaling network. Functionally, semaglutide stabilized cellular calcium activity patterns under metabolic stress. [DISCUSSION] These findings highlight the role of cholesterol homeostasis in maintaining neuronal integrity and position GLP-1R signaling as a candidate protective axis under metabolic stress, offering insights into therapeutic strategies for AD and broader neurodegenerative disorders.","url":"https://pubmed.ncbi.nlm.nih.gov/42805933/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:25+00:00","study_design":"cellular_in_vitro","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"alzheimers\", \"neuroinflammation\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":891,"doi":"10.1002/ncp.70180","pmid":"42808923","nct_ids":"[]","title":"Gastrointestinal adverse effects of GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists: A narrative expert review of approved therapies, oral formulations, and pipeline agents","authors":"[\"Singhani V\", \"Ehsan M\", \"Valencia S\", \"Nadeem A\", \"Moazzam E\", \"Butsch WS\", \"Garg S\"]","journal":"Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed the management of type 2 diabetes and obesity. Gastrointestinal (GI) adverse events are the most common limitation of these therapies and a leading cause of discontinuation. [METHODS] This narrative expert review synthesizes evidence from randomized controlled trials, observational studies, meta-analyses, and pharmacovigilance data to characterize the incidence, mechanisms, and clinical implications of GI adverse effects across approved agents and late-stage pipeline therapies. [RESULTS] Nausea, vomiting, diarrhea, and constipation are established class effects, occurring in approximately 30%-50% of patients, typically during initiation and dose escalation. These events are generally mild to moderate and manageable with dose titration and dietary modification. Mechanisms include delayed gastric emptying, central activation of emetic pathways, altered intestinal motility, and physiologic effects of rapid weight loss itself. Randomized trial data are reassuring for acute pancreatitis, with no class-level excess risk demonstrated; pharmacovigilance signals are most plausibly explained by diagnostic misclassification rather than true causal risk. Cholelithiasis shows a probable class-level association, substantially mediated by weight loss rather than direct receptor signaling. Peri-procedural data show increased residual gastric volume without confirmed aspiration events. Preliminary data on late-stage pipeline agents (retatrutide, survodutide, and cagrilintide-semaglutide) suggest a similar GI adverse event profile to approved agents, though evidence remains largely limited. [CONCLUSION] GI adverse events with GLP-1-based therapies are predictable and manageable. A proactive, patient-centered approach is essential to optimize adherence, safety, and clinical outcomes as newer agents expand the therapeutic landscape.","url":"https://pubmed.ncbi.nlm.nih.gov/42808923/","source_name":"pubmed","source_tier":1,"coi_statement":"Samita Garg reports receiving an Investigator Initiated grant from Abbott, research grants with Enterra and Atmo Biosciences, and serving as a speaker/consultant for Novo Nordisk and Ardelyx. W. Scott Butsch is an employee of Novo Nordisk. All other authors have no disclosures to declare.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\", \"survodutide\", \"cagrisema\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":952,"doi":"10.1016/j.eclinm.2026.104220","pmid":"42831062","nct_ids":"[]","title":"The effect of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors on stroke risk in type 2 diabetes: a nationwide longitudinal cohort study in Sweden with contextualisation analysis","authors":"[\"Mavridis A\", \"Abzhandadze T\", \"Buvarp D\", \"Simons K\", \"Eliasson B\", \"von Euler M\", \"Viktorisson A\", \"Sunnerhagen KS\"]","journal":"EClinicalMedicine","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The impact of SGLT2 inhibitors (SGLT2i), GLP-1 receptor agonists (GLP-1RA), and DPP-4 inhibitors (DPP-4i) on stroke risk in individuals with type 2 diabetes remains uncertain. Meta-analyses of randomised controlled trials (RCTs) show a protective effect for GLP-1RA but neutral findings for SGLT2i and DPP-4i, whereas observational studies often suggest broader stroke risk reductions. This study aimed to estimate the associations of SGLT2i, GLP-1RA, and DPP-4i with stroke risk in nationwide longitudinal data, and to contextualize these results within existing meta-analyses of RCTs and observational studies. [METHODS] This was a nationwide longitudinal study including individuals with type 2 diabetes first registered in the Swedish National Diabetes Register between January 1, 2013, and December 31, 2019. Individuals with a prior stroke or insufficient data for multiple imputation were excluded. The primary outcome was ischemic stroke. Treatments, comorbidities, and laboratory values were updated over time. Marginal structural models with inverse probability of treatment weighting and weighted Cox regression were used to estimate hazard ratios (HRs) for ischemic, hemorrhagic and total stroke pooled across five multiply imputed datasets. To contextualise the findings, PubMed was searched from inception to June 23, 2026, for meta-analyses of randomised controlled trials and observational studies reporting stroke outcomes for the three drug classes. [FINDINGS] We included 171,917 individuals with type 2 diabetes [59.2% males, baseline mean (SD) age 62.7 (11.6), mean (SD) follow-up 3.0 (1.9) years] contributing 1,617,462 clinical registrations. During follow-up, 2734 (1.59%) ischemic and 428 (0.25%) hemorrhagic strokes occurred. GLP-1RA use was associated with a lower risk of ischemic (HR 0.46, 95% CI 0.29-0.72) and total stroke (HR 0.51, 95% CI 0.33-0.79), whereas no clear associations were observed for hemorrhagic stroke. SGLT2i and DPP-4i showed no clear associations with any stroke outcome. The contextualisation identified 91 meta-analyses. RCT meta-analyses generally showed a protective effect for GLP-1RA and neutral effects for SGLT2i and DPP-4i, while observational meta-analyses suggested protective associations for GLP-1RA and SGLT2i. [INTERPRETATION] In this nationwide study, GLP-1RA were associated with reduced stroke risk, while SGLT2i and DPP-4i showed neutral effects. The overall direction of findings was consistent with evidence from RCT meta-analyses. Future research should investigate how these therapies can be optimally incorporated into treatment strategies for stroke prevention in individuals with type 2 diabetes. [FUNDING] Sahlgrenska University Hospital's funds, the Swedish National Stroke Association, the Swedish Brain Foundation, the Swedish Heart Lung Foundation, the Bygg-Göta Foundation for scientific research, the Winberg foundation, and the Swedish state under the ALF agreement between the Swedish government and the county councils.","url":"https://pubmed.ncbi.nlm.nih.gov/42831062/","source_name":"pubmed","source_tier":1,"coi_statement":"BE reports personal fees from Novo Nordisk, Eli Lilly, Sanofi, Abbott, and Amgen. All other authors declare no competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cerebrovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":957,"doi":"10.1093/ckj/sfag315","pmid":"42851342","nct_ids":"[]","title":"Gut-kidney signaling is impaired in individuals with type 2 diabetes","authors":"[\"Mosterd CM\", \"Wever BE\", \"van Baar MJB\", \"Muskiet MHA\", \"van den Born BH\", \"Nieuwdorp M\", \"Touw DJ\", \"Hoorn EJ\", \"Vogt L\", \"van Raalte DH\"]","journal":"Clinical kidney journal","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] In healthy individuals, oral sodium loading induces more rapid natriuresis than intravenous administration, suggesting a gut-kidney feed-forward mechanism. Whether this physiological response is impaired in type 2 diabetes (T2D), and whether pharmacological glucagon-like peptide-1 receptor agonism can restore it, remains unknown. [MATERIALS AND METHODS] We conducted a mechanistic, randomized, double-blind, placebo-controlled cross-over trial, in men with T2D. Participants adhered to a standardized sodium intake (<90 mmol/day) for 7 days before each study visit. Each participant underwent three experimental conditions in random order: (1) intravenous sodium loading (ISL), (2) oral sodium loading with placebo (OSL-placebo) infusion, and (3) OSL with concomitant exenatide infusion (OSL-exenatide). Each sodium load contained 154 mmol sodium. The primary endpoint was cumulative urinary sodium excretion over 24-h. Secondary endpoints included early natriuresis, fractional sodium excretion, ambulatory blood pressure, extracellular volume, and measured glomerular filtration rate. [RESULTS] Eleven men with T2D (mean age 60 ± 4.7 years, BMI 31.9 ± 3.9 kg/m2, HbA1c 7.5 ± 0.9%, systolic blood pressure 127 ± 22 mmHg) completed the study. Median cumulative 24 h sodium excretion did not differ significantly between ISL (105; IQR 55-156 mmol), OSL-placebo (101; 71-134 mmol), or OSL-exenatide (100; 63-123 mmol). Early natriuretic responses and fractional sodium excretion were similar across interventions. Daytime and nighttime blood pressure did not differ between interventions. [CONCLUSION] In contrast to observations in healthy individuals, OSL did not result in elevated natriuresis compared with ISL in T2D, consistent with impaired gut-kidney feed-forward regulation. Acute GLP-1R-activation with exenatide did not restore this response, suggesting additional entero-renal pathways mediate postprandial natriuretic regulation.","url":"https://pubmed.ncbi.nlm.nih.gov/42851342/","source_name":"pubmed","source_tier":1,"coi_statement":"C.M.M., B.E.W., M.J.J.B., D.J.T., B.H.B. report no conflicts of interest. M.H.A.M. reports consulting relationships and advisory board participation with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; all payments were made to his current or former institutions (Leiden University Medical Center or Amsterdam University Medical Center, respectively). M.N. is founder and a scientific advisory board member of Caelus Pharmaceuticals and Advanced Microbiome Interventions, the Netherlands. He is also on the board of directors of Diabeter Netherlands BV. E.J.H is associate editor of the Journal of the American Society of Nephrology. L.V. reports consultancy agreements with AstraZeneca, Bayer BV Netherlands, Boehringer Ingelheim, CSL Vifor, and NovoNordisk; research funding from Dutch Kidney Foundation and Health Holland. D.V.R. serves on advisory boards of AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and MSD and received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and MSD; all honoraria paid to his employer.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"crossover_trial","drugs":"[\"exenatide\"]","drug_details":"{\"comparator\": \"placebo infusion with oral sodium loading; intravenous sodium loading\", \"dose\": null, \"route\": null, \"treatment_duration\": \"acute single infusion\"}","domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"cumulative urinary sodium excretion over 24-h","endpoints":null,"effect_estimate":"No difference in median 24-h sodium excretion: OSL-exenatide 100 vs OSL-placebo 101 vs ISL 105 mmol; early natriuresis, fractional sodium excretion and blood pressure similar.","confidence_interval":null,"p_value":null,"sample_size":11,"follow_up":"24-h urinary collection per visit","direction":"null","population":"{\"mean_age\": \"60 ± 4.7 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"men only\", \"bmi_mean\": 31.9, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 11, \"inclusion_exclusion\": \"men with type 2 diabetes on a standardized sodium intake (<90 mmol/day) for 7 days before each visit\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all eleven participants were men with type 2 diabetes, mean BMI 31.9, mean age 60.","mediation":"unlikely","mediation_notes":"Unlikely: the result is null and the exposure was one acute infusion, too short for weight change.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Crossover trial\", \"sample_size\": 11, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo infusion with oral sodium loading; intravenous sodium loading\", \"follow_up_duration\": \"24-h urinary collection per visit\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"medians with IQR reported; no CI or p-value; eleven participants\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small (eleven-person) randomized double-blind crossover trial with a physiological biomarker outcome: LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Several authors report consulting, advisory board or grant relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and others; five authors report none.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Very small mechanistic crossover of eleven men with type 2 diabetes testing a single acute infusion; no women and no long-term outcomes.","plain_summary":"This randomized, double-blind crossover trial studied eleven men with type 2 diabetes (mean age 60 years, BMI 31.9) under three conditions: sodium given into a vein, sodium by mouth with a placebo infusion, and sodium by mouth with an exenatide infusion. Median sodium excretion over 24 hours did not differ (100 mmol with exenatide, 101 with placebo, 105 intravenously), and early sodium excretion and blood pressure were also similar. It was a very small, short mechanistic experiment, not a test of long-term treatment.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1182,"doi":"10.5489/cuaj.9689","pmid":"42900879","nct_ids":"[]","title":"Prescribing patterns and impact of glucagon-like peptide-1 receptor agonists in a kidney transplant evaluation cohort in British Columbia, Canada A single-center experience","authors":"[\"Chae HH\", \"Luo C\", \"Harriman D\", \"Nguan C\"]","journal":"Canadian Urological Association journal = Journal de l'Association des urologues du Canada","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated weight loss and cardiometabolic benefits in specific subpopulations. Studies of GLP-1RAs in Canadian end-stage renal disease (ESRD) and kidney transplantation (KT) patients are limited. [METHODS] This is a retrospective cohort study of patients evaluated for potential KT at the Vancouver General Hospital (VGH) between January 2014 and August 2024. We analyzed prescription patterns, weight changes, and post-transplant outcomes. [RESULTS] At evaluation, 63/2789 (2.3%) patients were on a GLP-1RA. The proportion of GLP-1RA users increased from 0% in 2014-2018, to 0.3% (1/366) in 2019, and 8.7% (20/231) in 2024. There was a mean weight change of -1.82 kg (-1.93%, 95% confidence interval [CI] -3.46 to -0.19, p=0.031; n=26) at six months and -2.50 kg (-2.62%, 95% CI -4.47 to -0.52, p=0.016; n=25) at 12 months post-initiation. Twenty-six patients received a KT and had a median followup of 1.14 (interquartile range [IQR] 0.19-1.79) years. Only 11 patients were on a GLP-1RA at one year post-transplant and had available post-transplant outcome data. No significant differences were detected in estimated glomerular filtration rate (eGFR) (67, IQR 65.5-78 vs. 59, IQR 45-75 mL/min/1.73 m2, p=0.18), graft failure (0% vs. 4.6%, p=1) and mortality (0% vs. 3.0%, p=1) between GLP-1RA users vs. non-users at one year post-KT. [CONCLUSIONS] GLP-1RA use in BC's KT evaluation cohort increased since 2019 and was associated with modest weight loss at six and 12 months post-initiation. No significant differences in post-transplant outcomes were detected. This provides preliminary support for GLP-1RAs as a potentially safe weight management strategy for Canadian KT candidates.","url":"https://pubmed.ncbi.nlm.nih.gov/42900879/","source_name":"pubmed","source_tier":1,"coi_statement":"COMPETING INTERESTS: The authors have no relevant conflicts of interest to report.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1206,"doi":"10.1111/nmo.70458","pmid":"42894471","nct_ids":"[]","title":"Gastrointestinal Symptom Events and Motility Alterations Associated With GLP-1 Receptor Agonists","authors":"[\"Cisneros JZ\", \"Lupianez-Merly C\", \"Dilmaghani S\", \"Lennon RJ\", \"Then S\", \"Fiero P\", \"Blundo R\", \"Farrugia G\", \"Camilleri M\", \"Grover M\"]","journal":"Neurogastroenterology and motility","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Gastrointestinal symptom events (GISE) are common with glucagon-like peptide-1 receptor agonists (GLP-1RA). We aimed to determine the prevalence of GISE and clinical factors associated with GISE. [METHODS] An integrated platform database was used to collect real-world data. Using a retrospective cohort study design, Kaplan-Meier analysis was used to estimate GISE-free survival over 60 months. To identify predictors of GISE, the cohort was randomly split 80/20 into training and testing sets. A LASSO-penalized Cox model was used to identify relevant associations, after which main-effect and interaction models were constructed. Gastric emptying scintigraphy (GES) of solids was extracted from electronic medical records, where available. [RESULTS] Among 78,277 patients, 87% reported no baseline GI symptoms. At 60 months, 53% reported at least one GISE, most commonly abdominal pain (28%) and nausea (25%). Women were at higher risk of GISE than men (Kaplan-Meier HR 1.4). In the prediction model, baseline diarrhea, constipation, abdominal pain, and nausea were associated with higher GISE risk (HRs 2.2, 2.0, 1.7, and 1.6, respectively), and male sex with lower risk (HR 0.79). Concomitant baseline use of metoclopramide (HR 1.6) was also associated with higher risk of GISE, with weaker associations for tricyclic antidepressants, GABA analogs, and opioids (HRs 1.1-1.2). Model discrimination was modest (C-index 0.64 training, 0.63 testing). Among 696 symptomatic patients clinically referred for GES after GLP-1RA initiation, 34.6% (N = 241) exhibited delayed GE. Constipation was more prevalent in those with delayed GE. [CONCLUSION] The 5-year incidence of GISE among patients initiating GLP-1RA therapy was over 50%. While the ability to predict GISE was modest, female sex, baseline GI symptoms, and concomitant medications were associated with an increased risk. Among the small, symptom-selected subgroup referred for testing, only a third had delayed GE.","url":"https://pubmed.ncbi.nlm.nih.gov/42894471/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:19+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"addiction\", \"mortality\", \"metabolic\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1210,"doi":"10.1093/ofid/ofag631","pmid":"42921178","nct_ids":"[\"NCT04019197\"]","title":"Durability of Semaglutide Effects After Treatment Discontinuation in HIV-Associated Lipohypertrophy: A Randomized, Double-Blind, Placebo-Controlled Phase 2b Clinical Trial","authors":"[\"Adekunle RO\", \"Wu Q\", \"Sattar A\", \"Ansari-Gilani K\", \"Labbato D\", \"Fletcher AA\", \"McComsey AD\", \"Eckard AR\"]","journal":"Open forum infectious diseases","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Human immunodeficiency virus (HIV)-associated lipohypertrophy is characterized by excess central and visceral adiposity and is associated with increased cardiometabolic risk among people with HIV (PWH). In a previously reported randomized trial, semaglutide significantly reduced body weight, regional adiposity, and insulin resistance over 32 weeks of active treatment. However, the durability of these benefits after treatment discontinuation is unknown. [METHODS] We conducted a randomized, placebo-controlled trial in PWH with HIV-associated lipohypertrophy. Participants were randomized to semaglutide or placebo for 32 weeks, followed by discontinuation of study drug and observational follow-up through week 56. The current analysis investigated effects of semaglutide at week 56, as compared to baseline and week 32. Outcomes included adipose tissue quantity by body compartment. Analyses were performed using intention-to-treat principles. This trial was registered at ClinicalTrials.gov (NCT04019197) and is complete. [RESULTS] Of 108 participants initially randomized, 92 completed the 32-week intervention and 80 participants (39 semaglutide, 41 placebo) completed the posttreatment phase. Participants previously assigned to semaglutide experienced increases in body weight, body mass index (BMI), waist circumference, total body fat, and visceral adipose tissue between weeks 32 and 56, accompanied by worsening glycemic indices and insulin resistance. Despite this rebound, net reductions in body weight, BMI, and waist circumference were retained at week 56 compared with baseline. Placebo-treated participants demonstrated relative stability across outcomes. [CONCLUSIONS] Discontinuation of semaglutide in PWH with lipohypertrophy resulted in partial loss of improvements in weight, adiposity, and metabolic parameters. These findings support that sustained pharmacologic exposure is likely needed to achieve long-term benefit.","url":"https://pubmed.ncbi.nlm.nih.gov/42921178/","source_name":"pubmed","source_tier":1,"coi_statement":"Potential conflicts of interest. A. R. E. served as an advisor for Gilead Sciences and Theratechnologies. All other authors report no potential conflicts.","assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"treatment_duration\": \"32 weeks\", \"comparator\": \"placebo\", \"dose\": null, \"route\": null}","domains":"[\"body_composition\", \"metabolic\", \"adverse_effects\", \"other_emerging\"]","outcome_type":"intermediate","primary_outcome":"adipose tissue quantity by body compartment at week 56, after discontinuation","endpoints":null,"effect_estimate":"No numbers given. After stopping, the semaglutide group regained body weight, BMI, waist, total fat and visceral fat between weeks 32 and 56 with worsening glycaemic indices and insulin resistance; net reductions in weight, BMI and waist were retained at week 56 vs baseline; placebo was relatively stable.","confidence_interval":null,"p_value":null,"sample_size":108,"follow_up":"observational follow-up through week 56","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"HIV-associated lipohypertrophy\", \"sample_size\": 108, \"inclusion_exclusion\": \"people with HIV and HIV-associated lipohypertrophy\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had HIV-associated lipohypertrophy, excess central and visceral fat with raised cardiometabolic risk that the target group lacks; no BMI, age or diabetes data are reported.","mediation":"not_applicable","mediation_notes":"Not applicable: the outcomes are weight, fat compartments and related measures after stopping the drug.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 108, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"observational follow-up through week 56\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; 80 of 108 completed the posttreatment phase\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small randomized trial (108 randomized, 80 completing follow-up) whose reported week-56 analysis is within-arm and observational after drug discontinuation: LOW.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"One author has advised Gilead Sciences and Theratechnologies; all other authors report no potential conflicts.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"The week-56 analysis compares the semaglutide group with its own baseline and week-32 values during unblinded observational follow-up after stopping, and only 80 of 108 randomized participants completed it; the population is people with HIV-associated lipohypertrophy.","plain_summary":"In this randomized, double-blind trial, people with HIV-associated lipohypertrophy took semaglutide or placebo for 32 weeks and were then followed after stopping, through week 56. Between weeks 32 and 56 the former semaglutide group regained weight, waist size, body fat and visceral fat, and its glycaemic indices and insulin resistance worsened, though net reductions in weight, BMI and waist circumference remained against baseline; the placebo group stayed relatively stable. Only 80 of 108 randomized participants completed follow-up, and the week-56 comparison is within the semaglutide group.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1214,"doi":"10.7759/cureus.118195","pmid":"42909983","nct_ids":"[]","title":"Diabetic Retinal Disease Onset and Progression During Established Semaglutide or Tirzepatide Treatment: A Retrospective Comparative Cohort Study With a Descriptive Regional Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) Review","authors":"[\"Muhsen J\"]","journal":"Cureus","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] This study aims to compare diabetic retinal disease onset or progression between established semaglutide or tirzepatide users and patients without documented exposure to either drug. Secondary exploratory objectives included medication-specific comparisons, adjusted analyses, and visual acuity assessment. Regional nonarteritic anterior ischemic optic neuropathy (NAION) case ascertainment was evaluated separately and descriptively. [METHODS] This retrospective cohort reviewed retinal records covering January 1, 2025, through March 31, 2026. Of 342 patients screened, 221 were excluded, leaving 121 records with two bilateral retinal assessments approximately one year apart. Analysis was at the patient-record level. Thirty patients received the same study drug before baseline and throughout follow-up; 91 had no documented exposure to either drug. Incident diabetic retinopathy (DR) and/or diabetic macular edema (DME) was evaluated among records without baseline disease, and progression was evaluated separately among records with baseline disease. Risk ratios (RRs), 95% confidence intervals (CIs), exact tests, and exploratory adjusted models were calculated. A separate regional NAION search covered January 1, 2022, through December 31, 2025, followed by investigator review of identified cases and medication histories. [RESULTS] The combined retinal endpoint occurred in 12/30 exposed and 46/91 unexposed records (40.0% versus 50.5%; RR: 0.79, 95% CI: 0.49-1.28; p = 0.400). Incident disease occurred in 7/14 versus 32/43 records (RR: 0.67; 95% CI: 0.39-1.17), and progression occurred in 5/16 versus 14/48 records (RR: 1.07; 95% CI: 0.46-2.51). Combined event proportions differed across semaglutide, tirzepatide, and unexposed categories (2/14, 10/16, and 46/91; global p = 0.017). No NAION was recorded in the retinal cohort. None of the seven separately identified regional NAION cases had documented study-drug use after investigator review. [CONCLUSIONS] No statistically significant association was detected for the combined retinal endpoint, but estimates were imprecise. Medication-specific findings were exploratory and do not establish comparative safety. Regional NAION findings were descriptive and could not quantify or exclude an association.","url":"https://pubmed.ncbi.nlm.nih.gov/42909983/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Al Dhafra Hospitals Research Ethics Committee (ADHREC) issued approval ADH REC 311025. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1349,"doi":"10.7759/cureus.117278","pmid":"42967089","nct_ids":"[]","title":"Non-ST Elevation Myocardial Infarction Following Significant Weight Loss During Tirzepatide Therapy: A Case Report","authors":"[\"Roy A\", \"Pabani UK\", \"Kyriakou A\", \"Elliott MK\"]","journal":"Cureus","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that produces substantial weight loss and improves multiple cardiometabolic risk factors. Current evidence supports its cardiovascular safety, with no established association between licensed tirzepatide therapy and acute coronary syndrome (ACS). As its clinical use continues to expand, reporting unusual cardiovascular presentations remains important for pharmacovigilance. We present a case of a 48-year-old South Asian man with obesity, diet-controlled prediabetes, a history of smoking, and a family history of premature coronary artery disease who had been receiving tirzepatide for approximately 18 months, achieving a weight loss of approximately 30 kg. Following increased physical activity, he developed progressive exertional chest pain and dyspnoea. Electrocardiography demonstrated inferolateral ischaemic changes, and serial high-sensitivity troponin T measurements were consistent with a non-ST elevation myocardial infarction (NSTEMI). Transthoracic echocardiography showed preserved left ventricular systolic function with inferior regional wall motion abnormalities. Coronary angiography revealed severe triple-vessel coronary artery disease involving the left anterior descending, left circumflex, and right coronary arteries. He subsequently underwent successful coronary artery bypass grafting with an uncomplicated postoperative recovery. Although a temporal association existed between prolonged tirzepatide therapy, substantial weight loss, and presentation with NSTEMI, the presence of advanced multivessel coronary artery disease suggests longstanding atherosclerosis rather than a direct adverse effect of tirzepatide. A more plausible explanation is that significant weight loss improved functional capacity, allowing increased physical activity that unmasked previously silent obstructive coronary artery disease. This interpretation is consistent with current evidence demonstrating favourable cardiovascular effects of tirzepatide while acknowledging that causality cannot be established from a single case. This case highlights the importance of thoroughly evaluating new exertional chest pain in patients receiving tirzepatide despite marked improvements in weight and metabolic health. Clinicians should remain vigilant for underlying coronary artery disease in individuals with traditional cardiovascular risk factors. This report describes a temporal association rather than a causal relationship and contributes to the growing body of real-world experience with tirzepatide.","url":"https://pubmed.ncbi.nlm.nih.gov/42967089/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:44+00:00","study_design":"pharmacovigilance","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"addiction\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1434,"doi":"10.7759/cureus.117500","pmid":"42985248","nct_ids":"[]","title":"GLP-1 Receptor Agonists Across the Coronary Disease Continuum in Type 2 Diabetes: A Systematic Review of Ischemic Events, Revascularization, and Stent Healing","authors":"[\"Abuzenah BI\", \"Abuzenah H\", \"Abuzenah M\"]","journal":"Cureus","publication_date":"2026-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 2 diabetes is associated with accelerated coronary atherosclerosis, recurrent ischemic events, and impaired vascular healing after percutaneous coronary intervention (PCI); however, the effects of glucagon-like peptide-1 (GLP-1) receptor agonists across these distinct coronary outcomes remain incompletely characterized. This systematic review synthesized randomized evidence on myocardial infarction (MI), acute coronary syndrome (ACS), coronary revascularization, post-PCI healing, and mechanistic markers of coronary disease. MEDLINE via PubMed, Scopus, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials (CENTRAL) were initially searched for eligible reports published from January 1, 2020, through December 31, 2025. All four database searches were updated on August 31, 2026, extending publication eligibility through that date; no additional eligible reports were identified. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Seven eligible reports derived from seven parent randomized trials, involving 37,033 participants, were included. Two presented primary findings from independent randomized trials, three were prespecified analyses of parent randomized trials, and two were post hoc analyses. Owing to substantial clinical and outcome heterogeneity, the findings were synthesized narratively. Albiglutide reduced first and recurrent MI, including type 1 and type 2 events, whereas higher-dose efpeglenatide yielded more favorable cardiovascular effect estimates than the lower dose. Across separate reports, semaglutide favorably modified epicardial adipose tissue, a surrogate imaging measure, and reduced the composite of cardiovascular death, MI, or stroke in patients with diabetic kidney disease. Liraglutide was associated with lower risks of broader cardiovascular composites compared with the other glucose-lowering therapies combined, although individual MI and revascularization outcomes were not significantly reduced. Exenatide did not significantly reduce the composite of hospitalization for ACS or coronary revascularization, and the only PCI-specific trial demonstrated no significant improvement in early stent coverage, neointimal thickness, or in-stent obstruction. Of the seven included reports, one was judged to have a low risk of bias, whereas six raised some concerns, primarily because of post hoc analyses, open-label treatment, incomplete methodological reporting, or limited imaging follow-up. Across the included reports, findings were more favorable for MI and broader cardiovascular events than for coronary revascularization or post-stent healing. However, the small number of heterogeneous reports, reliance on several secondary or post hoc analyses, and absence of quantitative meta-analysis limit firm conclusions and do not establish a definitive class-wide coronary effect. Potential differences by agent, dose, and patient phenotype require further investigation, while treatment-initiation timing remains largely untested.","url":"https://pubmed.ncbi.nlm.nih.gov/42985248/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"exenatide\", \"efpeglenatide\", \"albiglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":543,"doi":"10.1096/fj.202602960r","pmid":"42762056","nct_ids":"[]","title":"A Novel Dual Therapy for Diabetic Ischemic Heart Injury: Sinomenine and Liraglutide Restore Mitochondrial Homeostasis and Suppress Pyroptosis","authors":"[\"Duan B\", \"Han R\"]","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","publication_date":"2026-09-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 2 diabetes mellitus (T2DM) significantly amplifies the risk and severity of myocardial ischemia-reperfusion (IR) injury, contributing to the disproportionately high cardiovascular mortality observed in diabetic patients. This study investigated the combined cardioprotective effects of sinomenine and liraglutide in a rat model of T2DM with myocardial IR injury and elucidated the underlying molecular mechanisms. Male Sprague Dawley rats were induced to T2DM with a high-fat diet and low-dose streptozotocin. After the induction of diabetes, the rats underwent 30 min of occlusion of the left anterior descending coronary artery, followed by 24 h of reperfusion. Before the IR procedure, diabetic rats were pretreated with sinomenine and/or liraglutide for 7 days. A comprehensive suite of techniques was employed to evaluate various endpoints, including echocardiographic and hemodynamic profiles, infarct size, histopathological alterations, cardiac troponin I (cTn-I) levels, pyroptosis-related proteins (NLRP3 and cleaved caspase-1), mitophagy-related markers (PINK-1 and Parkin), oxidative stress indicators (MDA, SOD, and GPx), and pro-inflammatory cytokines (IL-18 and IL-1β). The combination of sinomenine and liraglutide significantly improved cardiac function, reduced infarct size, attenuated histopathological damage, and decreased serum cTn-I levels (p < 0.05). It also downregulated the expression of pyroptosis-related proteins, upregulated the expression of mitophagy-related proteins, mitigated oxidative stress, and reduced pro-inflammatory cytokine levels (p < 0.05). The cardioprotective effects of the combined therapy were largely abrogated by pretreatment with mitochondrial division inhibitor 1. The combination of sinomenine and liraglutide showed remarkable cardioprotective effects against IR injury in diabetic rats, which were associated with the the attenuation of NLRP3-driven pyroptosis and the enhancement of PINK-1/Parkin-mediated mitophagy, suggesting a mechanistic link warranting further validation.","url":"https://pubmed.ncbi.nlm.nih.gov/42762056/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:06+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":822,"doi":"10.1002/jso.70411","pmid":"42813380","nct_ids":"[]","title":"The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Peri- and Postmenopausal Breast Cancer Outcomes","authors":"[\"Den J\", \"Nelson N\", \"Vaghjiani R\", \"Suzanne Klimberg V\"]","journal":"Journal of surgical oncology","publication_date":"2026-09-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Studies have shown that obesity increases the risk of postmenopausal breast cancer (BC) by 30%-60% and is associated with poorer outcomes. This is believed to be related to continued exposure to estrogen and prolonged inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been suggested to significantly lower the risk of several obesity-associated cancers (OACs). We hypothesize that GLP-1RAs can improve outcomes in peri- and postmenopausal BC patients with obesity. [METHODS] We conducted a retrospective cohort study using the TriNetX database to compare the outcomes of female BC patients ≥ 45 years old with a BMI of ≥ 35 kg/m2. We created two cohorts: those who took GLP-1RAs with a Stage I-III BC diagnosis and those who never had exposure to GLP-1RAs. Patients' propensity score was matched based on age, BMI, diabetes, socioeconomic status, and genetic carrier status. Our outcomes of interest were 10-year overall survival (OS) and local recurrence (LR). [RESULTS] We identified 10 498 patients who used GLP-1RAs and 93 174 patients who did not. After matching, 19 348 patients were identified, with 9674 per cohort. 10-year OS with the Kaplan-Meier analysis was significantly greater in patients on GLP-1RAs (79%) compared to those not on GLP-1RAs (71%), log-rank test p < 0.0001. The HR for OS was 0.54, 95% CI (0.49-0.60). The risk of LR was significantly lower (HR 0.481, 95% CI (0.425-0.546)). [CONCLUSIONS] Among peri- and postmenopausal breast cancer patients with BMI ≥ 35 kg/m2, GLP-1RA use after diagnosis was associated with improved 10-year OS and lower LR. These findings are hypothesis-generating but suggest a potential therapeutic role for GLP-1RAs, warranting prospective investigation in this high-risk population.","url":"https://pubmed.ncbi.nlm.nih.gov/42813380/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":839,"doi":"10.1016/s0140-6736(26)01865-9","pmid":"42815506","nct_ids":"[\"NCT05803421\"]","title":"Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial","authors":"[\"Klein KR\", \"Wysham C\", \"Tuttle KR\", \"Davies MJ\", \"Cox D\", \"Chen J\", \"Wu WS\", \"Denning M\", \"Liu R\", \"Ludwig L\", \"Meskimen ER\"]","journal":"Lancet (London, England)","publication_date":"2026-09-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Orforglipron is an oral, non-peptide GLP-1 receptor agonist. While some peptide GLP-1 receptor agonists have established cardiovascular benefit, the cardiovascular safety of non-peptide GLP-1 receptor agonists has not been studied. This study aimed to compare the effect of orforglipron with insulin glargine on the incidence of major adverse cardiovascular events in individuals with type 2 diabetes and obesity or overweight who are at increased risk for cardiovascular events. [METHODS] This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories. Adults with type 2 diabetes at increased cardiovascular risk with glycated haemoglobin (HbA1c) concentrations between 7·0% and 10·5% (53-91 mmol/mol) and a BMI of 25 kg/m2 or more, treated with up to three glucose-lowering medications (metformin, a sulfonylurea, and/or an SGLT2 inhibitor), were randomly assigned (1:1) to oral orforglipron maximum tolerated dose (up to 36 mg capsule [equivalent to 17·2 mg tablet]) or injectable titrated insulin glargine, each administered once daily. All participants had established cardiovascular or chronic kidney disease. The primary outcome was time to occurrence of four-component major adverse cardiovascular events (MACE-4), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Non-inferiority of orforglipron to insulin glargine was declared if the upper limit of the two-sided 95% CI for the hazard ratio (HR; orforglipron vs insulin glargine) was less than 1·8. The primary endpoint and other safety endpoints were assessed in all participants who took at least one dose of assigned treatment using all datapoints from baseline until withdrawal or study completion, regardless of treatment adherence. This trial was registered on ClinicalTrials.gov (NCT05803421) and is completed. [FINDINGS] Between May 1, 2023, and Sept 5, 2024, 2749 participants were randomly assigned (1371 to orforglipron and 1378 to insulin glargine). 1032 (38%) participants were female and 1717 (62·5%) male. 2362 (85·9%) participants had established cardiovascular disease and 1033 (37·6%) had chronic kidney disease. Mean baseline age, HbA1c, and BMI were 63·1 years (SD 9·9), 8·2% (1·0), and 33 kg/m2 (6·2), respectively. Over a median follow-up of 2 years, the primary outcome occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants, showing non-inferiority to insulin glargine for MACE-4 (HR 0·84; 95% CI 0·59-1·20; p<0·0001 for non-inferiority). Gastrointestinal adverse events were reported in 851 (62·1%) of 1371 orforglipron participants and 193 (14·2%) of 1355 insulin glargine participants; clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]) occurred in 93 (6·8%) of 1371 orforglipron participants and 260 (19·2%) of 1355 insulin glargine participants. 62 deaths were reported during the study: 19 (1·4%) of 1371 participants receiving orforglipron and 43 (3·2%) of 1355 participants receiving insulin glargine; all deaths except one (in the insulin glargine group) were deemed unrelated to treatment. [INTERPRETATION] In people with type 2 diabetes at increased cardiovascular risk, the cardiovascular safety of orforglipron was confirmed by demonstrating non-inferiority to insulin glargine for MACE-4. Gastrointestinal adverse events were the most frequent adverse event and most common reason for orforglipron treatment discontinuation with orforglipron, while clinically significant hypoglycaemia occurred less frequently with orforglipron than with insulin glargine. These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk. [FUNDING] Eli Lilly and Company.","url":"https://pubmed.ncbi.nlm.nih.gov/42815506/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests KRK has received advisory or consulting fees support from Antag Therapeutics, Corxel, Eli Lilly and Company, Metsera, Novo Nordisk, Roche Pharmaceuticals, Vertex Pharmaceuticals, and vTv Therapeutics; and has received research-related contracts (paid to the institution) from Bayer, Boehringer Ingelheim, Carmot, Diasome, Eli Lilly and Company, Gentibio, Novo Nordisk, Rhythm Pharmaceuticals, Roche Pharmaceuticals, and vTv Therapeutics. CW reports receiving research funding from Eli Lilly, Novo Nordisk, and AbbVie; consultancy fees from Abbott Diabetes, Eli Lilly, Novo Nordisk, and Medscape; fees for speaking from Eli Lilly and Novo Nordisk; and currently serves as Chair of the Board of Trustees for the Hormone Foundation. KRT is supported by US federal research grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, and the National Institutes of Health Director's Office, as well as the Centers for Disease Control and Prevention; has received investigator-initiated grant support from Travere, Bayer, Otsuka, Doris Duke Charitable Foundation, Benaroya Research Institute, and Breakthrough T1D (formerly the Juvenile Diabetes Research Foundation); reports consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Glaxo Smith Kline, Novo Nordisk, Bayer, ProKidney, Alnylam, Otsuka, and Roche as well as speaker fees from Novo Nordisk, Bayer, Boehringer Ingelheim, AstraZeneca, and Travere; is chair of data safety monitoring boards for the NIDDK and George Clinical Institute, and member of the data safety monitoring board for AstraZeneca; and has leadership roles as chair for the Diabetic Kidney Disease Collaborative and chair for the Kidney Week 2025 Program Committee, both for the American Society of Nephrology. MJD has acted as a consultant or advisor and speaker for Eli Lilly and Company, Novo Nordisk, and Sanofi, and as a consultant or advisor for Kailera, ADARx, Structure Therapeutics, and Wave; has attended advisory boards for AbbVie, Amgen, AstraZeneca, Biomea Fusion, Carmot/Roche, Daewoong Pharmaceutical, Sanofi, Zealand Pharma, Regeneron, GSK, Innovent Bio, and EktaH; has acted as a speaker for AstraZeneca, Boehringer Ingelheim, Obesity Alliance, and Zuellig Pharma; and has received grants from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. DC, JC, W-SW, MD, RL, LL, and ERM are employees and shareholders of Eli Lilly and Company.","assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-11-11T20:27:42+00:00","study_design":"rct","drugs":"[\"orforglipron\"]","drug_details":"{\"dose\": \"maximum tolerated dose (up to 36 mg capsule [equivalent to 17·2 mg tablet]), once daily\", \"comparator\": \"insulin glargine (injectable, titrated)\", \"route\": \"oral\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"time to four-component MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina)","endpoints":null,"effect_estimate":"MACE-4 HR 0·84 (95% CI 0·59-1·20), non-inferior to insulin glargine: 57 (4·2%) vs 67 (5·0%) participants; deaths 19 (1·4%) vs 43 (3·2%); clinically significant or severe hypoglycaemia 93 (6·8%) vs 260 (19·2%); gastrointestinal adverse events 851 (62·1%) vs 193 (14·2%)","confidence_interval":"95% CI 0·59-1·20","p_value":"p<0·0001 for non-inferiority","sample_size":2749,"follow_up":"median follow-up of 2 years","direction":"mixed","population":"{\"mean_age\": \"63·1 years (SD 9·9)\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"1032 (38%) female; 1717 (62·5%) male\", \"bmi_mean\": 33, \"bmi_min\": 25, \"obesity_status\": \"overweight or obesity required (BMI of 25 kg/m2 or more)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"established cardiovascular or chronic kidney disease required; 2362 (85·9%) had established cardiovascular disease\", \"ckd_status\": \"mixed: 1033 (37·6%) had chronic kidney disease\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with overweight or obesity at increased cardiovascular risk, with established cardiovascular or chronic kidney disease\", \"sample_size\": 2749, \"inclusion_exclusion\": \"type 2 diabetes at increased cardiovascular risk; HbA1c between 7·0% and 10·5%; BMI of 25 kg/m2 or more; established cardiovascular or chronic kidney disease; up to three glucose-lowering medications\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes, BMI of 25 kg/m2 or more (mean 33 kg/m2) and established cardiovascular or chronic kidney disease, though mean age 63·1 years is in the target range.","mediation":"unlikely","mediation_notes":"Unlikely by owner ruling M2: the primary result is null (non-inferior for MACE-4, HR 0·84 with a CI crossing 1), so there is no effect to attribute to weight change. No weight change or mediation analysis is reported in the abstract.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 2749, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"insulin glargine (injectable, titrated)\", \"follow_up_duration\": \"median follow-up of 2 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0·59-1·20\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"HIGH: a large phase 3 randomised trial (2749 participants) with an event-driven hard cardiovascular outcome; open-label, and the active comparator and non-inferiority design limit it to a safety conclusion.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly and Company","author_conflicts":"Several authors are employees and shareholders of Eli Lilly and Company; others report consulting, speaker, advisory and research fees from Eli Lilly, Novo Nordisk and many other companies","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly and Company (employment and shareholding, consulting and speaker fees, research funding)","adverse_events":"Gastrointestinal adverse events 851 (62·1%) with orforglipron vs 193 (14·2%) with insulin glargine, and the most common reason for stopping orforglipron; clinically significant or severe hypoglycaemia 93 (6·8%) vs 260 (19·2%); deaths 19 (1·4%) vs 43 (3·2%)","limitations":"Open-label and industry-funded; tested for non-inferiority against insulin glargine rather than placebo, so it shows cardiovascular safety, not benefit; everyone had type 2 diabetes, overweight or obesity and cardiovascular or kidney disease.","plain_summary":"This open-label randomised trial compared oral orforglipron with insulin glargine in 2749 adults with type 2 diabetes, overweight or obesity and cardiovascular or kidney disease. Over a median follow-up of 2 years, major cardiovascular events occurred in 57 (4·2%) versus 67 (5·0%) participants, meeting the non-inferiority test without a significant difference (HR 0·84; 95% CI 0·59-1·20). Gastrointestinal adverse events were much more common with orforglipron (62·1% versus 14·2%), while clinically significant or severe hypoglycaemia was less common (6·8% versus 19·2%).","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":840,"doi":"10.1159/jvr/adiag003","pmid":"42814650","nct_ids":"[]","title":"Endothelial-Fibroblast Organoids Generated in Hydrogel Microchamber Arrays: A Translational Model of Vascular Dysfunction in Cardio-Kidney-Metabolic Disease","authors":"[\"Zitman-Gal T\", \"Sobolev M\", \"Talash A\", \"Tartakover Matalon S\", \"Topaz G\", \"Chen J\", \"Pereg D\", \"Rashid G\", \"Nacasch N\", \"Dahan A\", \"Deutsch M\", \"Cohen-Hagai K\"]","journal":"Journal of vascular research","publication_date":"2026-09-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[UNLABELLED] Cardio-kidney-metabolic disease comprises interconnected cardiovascular, renal, and metabolic disorders in which endothelial dysfunction drives microvascular and macrovascular injury. Although novel treatments improve clinical outcomes, the cellular and molecular mechanisms underlying these effects remain incompletely understood. We developed and characterized a three-dimensional (3D) endothelial-fibroblast co-culture platform to study endothelial morphogenesis and responses to metabolic and pharmacological stimuli. [METHODS] A hydrogel microchamber array (HMC) platform was used to generate reproducible endothelial spheroids and extracellular matrix embedded organoids. Endothelial cells were cultured alone or with fibroblasts. Morphometric changes were quantified over time following glucose exposure and treatment with the GLP-1 receptor agonist/insulin combination (Xultophy). [RESULTS] The HMC platform enabled reproducible formation of spheroids and organoids. Fibroblast co-culture enhanced endothelial organization and structural complexity. Glucose induced organoid expansion and reduced circularity, consistent with structural remodeling. Xultophy attenuated these changes and preserved organoid morphology. Responses were dependent on the sequence of stimulation, with partial mitigation of glucose-induced effects by Xultophy. Organoids demonstrated greater sensitivity than spheroids, highlighting the importance of extracellular matrix context. [CONCLUSIONS] The HMC platform provides a reproducible and physiologically relevant 3D system for investigating endothelial-stromal interactions, metabolic stress, and therapeutic modulation in cardio-kidney-metabolic disease.","url":"https://pubmed.ncbi.nlm.nih.gov/42814650/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:20+00:00","study_design":"cellular_in_vitro","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1457,"doi":"10.1017/s1047951126124317","pmid":"42969830","nct_ids":"[]","title":"Patient-centred outcomes with incretin-based therapies and sodium-glucose cotransporter 2 inhibitors in obesity-related heart failure with preserved ejection fraction: a programme-level systematic review and meta-analysis","authors":"[\"Khan MD\", \"Ul Haq MS\", \"Shaukat MI\", \"Khan MA\", \"Shahzad S\", \"Shahzad S\", \"Jamil M\", \"Farooq F\"]","journal":"Cardiology in the young","publication_date":"2026-09-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity-related heart failure with preserved ejection fraction is characterised by symptom burden, impaired mobility, and reduced health status. Direct comparative evidence between incretin-based therapies and sodium-glucose cotransporter 2 inhibitors is lacking. [METHODS] We conducted a PRISMA-guided systematic review and programme-level meta-analysis, using the independent parent randomised trial programme as the unit of analysis to avoid double-counting linked reports. The primary endpoint was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, and the secondary endpoint was the six-minute walk distance. Random-effects models used restricted maximum likelihood estimation with Knapp-Hartung inference. [RESULTS] Six parent programmes were included: STEP-heart failure with preserved ejection fraction, STEP-heart failure with preserved ejection fraction DM, SUMMIT, PRESERVED-HF, EMPEROR-Preserved, and DELIVER. In obesity-focused incretin programmes, pooled mean differences were 7.38 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score points (95% confidence interval, 6.29 to 8.48; I2 = 0.00%) and 17.60 m for six-minute walk distance (95% confidence interval, 10.69 to 24.52; I2 = 0.00%). The secondary sodium-glucose cotransporter 2 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score synthesis showed a pooled mean difference of 2.53 points (95% confidence interval, −1.97 to 7.03; I2 = 82.21%). No parent programme was judged to be at high risk of bias. [CONCLUSIONS] Incretin-based therapies showed consistent patient-centred improvements in obesity-related heart failure with preserved ejection fraction, whereas sodium-glucose cotransporter 2 inhibitor evidence was derived from broader heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction populations and was more heterogeneous. Cross-class comparisons remain exploratory because of population differences, follow-up differences, limited six-minute walk distance availability, and the absence of direct comparative trials; these findings do not establish class superiority.","url":"https://pubmed.ncbi.nlm.nih.gov/42969830/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":795,"doi":"10.1016/s0140-6736(26)01861-1","pmid":"42810372","nct_ids":"[\"NCT05929079\"]","title":"Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial","authors":"[\"Bellido V\", \"le Roux CW\", \"Ekinci EI\", \"Bjornstad P\", \"Frias JP\", \"Giblin K\", \"Eyde S\", \"Park SY\", \"Ferro J\", \"Johnson C\", \"Taylor A\"]","journal":"Lancet (London, England)","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide is an agonist of GIP, GLP-1, and glucagon receptors, and is currently under investigation for the treatment of obesity, type 2 diabetes, and other comorbidities, including knee osteoarthritis and obstructive sleep apnoea. We aimed to assess the efficacy and safety of retatrutide in adults with obesity and type 2 diabetes. [METHODS] TRIUMPH-2 was a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial conducted at 92 medical and research centres and hospitals across eight countries. We enrolled adults (aged ≥18 years) with a BMI of 27 kg/m2 or higher and type 2 diabetes (glycated haemoglobin [HbA1c] 6·5-10·5%) on stable treatment for type 2 diabetes for at least 90 days before screening (diet or exercise alone, or up to three oral glucose-lowering medications), and a history of at least one self-reported unsuccessful dietary effort to reduce bodyweight. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to receive once-weekly subcutaneous injections (self-administered) of placebo or retatrutide 4 mg, 9 mg, or 12 mg. The primary endpoint was the percentage change from baseline to week 80 in bodyweight for the retatrutide 9 mg and 12 mg doses versus placebo, with 4 mg versus placebo a key secondary endpoint. Efficacy analyses included all randomly assigned participants, with missing data imputed with a primary multiple imputation strategy for the treatment regimen estimand. Safety analyses included all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05929079 (completed). [FINDINGS] Between July 11, 2023, and Nov 1, 2024, 2047 participants were screened, and 1152 (mean age 55·1 years [SD 10·8], 554 [48%] females and 598 [52%] males, and 672 [58%] of White ethnicity) were randomly assigned to retatrutide 4 mg (n=292), 9 mg (n=284), or 12 mg (n=287), or placebo (n=289). At baseline, the mean BMI was 38·2 kg/m2 (SD 7·4), mean HbA1c was 7·71% (1·07), median duration of obesity was 21 years (IQR 11-31), and median duration of diabetes was 5·6 years (2·6-10·4). At baseline, 1055 (92%) of 1152 participants were on any oral glucose-lowering medication, including biguanides, SGLT2 inhibitors, sulfonylureas, and other oral glucose-lowering medications. Of 1152 participants, 965 (84%) completed the study drug. For the treatment regimen estimand, the mean percentage change from baseline in bodyweight at week 80 was -11·9% (SE 0·6) with retatrutide 4 mg, -16·8% (0·7) with retatrutide 9 mg, -18·8% (0·7) with retatrutide 12 mg, and -5·1% (0·7) with placebo. Estimated treatment differences compared with placebo for percentage change in bodyweight were -6·9% (95% CI -8·7 to -5·1) with retatrutide 4 mg, -11·8% (-13·7 to -9·8) with retatrutide 9 mg, and -13·8% (-15·8 to -11·8) with retatrutide 12 mg (p<0·0001 for all). The most frequently reported adverse events were gastrointestinal, which were more common in the retatrutide groups than in the placebo group (diarrhoea occurred in 80 [27%] of 292 participants in the 4 mg group, 95 [34%] of 284 in the 9 mg group, and 96 [34%] of 286 in the 12 mg group vs 38 [13%] of 287 in the placebo group, and nausea occurred in 40 [14%], 59 [21%], and 80 [28%] vs 23 [8%]). Hypotension and dysesthesia were more frequent with retatrutide than with placebo (four [1%] in the 4 mg group, 14 [5%] in the 9 mg group, and 18 (6%) in the 12 mg group vs one [<1%] in the placebo group with hypotension; 13 [4%], 16 [6%], and 21 [7%] vs two [1%] in the placebo group with dysesthesia). Permanent treatment discontinuation due to adverse events or death was more frequent in participants treated with retatrutide 9 mg (33 [12%]) and 12 mg (22 [8%]) compared with retatrutide 4 mg (11 [4%]) and placebo (14 [5%]). Two participants died in the retatrutide 4 mg group, three in the 9 mg group, one in the 12 mg group, and one in the placebo group; all deaths were deemed to be unrelated to the study intervention by the investigator. [INTERPRETATION] Treatment with retatrutide resulted in substantial improvements in bodyweight and was associated with improvements in glycaemic control in participants with obesity and type 2 diabetes, with a safety profile generally consistent with other molecules with GLP-1 receptor agonism. These results show that retatrutide might be effective for the treatment of obesity in people with type 2 diabetes. [FUNDING] Eli Lilly and Company.","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests VB has served as a consultant or adviser for Abbott Diabetes Care, Boehringer Ingelheim, Dexcom, Eli Lilly, Insulet, Novo Nordisk, and Sanofi; has served as a speaker for Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Sanofi; and has participated in research activities for Novo Nordisk, Eli Lilly, and Sanofi. CWlR reports grants from the EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board; serves on advisory boards and speakers panels of AbbVie, Altimmune, Amgen, Arrowhead Pharma, AstraZeneca, Boehringer Ingelheim, Eli Lily, Gila Pharmaceuticals, Herbalife, Irish Life Health, Johnson & Johnson, Keyron, Medscape, Metsera, Morphic Medical, Novo Nordisk, Nymble, Olympus, Pfizer, Rhythm Pharma, Roche, Wave, and Zealand Pharma; is the Chair of the Irish Society for Nutrition and Metabolism; received stock options as payment for scientific advisory board functions from Nymble; and provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a co-owner of these clinics. PB reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk, Sidera Bio, Roche, and Horizon Pharma; serves or has served on the advisory boards or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Lilly, Roche, and XORTX; serves as Chair for a data monitoring committee for Bayer and a member of a data monitoring committee for Cytel; and reports grant funding from AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Merck, and Amgen/Horizon Pharma. EIE has received grant funding, paid to institution, from Abbott, AstraZeneca, Arrowhead Pharmaceuticals, Amgen, Boehringer Ingelheim, Eli Lilly, Endogenex, NewAmsterdam, Novartis, Novo Nordisk, Omnipod & Versanis Bio, the Australian National Health and Medical Research Council, Medical Research Future Fund, and Diabetes Victoria; and has served as a consultant for Eli Lilly, Novo Nordisk, Boehringer Ingelheim, and fees received are donated to EIE's institution. JPF reports research support from AbbVie, Eli Lilly, Novo Nordisk, Roche/Genentech, and Sparrow Pharmaceuticals; consulting for and participating on advisory boards for AbbVie, Adium, Biomea Fusion, Eli Lilly, Madrigal, Novo Nordisk, Sanofi, Sparrow Pharmaceuticals, and Zealand Pharmaceuticals; speakers bureaus for Eli Lilly, IONIS, and Madrigal; and is on the Board of Directors for T1D Exchange. KG, SE, JF, CJ, AT, and SYP are current employees and shareholders of Eli Lilly and Company.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"4, 9 or 12 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"80 weeks\", \"comparator\": \"placebo\"}","domains":"[\"metabolic\", \"body_composition\", \"adverse_effects\", \"gastrointestinal\", \"cardiovascular\"]","outcome_type":"intermediate","primary_outcome":"Percentage change in bodyweight from baseline to week 80 (9 mg and 12 mg vs placebo; 4 mg key secondary)","endpoints":null,"effect_estimate":"Bodyweight -11.9% (4 mg), -16.8% (9 mg), -18.8% (12 mg) vs -5.1% placebo; treatment differences -6.9, -11.8 and -13.8 percentage points","confidence_interval":"-8.7 to -5.1 (4 mg); -13.7 to -9.8 (9 mg); -15.8 to -11.8 (12 mg)","p_value":"<0.0001 for all doses","sample_size":1152,"follow_up":"80 weeks","direction":"benefit","population":"{\"mean_age\": 55.1, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": \"48% female\", \"bmi_mean\": 38.2, \"bmi_min\": 27, \"obesity_status\": \"BMI >= 27 required; median duration of obesity 21 years\", \"diabetes_status\": \"type 2 diabetes required (median duration 5.6 years; 92% on oral glucose-lowering drugs)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity with type 2 diabetes\", \"sample_size\": 1152, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity or overweight with type 2 diabetes was required and mean BMI was 38.2. Nothing in the abstract bears on normal-weight adults. Mean age 55 sits at the low end of the reference range.","mediation":"not_applicable","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1152, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"80 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -8.7 to -5.1 (4 mg); -13.7 to -9.8 (9 mg); -15.8 to -11.8 (12 mg)\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large multicentre double-blind placebo-controlled phase 3 RCT with 80-week follow-up. The primary outcome is bodyweight, a surrogate for this observatory's questions. Sponsor funded, designed and analysed. 16% did not complete study drug, with more discontinuation on the two higher doses. Abstract-level appraisal.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors declare consulting, speaking and research relationships with Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Sanofi and others; sponsor employees are co-authors.","sponsor_role":"Sponsor funded, designed and analysed the trial.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"Gastrointestinal events most frequent: diarrhoea 27-34% vs 13%, nausea 14-28% vs 8%. Hypotension 1%, 5% and 6% (4, 9, 12 mg) vs <1% placebo. Dysesthesia 4%, 6% and 7% vs 1%. Permanent discontinuation for adverse events or death 4%, 12% and 8% vs 5%. Seven deaths (six on retatrutide, one on placebo), all judged unrelated by the investigators.","limitations":"Assessed from the abstract. Bodyweight is the primary outcome; no clinical event outcomes. The population is obesity with type 2 diabetes. The mechanism, time course and reversibility of dysesthesia are not described in the abstract.","plain_summary":"Phase 3 TRIUMPH-2 trial of the triple agonist retatrutide: about 12 to 14 percentage points more weight loss than placebo at the 9 mg and 12 mg doses (about 7 points at 4 mg) over 80 weeks in adults with obesity and type 2 diabetes. Beyond the familiar gastrointestinal profile, two dose-related adverse effects stand out: hypotension and dysesthesia (abnormal skin sensation). Says nothing about normal-weight adults.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":801,"doi":"10.1111/dom.71400","pmid":"42811393","nct_ids":"[]","title":"Efficacy and Safety of Dual GLP-1/Glucagon Receptor Agonism in Overweight and Obesity: A Class-Specific Systematic Review and Meta-Analysis","authors":"[\"Amjad MM\", \"Khan MM\", \"Sarwar F\", \"Ali A\", \"Ali M\", \"Bakhash F\", \"Abid H\", \"Ibrahim F\", \"Mustafa K\", \"Ali DE\", \"Fayyaz MMN\", \"Hassan H\", \"Mian SM\", \"Yaseen M\", \"Qamar I\", \"Khan AH\", \"Ullah S\", \"Khan BW\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Dual glucagon-like peptide-1/glucagon receptor (GLP-1/GCGR) agonists represent a novel obesity treatment class, but existing meta-analyses often conflate them with GIP-containing agents (tirzepatide, retatrutide) or restrict analysis to one or two drugs, leaving class-specific efficacy and safety incompletely characterized. [METHODS] We systematically searched PubMed, Embase, Cochrane Library, Scopus and ClinicalTrials.gov through 20 July 2026 for randomized controlled trials of mazdutide, survodutide, cotadutide, and efinopegdutide in adults with overweight/obesity (PROSPERO CRD420261456447). Random-effects meta-analysis pooled mean differences (MDs) and risk ratios (RRs) with 95% CIs; heterogeneity, subgroup, sensitivity, GRADE and publication bias analyses were performed. [RESULTS] Nineteen RCTs were included. Dual agonists significantly reduced absolute body weight (MD: -6.65 kg, moderate certainty), relative weight (MD: -7.15%), and increased likelihood of ≥ 5% weight loss (RR: 4.75, low certainty), with mazdutide and survodutide showing the largest effects. Significant improvements occurred in HbA1c, BMI, waist circumference, systolic blood pressure and triglycerides. Any adverse events were more frequent with dual agonists (RR: 1.16), while serious adverse events did not differ from controls (RR: 0.90, high certainty). [CONCLUSION] Dual GLP-1/GCGR agonists produce meaningful weight loss and metabolic improvements with acceptable short-term safety, though longer head-to-head trials are needed to confirm durability and cardiovascular safety.","url":"https://pubmed.ncbi.nlm.nih.gov/42811393/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:32:36+00:00","study_design":"meta_analysis","drugs":"[\"mazdutide\", \"survodutide\", \"cotadutide\", \"efinopegdutide\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":"Body weight MD -6.65 kg (relative MD -7.15%); at least 5% weight loss RR 4.75; any adverse event RR 1.16; serious adverse events no difference (RR 0.90)","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"The abstract gives no confidence intervals\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Pooling 19 randomized trials of dual GLP-1/glucagon agonists (mazdutide, survodutide, cotadutide, efinopegdutide) in adults with overweight or obesity, the drugs reduced body weight (by about 6.7 kg, or 7.2%, more than control) and improved HbA1c, BMI, waist circumference, systolic blood pressure and triglycerides. Any adverse events were more common with the dual agonists (RR 1.16), while serious adverse events did not differ (RR 0.90). Longer head-to-head trials are needed to confirm durability and cardiovascular safety.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":824,"doi":"10.1210/endocr/bqag104","pmid":"42811814","nct_ids":"[]","title":"GHRH and GLP-1 receptor agonism promote human β-cell survival and improve glucose homeostasis in diabetic mice","authors":"[\"Louzada RA\", \"Gonzalez Medina M\", \"Pita-Grisanti V\", \"Blandino-Rosano M\", \"Crowley LA\", \"Cui T\", \"Sha W\", \"Cai R\", \"Wangpaichitr M\", \"Bernal-Mizrachi E\"]","journal":"Endocrinology","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 1 diabetes (T1D) is characterized by progressive loss of pancreatic β cell mass driven by inflammatory cytokine-induced apoptosis. Although glucagon-like peptide-1 receptor (GLP-1R) agonists improve β cell function and survival, their efficacy may be limited under hyperglycemic conditions. Growth hormone-releasing hormone receptor (GHRH-R) agonists have emerged as potential β cell-protective agents through activation of cAMP-dependent signaling pathways. Here, we investigated the effects of the GHRH-R agonist MR-409, alone or in combination with the GLP-1R agonist exendin-4 (Ex-4), on β cell survival and glucose homeostasis. In human islets, combined MR-409 and Ex-4 treatment enhanced glucose-stimulated insulin secretion and increased CREB phosphorylation. The combination also reduced cytokine-induced apoptosis, with decreased caspase 3/7 activity compared with MR-409 alone and reduced BAX protein levels compared with either individual treatment. MR-409 alone increased IRS2 protein levels, consistent with activation of pro-survival signaling pathways. In a multiple low-dose streptozotocin (STZ) mouse model, MR-409, Ex-4, and their combination improved glucose homeostasis and increased β cell mass compared with vehicle-treated mice. However, the combination did not confer additional metabolic benefit over single treatments. Notably, MR-409 treatment was associated with greater improvements in glucose tolerance and insulin levels. These findings support further investigation of GHRH receptor agonism as a strategy to preserve β-cell survival under diabetogenic stress.","url":"https://pubmed.ncbi.nlm.nih.gov/42811814/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:17+00:00","study_design":"preclinical_animal","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"mortality\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":847,"doi":"10.1016/j.eprac.2026.09.013","pmid":"42810620","nct_ids":"[]","title":"Comparative Weight-Loss Outcomes Following Initiation of GLP-1 Receptor Agonists versus SGLT2 Inhibitors: A Real-World Active Comparator Study","authors":"[\"Milanov V\"]","journal":"Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare 12-month weight loss between GLP-1 receptor agonist (GLP-1RA) and SGLT2 inhibitor (SGLT2i) initiators and assess effect modification by diabetes status, sex, and race/ethnicity in a diverse US cohort. [METHODS] Retrospective active comparator new-user cohort study using the NIH All of Us Research Program (2018-2023). We identified 2,932 SGLT2i-naïve GLP-1RA initiators and 941 GLP-1RA-naïve SGLT2i initiators aged 18-80 with BMI ≥27 kg/m2 and available weight measurements. Inverse probability of treatment weighting (IPTW) with a 17-covariate propensity score model - including heart failure and CKD - achieved balance on all 28 diagnostics (maximum SMD 0.077). The primary outcome was percent body weight change at 12 months; secondary outcomes included ≥10% weight loss, HbA1c, and blood pressure change. [RESULTS] After IPTW, GLP-1RA initiators lost more weight than SGLT2i initiators (difference -1.20 pp [95% CI, -1.91 to -0.48]; P = .001; OR 1.75 [95% CI, 1.40-2.19]; RR 1.61 [95% CI, 1.19-2.03]; NNT 14), concentrated in obesity-only patients (-1.96 pp; P <.001) but absent in type 2 diabetes (+0.08 pp; interaction P = .006). Sex modified the effect (P = .017): -1.71 pp in women vs +0.12 pp in men. HbA1c decreased more with GLP-1RA (-0.261%; P = .032); blood pressure did not differ significantly. [CONCLUSION] GLP-1RA initiators achieved greater weight loss than SGLT2i initiators, concentrated in women and patients without type 2 diabetes, supporting individualized treatment selection. Interaction findings are hypothesis-generating and require prospective confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42810620/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":848,"doi":"10.1016/j.metabol.2026.156790","pmid":"42810614","nct_ids":"[]","title":"Comparative outcomes of GLP-1 receptor agonist and SGLT2 inhibitor users after liver transplantation: An emulated target trial","authors":"[\"Yen FS\", \"Liao PL\", \"Hung YM\", \"Hsu CC\", \"Liu CS\", \"Hou MC\", \"Hwu CM\", \"Wei JC\"]","journal":"Metabolism: clinical and experimental","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] We emulated a target trial to compare glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) regarding hepatic, cardiovascular, and mortality outcomes among liver transplant recipients with diabetes. [METHODS] Using the TriNetX US Collaborative Network, we identified 33,161 liver transplant recipients with diabetes between 2015 and 2024. After propensity score matching, 564 pairs of new GLP-1 RA and SGLT2i users were analyzed. Risks of infection, graft rejection, cirrhosis, cardiovascular outcomes, hospitalization, and mortality were estimated using Cox proportional hazards models. [RESULTS] The mean age was 65.8 years (SD, 10.8), and 65.1% were male. Compared with SGLT2i use, GLP-1 RA use was associated with lower risks of cirrhosis (HR, 0.787; 95% CI, 0.619-0.999), ischemic heart disease (HR, 0.721; 95% CI, 0.582-0.892), heart failure (HR, 0.502; 95% CI, 0.388-0.650), and all-cause mortality (HR, 0.622; 95% CI, 0.433-0.894). No significant differences were observed for infection, graft rejection, liver failure, or all-cause hospitalization. Sensitivity analyses generally supported the cardiovascular and mortality findings, whereas the association with cirrhosis was less consistent across propensity score models. [CONCLUSIONS] Among liver transplant recipients with diabetes, GLP-1 RA use was associated with lower risks of ischemic heart disease, heart failure, and all-cause mortality compared with SGLT2i use. A lower risk of cirrhosis was also observed, although this association was of borderline statistical significance and was not consistently significant across alternative models. Given the observational design, these findings do not establish causality and warrant prospective confirmation.","url":"https://pubmed.ncbi.nlm.nih.gov/42810614/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication. All authors declare no competing interests that might bias their work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"liver\", \"immune\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":856,"doi":"10.1111/bph.70677","pmid":"42811773","nct_ids":"[]","title":"Positive modulation of glucagon-like peptide 1 (GLP-1) receptor by endogenous haemorphins with implications in glucose metabolism and diabetes","authors":"[\"Khan FB\", \"Alameri RM\", \"Raouf YS\", \"Maurel D\", \"Wani NA\", \"Shmygol A\", \"Anwar I\", \"See HB\", \"Johnstone EKM\", \"Dupuis E\", \"Trinquet E\", \"Pfleger KDG\", \"Oueis E\", \"Ayoub MA\"]","journal":"British journal of pharmacology","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND PURPOSE] Haemorphins are known to target G protein-coupled receptors and their reduced serum levels were associated with diabetes and obesity. This is consistent with inhibitory action on dipeptidyl peptidase IV, controlling GLP-1 levels. The modulation of the GLP-1 receptor by haemorphins as a mechanism for regulating glucose homeostasis was investigated. [EXPERIMENTAL APPROACH] The effect of LVV-haemorphin 7 (LVV-H7) on GLP-1 receptor was assessed in human embryonic kidney (HEK293) and rat insulinoma (INS-1 832/3) cells using bioluminescence resonance energy transfer, downstream signalling, cell viability, insulin synthesis experimental and computational ligand binding analysis. [KEY RESULTS] LVV-H7 has positive action on GLP-1 receptor occurring with GLP-1 but not orforglipron (LY3502970), indicating a peptide-peptide interaction, causing a left shift in GLP-1's dose responses. LVV-H7 also potentiated GLP-1-induced insulin expression and its protective effect against glucose-induced cytotoxicity. Moreover, LVV-H7 slightly reduced the GLP-1's association kinetics with no impact on its binding properties. Molecular docking supported by functional analysis showed the existence of a putative 'allosteric' binding site at the junction between the helical and the extracellular domains (ECDs) and highlighted the critical role of Trp6 of LVV-H7 and Ser31ECD/Glu34ECD/Arg299ECL2/Asp372ECL3/Arg380ECL3/™7of GLP-1 receptor. This also demonstrated that active GLP-1/GLP-1 receptor complex is required for the positive action of LVV-H7. [CONCLUSIONS AND IMPLICATIONS] LVV-H7 is active on the GLP-1 receptor-mediated metabolic pathways in pancreatic β-cells. This is consistent with reduced serum haemorphin levels in diabetes/obesity, suggesting implications in glucose homeostasis. This constitutes the first Class B GPCR modulated by haemorphins, illustrating the role of haemorphin-GPCR axis in physiology/pathophysiology.","url":"https://pubmed.ncbi.nlm.nih.gov/42811773/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:22+00:00","study_design":"preclinical_animal","drugs":"[\"orforglipron\"]","drug_details":null,"domains":"[\"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":858,"doi":"10.2215/cjn.0000001244","pmid":"42809365","nct_ids":"[]","title":"Comparative Renal Effectiveness of GLP-1RA and SGLT2i in US Veterans with Type 2 Diabetes and CKD","authors":"[\"Htoo PT\", \"Patorno E\", \"Ortega-Montiel J\", \"Wexler DJ\", \"Orkaby A\", \"Paik JM\"]","journal":"Clinical journal of the American Society of Nephrology : CJASN","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To address limited comparative evidence in older, clinically complex patients with type 2 diabetes and moderate-to-advanced chronic kidney disease (CKD), we compared nephroprotective outcomes after GLP-1RA versus SGLT2i initiation among US Veterans aged ≥65 years with type 2 diabetes and CKD stages 3-4 during 2016-2025. [METHODS] Within the U.S. Veterans Health Administration database, we identified individuals with type 2 diabetes and CKD stage 3-4 (eGFR 15 to <60 mL/min/1.73 m2) initiating GLP-1RA vs SGLT2i. GLP-1RA formulations approved for weight loss were excluded. The primary outcome was a composite of ESKD, sustained 40% decline in kidney function, or all-cause mortality, with individual components being secondary outcomes. After controlling for >100 covariates including comorbidities, medications, clinical parameters, and laboratory results using propensity score matching weights, we estimated hazard ratios and rate differences. Analyses were stratified by CKD stages, HbA1c, and body mass index. [RESULTS] We identified 28,365 GLP-1RA and 78,354 SGLT2i initiators [mean (SD) age: 74 (6) years vs. 76 (6) years]. Over a median follow-up of 11 months, the weighted risks for the primary outcome were similar between treatment groups [HR (95% CI): 1.00 (0.94, 1.07); RD per 1,000 person-years (95% CI): 0.0002 (-0.0037, 0.0042)], mainly attributed to the similar risk for all-cause mortality. The risks of the secondary outcomes were higher in GLP-1RA vs. SGLT2i initiators, but higher risks for sustained kidney function decline and ESKD. Findings were consistent across variations in baseline CKD stage, history of CVD, BMI, and HbA1c level. Absolute rate differences for major kidney disease events and ESKD were larger in patients with more advanced CKD stages. [CONCLUSIONS] These findings suggest broadly comparable overall kidney and survival outcomes, with potential advantages of SGLT2is for the risks of kidney function decline and incident ESKD across metabolic subgroups in this older adult cohort.","url":"https://pubmed.ncbi.nlm.nih.gov/42809365/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":868,"doi":"10.1056/nejmoa2604169","pmid":"42814954","nct_ids":"[\"NCT05929066\"]","title":"Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity","authors":"[\"Jastreboff AM\", \"Kaplan LM\", \"Davies MJ\", \"Wilding JPH\", \"Ahmad NN\", \"Murray M\", \"Du Y\", \"Makarova N\", \"Giblin K\", \"Schloot NC\", \"Wang Y\", \"TRIUMPH-1 Investigators\"]","journal":"The New England journal of medicine","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide is a triple-receptor agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. [METHODS] In this phase 3, randomized, double-blind trial, we assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. Primary outcomes (evaluated in the 9-mg and 12-mg groups each vs. placebo) were the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10, with higher scores indicating worse pain) in the subgroup of 574 participants with knee osteoarthritis and the change in the apnea-hypopnea index in the 243 participants with obstructive sleep apnea. For weight-related end points, intercurrent events were handled by a treatment-regimen estimand (intention-to-treat [ITT]). For end points in participants with knee osteoarthritis or obstructive sleep apnea, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events suggesting treatment failure; ITT results are also reported. [RESULTS] A total of 2339 participants underwent randomization. The mean percent change in body weight in the retatrutide groups was -17.6% (4-mg dose), -23.7% (9-mg dose), and -25.0% (12-mg dose) versus -3.9% in the placebo group (differences, -19.8 and -21.0 percentage points, respectively; P<0.001 for both comparisons). Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were -3.2, -3.5, and -3.6 versus -1.9 with placebo (differences, -1.6 and -1.8 points; both P<0.001); the corresponding changes for the ITT estimand were -3.4, -3.9, and -4.1 versus -2.5 with placebo (differences, -1.4 and -1.6 points; both P<0.001). Among the participants with obstructive sleep apnea, the corresponding changes in events per hour in the retatrutide groups for the hybrid-treatment estimand were -22.9, -34.3, and 31.7 versus -9.9 (differences, -24.4 and -21.9; both P<0.001); the corresponding changes for the ITT estimand were -22.8, -34.3, and -32.1 versus -9.6 (differences, -24.7 and -22.5; both P<0.001). The most common adverse events were gastrointestinal. [CONCLUSIONS] In adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea-hypopnea events in participants with obstructive sleep apnea. (Funded by Eli Lilly; TRIUMPH-1 ClinicalTrials.gov number, NCT05929066.).","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"4 mg, 9 mg, or 12 mg once weekly\", \"treatment_duration\": \"80 weeks\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"osteoarthritis\", \"sleep\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percent change in body weight; WOMAC pain score in participants with knee osteoarthritis (574); apnea-hypopnea index in participants with obstructive sleep apnea (243)","endpoints":null,"effect_estimate":"Body weight -17.6% (4 mg), -23.7% (9 mg) and -25.0% (12 mg) vs -3.9% with placebo (differences -19.8 and -21.0 percentage points for 9 mg and 12 mg; P<0.001); WOMAC pain differences -1.6 and -1.8 points (hybrid estimand; P<0.001); apnea-hypopnea index differences -24.4 and -21.9 events per hour (hybrid estimand; P<0.001)","confidence_interval":null,"p_value":"P<0.001","sample_size":2339,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required (adults with obesity)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity (with knee osteoarthritis or obstructive sleep apnea in subgroups)\", \"sample_size\": 2339, \"inclusion_exclusion\": \"adults with obesity without diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity; people with diabetes were excluded; age and BMI are not reported in the abstract.","mediation":"likely","mediation_notes":"Likely: the record reports substantial weight loss (-23.7% and -25.0% at 9 mg and 12 mg versus -3.9% on placebo), and knee pain and sleep apnoea events are outcomes weight loss is known to improve; no analysis separates them. The weight outcome itself is not a mediation question.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 2339, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; P values only; 2339 randomised (574 with knee osteoarthritis, 243 with obstructive sleep apnea)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a large phase 3 double-blind randomised trial (2339 participants) with intermediate outcomes (weight, pain score, apnea-hypopnea index); no confidence intervals in the abstract.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly and Company","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"The most common adverse events were gastrointestinal","limitations":"Industry-funded; the abstract gives no confidence intervals and little safety detail; the knee and sleep apnea results come from subgroups (574 and 243 participants); all participants had obesity; abstract only.","plain_summary":"This phase 3 double-blind trial randomized 2339 adults with obesity but without diabetes to once-weekly retatrutide (4 mg, 9 mg or 12 mg) or placebo for 80 weeks. Mean body weight changed by -17.6%, -23.7% and -25.0% with retatrutide versus -3.9% with placebo. Knee pain scores and apnea-hypopnea events also fell more than with placebo in the subgroups with knee osteoarthritis and obstructive sleep apnea. The most common adverse events were gastrointestinal.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":869,"doi":"10.1111/dom.71378","pmid":"42811415","nct_ids":"[]","title":"Genetically Proxied GIP-GIPR Pathway Perturbation and Fracture Risk","authors":"[\"Cheng W\", \"Liu W\", \"Wei J\", \"Zeng C\", \"Lyu H\", \"Zhao SS\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To determine whether genetic proxies for incretin pathway perturbation are associated with fracture risk and bone mineral density, providing human genetic evidence relevant to the skeletal safety of incretin-based therapies. [MATERIALS AND METHODS] We conducted drug-target Mendelian randomisation using cis genetic variants near GIP, GIPR, GCG, GLP1R in 401 983 unrelated UK Biobank participants. Instruments were scaled to 1 kg/m2 lower BMI or 1 mmol/mol lower HbA1c. Outcomes included fractures at major osteoporotic sites, combined spine-and-hip fractures, site-specific fractures and estimated bone mineral density (eBMD). We compared these estimates with genome-wide liability to lower BMI or HbA1c to contextualise the fracture associations observed for the target-proximal instruments. We used Cox models to estimate time-to-fracture associations per SD of target genetic risk score aligned to lower BMI or HbA1c. [RESULTS] GIP-GIPR perturbation was associated with lower odds of fractures at major osteoporotic sites when scaled to lower BMI (OR 0.80, 95% CI 0.66-0.98) or lower HbA1c. Associations were similar for combined spine-and-hip fractures under both scaling approaches (OR 0.68, 0.49-0.94). Genome-wide liability to lower BMI or HbA1c did not show the same fracture associations as GIP-GIPR perturbation. GCG-GLP1R estimates were imprecise. Genetically proxied incretin pathway perturbation was not associated with eBMD. In Cox analyses, GIP-GIPR genetic risk score was associated with lower risk of fractures at major osteoporotic sites (HR 0.976, 0.959-0.992) and combined spine-and-hip fractures (HR 0.971, 0.946-0.996). [CONCLUSIONS] Human genetic evidence suggests an association between genetically proxied GIP-GIPR pathway perturbation and lower fracture risk, supporting fracture-focused evaluation of GIPR-targeting therapies in clinical and post-marketing studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42811415/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"bone\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":890,"doi":"10.1038/s41591-026-04651-9","pmid":"42811187","nct_ids":"[\"NCT06672172\"]","title":"Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial","authors":"[\"Yu M\", \"Peng L\", \"Jiang C\", \"Zhang X\", \"Li Q\", \"Zhang L\", \"Su X\", \"Zeng Z\", \"Yan S\", \"Wang J\", \"Huang D\", \"Wang S\", \"Liu N\", \"Xu Y\", \"Tang G\", \"Dong F\", \"Ma Y\", \"Ye Z\", \"Xiao X\", \"OUTSTAND-1 Investigator Group\"]","journal":"Nature medicine","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety in OUTSTAND-1, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 46 sites in China. We randomized 284 adults with type 2 diabetes managed with diet and exercise alone (mean baseline HbA1c 7.95%, median diabetes duration 1.6 years, 33.1% women) to once-daily safiglipron 30 mg (n = 70), 60 mg (n = 70), 90 mg (n = 72) or placebo (n = 72) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, placebo-adjusted treatment differences in HbA1c change from baseline to week 32 were -1.22% (95% CI, -1.53 to -0.91), -1.20% (95% CI, -1.52 to -0.89) and -1.45% (95% CI, -1.75 to -1.14) for 30 mg, 60 mg and 90 mg, respectively (all P < 0.0001; treatment policy estimand). Secondary outcomes showed HbA1c < 7.0% in 71.4-77.8% versus 25.0%, HbA1c ≤ 6.5% in 58.6-68.1% versus 16.7% and placebo-adjusted fasting plasma glucose differences of -1.58, -1.68 and -2.08 mmol l-1, respectively (all P < 0.0001). Body weight differences were modest (-0.65%, -2.23% and -3.56% versus placebo). Other secondary outcomes generally favored safiglipron for HbA1c < 5.7% attainment, postprandial glycemia, homeostatic model assessment of β cell function (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), disposition index and waist circumference, with less rescue therapy use. Insulin and C-peptide responses varied by dose, and changes in treatment satisfaction were limited. Gastrointestinal adverse events were most common and mostly mild or moderate. Adverse events led to treatment discontinuation in 1.4%, 2.9%, 6.9% and 0% of participants receiving safiglipron 30 mg, 60 mg, 90 mg and placebo, respectively. These findings support once-daily oral safiglipron as an effective treatment option for type 2 diabetes. ClinicalTrials.gov identifier: NCT06672172 .","url":"https://pubmed.ncbi.nlm.nih.gov/42811187/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: L.P., Y.X., G.T., F.D., Y.M. and Z.Y. were employees of Jiangsu Hengrui Pharmaceuticals Co., Ltd. at the time of the study. L.P., Y.X. and Z.Y. declare a patent pending relating to safiglipron. All other authors declare no competing interests.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"safiglipron\"]","drug_details":"{\"comparator\": \"placebo\", \"treatment_duration\": \"32 weeks, followed by a 20-week active-treatment extension\", \"dose\": \"30 mg, 60 mg or 90 mg once daily\", \"route\": \"oral\"}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"placebo-adjusted change in HbA1c from baseline to week 32","endpoints":null,"effect_estimate":"Placebo-adjusted HbA1c change -1.22%, -1.20% and -1.45% for 30 mg, 60 mg and 90 mg (all P < 0.0001); fasting plasma glucose -1.58, -1.68 and -2.08 mmol l-1; body weight -0.65%, -2.23% and -3.56% versus placebo (described as modest); changes in treatment satisfaction limited","confidence_interval":"95% CI, -1.53 to -0.91 (30 mg); -1.52 to -0.89 (60 mg); -1.75 to -1.14 (90 mg)","p_value":"all P < 0.0001","sample_size":284,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"33.1% women\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required (managed with diet and exercise alone)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"early type 2 diabetes managed with diet and exercise alone\", \"sample_size\": 284, \"inclusion_exclusion\": \"adults with type 2 diabetes managed with diet and exercise alone\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes (managed with diet and exercise alone, mean baseline HbA1c 7.95%); BMI and age are not reported in the abstract.","mediation":"not_applicable","mediation_notes":"Not applicable: the primary outcome is HbA1c, a glycaemic measure; body weight differences versus placebo were reported as modest.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 284, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, -1.53 to -0.91 (30 mg); -1.52 to -0.89 (60 mg); -1.75 to -1.14 (90 mg)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a phase 3 double-blind placebo-controlled randomised trial of 284 participants with an intermediate glycaemic primary outcome.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Several authors were employees of Jiangsu Hengrui Pharmaceuticals Co., Ltd. at the time of the study, and some of them declare a patent pending relating to safiglipron; all other authors declare no competing interests","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Gastrointestinal adverse events most common, mostly mild or moderate; adverse events led to discontinuation in 1.4%, 2.9%, 6.9% and 0% with safiglipron 30 mg, 60 mg, 90 mg and placebo","limitations":"A moderate-sized trial at 46 sites in China with a glycaemic primary outcome over 32 weeks of placebo control; participants had early type 2 diabetes; BMI and age not reported, and no funder named, in the abstract.","plain_summary":"This double-blind randomized trial at 46 sites in China gave 284 adults with early type 2 diabetes once-daily oral safiglipron (30 mg, 60 mg or 90 mg) or placebo. At week 32, the placebo-adjusted HbA1c changes were -1.22%, -1.20% and -1.45% (all P < 0.0001), while body weight differences were modest. Gastrointestinal adverse events were most common and mostly mild or moderate, and adverse events led to stopping treatment in 1.4%, 2.9% and 6.9% on safiglipron versus 0% on placebo.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":899,"doi":"10.20944/preprints202609.2396.v1","pmid":null,"nct_ids":"[]","title":"Increasing Direct-to-Consumer Use of Semax and Selank Peptides Decoded from LLM-Curated Clinical Notes and Physician Adjudication","authors":"[\"Marwaha A\", \"Venkatakrishnan A\", \"Varma G\", \"Shiv S\", \"Hollmer N\", \"Murugadoss K\", \"Gregg CJ\", \"Soundararajan V.\"]","journal":"preprint server","publication_date":"2026-09-29","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Semax and Selank are synthetic regulatory peptides that are not FDA-approved for human use but are marketed direct-to-consumer for cognition, mood and stress resilience. The extent of the documented use of these unapproved peptides in routine clinical care remains poorly characterized and, because neither is dispensed through regulated pathways, is largely absent from structured medication data of Electronic Health Records (EHRs). Using Large Language Model (LLM) curation of de-identified clinical notes from the nference federated data network with manual adjudication of the LLM-curated insights, here we characterize the clinically documented use of each peptide and the real-world medical contexts in which their use occurs. Clinical note documentation of both Semax and Selank increased starting in 2024, with an average quarter-over-quarter growth of 14% for Semax and 16% for Selank over the past year. Among 43 and 39 patients with clinical note-mentions of Semax or Selank, use was confirmed via LLM curation in 22 (51%) and 27 (69%) patients, respectively. Physician adjudication agreed with the LLM’s use classification in 164 of 165 individual note-level assessments (99.4%) across patients with a Semax or Selank mention, including patients whose use was not confirmed. In the pooled cohort of patients with confirmed Semax or Selank use (N = 49), cognitive enhancement (28.6%) and mood/anxiety/stress support (28.6%) were the most common reasons for use provided by the patients, with less common reasons including energy or performance, sleep, musculoskeletal and gastrointestinal indications. Manual adjudication showed 86.7% agreement with the LLM-curated reasons for use. Both peptides were commonly administered intranasally (37%), and there was documentation of “stacking” with other peptides in 33 patients (67%), such as CJC-1295, ipamorelin, semaglutide, and tirzepatide. In the pooled cohort, clinical notes recorded patient-reported positive or effective responses in 16 of 49 patients (33%) and product- or administration-related safety concerns or adverse-event sentiments in 13 of 49 (27%). Manual adjudication agreed with LLM-curated self-reported-effect classifications in 94.2% of 103 reviewed records. Manual review showed isolated dyspnea, palpitations, flushing, and emergency department visits during the temporal periods overlapping with patient-reported use of Semax or Selank (n&lt;11). This study is not designed to evaluate the effectiveness or harm of Semax or Selank. Rather, it highlights the rising use of unapproved direct-to-consumer peptides without any structured coding mechanism in EHR systems, emphasizing the need for greater awareness among healthcare practitioners.","url":"https://doi.org/10.20944/preprints202609.2396.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:51+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cognition\", \"sleep\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1135,"doi":"10.1021/acsnano.6c08460","pmid":"42915765","nct_ids":"[]","title":"Intestinal Macrophage-Mediated Exosomal Repackaging Establishes Bioactive Reservoirs for Long-Acting Oral Peptide Therapy","authors":"[\"Wu L\", \"Bao X\", \"Ben Z\", \"Zhang Z\", \"Cui Y\", \"Tan X\", \"Sun X\", \"Ying X\", \"Shen Y\", \"Yang Y\", \"Xu D\", \"Han M\"]","journal":"ACS nano","publication_date":"2026-09-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Oral peptide delivery systems are conventionally engineered to improve intestinal absorption, but they rarely address the progressive and systemic nature of chronic inflammatory disorders such as type-2 diabetes (T2D), which requires both durable glycemic control and immunometabolic management. Here, we report an oral delivery system based on porous calcium carbonate/sodium alginate (PCC/SA) microparticles loaded with exenatide-chitosan oligosaccharide (EXE-COS). The PCC/SA carrier facilitates the efficient intestinal absorption and transepithelial transport of EXE-COS. Notably, in the lamina propria, EXE-COS can be selectively internalized by intestinal macrophages (ITMs) in vivo, driving their polarization toward anti-inflammatory M2-phenotypes. These M2-macrophages enable endogenous repackaging of exenatide into exosomes through orchestrated modulation of exosome biogenesis and trafficking. Through gut-organ axes, exosomes target diabetes-associated inflamed metabolic sites (pancreas, liver, and adipose tissue), establishing long-lived bioactive reservoirs to precisely restore tissue homeostasis and sustain glycemic control. Critically, a single oral dose of EXE-COS@PCC/SA achieved up to 8 day hypoglycemic effects in db/db mice following long-term administration, while concurrently improving systemic inflammation, lipid metabolism, and insulin resistance. This intestinal macrophage-mediated in situ exosomal biogenesis and endogenous drug repackaging represents a versatile long-acting oral peptide platform, showing promise for durable and safe management of T2D and other chronic inflammatory diseases.","url":"https://pubmed.ncbi.nlm.nih.gov/42915765/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:05+00:00","study_design":"preclinical_animal","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"immune\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":879,"doi":"10.1111/bph.70678","pmid":"42805610","nct_ids":"[]","title":"The dual incretin agonist tirzepatide blunts nicotine-induced behaviours and neurochemistry in male mice","authors":"[\"Edvardsson CE\", \"Emous TA\", \"Witley S\", \"Ericson M\", \"Adermark L\", \"Jerlhag E\"]","journal":"British journal of pharmacology","publication_date":"2026-09-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND PURPOSE] Nicotine dependence remains one of the leading causes of morbidity and mortality worldwide, with high relapse rates and post-cessation weight gain representing persistent barriers to sustained abstinence. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have emerged as novel treatment targets, as they appear to influence both reward-related behaviours associated with addictive substances and body weight regulation. Whether recently developed multi-receptor incretin agonists such as tirzepatide, a long-acting dual GIP/GLP-1 receptor agonist, affect nicotine-induced behaviours remains unstudied. [EXPERIMENTAL APPROACH] We investigated whether tirzepatide affects nicotine-induced behaviours (locomotor stimulation and expression of locomotor sensitisation, expression and reinstatement of conditioned place preference) and related neurochemistry (in vivo microdialysis and ex vivo tissue neurochemical analysis) in male mice. [KEY RESULTS] Tirzepatide attenuated nicotine-induced locomotor stimulation in a dose-related manner, and reduced nicotine-induced place preference, and in vivo accumbal dopamine release. Furthermore, tirzepatide suppressed reinstatement of nicotine place preference and prevented the expression of locomotor sensitisation, indicating effects beyond acute reward processing. Ex vivo neurochemical analysis of addiction-related brain regions in nicotine-sensitised mice revealed that tirzepatide blocked nicotine-induced dopamine elevations in the nucleus accumbens, ventral tegmental area and lateral septum. Furthermore, tirzepatide restored levels of multiple neurotransmitter systems, such as GABA, in a brain region-specific manner, suggesting possible effects beyond dopaminergic signalling alone. [CONCLUSIONS AND IMPLICATIONS] Collectively, these findings indicate that tirzepatide attenuates nicotine-induced locomotor stimulation and dopamine release, as well as the expression and reinstatement of place preference, and the expression of locomotor sensitisation, in mice.","url":"https://pubmed.ncbi.nlm.nih.gov/42805610/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:35+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"parkinsons\", \"addiction\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":881,"doi":null,"pmid":"42808150","nct_ids":"[]","title":"Non-Arteritic Anterior Ischaemic Optic Neuropathy Associated with Semaglutide use","authors":"[\"Kearney M\", \"Smyth NM\", \"Hassan HSA\", \"Khan MS\"]","journal":"Irish medical journal","publication_date":"2026-09-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PRESENTATION] Non-arteritic ischaemic optic neuropathy (NAION) is a common cause of acute, painless monocular visual disturbance in older adults. This case discusses a woman in her 70s with vascular risk factors who presented with a three-day history of progressive left sided visual disturbance. Examination demonstrated a left relative afferent pupillary defect and inferior quadrantopia. [DIAGNOSIS] Haematological investigations and neuroimaging were unremarkable. Formal ophthalmological assessment demonstrated superior optic disc swelling with an inferior visual field defect, consistent with NAION. [TREATMENT] The patient had been taking semaglutide, as prescribed, for the six months prior to presentation. This was identified as a potential contributory agent and was discontinued. Visual acuity partially improved following cessation of semaglutide. [DISCUSSION] This case seeks to highlight a possible association between semaglutide use and NAION. Although causality remains unproven, it underscores the importance of pharmacovigilance when manging patients presenting with ophthalmological symptoms.","url":"https://pubmed.ncbi.nlm.nih.gov/42808150/","source_name":"pubmed","source_tier":1,"coi_statement":"None declared.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:37+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":854,"doi":"10.1111/dom.71375","pmid":"42802242","nct_ids":"[]","title":"Effectiveness of Adding GLP-1 Receptor Agonists to SGLT2 Inhibitor Therapy in Chronic Kidney Disease: A Population Based Study","authors":"[\"Salim H\", \"Qureshi S\", \"Gulsin GS\", \"Khan HR\", \"Waqas SA\", \"McCann GP\", \"Garg A\", \"Shurrab M\", \"Khunti K\", \"Rashid M\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Individually, sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce major kidney and cardiovascular events in patients with chronic kidney disease (CKD). However, evidence supporting combined GLP-1RA and SGLT2i therapy in this population remains limited. [METHODS] We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with CKD treated with SGLT2i alone or SGLT2i with subsequent initiation of GLP-1RA between June 2020 and December 2023. Propensity score matching (1:1) adjusted for demographics, comorbidities, medications, and laboratory values. The primary outcome was major adverse kidney events (MAKE); secondary outcomes included all-cause mortality and major adverse cardiovascular events (MACE). Time-to-event analyses were performed using Cox proportional hazards models. [RESULTS] Among 112 596 patients with CKD, 16460 received SGLT2i and GLP-1RA combination therapy, and 96 136 received SGLT2i monotherapy. The matched cohort included 32 448 patients (16 224 per group). Over a median follow-up of 12 months, the addition of a GLP-1RA was associated with lower rates of the primary outcome of MAKE (HR 0.70; 95% CI 0.65-0.74; p < 0.001) compared with SGLT2i monotherapy. Combination therapy was also associated with lower risks of MACE (HR 0.83; 95% CI 0.78-0.87) and all-cause mortality (HR 0.55; 95% CI 0.50-0.61). Benefits were consistent across CKD stages and diabetes status, with significantly more pronounced effects observed in patients with obesity, heart failure, and ischemic heart disease. Combination therapy was associated with increased gastrointestinal symptoms, genital infections, and retinopathy progression, but lower risks of volume-depletion events and acute kidney injury. [CONCLUSIONS] In this real-world CKD cohort, GLP-1RA added to SGLT2i therapy was associated with substantial incremental reductions in kidney disease progression and cardiovascular events. These findings suggest an additive cardiorenal benefit, particularly in patients with obesity, supporting the evaluation of combination therapy in future randomised trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42802242/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"gastrointestinal\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":864,"doi":"10.1007/s11102-026-01760-z","pmid":"42801380","nct_ids":"[]","title":"Hypothalamic obesity in pediatric vs. adult craniopharyngioma: mechanisms, management, and cardiometabolic outcomes","authors":"[\"Gupta K\", \"Zeinali M\", \"Altschul D\", \"Agarwal V\", \"Karsy M\"]","journal":"Pituitary","publication_date":"2026-09-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Hypothalamic obesity (HO) is a treatment-related complication in craniopharyngioma (CP) survivors that markedly impairs long-term health and quality of life. Although overall survival exceeds 90% for both pediatric and adult CP, HO prevalence and clinical course differ substantially by age at onset. We aimed to compare HO manifestations, mechanisms, and treatment response between pediatric and adult CP cohorts. [METHODS] We conducted a scoping review of studies published between 2000 and 2025, comparing pediatric (childhood-onset) versus adult-onset CP cohorts, classified by age at diagnosis. Data on obesity prevalence, mechanistic pathways, therapeutic interventions, and cardiometabolic outcomes were extracted and synthesized. [RESULTS] In pediatric CP survivors, obesity rates rise from 5.7% pre-treatment to 57% post-treatment; in adults, from 19.2% to 29.2%. HO severity correlates with the extent of hypothalamic damage by Puget and QST grading. Key mechanisms include disrupted melanocortin signaling, central leptin and insulin resistance, and neuroinflammation via resistin-TLR4 and NLRP3 pathways. GLP-1 receptor agonists (exenatide, semaglutide) have produced marked weight loss in small case series (up to 17% over 6 months with semaglutide), but randomized trials did not meet their primary weight outcomes and direct pediatric-versus-adult comparisons are lacking. Bariatric procedures yield moderate success; sleeve gastrectomy achieves 5-year weight loss comparable to that in non-CP controls (21.7% vs. 21.8%), whereas Roux-en-Y gastric bypass is less effective than in controls (22.7% vs. 32.0%). Both cohorts face significant long-term risks: 2.2-fold higher all-cause mortality and 9.3-fold higher diabetes risk in adults, non-alcoholic fatty liver disease in 47% of pediatric survivors, metabolic dysfunction-associated fatty liver disease in 67.4% of adults, and insulin resistance in approximately 30% of pediatric patients. [CONCLUSION] HO following CP shows distinct age-dependent trajectories in prevalence, underlying mechanisms, and clinical course; suggested age-related differences in treatment response remain to be confirmed in direct comparative studies. Tailored management integrating mechanistic insights and age-specific therapies is critical to mitigating the cardiometabolic burden in these patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42801380/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval: Not applicable. This article is a scoping review of previously published literature and did not involve human participants, animal subjects, or identifiable patient data. Consent to participate: Not applicable. Consent to publish: Not applicable. Generative artificial intelligence use: Generative artificial intelligence was used to assist with language editing, formatting, and citation consistency checking during the preparation of this manuscript. All scientific content and citations were reviewed and verified by the authors, who take full responsibility for the integrity of the work. Competing interests: The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"case_series","drugs":"[\"semaglutide\", \"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"neuroinflammation\", \"liver\", \"cancer\", \"addiction\", \"mortality\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":872,"doi":"10.1016/j.bmcl.2026.130786","pmid":"42801961","nct_ids":"[]","title":"Discovery of Fisetin as a potent and cell-active ACVR2A inhibitor","authors":"[\"Bu X\", \"Dai M\", \"Fang Z\", \"Zou J\", \"Yang S\"]","journal":"Bioorganic & medicinal chemistry letters","publication_date":"2026-09-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Current weight-loss drugs, such as GLP-1 receptor agonists, are effective at reducing body weight but are often associated with concomitant loss of muscle mass. Thus, there is growing interest in developing next-generation anti-obesity agents that preserve muscle tissue. ACVR2A has emerged as a promising target in this context, as its inhibition may uncouple fat loss from muscle wasting. While several anti-ACVR2A monoclonal antibodies have advanced into clinical trials, small-molecule inhibitors remain scarcely reported. In this study, virtual screening followed by experimental validation was employed to identify the natural product fisetin as a potent ACVR2A inhibitor. Fisetin exhibited robust enzymatic inhibitory activity, with an IC₅₀ value of 0.27 ± 0.06 μM, and demonstrated high binding affinity, with a KD of 0.12 ± 0.03 μM. Cellular assays further confirmed that fisetin suppressed TGF-β/Smad signaling and successfully protected C2C12 myotubes from Activin A-induced atrophy by downregulating atrogenes. Despite its favorable in vitro profile, fisetin showed poor pharmacokinetic properties that currently limit its in vivo application; therefore, preliminary structural modifications were explored to guide future optimization. Collectively, these findings position fisetin as a promising lead compound for the development of ACVR2A-targeted therapies aimed at combating obesity while preserving muscle mass.","url":"https://pubmed.ncbi.nlm.nih.gov/42801961/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:27+00:00","study_design":"cellular_in_vitro","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"muscle\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":717,"doi":"10.1007/s40265-026-02380-4","pmid":"42791433","nct_ids":"[]","title":"GLP-1 Receptor Agonists in Heart Failure: A Systematic Review and Meta-analysis with Phenotype-Specific Effects and Dual Analytical Frameworks","authors":"[\"Yuan Y\", \"Chen C\", \"Li X\", \"Guo J\", \"Liu Q\", \"Lin Y\", \"Sun L\", \"Fan G\"]","journal":"Drugs","publication_date":"2026-09-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2D), evidence in heart failure (HF) has expanded across diverse trial populations and HF phenotypes but remains fragmented. We therefore performed an integrated systematic review and meta-analysis to evaluate the effects of GLP-1 RAs across the spectrum of HF using complementary trial-level and phenotype-based analyses. [METHODS] PubMed, Embase, and Web of Science were systematically searched for studies published from inception to August 10, 2025. To provide an integrated assessment across heterogeneous HF populations, treatment effects were evaluated using dual analytical frameworks: trial-level analyses according to study design (dedicated HF with preserved ejection fraction [HFpEF] trials, HF with reduced ejection fraction [HFrEF] trials, and HF subgroups from cardiovascular outcome trials [CVOTs]) and phenotype-based analyses according to left ventricular ejection fraction (HFpEF vs HFrEF using a pragmatic threshold of 40%). A prespecified targeted analysis was conducted to specifically assess the efficacy of semaglutide. The primary outcomes were major adverse cardiovascular events (MACE), and the secondary outcomes included hospitalization for HF (HHF), the composite of cardiovascular death or any worsening HF events, cardiovascular death alone, and all-cause mortality. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random‑effects models. [RESULTS] This meta-analysis included 14 trials, with a pooled total of 15,882 patients with HF. In phenotype‑based analyses for HFpEF, GLP‑1 RAs significantly reduced MACE (HR 0.79; 95% CI 0.66-0.94; p = 0.010), HHF (HR 0.48; 95% CI 0.27-0.85; p = 0.012), the composite of cardiovascular death or worsening HF (HR 0.57; 95% CI 0.37-0.89; p = 0.013), and all‑cause mortality (HR 0.75; 95% CI 0.62-0.89; p = 0.001). In contrast, in HFrEF, no significant reductions were observed for HHF, the composite of cardiovascular death or worsening HF, all-cause mortality, or MACE, although a reduction in cardiovascular death was noted (HR 0.71; 95% CI 0.54-0.95; p = 0.019). Trial-level analyses showed that cardiovascular benefits were primarily observed in HF subgroups from CVOTs, including reductions in MACE (HR 0.82; 95% CI 0.73-0.92; p = 0.001), cardiovascular death (HR 0.88; 95% CI 0.77-1.00; p = 0.05) and myocardial infarction (MI)/non-fatal MI (HR 0.84; 95% CI 0.70-1.00; p = 0.046). Semaglutide showed benefits in HHF and the composite of cardiovascular death or worsening HF events predominantly among overweight or obese patients with HFpEF. GLP-1 RAs also improved functional capacity and quality of life in HFpEF. [CONCLUSION] GLP-1 RAs were associated with favorable cardiovascular and HF-related outcomes in HFpEF, predominantly among overweight or obese individuals, whereas evidence of benefit in HFrEF remains limited. In trial-level analyses, benefits were primarily observed for atherosclerotic endpoints in HF subgroups from CVOTs. By integrating evidence, this study provides a unified overview of the effects of GLP-1 RAs across the spectrum of HF and supports further phenotype-specific randomized trials, particularly dedicated studies in HFrEF. [TRIAL REGISTRATION] Protocol registration PROSPERO (CRD420251079970).","url":"https://pubmed.ncbi.nlm.nih.gov/42791433/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Funding: This study was supported by the Guangdong Provincial Department of Science and Technology (YN2021DB02). Conflict of Interest: Yahui Yuan, Chun Chen, Xiuming Li, Jingyi Guo, Qiaoyun Liu, YuPing Lin, Lu Sun, Wei Song, and Guanjie Fan declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. CRediT Authorship Contribution Statement: Yahui Yuan: writing—original draft, writing–review & editing, methodology, data curation, conceptualization. Chun Chen: investigation, data curation, writing–original draft. Xiuming Li and Jingyi Guo: investigation, data curation, writing–review & editing. Qiaoyun Liu and Yuping Lin: investigation, data curation, writing–review & editing. Lu Sun: investigation, data curation, writing–review & editing. Guanjie Fan: methodology, investigation, funding acquisition, conceptualization, writing–review & editing. Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethical Approval: Not applicable. Code Availability: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"not reported in abstract\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"major adverse cardiovascular events (MACE)","endpoints":null,"effect_estimate":"HFpEF: MACE HR 0.79, HF hospitalization HR 0.48, cardiovascular death or worsening HF HR 0.57, all-cause mortality HR 0.75; HFrEF: no significant reductions in HF hospitalization, the composite, all-cause mortality or MACE, but cardiovascular death HR 0.71; HF subgroups of CVOTs: MACE HR 0.82","confidence_interval":"95% CI 0.66-0.94 (HFpEF, MACE)","p_value":"p = 0.010 (HFpEF, MACE)","sample_size":15882,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"heart failure required (HFpEF and HFrEF)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure (HFpEF and HFrEF)\", \"sample_size\": 15882, \"inclusion_exclusion\": \"dedicated HFpEF and HFrEF trials and HF subgroups from cardiovascular outcome trials\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all pooled patients had heart failure, a cardiovascular disease the target group lacks; BMI and diabetes status are not reported for the pooled population.","mediation":"possibly","mediation_notes":"No weight change, HbA1c or mediation analysis is reported; semaglutide's HFpEF benefits were seen predominantly in overweight or obese patients, which does not separate drug effects from weight loss (possibly).","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 15882, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not reported in abstract\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0.66-0.94 (HFpEF, MACE)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a pooled meta-analysis of 14 trials with hard outcomes, weakened by heterogeneous trial types including HF subgroups of cardiovascular outcome trials and phenotype-dependent results.","funding_source":"Guangdong Provincial Department of Science and Technology (YN2021DB02)","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Pools heterogeneous trials and HF subgroups of cardiovascular outcome trials, with phenotype assigned by a pragmatic ejection-fraction threshold; the abstract does not say the trials were randomised; the authors say evidence in HFrEF remains limited; everyone had heart failure.","plain_summary":"This systematic review and meta-analysis pooled 14 trials of GLP-1 receptor agonists in 15,882 patients with heart failure. In heart failure with preserved ejection fraction, the drugs were associated with fewer major cardiovascular events (HR 0.79; 95% CI 0.66-0.94), fewer heart failure hospitalisations (HR 0.48) and lower all-cause mortality (HR 0.75). In heart failure with reduced ejection fraction, there was no significant reduction in major cardiovascular events, hospitalisation or all-cause mortality, though cardiovascular death was lower (HR 0.71).","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":772,"doi":"10.1016/j.yrtph.2026.106252","pmid":"42800499","nct_ids":"[]","title":"Suitability of the ICH S1B(R1) Weight-of-Evidence Framework to Evaluate Glucagon-Like Protein-1 Receptor Agonist (GLP-1RA) Carcinogenicity Risk","authors":"[\"Roach KA\", \"Khazaee M\", \"Mohar I\", \"Boon D\", \"Cronin B\", \"Gauthier AG\"]","journal":"Regulatory toxicology and pharmacology : RTP","publication_date":"2026-09-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are an established treatment for management of type 2 diabetes mellitus (T2DM) and obesity. While these agents provide clinical benefits, chronic rodent bioassays have shown a consistent increase in thyroid C-cell tumors, raising regulatory concerns for human carcinogenicity risk and resulting in a boxed warning for medullary thyroid carcinoma (MTC). However, the human relevance of the rodent tumors is unclear due to species differences in GLP-1 receptor (GLP-1R) biology. Carcinogenicity testing of pharmaceuticals is described in ICH S1 guidelines. ICH S1B(R1) outlines experimental approaches to carcinogenicity evaluation including a weight-of-evidence (WoE) framework to determine whether long-term rat carcinogenicity studies add value to human cancer risk assessments. This manuscript applies that framework across seven approved GLP-1RAs: lixisenatide, exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, and albiglutide, to evaluate the relevance of rodent thyroid tumors and the utility of 2-year bioassays for this drug class. Across all six WoE domains, the evidence supports concluding that GLP1-RAs are tumorigenic in rats via a known human-irrelevant mechanism. Thus, within the S1B(R1) WoE framework, future carcinogenicity testing in rats is unlikely to provide additional value for regulatory decision-making for this class of pharmaceuticals.","url":"https://pubmed.ncbi.nlm.nih.gov/42800499/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:25+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"albiglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cancer\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":882,"doi":"10.15403/jgld-6863","pmid":"42803248","nct_ids":"[]","title":"Outcomes of GLP-1 Receptor Agonist Therapy after Liver Transplantation in Patients with Type 2 Diabetes: A Real-World Cohort Study","authors":"[\"Nguefang GL\", \"Boateng S\", \"Gyabaah S\", \"Konlack JG\", \"Issaka Y\", \"Luna Landa E\", \"Chukwu T\", \"Eze E\", \"Njei B\"]","journal":"Journal of gastrointestinal and liver diseases : JGLD","publication_date":"2026-09-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to manage type 2 diabetes mellitus (T2DM) in liver transplant (LT) recipients, but their impact on graft outcomes remains unclear. This study evaluated clinical and graft-related outcomes associated with GLP-1 RA therapy. [METHODS] We conducted a retrospective cohort study using the TriNetX Network, identifying adults with LT and T2DM. Two cohorts were defined: LT recipients treated with GLP-1 RAs and those receiving conventional antidiabetic therapy. Propensity score matching (1:1) was applied based on demographics, comorbidities, and immunosuppressive regimens. The index date was the first GLP-1 RA prescription within six months before or after LT. Outcomes assessed at one year included all-cause mortality, graft rejection, graft failure, biliary stricture, hepatic artery thrombosis, and transplant-related infections. Analyses used Kaplan-Meier survival curves and Cox proportional hazards models. [RESULTS] After matching, 704 patients were included in each cohort. GLP-1 RA use was associated with significantly lower mortality (4.2% vs. 12.6%; HR=0.33, 95%CI: 0.22-0.50; p<0.0001) and reduced risks of rejection (9.0% vs. 15.5%; HR=0.55; p=0.0008), graft failure (7.1% vs. 13.8%; HR=0.50; p=0.0002), biliary stricture (4.1% vs. 6.7%; HR=0.60; p=0.0342), infections (5.7% vs. 10.1%; HR=0.54; p=0.0032), and hepatic artery thrombosis (5.4% vs. 10.7%; HR=0.48; p=0.0007). [CONCLUSIONS] GLP-1 RA therapy was associated with improved survival and lower rates of major post-transplant complications, suggesting a potential role as preferred antidiabetic therapy in LT recipients with T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/42803248/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"liver\", \"immune\", \"mortality\", \"metabolic\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":898,"doi":"10.64898/2026.09.21.26363546","pmid":null,"nct_ids":"[]","title":"New-Onset Heart Failure in Patients with Obesity using Tirzepatide or Semaglutide","authors":"[\"Al-Nusair M\", \"Haddad TA\", \"Khurana S\", \"Al-Nusair J.\"]","journal":"preprint server","publication_date":"2026-09-26","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>ABSTRACT</h4>  <h4>Background</h4>  Tirzepatide and semaglutide improve functional status and heart failure (HF) events in patients with obesity and HF with preserved ejection fraction. Tirzepatide has been associated with greater control of cardiometabolic risk factors in patients with obesity compared to semaglutide. Whether tirzepatide is associated with lower risk of new-onset HF than semaglutide in patients with obesity is underexplored. <h4>Methods</h4>  A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with obesity who initiated therapy with tirzepatide or semaglutide during the period Jun 4, 2021 to Aug 13, 2026 were identified and 1:1 propensity-score matched to produce two study cohorts. The one-year incidence of new-onset HF was calculated and compared between the two cohorts. Secondary outcomes included new-onset systolic HF, new-onset diastolic heart failure, new-onset atrial fibrillation or flutter, all-cause mortality, and hospital encounters. Cox proportional hazards models were fitted to calculate hazard ratios (HR) along with 95% confidence intervals (CI). <h4>Results</h4>  Two well-matched cohorts (N=424,269 in each) were formed. The incidence of new-onset HF was lower in the tirzepatide group (1.0% vs. 1.3%; absolute risk difference −0.3%, 95% CI −0.35 to −0.26; HR 0.9, 95% CI 0.86─0.93). The tirzepatide group were also at lower risk of all-cause mortality (HR, 95% CI: 0.8, 0.77─0.91) and new-onset systolic HF (0.8, 0.79─0.92). All other secondary outcomes occurred at similar rates in both study groups. <h4>Conclusion</h4>  Among patients with obesity, tirzepatide therapy was associated with lower risk of new-onset HF compared to semaglutide although the effect sizes were modest.","url":"https://doi.org/10.64898/2026.09.21.26363546","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:51+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":852,"doi":"10.1016/j.jdiacomp.2026.109419","pmid":"42805130","nct_ids":"[]","title":"Real-world effectiveness of 6-month tirzepatide therapy on body weight and composition in adults with overweight and obesity","authors":"[\"Brancato D\", \"Maggio V\", \"Vaccaro F\", \"Muratore E\", \"Pirrello D\", \"Cittadini E\", \"Patti AM\", \"Di Falco F\", \"Agnello L\", \"Ciaccio M\", \"Rizzo M\"]","journal":"Journal of diabetes and its complications","publication_date":"2026-09-25","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS/HYPOTHESIS] Obesity drives cardiometabolic dysfunction and increases cardiovascular risk, with excess fat mass and impaired body composition playing a key role in metabolic outcomes. This clinical study aimed to evaluate the real-world effectiveness (RWE) of tirzepatide on body weight, body composition, and metabolic parameters in adults with obesity or overweight and at least one obesity-associated comorbidity. [METHODS] A 24-week retrospective observational analysis included 122 adults (80% women; mean age 44 ± 15 years) with overweight or obesity, and without diabetes. Participants received tirzepatide in combination with a standardized low-carbohydrate diet and tailored physical activity. Tirzepatide was initiated at a dose of 2.5 mg once weekly and increased to 5 mg after 4 weeks. Subsequent dose adjustments were individualized. Anthropometric measurements, bioelectrical impedance analysis and metabolic parameters were assessed at baseline and after 24 weeks. [RESULTS] The mean dose of tirzepatide at the end of the study was 5.32 mg. In comparison to baseline, we found after 24 weeks an improvement in body weight (from 95 ± 20 to 80 ± 22 kg), BMI (from 35 ± 6 to 29 ± 7 kg/m2) waist circumference (from 109 ± 16 to 92 ± 12 cm) and waist-to-height ratio (from 0.66 ± 0.1 to 0.56 ± 0.1), all p < 0.001. Fat mass (FM) largely reduced by 35%, fat-free mass slightly decreased by 5% (p < 0.001 for both), while skeletal muscle mass was preserved (p = ns). Metabolic parameters were also improved, including HbA1c (from 5.5 ± 0.4% to 5.2 ± 0.1%, p = 0.007), fasting plasma glucose (from 93 ± 12 to 84 ± 9 mg/dL, p < 0.001), fasting insulin (from 17 ± 15 to 12 ± 9 μIU/mL, p = 0.002) and HOMA-IR (from 4.2 ± 4.7 to 2.5 ± 2.1, p = 0.001). Correlation analysis revealed that the reduction in FM was significantly associated with the reduction in both insulin (r = 0.498, p < 0.05) and HOMA-IR (r = 0.513, p < 0.05). Interestingly, the weight loss found in our real-world cohort after 24 weeks of tirzepatide therapy (-16%) was identical to that found in the SURMOUNT-1 trial but after 72 weeks. [CONCLUSIONS] In this RWE study, 24 weeks of tirzepatide treatment led to significant improvement on body weight, BMI and fat mass, together with preservation of lean skeletal muscle mass, as well as improved glycemic control and insulin sensitivity. Our findings suggest that a comprehensive clinical approach to obesity in real-world settings may be more beneficial than what observed in clinical trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42805130/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"muscle\", \"lean_mass\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":901,"doi":"10.64898/2026.09.23.26363640","pmid":null,"nct_ids":"[]","title":"Effects of Reimbursement Policy Change on Utilization of Injectable Semaglutide for Type 2 Diabetes and on Glycemic Control Among Discontinuers: A Danish Nationwide Cohort Study","authors":"[\"Simonsen E\", \"Ernst MT\", \"Christensen DH\", \"Kildegaard H\", \"Søndergaard J\", \"Thomsen RW\", \"Pottegård A.\"]","journal":"preprint server","publication_date":"2026-09-25","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Objectives</h4>  To evaluate the impact of reimbursement restrictions for glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes, introduced in Denmark in November 2024, on injectable semaglutide (Ozempic®) utilization patterns and subsequent HbA1c changes among discontinuers. <h4>Design</h4>  Nationwide registry-based cohort study. <h4>Setting</h4>  Denmark. <h4>Participants</h4>  Adults treated with injectable semaglutide for diabetes (January 2018 to December 2025). <h4>Main outcome measures</h4>  We described temporal patterns in injectable semaglutide use before and after the policy change. Among semaglutide continuers after the policy change, we assessed whether continuation met a key criterion in the new policy: non-feasibility of sodium-glucose cotransporter 2 inhibitor use and high cardiovascular risk. We characterized semaglutide discontinuers around the policy implementation (March 2024 to November 2024) and subsequent treatment switches. Among discontinuers, we evaluated HbA1c changes and performed interrupted time series (ITS) analyses. <h4>Results</h4>  Following the policy change, use of injectable semaglutide declined modestly before subsequently increasing. Among 61,120 individuals classified as semaglutide continuers, 27,143 (44%) were already using an SGLT2i. Of the remaining 33,977 (56%), only 1,862 (5.5%) met a key reimbursement criterion (i.e., non-feasibility of SGLT2i use and high cardiovascular risk). Among 79,305 individuals with a semaglutide fill between March 2024 and November 2024, 22,096 (28%) were classified as discontinuers. Within six months, ∼40% of discontinuers switched to other glucose-lowering therapies, most commonly SGLT2is (24%). 37% of discontinuers later reinitiated semaglutide. Among individuals with an on-treatment HbA1c measurement (within 12 months before their last semaglutide fill) and an off-treatment HbA1c measurement (6-12 months after their last semaglutide fill) (n=13,017), mean HbA1c increased from 49 to 57 mmol/mol (mean change +7.4 mmol/mol, 95% CI 7.2-7.6). ITS analysis showed that HbA1c increased by 5.9 mmol/mol (95% CI 5.1-6.7) at six months post-discontinuation, which attenuated to 3.1 mmol/mol (95% CI 2.2-4.1) at 12 months; raw monthly means (not included in the ITS model) suggested this persisted through 18 months. <h4>Conclusions</h4>  Following the policy change, population-level use of injectable semaglutide declined modestly before increasing again. Most discontinuers did not initiate another glucose-lowering therapy and experienced an increase in HbA1c that did not fully return to pre-discontinuation levels during follow-up. <h4>What is already known on this topic</h4>  The rapid uptake and high costs of GLP-1 receptor agonists, including injectable semaglutide for diabetes (Ozempic®), have prompted health systems to consider how access to these treatments should be prioritized and reimbursed. Little is known about how reimbursement restrictions on GLP-1 receptor agonists influence treatment patterns and glycemic control after treatment discontinuation. <h4>What this study adds</h4>  Following a national reimbursement restriction in Denmark, more than one in four patients discontinued injectable semaglutide for diabetes, and among those who switched treatment, SGLT2 inhibitors were the most common alternative, while most discontinuers did not initiate another glucose-lowering drug within six months. Approximately one in three discontinuers reinitiated their semaglutide therapy more than six months after stopping. Discontinuation of injectable semaglutide for diabetes was followed by a rise in HbA1c that, despite improvement over time, did not return to pre-discontinuation levels over 18 months, highlighting a potential clinical consequence of restricting access to an effective glucose-lowering treatment option.","url":"https://doi.org/10.64898/2026.09.23.26363640","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":721,"doi":"10.1016/j.diabet.2026.101794","pmid":"42785671","nct_ids":"[]","title":"Clinical outcomes associated with glucagon-like peptide-1 receptor agonist therapy in patients with peripheral artery disease and diabetes","authors":"[\"Khadija HA\", \"Alnees M\", \"Abdullah A\", \"Ibraheem K\", \"Makhlouf TZ\", \"Cohen R\", \"Najajra D\", \"Twito O\", \"Schiller T\", \"Kirzhner A\"]","journal":"Diabetes & metabolism","publication_date":"2026-09-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] Peripheral artery disease (PAD) and diabetes are associated with high risks of limb complications and mortality. Although glucagon-like peptide-1 receptor agonists (GLP1-RAs) improve cardiovascular outcomes, their effect on limb outcomes in PAD remains uncertain. [METHODS] We conducted a retrospective cohort study using the Clalit Health Services database. Adults with PAD and diabetes were classified according to GLP1-RA dispensing exposure, and inverse probability of treatment weighting was used to balance measured baseline characteristics in the primary analysis. The primary outcome was major adverse limb events (MALE), defined as lower-limb revascularization or amputation. To address potential immortal time bias, all-cause mortality was additionally evaluated using an incident-treatment risk-set approach aligned to the qualifying GLP1-RA exposure date, while sustained GLP1-RA exposure was evaluated for MALE using a time-varying persistent-use model. [RESULTS] Among 20,031 patients, 5,960 met the original GLP1-RA exposure definition and 14,071 were classified as non-users. In the original IPTW-weighted analysis, GLP1-RA exposure was associated with lower risks of MALE, revascularization, major amputation, and all-cause mortality. In the time-aligned risk-set analysis, GLP1-RA exposure remained associated with lower all-cause mortality (HR 0.80, 95% CI 0.73-0.88; P < 0.001). In a time-varying analysis of sustained exposure, persistent GLP1-RA use was associated with a lower hazard of MALE (adjusted HR 0.65, 95% CI 0.44-0.94; P = 0.022). [CONCLUSION] In patients with PAD and diabetes, GLP1-RA exposure was associated with favorable clinical outcomes. Time-aligned analyses demonstrated a lower risk of all-cause mortality, while sustained GLP1-RA exposure was associated with lower MALE risk. Given the observational design, these findings should be interpreted as associations rather than causal treatment effects.","url":"https://pubmed.ncbi.nlm.nih.gov/42785671/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alena Kirzhner reports statistical analysis was provided by Novo Nordisk Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":766,"doi":"10.1016/j.clindermatol.2026.09.018","pmid":"42777891","nct_ids":"[]","title":"GLP-1 Receptor Agonists in Dermatology: Prescribing Frameworks, Access, and the Emerging Pipeline","authors":"[\"Bridges AG\"]","journal":"Clinics in dermatology","publication_date":"2026-09-23","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The rapid expansion of glucagon-like peptide-1 receptor agonist (GLP-1 RA) approvals has created a complex regulatory and practice environment for dermatologists. No GLP-1 RA currently holds a United States Food and Drug Administration (FDA)-approved dermatologic indication; all prescribing for cutaneous conditions - including psoriasis, hidradenitis suppurativa, and wound healing - remains off-label. This chapter examines the regulatory frameworks governing GLP-1 RA use in dermatology, encompassing the current FDA-approved landscape, legal and professional standards for off-label prescribing, obesity medicine certification as a competency pathway, the compounding controversy, and access, cost, and reimbursement barriers. Particular attention is given to the Anti-Kickback Statute (AKS) implications of manufacturer copay cards for Medicare beneficiaries, the Treat and Reduce Obesity Act, and evolving patient assistance strategies. Multidisciplinary collaboration, adverse event surveillance, the next-generation incretin pipeline, and ethical and equity considerations are also addressed. Practical recommendations are provided to guide dermatologists in navigating prescribing authority, reimbursement, pharmacovigilance, and the evolving evidence base.","url":"https://pubmed.ncbi.nlm.nih.gov/42777891/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The author declares no conflicts of interest relevant to this chapter.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:19+00:00","study_design":"pharmacovigilance","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"rheumatologic\", \"adverse_effects\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":739,"doi":"10.1002/oby.70301","pmid":"42768905","nct_ids":"[]","title":"Trends in GLP-1 Receptor Agonist Prescribing Without an Apparent FDA-Approved Indication","authors":"[\"Orandi BJ\", \"Yan L\", \"Levan ML\", \"Lofton HF\", \"Chhabra KR\", \"Ren-Fielding CJ\", \"Husain SA\", \"McAdams-DeMarco MA\", \"Segev DL\", \"Mankowski MA\", \"Massie AB\"]","journal":"Obesity (Silver Spring, Md.)","publication_date":"2026-09-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This study evaluated temporal trends and patient characteristics associated with glucagon-like peptide-1 (GLP-1) receptor agonist prescribing among US adults without an apparent FDA-approved indication. [METHODS] This retrospective cohort study used Cosmos electronic health records (01/2021-12/2025). Adults prescribed liraglutide, semaglutide, or tirzepatide without a documented indication (type 2 diabetes or obesity with qualifying comorbidities) were included. Patients without a recorded weight ≥ 6 months prior to first prescription were excluded. Demographic and clinical characteristics were compared using t-tests and χ2 tests. [RESULTS] Among 92,415,648 adults without an apparent FDA-approved indication, 1,133,953 (1.2%) were prescribed GLP-1 receptor agonists. Prescribing increased from 0.1% in 2021 to 1.5% in 2025 (15-fold). Recipients had higher median BMI (25.9 vs. 24.5 kg/m2) and were more often female (85.5%) and White (60.0%). Hypertension and dyslipidemia were more common, while coronary artery disease and heart failure were less prevalent. Notably, 35.1% had normal BMI; eating disorders were more frequent (1.8% vs. 0.3%). GLP-1 receptor agonist use was associated with lower social vulnerability and private insurance. [CONCLUSIONS] GLP-1 receptor agonist prescribing without an apparent FDA-approved indication has increased rapidly and disproportionately involves socioeconomically advantaged populations, including individuals without obesity. The risk-benefit profile in these populations remains uncertain.","url":"https://pubmed.ncbi.nlm.nih.gov/42768905/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":741,"doi":"10.1093/aje/kwag236","pmid":"42768735","nct_ids":"[]","title":"Real-world cardiovascular effects of liraglutide: transportability analysis of the LEADER trial","authors":"[\"Josey K\", \"Liu W\", \"Warsavage T\", \"Medici M\", \"Kvist K\", \"Derington CG\", \"Reusch JEB\", \"Ghosh D\", \"Raghavan S\"]","journal":"American journal of epidemiology","publication_date":"2026-09-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Appropriate use of recently approved type 2 diabetes treatments depends on external validity of landmark clinical trials (RCTs) in real-world populations that may differ from trial participants. This study transported effect estimates from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, a placebo-controlled RCT of liraglutide on cardiovascular outcomes, onto real-world cohorts within the Veterans Affairs (VA) healthcare system. Risk differences (RD) in survival outcomes, approximated using pseudo-observations of individual survival probabilities, were estimated with augmented inverse probability weighting after balancing baseline characteristics between RCT and target samples using approximate balancing weights. Transported effects of liraglutide compared to placebo on major adverse cardiovascular events (MACE) and all-cause mortality in veterans (\"VA-weighted LEADER\") were larger than, though statistically consistent with, the treatment effects observed in LEADER: MACE RD at 3 years of 4.6% [95% CI 2.2, 7.0] in VA-weighted LEADER versus 1.6% [0.3, 2.9] in LEADER; all-cause mortality RD at 3 years of 2.9% [0.8, 5.1] in VA-weighted LEADER versus 0.9% [-0.09, 1.9] in LEADER. These estimates of the effects of liraglutide in veterans with diabetes provide real-world evidence that can guide diabetes treatment decisions and formulary policies for a high-risk population underrepresented in RCTs.","url":"https://pubmed.ncbi.nlm.nih.gov/42768735/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":742,"doi":"10.1007/s00210-026-05908-3","pmid":"42768195","nct_ids":"[]","title":"Future GLP-1 receptor co-agonists and their cardiac effects","authors":"[\"Neumann J\", \"Kirchefer U\", \"Hofmann B\", \"Gergs U\"]","journal":"Naunyn-Schmiedeberg's archives of pharmacology","publication_date":"2026-09-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Agonists at glucagon-like-peptide-1 receptors (GLP-1R) are becoming approved drugs to treat not only type 2 diabetes and obesity but also cardiac diseases such as coronary heart disease, myocardial infarction and heart failure. Agonism at the GLP-1R can be combined with agonism at additional receptors (co-agonists) to obtain drugs which are more potent to induce weight loss. Therefore, new co-agonists were developed that not solely stimulate GLP-1R. We discuss here the known (for tirzepatide and retatrutide) or predicted contractile effects of such co-agonists on isolated cardiac preparations of experimental animals, mainly in mice and compare these results with data in isolated human cardiac preparations. We point out where preclinical studies in mice may be misleading in order to study cardiac effects of the drugs of interest in the human heart and as potential drugs for heart diseases. We address in some detail which additional receptors are or might be involved, the receptor expression of such additional receptors in the heart of various experimental animals. We will discuss not only receptor agonists but also a receptor antagonist (AMG133). We identify research needs and controversies in the literature. We make suggestions for further preclinical research and what improvements in drug design for treatment may lie ahead.","url":"https://pubmed.ncbi.nlm.nih.gov/42768195/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval: Does not apply. Consent to participate: Does not apply. Consent for publication: All authors declare that they have seen and approved the submitted version of this manuscript. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:11+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\", \"retatrutide\", \"maridebart\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":792,"doi":"10.21203/rs.3.rs-11082091/v1","pmid":null,"nct_ids":"[]","title":"Semaglutide reduces proteomic organ-specific biological age across randomized clinical trials","authors":"[\"Dermit M\", \"Colhoun HM\", \"Goeminne LJE\", \"Ryan D\", \"Adelborg K\", \"Belmont-Rausch D\", \"Kolnes KJ\", \"Knop FK\", \"Voisin SAC\", \"Gladyshev VN\", \"Knudsen LB\", \"Orozco AA.\"]","journal":"preprint server","publication_date":"2026-09-22","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>Semaglutide confers cardiovascular and kidney benefits and reduces all-cause mortality in high-risk populations. Whether biological-age metrics capture these effects and provide mechanistic insight remains unclear. We analyzed proteomics from 10,052 participants across five placebo-controlled semaglutide trials using externally trained organ-specific mortality clocks, proteomic frailty scores and disease-risk models. Semaglutide reduced heart biological age by approximately 2 to 4 years versus placebo, with reductions of 1 to 4 years across kidney, brain, pancreas, lung and multiorgan clocks. Proteomic frailty and cardiometabolic disease-risk scores improved during up to 156 weeks of follow-up. Effects were not fully mediated by weight loss, glycated hemoglobin or C-reactive protein. Exploratory mediation analyses suggested that heart biological-age changes may account for 34% to 49% of effects on selected outcomes. These findings demonstrate reproducible remodeling of mortality-associated proteomic signatures across populations and durations, supporting their potential as treatment-response readouts without establishing biological rejuvenation, causal mediation or surrogate validity.</p>","url":"https://doi.org/10.21203/rs.3.rs-11082091/v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"aging\", \"mortality\"]","outcome_type":"biomarker","primary_outcome":"organ-specific proteomic biological age (mortality clocks), proteomic frailty and disease-risk scores","endpoints":null,"effect_estimate":"Heart biological age reduced by approximately 2 to 4 years versus placebo; reductions of 1 to 4 years across kidney, brain, pancreas, lung and multiorgan clocks; proteomic frailty and cardiometabolic disease-risk scores improved","confidence_interval":null,"p_value":null,"sample_size":10052,"follow_up":"up to 156 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 10052, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract does not describe the five trials' populations, so age, BMI and diabetes status cannot be determined.","mediation":"specifically_tested","mediation_notes":"The authors report that effects were not fully mediated by weight loss, HbA1c or C-reactive protein, from analyses of participant data across 10,052 participants; the analyses are described as exploratory and the abstract does not give the method.","adjusted_for":"[\"body-weight change\", \"HbA1c\", \"other\"]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 10052, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"up to 156 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no CI or p value reported; 10,052 participants across five trials\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a preprint, not yet peer reviewed, analysing biomarker outcomes (proteomic clocks) from five placebo-controlled trials.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A preprint secondary analysis of proteomic biomarkers; the mediation analyses are described as exploratory; the authors say the findings do not establish biological rejuvenation, causal mediation or surrogate validity; the trial populations are not described in the abstract.","plain_summary":"This preprint analysed blood proteins from 10,052 participants in five placebo-controlled semaglutide trials, using protein-based estimates of organ biological age. Semaglutide lowered estimated heart biological age by approximately 2 to 4 years versus placebo, with reductions of 1 to 4 years in other organ clocks, and the authors report the effects were not fully explained by weight loss, HbA1c or C-reactive protein. These are biomarker results, and the authors say they do not establish biological rejuvenation, causal mediation or that the clocks stand in for outcomes.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":818,"doi":"10.64898/2026.09.20.752954","pmid":"42818175","nct_ids":"[]","title":"Targeting PFKFB3 Metabolic Gatekeeping of β-Cell Dysfunctional States Enables Durable Glucose Tolerance in Type 2 Diabetes","authors":"[\"Raval K\", \"Ilegems E\", \"Title AC\", \"Fishburn E\", \"Bhardwaj G\", \"Mirguet O\", \"Ratcliffe P\", \"Greeff O\", \"Van Wyk A\", \"Tudzarova S\"]","journal":"bioRxiv : the preprint server for biology","publication_date":"2026-09-22","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"[UNLABELLED] Progressive β-cell dysfunction underlies type 2 diabetes (T2D), yet existing therapies fail to correct the dysfunctional cellular states that accumulate during disease progression. We show that pharmacological inhibition of PFKFB3 markedly reduced the population of PFKFB3⁺ dysfunctional β-cells while preserving functional islet mass, consistent with selective depletion or phenotypic reprogramming of compromised β-cells. In transgenic diabetic mice expressing human IAPP, PFKFB3 inhibitor AZ67 improved glucose-stimulated insulin secretion and glucose tolerance through a mechanism consistent with direct restoration of β-cell function and distinct from incretin-based therapy. Critically, glycemic improvement persisted after treatment withdrawal, consistent with durable remodeling of islet functional states rather than transient pharmacological suppression. In human islet microtissues under glucotoxic and cytokine stress, AZ67 and its analogue AZ26 improved insulin secretion and proinsulin processing in a stress- and compound-dependent manner while reducing PFKFB3⁺ dysfunctional endocrine populations. Transcriptomic profiling identified suppression of inflammatory programs and activation of cholesterol homeostasis and adaptive metabolic pathways. These findings establish PFKFB3 inhibition as a potential disease-modifying therapeutic strategy for T2D. [ONE SENTENCE SUMMARY] Inhibiting PFKFB3 clears dysfunctional β-cells and durably restores glucose control in diabetic mice and human islets.","url":"https://pubmed.ncbi.nlm.nih.gov/42818175/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:17+00:00","study_design":"preclinical_animal","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":903,"doi":"10.64898/2026.09.21.26363576","pmid":null,"nct_ids":"[]","title":"Cardiovascular Outcomes in Patients with Type 2 Diabetes and Heart Failure with Reduced Ejection using Glucagon-like Peptide-1 Receptor Agonists","authors":"[\"Al-Nusair, M.\", \"Maini, A.\", \"Khurana, S.\", \"Al-Nusair, J.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-22","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"BackgroundGlucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D) and obesity, and more recently they have been shown to be beneficial in patients with obesity and heart failure with preserved ejection fraction. Their role in patients with heart failure and reduced ejection fraction (HFrEF) and T2D remains underexplored.\n\nMethodsA retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with T2D and HFrEF who were initiated on GLP1-RA therapy during the period May-13-2026 to Jun-6-2026 were identified. One:one propensity-score matching with controls was performed. Time-to-event analysis was conducted to compare the one-year incidences of all-cause mortality and a primary composite outcome of acute myocardial infarction, ischemic stroke and acute heart failure, between the two matched-cohorts. Secondary outcomes included individual components of the primary composite outcome and any inhospital encounter.\n\nResultsTwo well-matched cohorts with 38,879 patients in each were formed. Patients treated with GLP1-RAs had a lower incidence of all-cause mortality (4.2% vs. 12%; absolute risk difference [ARD] -7.8, 95% CI -8.17 to -7.41; HR 0.4, 95% CI 0.34[boxh]0.38) and the primary composite outcome (32.5% vs. 48.3%; ARD -15.8, 95% CI -16.47 to -15.11; HR 0.6, 95% CI 0.57[boxh]0.60) compared to the control group. The GLP1-RA group were also at lower risk of all secondary outcomes compared to the control group.\n\nConclusionIn a real-world study, GLP1-RA therapy was associated with lower risk of all-cause mortality and cardiovascular outcomes in patients with T2D and HFrEF.","url":"https://www.medrxiv.org/content/10.64898/2026.09.21.26363576","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":713,"doi":"10.1016/j.amjcard.2026.09.016","pmid":"42767411","nct_ids":"[]","title":"GLP-1 Analogues and Long-term Outcomes in Adults with Obesity and Elevated CRP: A Real-world Matched Cohort Study","authors":"[\"Shah S\", \"Abusafia M\", \"Sheashaa H\", \"Jadam S\", \"Ospina S\", \"Kaelber D\", \"Keen SK\", \"Cho L\", \"Desai MY\"]","journal":"The American journal of cardiology","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity is frequently accompanied by low-grade systemic inflammation and increased cardiovascular risk. We evaluated whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) exposure was associated with improved long-term outcomes among adults with obesity and C-reactive protein (CRP) levels of 3-10 mg/L. Using the TriNetX Global Collaborative Network, adults with body mass index ≥30 kg/m² who received a GLP-1 RA were compared with an active-comparator cohort receiving metformin, orlistat, or phentermine without GLP-1 RA exposure. Following 1:1 propensity-score matching, 50,009 patients were included in each cohort and followed for up to 3,650 days. GLP-1 RA exposure was associated with a lower hazard of the primary composite outcome of all-cause mortality, acute myocardial infarction, and ischemic stroke (hazard ratio[HR] 0.799, 95% confidence interval[CI] 0.772-0.825; P<0.001), driven primarily by lower all-cause mortality (HR 0.608, 95% CI 0.578-0.640; P<0.001). Ischemic stroke, arrhythmias, and heart failure with reduced ejection fraction were modestly lower, whereas acute myocardial infarction and incident heart failure with preserved ejection fraction did not differ significantly between cohorts. In conclusion, GLP-1 RA exposure was associated with lower long-term composite clinical events among adults with obesity and CRP levels of 3-10 mg/L, predominantly reflecting lower mortality; prospective studies incorporating longitudinal weight and CRP measurements are needed to evaluate potential mediating mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42767411/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":740,"doi":"10.1111/dom.71358","pmid":"42768849","nct_ids":"[]","title":"Comparative Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Among Glucagon-Like Peptide-1 Receptor Agonists: An Integrated Safety and Mechanistic Analysis","authors":"[\"Sun H\", \"Xin X\", \"Yan J\", \"Huang T\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for Type 2 diabetes (T2DM) and obesity, but emerging evidence links them to nonarteritic anterior ischemic optic neuropathy (NAION). Whether this risk differs across agents and the underlying mechanisms remains unclear. We aimed to compare the risks of NAION associated with different GLP-1RAs and to explore the potential molecular mechanisms underlying this adverse reaction. [MATERIALS AND METHODS] A network meta-analysis was performed to quantitatively compare the differences in NAION risk. Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) were used for validation. Network toxicology was further applied to identify central hub targets and signalling pathways. Molecular docking was conducted to evaluate the binding capacity of GLP-1RAs to central hub targets. [RESULTS] The network meta-analysis revealed significant differences in NAION risk across GLP-1RAs. Compared with non-GLP-1RA treatments, semaglutide showed the highest risk (HR = 1.538, 95% CI: 1.305-1.816), followed by liraglutide (HR = 1.251, 95% CI: 1.080-1.450). FAERS pharmacovigilance analysis suggested a strong disproportionate signal for semaglutide (ROR = 94.534, 95% CI: 83.093-107.552) and a statistically significant but weaker signal for liraglutide (ROR = 4.519, 95% CI: 2.617-7.802). Network toxicology identified CASP3 as the central hub target, and pathway enrichment analysis revealed that the underlying mechanisms were primarily related to Alzheimer's disease, neurodegeneration pathways, and lipid and atherosclerosis pathways. Molecular docking suggested that semaglutide and liraglutide had high binding affinity to CASP3. [CONCLUSIONS] The combined strategy of network meta-analysis, pharmacovigilance, network toxicology and molecular docking provides insights into possible risk differences and potential mechanisms, and may guide future research on the safety profile of GLP-1RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/42768849/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T20:45:21+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"comparator\": \"non-GLP-1RA treatments\", \"dose\": null, \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"alzheimers\", \"neuroinflammation\", \"metabolic\", \"adverse_effects\", \"ophthalmologic\"]","outcome_type":"hard","primary_outcome":"Risk of nonarteritic anterior ischemic optic neuropathy (NAION) across GLP-1 receptor agonists","endpoints":null,"effect_estimate":"Network meta-analysis against non-GLP-1RA treatments: semaglutide HR 1.538, liraglutide HR 1.251 for NAION; FAERS disproportionality: semaglutide ROR 94.534, liraglutide ROR 4.519","confidence_interval":"95% CI: 1.305-1.816 (semaglutide HR); 95% CI: 1.080-1.450 (liraglutide HR)","p_value":null,"sample_size":null,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: the abstract gives no age, BMI or diabetes data for the pooled populations; type 2 diabetes and obesity appear only as the drugs' uses in the background, which is not a description of who was studied.","mediation":"possibly","mediation_notes":"No weight, HbA1c or mediation data are reported, so under the default rule the NAION association cannot be separated from weight or glycaemic change. The network-toxicology and docking steps propose molecular targets but do not test mediation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"non-GLP-1RA treatments\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CIs reported for the pooled HRs and the FAERS RORs; number of included studies, participants and events not stated in the abstract\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: the headline result is a pooled network meta-analysis, but the abstract does not say which studies were pooled (hazard ratios suggest observational cohorts), how many, or how large, so it is not credited as a meta-analysis of trials. The FAERS step is pharmacovigilance (VERY_LOW on its own) and the network-toxicology and docking steps are computational, so they do not raise the tier.","funding_source":"Young Clinical Scientist Training Program at Shanghai Medical College of Fudan University","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"NAION risk raised for semaglutide (HR 1.538) and liraglutide (HR 1.251) against non-GLP-1RA treatments in the network meta-analysis; strong FAERS signal for semaglutide (ROR 94.534) and a weaker significant signal for liraglutide (ROR 4.519)","limitations":"Abstract only: it does not say which studies or designs were pooled, how many participants or events there were, or who the populations were. The FAERS step is a spontaneous-report disproportionality signal that cannot give incidence or show causation, and the network-toxicology and docking steps are computational, not clinical evidence.","plain_summary":"This paper combined a network meta-analysis of earlier studies, an analysis of reports to the US FDA's adverse event database, and computer modelling to compare the risk of NAION, a sudden loss of blood supply to the optic nerve that can cost vision, across GLP-1 drugs. Against non-GLP-1 treatments, semaglutide was linked to the highest risk (hazard ratio 1.538) and liraglutide to a smaller raised risk (1.251), and both drugs were reported more often than expected in the FDA database (reporting odds ratios 94.534 and 4.519). The abstract does not say which studies or how many people were pooled, or who they were, and report databases and computer modelling cannot show that the drugs caused NAION or how often it happens.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":744,"doi":"10.1007/s00592-026-02778-2","pmid":"42766134","nct_ids":"[]","title":"Modulation of circulating osteocalcin-expressing monocytes by glucagon like peptide-1 receptor agonists in type 2 diabetes: an exploratory pilot study","authors":"[\"Carafa A\", \"Sessa RL\", \"Amendolara R\", \"Zampetti S\", \"Mignogna C\", \"Sciarra F\", \"D'Onofrio L\", \"Risi R\", \"Venneri MA\", \"Cavallari I\", \"Maddaloni E\", \"Buzzetti R\"]","journal":"Acta diabetologica","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[CONTEXT] The phenotypic drift of circulating monocytes toward osteoblast-like cells expressing osteocalcin (OCN) has been linked to vascular calcification in individuals with type 2 diabetes (T2D). The synergistic action of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and metformin may reduce the cardiovascular risk by modulating OCN-expressing monocytes, representing a novel mechanism of cardiovascular protection. [OBJECTIVE] To investigate the impact of GLP-1 RA add-on metformin therapy on the percentage of circulating CD14+OCN+ monocytes. [RESEARCH DESIGN AND METHODS] This longitudinal study enrolled patients with T2D receiving metformin monotherapy who either initiated GLP-1 RA therapy (Group A, n = 7) or did not (Group B, n = 28). Clinical parameters and circulating CD14+OCN+ cell levels were assessed at baseline (V0), after 1 week (V1) and after 12 weeks (V2). In vitro experiments were conducted using peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 10), treated with metformin or exendin-4 for 24 h. [RESULTS] In group A, the percentage of CD14+OCN+ significantly decreased from baseline (4.5 [2.5-7.6]) to V2 (2.2 [1.73-4.9]% p = 0.019). This reduction was already significant at V1 (p = 0.039). No significant change over time was observed in Group B (p = 0.31). In vitro treatment of PBMCs with metformin significantly reduced the percentage of CD14+OCN+ cell (- 34.9%, p < 0.0001), whereas exendin-4 yielded a non-significant downward trend (- 8.5%, p = 0.1). [CONCLUSION] GLP-1 RA add-on therapy to metformin reduces OCN expression in circulating monocytes in patients with T2D. In vitro data suggest that this effect might not result from a direct effect on mononuclear cells, but rather from indirect systemic mechanisms that warrant further investigation. These findings identify OCN-expressing monocytes as a potential novel therapeutic target for GLP-1 RA to reduce cardiovascular risk in T2D.","url":"https://pubmed.ncbi.nlm.nih.gov/42766134/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: LDO declare receipt of honoraria from Eli-Lilly. EM and RB declare receipt of honoraria for consultancy/speaker fee from Eli-Lilly, AstraZeneca and NovoNordisk. All other authors report no conflicts of interests related to this manuscript.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"cellular_in_vitro","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":754,"doi":"10.1111/dom.71371","pmid":"42768825","nct_ids":"[]","title":"Oral Semaglutide in Routine Clinical Practice: 24-Month Real-World Effectiveness, Persistence and Safety in Adults With Type 2 Diabetes","authors":"[\"Baldassarre MPA\", \"Di Dalmazi G\", \"Carrieri F\", \"Centorame G\", \"Piacentino L\", \"Coluzzi S\", \"Formoso G\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Real-world long-term data on oral semaglutide are limited. We evaluated its 24-month effectiveness, persistence, and safety in adults with type 2 diabetes (T2D). [MATERIALS AND METHODS] This retrospective real-world study included 232 adults with T2D initiating oral semaglutide at an Italian diabetes clinic. Changes in HbA1c, body weight, eGFR, urinary albumin-to-creatinine ratio (UACR) and lipid profile were assessed using linear mixed models. The composite endpoint of HbA1c ≤ 7% and ≥ 5% weight loss was assessed over follow-up. Treatment persistence was evaluated by Kaplan-Meier analysis, and predictors of discontinuation by multivariable Cox regression with time-dependent covariates. HbA1c and body weight before and after switching to another GLP1 receptor agonist were also evaluated. [RESULTS] Over 24 months, oral semaglutide significantly reduced HbA1c (-0.8%; p < 0.0001) and body weight (-5.7 kg; p < 0.0001). The composite endpoint was progressively achieved by 44.0% of individuals at 24 months. Non-breakfast administration was independently associated with lower HbA1c after adjustment for BMI, age and sex (β = -0.32; p = 0.041). eGFR and UACR remained stable while total and LDL cholesterol decreased significantly (both p < 0.0001). Treatment persistence at 24 months was 68.5% (mean 19.4 months). Among discontinuers, switching to another GLP1 receptor agonist was the most common strategy (36.2%) and resulted in a further HbA1c reduction (Δ = -0.98%; p = 0.005). No safety concerns emerged. [CONCLUSIONS] In this real-world cohort, oral semaglutide provided sustained improvements in glycaemic control, body weight, and lipid profile, with preserved renal function and high treatment persistence over 24 months.","url":"https://pubmed.ncbi.nlm.nih.gov/42768825/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:13+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"kidney\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":755,"doi":"10.1053/j.ajkd.2026.06.013","pmid":"42767321","nct_ids":"[]","title":"Safety of Sodium/Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes and CKD","authors":"[\"Ortega-Montiel J\", \"Alkabbani W\", \"Hahn G\", \"Liu J\", \"Byrne CF\", \"Wexler DJ\", \"Patorno E\", \"Paik JM\"]","journal":"American journal of kidney diseases : the official journal of the National Kidney Foundation","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[RATIONALE & OBJECTIVE] Patients with chronic kidney disease (CKD) are often underrepresented in clinical trials evaluating the safety profile of newer medication classes for type 2 diabetes (T2D). Given the high burden of comorbidities and polypharmacy in this population, further safety research is needed. This study aimed to detect potential adverse events associated with sodium/glucose cotransporter 2 (SGLT2) inhibitors in patients with T2D and CKD, using a tree-based scan statistic approach. [STUDY DESIGN] New-user active comparator cohort study. [SETTING & PARTICIPANTS] Medicare Fee-for-service data (October 2016 - December 2020) and the Merative MarketScan commercial claims database (October 2016 - December 2022) used to identify patients aged ≥65 years (Medicare) or ≥18 years (MarketScan) with T2D and CKD (Stages III-IV). [EXPOSURES] New use of SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RA). [OUTCOMES] ICD-10 coded adverse outcome events, in outpatient, inpatient, or emergency department settings. [ANALYTIC APPROACH] After 1:1 propensity-score matching, a hierarchical data-mining surveillance method using ICD-10 outcomes, a tree-based scan statistic, to identify signals for incident adverse events. [RESULTS] We identified 22,328 matched pairs in Medicare (mean age, 74 years; 45% female) and 8,918 matched pairs in MarketScan (mean age, 65 years; 42% female). In both cohorts, based on outpatient diagnosis codes, SGLT2 inhibitor initiation showed safety signals for genital infections in both females and males (p < 0.001). However, the tree-based scan statistic did not detect any safety signals based on inpatient/ED diagnosis codes. [LIMITATIONS] Residual confounding, potential misclassification, and limited power. [CONCLUSIONS] In two large real-world cohorts of patients with T2D and CKD, the tree-based scan statistic identified previously known adverse events, but no new safety signals associated with SGLT2 inhibitor use compared with GLP-1RA use.","url":"https://pubmed.ncbi.nlm.nih.gov/42767321/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":787,"doi":"10.1111/dom.71373","pmid":"42768828","nct_ids":"[]","title":"Real-World Adverse Event Reporting Patterns of Tirzepatide Versus Semaglutide: A Stratified Study of General and Healthcare Professional Cohorts in FAERS","authors":"[\"Liu X\", \"Wang W\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Both the GLP-1 receptor agonist semaglutide and the novel dual GIP/GLP-1 receptor agonist tirzepatide have emerged as first-line therapeutic options for metabolic diseases. However, their real-world comparative safety profiles are difficult to interpret due to differential reporting composition in spontaneous reporting databases. This study compared their post-marketing adverse event (AE) reporting patterns and examined how reporter identity influences signal prominence. [METHODS] AE reports (May 2022-June 2026) from FAERS were analysed using ROR, PRR, information component (IC) and empirical Bayes geometric mean (EBGM); a signal required simultaneous four-method convergence; additionally, the Benjamini-Hochberg false discovery rate (FDR) procedure was used to ensure signal robustness against multiple testing. Head-to-head comparisons used the ratio of reporting odds ratios (RORR) with 95% CIs, run in parallel across general population and healthcare professional (HCP)-restricted subset, with sensitivity analyses by indication, seriousness, geography and calendar quarter. [RESULTS] A total of 151 654 tirzepatide and 64 987 semaglutide reports were analysed (HCP: 5.04% vs. 23.42%). Only semaglutide met four-method criteria for gastrointestinal (ROR 3.64) and metabolic (ROR 4.25) disorders in the general population (GI RORR 0.58, 95% CI 0.57-0.59). Pancreatitis signalled for both agents but attenuated to equivalence within T2DM (RORR 0.98, 95% CI 0.83-1.15). Diabetic ketoacidosis signalled exclusively for semaglutide in the HCP cohort (ROR 3.52); tirzepatide showed higher hypoglycaemia reporting (RORR 1.91, 95% CI 1.49-2.44). In the HCP cohort, tirzepatide GI ROR rose to 2.53 and semaglutide acquired eye disorder reporting signals (ROR 2.61). All sensitivity analyses (stratified by indication, seriousness, geography restriction and calendar quarter) confirmed directional stability of these comparative reporting patterns across subgroups. [CONCLUSION] This FAERS-based analysis identifies distinct AE reporting patterns between tirzepatide and semaglutide that are sensitive to reporter type; all findings are hypothesis-generating and require confirmation with defined exposure denominators.","url":"https://pubmed.ncbi.nlm.nih.gov/42768828/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:34+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":788,"doi":"10.1016/j.clindermatol.2026.09.017","pmid":"42767469","nct_ids":"[]","title":"Hair and Scalp Effects of GLP-1 Receptor Agonists in Practice","authors":"[\"Bridges AG\", \"Jackson T\"]","journal":"Clinics in dermatology","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Hair loss is an emerging and clinically significant adverse effect associated with glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy, occurring in approximately 3%-5% of treated patients across pivotal clinical trials, with a pooled risk ratio of approximately 3.3 compared with placebo. The predominant mechanism is telogen effluvium (TE) secondary to rapid weight loss and caloric restriction, though direct effects on the hair follicle via GLP-1 receptor expression in dermal white adipose tissue (dWAT), hormonal shifts, and nutritional insufficiency also contribute. Pharmacovigilance data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and large real-world cohort studies further support a clinically meaningful signal. This chapter reviews the epidemiology and agent-specific differences in GLP-1 RA-associated alopecia, the pathophysiologic mechanisms, potential beneficial effects on androgenetic alopecia (AGA) and cicatricial conditions, and a systematic approach to clinical evaluation and management. Management strategies include nutritional optimization with protein targets of 1.2-2.0 g/kg/day based on adjusted body weight, patient counseling on the anticipated time course of hair shedding, and pharmacologic options including low-dose oral minoxidil. The hair loss profile of GLP-1 RAs is compared with that of bariatric surgery, where pooled incidence ranges from 47%-57%. Practical guidance for the clinician is provided throughout.","url":"https://pubmed.ncbi.nlm.nih.gov/42767469/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare no conflicts of interest relevant to this chapter.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:34+00:00","study_design":"pharmacovigilance","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"body_composition\", \"adverse_effects\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":794,"doi":"10.64898/2026.09.18.26363449","pmid":null,"nct_ids":"[]","title":"GLP-1 Receptor Agonists, Stroke, and Cognitive Outcomes: Systematic Review and Meta-Regression","authors":"[\"Danielli M\", \"Sibal R\", \"Collett G\", \"Awan H\", \"Sharma C\", \"Steckelmacher J\", \"Kennedy C\", \"Gupta A.\"]","journal":"preprint server","publication_date":"2026-09-21","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Importance</h4>  Randomised-controlled trials (RCTs) suggest glucagon-like-peptide-1 receptor agonists (GLP-1RAs) reduce the risk of stroke in type 2 diabetes (T2DM); however, the mechanisms remain unclear. If benefits were driven principally by blood pressure (BP) lowering, similar effects on cognitive impairment may be expected. Evaluating data from trials with robust ascertainment and prespecified stroke and/or cognitive outcomes may provide greater clarity. <h4>Objective</h4>  To confirm the effect of GLP-1RAs on stroke risk in RCTs with prespecified, adjudicated stroke endpoints; to explore whether risk reduction is associated with trial-level changes in systolic BP (SBP), glycated haemoglobin (HbA1c), or body weight; to establish whether a parallel cognitive signal exists. <h4>Data Sources</h4>  PubMed, Cochrane, Embase, and CINAHL, from inception to August 2026 (PROSPERO CRD420261305938). <h4>Study Selection</h4>  RCTs comparing GLP-1RAs with placebo/usual care in adults, with ≥12 months follow-up, and prespecified stroke and/or cognitive outcomes. <h4>Data Extraction and Synthesis</h4>  Hazard ratios (HRs) for stroke were pooled using inverse-variance random-effect meta-analysis. Univariable meta-regression related logHR for stroke to trial-level between-group differences in SBP, HbA1c and weight, with permutation-based inference and leave-one-out sensitivity analyses. The pooled effect was benchmarked against that predicted from achieved SBP differences. Heterogeneous cognitive outcomes were synthesized narratively. <h4>Main Outcomes and Measures</h4>  Adjudicated stroke events and prespecified cognitive endpoints. <h4>Results</h4>  Among 7 RCTs (n=50,617), GLP-1RA therapy was associated with 17% lower stroke risk (pooled HR 0.83; [95% CI 0.75-0.92]; p<.001). Meta regression showed an association with SBP (β = 0.371; [95% CI 0.013-0.729]; p=.043), but not HbA1c (0.432; [-0.064-0.928]; p=.088) or weight (0.109; [-0.038-0.256]; p=.148). The mean between-group SBP difference (∼1.45 mmHg) predicts a stroke reduction of roughly 4%, versus the 17% observed, leaving approximately three quarters of the log-effect unexplained by BP lowering. Four trials (n=4,206) in established neurodegenerative disease showed no cognitive benefit. <h4>Conclusions and Relevance</h4>  GLP-1RA therapy reduces stroke risk by 17% among individuals with T2DM at high cardiovascular risk, a benefit not fully accounted for by conventional cardiometabolic risk factor change. Additional mechanisms warrant evaluation. The absence of cognitive signal suggests the benefit may have cerebrovascular origin, but whether GLP-1RAs prevent vascular cognitive impairment in cardiometabolic populations remains untested.","url":"https://doi.org/10.64898/2026.09.18.26363449","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"placebo/usual care\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"cognition\", \"neuroinflammation\", \"metabolic\"]","outcome_type":"hard","primary_outcome":"adjudicated stroke events and prespecified cognitive endpoints","endpoints":null,"effect_estimate":"Stroke pooled HR 0.83 (17% lower risk) in 7 RCTs; meta-regression associated with SBP (β = 0.371) but not HbA1c (0.432) or weight (0.109); four trials in established neurodegenerative disease showed no cognitive benefit","confidence_interval":"95% CI 0.75-0.92","p_value":"p<.001","sample_size":50617,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes (stroke trials); not reported for the cognitive trials\", \"cvd_status\": \"high cardiovascular risk (stroke trials)\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes at high cardiovascular risk (stroke trials); established neurodegenerative disease (cognitive trials)\", \"sample_size\": 50617, \"inclusion_exclusion\": \"RCTs of GLP-1RAs vs placebo/usual care in adults, ≥12 months follow-up, prespecified stroke and/or cognitive outcomes\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the stroke trials enrolled people with type 2 diabetes at high cardiovascular risk, and the cognitive trials people with established neurodegenerative disease; no BMI or age data.","mediation":"possibly","mediation_notes":"Possibly: a trial-level meta-regression linked the stroke effect to systolic blood pressure differences but not to HbA1c or weight, and the authors estimate blood pressure lowering explains only part of it. A between-trial meta-regression is not a participant-level mediation analysis (owner ruling N3 is consistent with both passes).","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 50617, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo/usual care\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0.75-0.92\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"PRELIMINARY: a meta-analysis of 7 RCTs with a pooled hard outcome, posted as a preprint and not yet peer reviewed.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"A preprint whose mechanism analysis is a between-trial meta-regression over few trials; cognitive outcomes were synthesised only narratively, in trials of people with established neurodegenerative disease.","plain_summary":"This preprint systematic review pooled 7 randomised trials (n=50,617) of GLP-1 receptor agonists, mostly in people with type 2 diabetes at high cardiovascular risk. The drugs were associated with 17% lower stroke risk (pooled HR 0.83; 95% CI 0.75-0.92), only partly explained by blood-pressure differences between trials. Four trials in people with established neurodegenerative disease showed no cognitive benefit.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1178,"doi":"10.1016/j.soard.2026.09.014","pmid":"42907282","nct_ids":"[]","title":"Metabolic bariatric surgery versus GLP-1 receptor agonists in dialysis patients with diabetes and obesity: a target trial emulation study","authors":"[\"Gao C\", \"Menon G\", \"Chen Y\", \"Li Y\", \"Bae S\", \"Lonze BE\", \"Ren-Fielding CJ\", \"Chhabra KR\", \"Segev DL\", \"McAdams-DeMarco MA\", \"Orandi BJ\"]","journal":"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery","publication_date":"2026-09-21","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic and bariatric surgery (MBS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for obesity and type 2 diabetes, but their comparative survival and waitlisting benefits in end-stage kidney disease (ESKD) remain unclear. [OBJECTIVES] To compare survival and kidney transplant (KT) waitlisting after MBS and GLP-1RA use among patients with ESKD, using dipeptidyl peptidase-4 inhibitors (DPP-4is) as an active comparator. [SETTING] US Renal Data System, 2010-2022. [METHODS] We included adults with ESKD, type 2 diabetes, and ≥class II obesity treated with MBS, GLP-1RA, or DPP-4i. Three target trials were emulated: MBS versus GLP-1RA (N = 1818), MBS versus DPP-4i (N = 2111), and GLP-1RA versus DPP-4i (N = 4338). Cox models estimated adjusted hazard ratios (aHRs) for all-cause mortality and KT waitlisting over 1-5 years. [RESULTS] MBS recipients were younger at dialysis initiation than matched GLP-1RA and DPP-4i users. MBS was associated with higher short-term mortality than matched GLP-1RA (1-year aHR = 2.68, 95% confidence interval [CI]:1.98-3.63; 3-year aHR = 1.34, 95% CI: 1.09-1.64) and DPP-4i users (1-year aHR = 1.74, 95% CI: 1.35-2.25), but comparable longer-term mortality. GLP-1RA users had consistently lower mortality than matched DPP-4i users. MBS was associated with higher KT waitlisting than GLP-1RA and DPP-4i use, with no differences between GLP-1RA and DPP-4i users. [CONCLUSIONS] Among patients with ESKD, type 2 diabetes, and obesity, MBS was associated with higher short-term but comparable long-term mortality, whereas GLP-1RA use was associated with lower mortality than DPP-4i use. MBS was also associated with higher KT waitlisting than GLP-1RA and DPP-4i use, suggesting distinct risk-benefit profiles of metabolic treatment in this high-risk population.","url":"https://pubmed.ncbi.nlm.nih.gov/42907282/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosures DL Segev receives consulting fees from AstraZeneca, CareDx, Moderna Therapeutics, Medscape, Novavax, Regeneron, Springer Publishing, Hansa, Optum, OrgonOx, and Roche. DL Segev also receives honoraria from AstraZeneca, CareDx, Houston Methodist, Northwell Health, Optum Health Education, Sanofi, WebMD, Roche, and ASN. DL Segev is the editor of and receives payment from Springer. KR Chhabra has received payments from GI Windows Surgical and Olympus unrelated to the submitted work. BJ Orandi is on the editorial board for Obesity and has served on an advisory board for Boehringer Ingelheim. The remaining authors have no conflicts of interest to declare.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":747,"doi":"10.1111/dom.71334","pmid":"42764409","nct_ids":"[]","title":"Sex and Socioeconomic Differences in the Initiation of SGLT2 Inhibitors and GLP-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Nationwide Cohort Study","authors":"[\"Calderon E\", \"Bjerg L\", \"Isaksen AA\", \"Sandbæk A\", \"Funck KL\", \"Grove EL\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Cardioprotective glucose-lowering drugs (GLDs) remain underutilised in individuals with Type 2 diabetes (T2D) and cardiovascular disease (CVD). We aimed to estimate the association between sex and socioeconomic status and initiation of cardioprotective GLDs and to identify factors associated with non-initiation of cardioprotective GLDs. [MATERIALS AND METHODS] Using Danish health registries, we identified individuals with both T2D and CVD between 2015 and 2022. Initiation of cardioprotective GLDs, sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) were assessed by sex and socioeconomic status. We estimated crude cumulative proportions, incidence rates (IR) and adjusted incidence rate ratios (IRR). Risk factors for non-initiation were analyzed using poisson regression. [RESULTS] Among 81 361 individuals with newly diagnosed concomitant T2D and CVD (37% women), crude initiation rates of GLDs per 1000 person-years increased with higher educational level. This gradient disappeared after multivariable adjustment, with IRRs for females 0.95 (95% CI: 0.86-1.05) and males 1.00 (95% CI: 0.94-1.07). Marital and occupational status showed clear associations: compared with employed women, IRRs for initiation were 0.81 (95% CI: 0.75-0.88) for unemployed and 0.88 (95% CI: 0.79-0.97) for retired women. Compared with employed men, IRRs for unemployed and retired men were 0.77 (95% CI: 0.73-0.81) and 0.83 (95% CI: 0.78-0.88), respectively. Divorced, widowed and unmarried individuals also had lower IRR than married individuals. [CONCLUSION] Among individuals with newly diagnosed T2D and CVD, lower initiation of guideline-recommended cardioprotective GLDs was observed among individuals with low socioeconomic status in both men and women.","url":"https://pubmed.ncbi.nlm.nih.gov/42764409/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":765,"doi":"10.1111/dom.71323","pmid":"42764399","nct_ids":"[\"NCT05646706\"]","title":"Effect of Semaglutide on Thigh Skeletal Muscle Volume, Fat Infiltration and Physical Function in People With Obesity: Secondary Analysis of STEP UP","authors":"[\"Hjelmesæth J\", \"Bhat S\", \"Garvey WT\", \"Kolnes KJ\", \"Linge J\", \"Lingvay I\", \"Rasmussen NK\", \"Rosenstock J\", \"Wharton S\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To assess the effect of semaglutide on body composition and physical function. [MATERIALS AND METHODS] The phase 3b STEP UP trial randomised adults with body mass index ≥ 30 kg/m2 to once-weekly subcutaneous semaglutide 7.2 mg, semaglutide 2.4 mg or placebo for 72 weeks. This prespecified secondary analysis assessed changes in MRI body composition and physical function. [RESULTS] Of 1407 participants, 55 with a valid baseline scan were included (semaglutide 7.2 mg, n = 43, 2.4 mg, n = 6 [pooled semaglutide group, n = 49]; placebo, n = 6). Estimated treatment differences (95% confidence intervals; p-values) for absolute changes in adipose/muscle compartment volumes for the pooled semaglutide versus placebo group, respectively, were: -11.1 L (-16.5 to -5.7; p < 0.0001) for adipose body tissue, -1.5 L (-2.9 to -0.1; p = 0.04) for visceral adipose tissue, -1.7 L (-4.0 to 0.7; p = 0.16) for lean body tissue, -1.1 L (-2.3 to 0.1; p = 0.07) for thigh skeletal muscle volume and -0.92%-points (-1.41 to -0.42; p = 0.001) for thigh muscle fat infiltration. Similar results were seen for relative changes in adipose/muscle compartment volumes. A sensitivity analysis for the semaglutide 7.2 mg group versus placebo showed similar results. A mean of 13 sit-to-stand repetitions in 30 s at baseline, and 15 repetitions at Week 72, was observed in the pooled semaglutide and placebo groups. [CONCLUSIONS] Semaglutide plus lifestyle intervention was associated with reductions in adipose tissue volume, skeletal muscle volume and skeletal muscle fat infiltration, with a preserved number of sit-to-stand repetitions. Further research to assess the impact of weight loss on skeletal muscle composition and function should be explored in the future. [TRIAL REGISTRATION] ClinicalTrials.gov identifier NCT05646706.","url":"https://pubmed.ncbi.nlm.nih.gov/42764399/","source_name":"pubmed","source_tier":1,"coi_statement":"Jøran Hjelmesæth has received fees or honoraria for academic presentations from Novo Nordisk A/S, Eli Lilly & Co, VIVUS, and AstraZeneca; and has received fees or honoraria to participate on advisory boards for Novo Nordisk, Eli Lilly & Co, and VIVUS, with all payments made to his institution since 2024. Suhas Bhat is an employee of Novo Nordisk. W. Timothy Garvey has received grants as a principal investigator from Novo Nordisk, Eli Lilly & Co, Pfizer, Epitomee, Neurovalens, Zealand, Carmot/Roche, Terns Pharmaceuticals, Viking Therapeutics, and Pfizer, and for research from the UAB Diabetes Research Center (DK079626) funded by the US National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases, with all payments made to his institution; has received consulting fees as an advisory board member from Boehringer Ingelheim, Eli Lilly & Co, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Allurion, Carmot/Roche, Terns Pharmaceuticals, Neurocrine, KEROS Therapeutics, Gan & Lee, NodThera, and Regeneron; has received fees to participate on a data safety monitoring board or advisory board for Boehringer Ingelheim and Eli Lilly & Co; and is an unpaid member of ","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T17:07:09+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"7.2 mg or 2.4 mg once weekly (pooled for the main analysis)\", \"route\": \"subcutaneous\", \"comparator\": \"placebo (both groups with lifestyle intervention)\", \"treatment_duration\": \"72 weeks\"}","domains":"[\"muscle\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"changes in MRI body composition (adipose, lean, visceral fat, thigh muscle volume and fat infiltration) and sit-to-stand repetitions","endpoints":null,"effect_estimate":"Pooled semaglutide vs placebo: adipose body tissue -11.1 L (p < 0.0001), visceral adipose tissue -1.5 L (p = 0.04), thigh muscle fat infiltration -0.92%-points (p = 0.001); lean body tissue -1.7 L (p = 0.16) and thigh skeletal muscle volume -1.1 L (p = 0.07), not significant; sit-to-stand repetitions similar in both groups (13 at baseline, 15 at Week 72)","confidence_interval":"95% CIs: adipose body tissue -16.5 to -5.7; visceral adipose tissue -2.9 to -0.1; lean body tissue -4.0 to 0.7; thigh skeletal muscle volume -2.3 to 0.1; thigh muscle fat infiltration -1.41 to -0.42","p_value":"p < 0.0001 (adipose body tissue); p = 0.04 (visceral adipose tissue); p = 0.16 (lean body tissue); p = 0.07 (thigh skeletal muscle volume); p = 0.001 (thigh muscle fat infiltration)","sample_size":55,"follow_up":"72 weeks","direction":"mixed","population":"{\"mean_age\": \"45 (SD 12) years\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"78.2% female (43 of 55)\", \"bmi_mean\": 39.3, \"bmi_min\": 30, \"obesity_status\": \"obesity required (BMI ≥ 30 kg/m2)\", \"diabetes_status\": \"excluded (history of type 1 or type 2 diabetes, or HbA1c ≥ 6.5%); 38.2% had prediabetes\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity (BMI ≥ 30 kg/m2)\", \"sample_size\": 55, \"inclusion_exclusion\": \"adults with BMI ≥ 30 and at least one unsuccessful dietary weight-loss effort; diabetes excluded; MRI subpopulation: bodyweight < 149 kg, no metal implants, suitable for MRI\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (BMI ≥ 30 kg/m2; mean BMI 39.3) and mean age was 45; diabetes was excluded.","mediation":"not_applicable","mediation_notes":"The outcomes are body composition measures (with a sit-to-stand test), so weight-loss mediation is not applicable. The semaglutide group lost 19.5 kg against 0.4 kg on placebo; the authors note sit-to-stand change may reflect body-weight loss more than muscle function.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 55, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (both groups with lifestyle intervention)\", \"follow_up_duration\": \"72 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported; 55 analysed (pooled semaglutide n = 49, placebo n = 6); the authors call the analyses exploratory owing to the small placebo group\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: randomized, double-blind and prespecified, but the analysis covers 55 of 1407 trial participants with only 6 on placebo, outcomes are intermediate (MRI body composition, sit-to-stand), and the authors call the results exploratory and hypothesis generating: a small randomized comparison.","funding_source":"Novo Nordisk A/S","industry_funded":"yes","manufacturer":"Novo Nordisk A/S","author_conflicts":"Three authors are Novo Nordisk employees (two also hold shares); one is an employee and shareholder of AMRA Medical; the others report grants, honoraria, advisory or consulting fees from Novo Nordisk, Eli Lilly and many other companies.","sponsor_role":"Novo Nordisk A/S funded the study and paid for medical writing; the data analysis was performed by an author (S.B.) who is a Novo Nordisk employee; all authors had full data access and final responsibility for submission.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Adverse events in 95.3% (7.2 mg), 83.3% (2.4 mg) and 66.7% (placebo); gastrointestinal events in 86.0%, 50.0% and 33.3%; musculoskeletal and connective tissue events in 7.0% of the 7.2 mg group and none in the other groups","limitations":"A small secondary analysis of one trial's MRI subgroup (only 6 on placebo) with limited power, which the authors call exploratory; participants were mostly female, White and relatively young, and MRI covered only T9 to the knees, so lean mass loss is likely underestimated.","plain_summary":"In an MRI substudy of the randomised STEP UP trial, 55 adults with obesity (mean age 45) received weekly semaglutide (7.2 mg or 2.4 mg) or placebo, alongside diet and activity advice, for 72 weeks. Compared with placebo, semaglutide was linked to larger falls in body fat, visceral fat and fat within the thigh muscle. Lean tissue and thigh muscle volume also fell, but the differences from placebo were not statistically significant, and sit-to-stand repetitions were similar in both groups. Only 6 people were on placebo, so the authors treat the results as exploratory.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":793,"doi":"10.21203/rs.3.rs-10951421/v1","pmid":null,"nct_ids":"[]","title":"Duration of GLP-1 Receptor Agonist Therapy and Nephrolithiasis Risk in Type 2 Diabetes: A Multicenter Retrospective Cohort Study","authors":"[\"Othman L\", \"Nguyen A\", \"Kassim A\", \"DiGiovanni A\", \"Niranchchan S\", \"Khosla L\", \"Amasyali AS.\"]","journal":"preprint server","publication_date":"2026-09-20","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>Purpose  Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycemic control and metabolic health, but their association with nephrolithiasis remains poorly defined. We evaluated the relationship between GLP-1 RA exposure duration and incident nephrolithiasis among adults with type 2 diabetes mellitus (T2DM). Methods  Using the TriNetX Research Network, adults with T2DM were stratified according to GLP-1 RA exposure as no exposure, < 1 year, 1–3 years, or 3–5 years. Patients with chronic kidney disease, prior nephrolithiasis, bariatric surgery, or prior sodium-glucose cotransporter-2 inhibitor exposure were excluded. Pairwise propensity score matching and time-to-event analyses were performed. Two complementary analyses were conducted: a broader T2DM cohort evaluating nephrolithiasis risk across GLP-1 RA exposure durations and a secondary cohort restricted to patients with at least 5 years of established T2DM. Results  In the broader T2DM cohort, shorter GLP-1 RA exposure was associated with higher nephrolithiasis risk. No exposure was associated with greater risk than < 1 year of exposure (HR 1.037, 95% CI 1.010–1.065; p = 0.006), < 1 year was associated with greater risk than 1–3 years (HR 1.071, 95% CI 1.008–1.138; p = 0.028), and 1–3 years was associated with greater risk than 3–5 years (HR 1.189, 95% CI 1.075–1.315; p = 0.001). In the cohort restricted to patients with at least 5 years of T2DM, no significant differences were observed among the longer GLP-1 RA exposure-duration comparisons, indicating the absence of a progressive duration-response relationship in patients with established diabetes. Conclusion  Longer GLP-1 RA exposure was associated with lower nephrolithiasis risk in the broader T2DM population. However, this duration-response relationship was not observed among patients with at least 5 years of established T2DM. These findings suggest that the association between GLP-1 RA exposure duration and nephrolithiasis may differ according to diabetes chronicity and warrant prospective investigation.</p>","url":"https://doi.org/10.21203/rs.3.rs-10951421/v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":541,"doi":"10.1016/j.taap.2026.118045","pmid":"42763059","nct_ids":"[]","title":"Reprogramming NAD+ homeostasis and FOXO3a-Nrf2 signaling mitigates bleomycin-driven pulmonary fibrosis","authors":"[\"Mo'men M\", \"Saber S\", \"Amer AE\", \"El-Kashef HA\"]","journal":"Toxicology and applied pharmacology","publication_date":"2026-09-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Pulmonary fibrosis arises from intertwined oxidative, inflammatory, and profibrotic processes, whereas current therapies target only parts of this network. Here, we evaluated an adjunctive strategy in which nicotinic acid (NA), a NAD+-supporting supplement/adjuvant, was added to semaglutide (SEMA), a GLP-1 receptor agonist. The prespecified objective was to determine whether adding NA to SEMA provides greater protection than SEMA alone in bleomycin (BLM)-induced pulmonary fibrosis. Rats were challenged with BLM and treated with SEMA, NA, or SEMA+NA for 21 days. Biochemical, molecular, histological, and western blot endpoints were assessed, and the fixed-dose Highest Single Agent (HSA) and Bliss independence models were used as exploratory interaction metrics. BLM induced oxidative stress, inflammatory cytokine elevation, NAD+ and SIRT1 depletion, FOXO3a suppression, TGF-β/SMAD activation, and collagen deposition. Compared with SEMA alone, SEMA+NA produced broader protection, restoring NAD+/SIRT1-FOXO3a-Nrf2 pathway-associated readouts and suppressing NF-κB/TGF-β-linked inflammatory and fibrotic markers. Exploratory HSA and Bliss analyses suggested enhanced fixed-dose effects across several endpoints but were interpreted descriptively, not as definitive pharmacological synergy. These findings indicate that NA-driven NAD+ metabolic support can amplify the protective profile of SEMA in experimental pulmonary fibrosis. Dose-response matrices, pathway-inhibition studies, temporal profiling, and lung-function testing remain required to establish definitive synergy, mechanism, and translational relevance.","url":"https://pubmed.ncbi.nlm.nih.gov/42763059/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:06+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":604,"doi":"10.1016/j.neubiorev.2026.106990","pmid":"42762879","nct_ids":"[]","title":"Central Nervous System Effects of GLP-1 Receptor Agonists: A Systematic Review of Human Neuroimaging Studies","authors":"[\"Brucar LR\", \"Miller KB\", \"Volkow ND\"]","journal":"Neuroscience and biobehavioral reviews","publication_date":"2026-09-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Interest in glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded beyond obesity and diabetes, with growing preclinical and clinical evidence supporting potential applications in psychiatric and neurodegenerative disorders. However, the central nervous system (CNS) mechanisms engaged by GLP-1RAs remain poorly characterized, limiting the capacity to optimize their therapeutic potential. This systematic review synthesized the literature examining GLP-1RA-related CNS effects, focusing on treatment-related neural responsivity, temporal dynamics, and modulators of CNS response. PubMed and Embase were systematically searched from inception to January 2026 for human studies across structural magnetic resonance imaging (MRI), task-based and resting-state functional MRI, molecular imaging, and neurophysiological approaches. Thirty-seven studies met inclusion criteria. The reviewed evidence suggests that GLP-1RAs engage distributed cortical and subcortical brain systems. Attenuation of reward-related responsivity following acute GLP-1RA administration was among the more consistent findings. Notably, evidence suggests that GLP-1RAs differentially modulate reward-related processes rather than uniformly attenuate reward function, with neural effects further varying according to metabolic status and underlying phenotype. Several studies additionally indicated that CNS effects evolve over the course of treatment, with more pronounced neural modulation during short-term treatment and diminished or altered effects following prolonged exposure. However, the current neuroimaging literature is constrained by small sample sizes and methodological heterogeneity, limiting direct comparisons across studies and underscoring the need for greater standardization. This review provides insight into the neurobiological mechanisms engaged by GLP-1RAs, identifies emerging patterns of CNS response with potential implications for mechanistically informed treatment strategies, and highlights key mechanistic considerations and priorities for future neuroimaging research.","url":"https://pubmed.ncbi.nlm.nih.gov/42762879/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Interests The authors declare no competing interest.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"systematic_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": null, \"treatment_duration\": null}","domains":"[\"neuroinflammation\", \"addiction\", \"psychiatric\"]","outcome_type":"biomarker","primary_outcome":"CNS effects of GLP-1RAs on human neuroimaging (neural responsivity, temporal dynamics, modulators of response)","endpoints":null,"effect_estimate":"Qualitative synthesis only: attenuated reward-related responsivity after acute GLP-1RA administration was among the more consistent findings; effects varied with metabolic status and phenotype and changed over treatment; no pooled estimate","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": null, \"inclusion_exclusion\": \"human neuroimaging studies (structural MRI, task and resting-state fMRI, molecular imaging, neurophysiology) of GLP-1RAs\", \"healthy_volunteers\": null, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: a review of human neuroimaging studies; the abstract gives no age, BMI or diabetes data for the participants.","mediation":"possibly","mediation_notes":"No weight or HbA1c changes or mediation analysis reported; the review notes that neural effects varied with metabolic status, which is not a test of mediation.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"n/a\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"no pooled estimate or CI reported; qualitative synthesis of small, heterogeneous studies\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a systematic review with a qualitative synthesis and no pooled estimate adds no new primary outcome data.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Qualitative systematic review with no pooled estimate; the authors note small sample sizes and methodological heterogeneity across the neuroimaging studies, limiting direct comparison.","plain_summary":"Thirty-seven human brain-imaging studies of GLP-1 receptor agonists were included in this systematic review. The most consistent finding was a dampened brain response to reward after a first dose, but effects differed by metabolic status and changed over longer treatment. The studies were small and varied in method, and no results were pooled, so the review describes patterns rather than measuring an effect.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":694,"doi":"10.3390/medsci14050590","pmid":"42783463","nct_ids":"[]","title":"Effects of Liraglutide and Semaglutide on Cardiometabolic Dysregulation and Oxidative Stress in an Experimental Model of Metabolic Syndrome","authors":"[\"Ravić MP\", \"Srejović IM\", \"Andjić MM\", \"Murić MD\", \"Sretenović JZ\", \"Jeremić NS\", \"Milosavljević IM\", \"Vuletić ML\", \"Murić NN\", \"Ravić KR\", \"Bolevich SB\", \"Sergeeva SP\", \"Gorbunov AA\", \"Bolevich SS\", \"Jakovljević VL\", \"Novaković JN\"]","journal":"Medical sciences (Basel, Switzerland)","publication_date":"2026-09-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/OBJECTIVES] Metabolic syndrome (MetS) increases susceptibility to myocardial ischemia/reperfusion (I/R) injury through metabolic disturbance, hypertension, and oxidative stress. This study aimed to compare the effects of liraglutide and semaglutide on post-ischemic cardiac function, oxidative stress, and histomorphological changes in rats with MetS. [METHODS] MetS was induced in male Wistar rats by a high-fat diet followed by low-dose streptozotocin. After confirmation of MetS, animals were treated with saline, liraglutide, or semaglutide for 6 weeks. Blood pressure, glycemia, oral glucose tolerance, and lipid profile were assessed during the protocol. In vivo cardiac function was evaluated by echocardiography, whereas ex vivo I/R injury was induced using the Langendorff technique. Cardiodynamic parameters, coronary flow, oxidative stress markers, and histological changes in the heart, liver, and pancreas were analyzed. [RESULTS] Both liraglutide and semaglutide improved the cardiometabolic profile of MetS rats, with semaglutide showing a more evident effect on body weight control. In the Langendorff model, both treatments improved post-ischemic recovery of myocardial contractility and relaxation during reperfusion. Treated animals also showed a more favorable oxidative stress profile, particularly lower superoxide anion levels and enhanced antioxidant defense. Histologically, both agents attenuated myocardial hypertrophy and collagen deposition, improved hepatic architecture by reducing inflammatory changes, and preserved pancreatic structure with less lipid accumulation and tissue injury. [CONCLUSIONS] Liraglutide and semaglutide exerted significant cardioprotective and tissue-protective effects in experimental MetS complicated by myocardial I/R injury. These findings support their potential in limiting post-ischemic cardiac dysfunction and multiorgan damage in metabolically compromised conditions.","url":"https://pubmed.ncbi.nlm.nih.gov/42783463/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:07+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":580,"doi":"10.1007/s13300-026-01919-8","pmid":"42753116","nct_ids":"[]","title":"Comparing Cardiovascular Outcomes in New Users of Oral Semaglutide Versus Other Noninsulin Glucose-Lowering Therapies Among Adults with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease","authors":"[\"Tan X\", \"Liang Y\", \"Zhong C\", \"Xie L\", \"Guevarra M\", \"Swift C\", \"de Havenon A\"]","journal":"Diabetes therapy : research, treatment and education of diabetes and related disorders","publication_date":"2026-09-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Clinical trials have found semaglutide reduces the risk of major adverse cardiovascular events (MACE) among people with type 2 diabetes (T2D) at high risk of MACE. Less is known about oral semaglutide's impact on real-world cardiovascular risk. [METHODS] This observational cohort study used administrative claims data from Optum's deidentified Clinformatics® Data Mart Database to compare 3-, modified 3-, 5-, modified 5-, and 2-point MACE, ischemic stroke (IS), myocardial infarction (MI), and all-cause and cardiovascular-related death rates among people with T2D and atherosclerotic cardiovascular disease (ASCVD) who initiated oral semaglutide vs other noninsulin glucose-lowering therapies (ONIGLTs). Cardiovascular outcomes were compared between new users of oral semaglutide and propensity score-matched new users of dipeptidyl peptidase 4 inhibitors (DPP4is) or sodium-glucose cotransporter 2 inhibitors (SGLT2is). [RESULTS] Oral semaglutide users (n = 10,878) had risk reductions of 17% and 21% in 3- and modified 3-point MACE, respectively, and significant risk reductions in 5-, modified 5-, and 2-point MACE, IS, and all-cause death vs ONIGLT users (n = 28,639). People who initiated oral semaglutide (n = 7218) had 22% and 24% lower risks of 3- and modified 3-point MACE, respectively, and significantly lower risks of 5- and modified 5-point MACE, IS, and all-cause death vs people who initiated DPP4is (n = 7218). Compared with SGLT2i users (n = 21,572), oral semaglutide users (n = 7491) had 21% and 22% lower risks of 3- and modified 3-point MACE, respectively, and significantly lower risks of 5-, modified 5-, and 2-point MACE. [CONCLUSION] Consistent with clinical trial evidence, oral semaglutide was associated with a lower risk of cardiovascular outcomes among people with T2D and ASCVD in real-world settings.","url":"https://pubmed.ncbi.nlm.nih.gov/42753116/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of Interest: Xi Tan, Yuanjie Liang, Caichen Zhong, Lin Xie, Mico Guevarra, and Caroline Swift are employees of Novo Nordisk Inc. Adam de Havenon reports NIH/NINDS funding, investigator-initiated clinical research funding from AAN, consultant fees from Novo Nordisk, royalty fees from UpToDate, and equity in Titin KM and Certus. Ethical Approval: This study was conducted in accordance with the Declaration of Helsinki. This study involved retrospectively collected deidentified data, which was analyzed without interaction with the human subjects or reidentifying subjects. It was deemed to be exempt from institutional review board (IRB) review as determined by WCG IRB was exempt under 45 CFR § 46.104(d)(4). This study analyzed secondary data from Optum’s deidentified CDM Database data without direct subject contact or intervention; per 45 CFR 46, analyses of secondary, deidentified data are not human subjects research and do not require consent.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":581,"doi":"10.1097/qad.0000000000004624","pmid":"42752515","nct_ids":"[\"NCT04019197\"]","title":"Effects of semaglutide on subclinical cardiovascular health in people with HIV","authors":"[\"Daher J\", \"Koberssy Z\", \"Moussallem N\", \"Wu Q\", \"Sattar A\", \"Fletcher AA\", \"McComsey CM\", \"Funderburg NT\", \"Ailstock K\", \"Eckard AR\"]","journal":"AIDS (London, England)","publication_date":"2026-09-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[DESIGN AND OBJECTIVE] Lipohypertrophy, characterized by central adipose tissue accumulation, is common in people with HIV (PWH) and contributes to cardiometabolic risk. In a recent randomized, double-blind, placebo-controlled phase 2b trial, semaglutide significantly improved weight, total fat, visceral adiposity, blood pressure, glucose metabolism, and lipids over 32 weeks in PWH with lipohypertrophy. This prespecified secondary analysis evaluated semaglutide's effects on subclinical cardiovascular health. [METHODS] Virologically suppressed adults with HIV without known diabetes, receiving stable antiretroviral therapy, with body mass index >25 kg/m2 and increased waist circumference/waist-to-hip ratio were enrolled. Participants were randomized 1 : 1 to semaglutide or placebo for 32 weeks. Pulse wave velocity (PWV) and endothelial peripheral arterial tonometry (endoPAT) assessed arterial stiffness and endothelial function, and coronary artery calcium (CAC) score assessed calcified coronary atherosclerosis. Indirect calorimetry measured resting energy expenditure (REE) and oxygen consumption (VO2). 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated. Analyses followed intention-to-treat principles using sex-adjusted multiplicative regression. [RESULTS] One hundred eight participants (n = 54 semaglutide) were enrolled (median age 53 years; 60% male; 65% non-White; 35% smokers). Semaglutide had no significant effect on PWV, CAC score, reactive hyperemia index, augmentation index, or REE. VO2 showed a downward trend (β -43 ml/min; P = 0.087). At week 32, significant reductions were observed in 10-year ASCVD risk (-32.6%; P = 0.026) and hsCRP (-23.4%; P = 0.02) in the semaglutide group relative to placebo. [CONCLUSION] Semaglutide did not improve subclinical vascular markers over 32 weeks but significantly improved overall cardiometabolic health and cardiovascular disease risk. Longer and larger studies of GLP-1 RAs are indicated in HIV to further assess their effects on long-term cardiovascular disease outcomes. [TRIAL REGISTRATION] NCT04019197.","url":"https://pubmed.ncbi.nlm.nih.gov/42752515/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo\", \"treatment_duration\": \"32 weeks\", \"dose\": null, \"route\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"metabolic\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":"subclinical cardiovascular health: arterial stiffness (PWV), endothelial function (endoPAT) and coronary artery calcium","endpoints":null,"effect_estimate":"No significant effect on PWV, CAC score, reactive hyperemia index, augmentation index or REE; VO2 downward trend (β -43 ml/min; P = 0.087); 10-year ASCVD risk -32.6%; P = 0.026 and hsCRP -23.4%; P = 0.02 vs placebo","confidence_interval":null,"p_value":"P = 0.026 (10-year ASCVD risk); P = 0.02 (hsCRP)","sample_size":108,"follow_up":"32 weeks","direction":"mixed","population":"{\"mean_age\": \"median 53 years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"60% male\", \"bmi_mean\": null, \"bmi_min\": \">25 kg/m2\", \"obesity_status\": \"overweight or obesity required (BMI >25 kg/m2 with increased waist circumference/waist-to-hip ratio)\", \"diabetes_status\": \"excluded (without known diabetes)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"HIV with lipohypertrophy\", \"sample_size\": 108, \"inclusion_exclusion\": \"virologically suppressed adults with HIV on stable antiretroviral therapy, no known diabetes, BMI >25 kg/m2 and increased waist circumference/waist-to-hip ratio\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had HIV with lipohypertrophy and BMI >25 kg/m2 with increased waist circumference; median age 53 years, below the target range.","mediation":"possibly","mediation_notes":"The parent trial reported improved weight, visceral fat, blood pressure, glucose and lipids with semaglutide; this analysis was only sex-adjusted and did not separate those changes from the ASCVD-risk and hsCRP results. Weight loss is not quantified, so possibly rather than likely.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 108, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"32 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; P values only\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a prespecified secondary analysis of a small randomized trial with biomarker and modelled-risk outcomes.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Prespecified secondary analysis of a small, 32-week phase 2b trial in people with HIV and lipohypertrophy; no confidence intervals are reported, and the authors call for longer and larger studies.","plain_summary":"One hundred eight adults with HIV, central fat build-up and a BMI above 25 took part in this secondary analysis of a 32-week placebo-controlled trial. Semaglutide did not change measures of artery stiffness, blood-vessel function or coronary calcium, but it lowered a calculated 10-year heart-disease risk score by 32.6% and the inflammation marker hsCRP by 23.4% compared with placebo. These are markers and risk estimates, not heart attacks or strokes.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":611,"doi":"10.1136/bmjopen-2026-123779","pmid":"42754274","nct_ids":"[]","title":"Semaglutide as adjunct treatment for obesity in adolescents receiving antipsychotic medication (the GOAL trial): protocol for a single-arm, open-label feasibility study","authors":"[\"Giraldi LV\", \"Andersen JT\", \"Jespersen J\", \"Baden CS\", \"Fonvig CE\", \"Riis T\", \"Dalhoff KP\", \"Holm JC\", \"Fink-Jensen A\", \"Pagsberg AK\", \"Christensen MB\", \"Gade C\"]","journal":"BMJ open","publication_date":"2026-09-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Adolescents treated with antipsychotic medication are at increased risk of obesity and metabolic complications, yet evidence-based interventions in this group remain limited. Glucagon-like peptide-1 receptor agonists have demonstrated efficacy in the treatment of obesity in both adults and adolescents. The aim of this trial is to assess the feasibility of a 36-week treatment period with a glucagon-like peptide-1 receptor agonist as an adjunct to standard care in adolescents with antipsychotic-associated obesity, defined as completion from baseline to end of treatment. The findings from this feasibility trial will inform the design and support the scale-up of a subsequent randomised controlled trial. [METHODS AND ANALYSIS] The GOAL trial is a single-arm, open-label feasibility study conducted at Copenhagen University Hospital, Bispebjerg, Denmark, in collaboration with the Child and Adolescent Mental Health Center. A total of 34 adolescents aged 12-18 years with obesity, defined as body mass index SD score equal to or greater than +1.28 and body fat percentage at or above the 95th percentile, receiving stable antipsychotic treatment will be enrolled. The study population includes adolescents with a range of psychiatric diagnoses requiring antipsychotic treatment, including psychotic disorders, mood disorders and neurodevelopmental disorders. Adolescents receiving antipsychotic treatment under coercion are excluded. Participants will receive once-weekly subcutaneous semaglutide at a dose up to 2.4 milligrams for 36 weeks in addition to standard care, followed by an 18-month observational follow-up period. The primary outcome is study completion rate. Additional feasibility outcomes include recruitment rate, treatment adherence and completion of study procedures. Secondary outcomes include changes in body mass index SD score, body composition, metabolic biomarkers and psychiatric outcomes. Feasibility outcomes will be analysed descriptively. Exploratory longitudinal analyses will be conducted using linear mixed-effects models. [ETHICS AND DISSEMINATION] The study complies with the Declaration of Helsinki and European Union Clinical Trials Regulation (536/2014) and is approved in the Clinical Trials Information System (2024-5 17 471-21-02). Written informed consent will be obtained from participants and their legal guardians. Results will be disseminated through peer-reviewed publications and scientific conferences. [TRIAL REGISTRATION NUMBER] 2024-5 17 471-21-02.","url":"https://pubmed.ncbi.nlm.nih.gov/42754274/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: None declared.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"clinical_trial","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"body_composition\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":639,"doi":"10.14444/8954","pmid":"42754392","nct_ids":"[]","title":"Do Preoperative Glucagon-Like Peptide-1 Receptor Agonists Influence Lumbar Fusion Outcomes? A Systematic Review and Meta-Analysis","authors":"[\"Alves MLM\", \"Moura Costa AODS\", \"Costa JDVM\", \"Ferreira JSN\", \"Porto LLB\", \"Garrido GA\", \"Gonzalez JVP\", \"Tome JOD\", \"Rodrigues LMR\", \"Pereira BA\"]","journal":"International journal of spine surgery","publication_date":"2026-09-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in patients with obesity and type 2 diabetes, but lumbar fusion-specific associations with postoperative outcomes remain uncertain. [OBJECTIVE] To evaluate the association between preoperative GLP-1RA exposure and surgical and postoperative outcomes in adults undergoing lumbar fusion. [METHODS] PubMed, Embase, and the Cochrane Library were searched from inception through 14 May 2026. Comparative studies of adults undergoing lumbar fusion with and without preoperative GLP-1RA exposure were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). Random-effects meta-analyses generated odds ratios with 95% confidence intervals. The protocol was prospectively registered in PROSPERO (CRD420261414637). [RESULTS] Seven retrospective cohorts involving 28,525 patients were included; 6 used propensity score matching or another matching strategy. No statistically significant associations were observed between preoperative GLP-1RA exposure and reoperation or revision (OR: 0.74, 95% CI: 0.44-1.24; P = 0.25), postoperative infection (OR: 0.83, 95% CI: 0.68-1.00; P = 0.05), wound complications (OR: 0.86, 95% CI: 0.65-1.12; P = 0.26), or postoperative respiratory complications (OR: 1.08, 95% CI: 0.63-1.84; P = 0.69). Deep vein thrombosis, pulmonary embolism, and unplanned emergency department visits also did not differ significantly. All included studies were observational and predominantly used large administrative data sources. [CONCLUSIONS] Across the evaluated outcomes, the available observational evidence did not identify a signal of increased postoperative risk associated with preoperative GLP-1RA exposure after lumbar fusion. Prospective studies with standardized exposure definitions and perioperative management protocols are warranted to confirm these findings and better define their clinical implications. [CLINICAL RELEVANCE] Current observational evidence does not establish preoperative GLP-1RA exposure alone as an independent risk factor for adverse outcomes after lumbar fusion.","url":"https://pubmed.ncbi.nlm.nih.gov/42754392/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Conflicting Interests : The authors report no conflicts of interest in this work.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": \"no preoperative GLP-1RA exposure\", \"treatment_duration\": null}","domains":"[\"immune\", \"perioperative\"]","outcome_type":"hard","primary_outcome":"reoperation/revision and postoperative complications after lumbar fusion","endpoints":null,"effect_estimate":"Reoperation or revision OR: 0.74 (P = 0.25); postoperative infection OR: 0.83 (P = 0.05); wound complications OR: 0.86 (P = 0.26); respiratory complications OR: 1.08 (P = 0.69); none statistically significant; DVT, PE and unplanned ED visits did not differ","confidence_interval":"95% CI: 0.44-1.24 (reoperation or revision)","p_value":"P = 0.25 (reoperation or revision)","sample_size":28525,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"adults undergoing lumbar fusion\", \"sample_size\": 28525, \"inclusion_exclusion\": \"comparative studies of adults undergoing lumbar fusion with vs without preoperative GLP-1RA exposure\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"UNKNOWN: patients defined by a procedure (lumbar fusion) with no BMI, age or diabetes data reported in the abstract.","mediation":"unlikely","mediation_notes":"Main results null; no weight or HbA1c data reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 28525, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"no preoperative GLP-1RA exposure\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI: 0.44-1.24 (reoperation or revision)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: meta-analysis of 28,525 patients, but every included study was a retrospective observational cohort, mostly from administrative data, so the observational cap applies.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No significant difference in reoperation/revision, infection, wound or respiratory complications, deep vein thrombosis, pulmonary embolism or unplanned emergency department visits","limitations":"All seven included studies were retrospective observational cohorts, mostly from administrative data, so confounding cannot be excluded; the authors call for prospective studies with standardised exposure definitions.","plain_summary":"This meta-analysis pooled seven retrospective cohort studies of 28,525 adults having lumbar spine fusion, comparing those who had and had not been taking GLP-1 drugs before surgery. Prior GLP-1 use was not linked to a significant difference in reoperation (OR 0.74), infection (OR 0.83), wound or breathing complications, blood clots or emergency visits. All the studies were observational, so these are associations, not proof of safety.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":587,"doi":"10.1001/jamacardio.2026.3566","pmid":"42747817","nct_ids":"[\"NCT03574597\"]","title":"Efficacy and Safety of Semaglutide According to Frailty Status: A Post Hoc Analysis of the SELECT Randomized Clinical Trial","authors":"[\"Ostrominski JW\", \"Plutzky J\", \"Scirica BM\", \"Hovingh GK\", \"Jeppesen OK\", \"Lincoff AM\", \"Lingvay I\", \"Hoffmann Morville T\", \"Quiroga M\", \"Sofer Y\", \"Urina-Triana M\", \"Aroda VR\", \"SELECT Trial Investigators\"]","journal":"JAMA cardiology","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Whether frailty influences the benefit-risk balance of glucagon-like peptide-1 receptor agonists (GLP-1 RA) is uncertain. [OBJECTIVE] To evaluate whether frailty modifies the efficacy and safety of the GLP-1 RA semaglutide in adults with cardiovascular disease and overweight/obesity. [DESIGN, SETTING, AND PARTICIPANTS] In this secondary analysis of a randomized clinical trial, participants were adults with a body mass index of 27 or higher and established cardiovascular disease without diabetes. A 31-item frailty index (FI) was constructed using the Rockwood cumulative deficit approach; participants were categorized as not frail (FI ≤0.210), more frail (FI 0.211-0.310), and most frail (FI ≥0.311). [INTERVENTIONS] Semaglutide, 2.4 mg, once weekly or placebo. [MAIN OUTCOMES AND MEASURES] The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Key secondary clinical outcomes, health-related quality-of-life (assessed by EuroQol 5-Dimension 5-Level [EQ-5D-5L] score), and safety events were additionally examined. [RESULTS] Of 17 604 participants, the mean (SD) age was 61.6 (8.9) years; 12 732 patients (72.3%) were male and 4872 were female (27.7%). A total of 5432 patients (31%) had an FI up to 0.210, 8349 (47%) had an FI of 0.211 to 0.310, and 3823 (22%) had an FI 0.311 or higher. The incidence of the primary outcome increased with higher baseline FI. Benefits of semaglutide vs placebo on the primary outcome appeared consistent across the FI categories (hazard ratio [HR], 0.84; 95% CI, 0.65-1.07, if the FI was ≤0.210; HR, 0.70; 95% CI, 0.59-0.82, if the FI was 0.211-0.310; HR, 0.92; 95% CI, 0.76-1.10, if the FI was ≥0.311; P = .09 for interaction). Similar findings were observed when the FI was examined continuously (P = .30 for interaction). Semaglutide additionally reduced the composite heart failure outcome (P = .82 for interaction), all-cause hospitalization (P = .71 for interaction), and all-cause mortality (P = .28 for interaction) regardless of FI category. Benefits of semaglutide on EQ-5D-5L scores appeared larger with higher FI (P = .02 for interaction). Between baseline and week 104, FI category was more likely to improve (odds ratio [OR], 2.46; 95% CI, 1.80-3.37), and less likely to worsen (OR, 0.47; 95% CI, 0.34-0.65) with semaglutide vs placebo. The HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower among participants with higher baseline FI (P < .001 for interaction). [CONCLUSIONS AND RELEVANCE] This study found that semaglutide demonstrated beneficial effects on a broad range of clinical outcomes in SELECT, without detectable heterogeneity by baseline FI. Benefits of semaglutide on health-related quality of life appeared greater with higher FI. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT03574597.","url":"https://pubmed.ncbi.nlm.nih.gov/42747817/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg, once weekly\", \"comparator\": \"placebo\", \"route\": null, \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"aging\", \"mortality\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke (MACE), by frailty category","endpoints":null,"effect_estimate":"Primary outcome HR, 0.84 (95% CI, 0.65-1.07) if FI ≤0.210; HR, 0.70 (95% CI, 0.59-0.82) if FI 0.211-0.310; HR, 0.92 (95% CI, 0.76-1.10) if FI ≥0.311; P = .09 for interaction; heart failure composite, all-cause hospitalization and all-cause mortality reduced regardless of FI; FI more likely to improve (OR, 2.46) and less likely to worsen (OR, 0.47) vs placebo","confidence_interval":"95% CI, 0.65-1.07 (FI ≤0.210); 95% CI, 0.59-0.82 (FI 0.211-0.310); 95% CI, 0.76-1.10 (FI ≥0.311)","p_value":"P = .09 for interaction (primary outcome)","sample_size":17604,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": \"mean 61.6 (SD 8.9) years\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"72.3% male; 27.7% female\", \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"overweight or obesity required (body mass index of 27 or higher)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"established cardiovascular disease required\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"established cardiovascular disease with overweight/obesity\", \"sample_size\": 17604, \"inclusion_exclusion\": \"adults with BMI 27 or higher and established cardiovascular disease, without diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had BMI 27 or higher and established cardiovascular disease (no diabetes); mean age 61.6 years, within the target range.","mediation":"possibly","mediation_notes":"The abstract reports no weight change, HbA1c change or mediation analysis; frailty-category comparisons are not a weight separation.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 17604, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, 0.65-1.07 (FI ≤0.210); 95% CI, 0.59-0.82 (FI 0.211-0.310); 95% CI, 0.76-1.10 (FI ≥0.311)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: a post hoc secondary analysis of a large randomized trial (17 604 participants) with hard outcomes; subgroup analyses of this kind sit below the main trial result.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"HRs for adverse events leading to permanent discontinuation of semaglutide vs placebo appeared lower with higher baseline frailty (P < .001 for interaction)","limitations":"Post hoc subgroup analysis of one trial by a constructed frailty index; for the primary outcome, two of the three frailty-category confidence intervals cross 1.","plain_summary":"This post hoc analysis of the SELECT trial looked at 17 604 adults with heart disease and a BMI of 27 or higher but no diabetes, grouped by how frail they were. Semaglutide's reduction in heart attack, stroke and cardiovascular death looked similar across frailty groups, though in the least and most frail groups the estimates were uncertain (HR 0.84 and 0.92, with confidence intervals crossing 1). Quality-of-life gains appeared larger in frailer people, and frailty was more likely to improve on semaglutide than on placebo.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":633,"doi":"10.1007/s12029-026-01523-w","pmid":"42745130","nct_ids":"[]","title":"Long-Term Association Between GLP-1 Receptor Agonist Use and Incident Pancreatic Cancer: A Propensity Score-Matched Retrospective Cohort Study Using the TriNetX Network","authors":"[\"Kazi MAI\", \"Khan J\", \"Mufarrih SM\", \"Siddiqui M\", \"Ansari HUH\", \"Ahmed M\", \"Qureshi I\", \"Al-Sabban A\", \"Karnik NP\", \"Gilman A\", \"Singh S\", \"Canakis A\"]","journal":"Journal of gastrointestinal cancer","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes mellitus (T2DM) and obesity. Whether GLP-1 RA use is associated with altered long-term pancreatic cancer risk remains uncertain, with conflicting evidence from prior observational studies. We aimed to evaluate the association between initiation of GLP-1 RA therapy and incident pancreatic cancer risk compared with six classes of antidiabetic agents. [METHODS] We conducted a retrospective, new-user cohort study using the TriNetX global federated electronic health record network. Adults with T2DM initiating GLP-1RA therapy were compared with incident users of insulin, metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones in six separate propensity score-matched analyses (1:1, greedy nearest-neighbor algorithm, caliper 0.1 pooled standard deviations). Matching was performed on 39 baseline covariates,, including demographics, comorbidities, procedures, and medication exposures. The primary outcome was incident pancreatic cancer (ICD-10-CM C25) occurring between 365 and 7,300 days after the index prescription. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. [RESULTS] After propensity score matching, GLP-1 RA users compared with insulin users had a lower hazard of pancreatic cancer (HR 0.43, 95% CI 0.35, 0.53; absolute risk: GLP-1 RA 0.15% vs. insulin 0.11%; absolute risk difference [ARD] 0.04% points). In contrast, users of metformin (HR 1.39, 95% CI 1.16, 1.66; ARD 0.04% points), sulfonylureas (HR 1.37, 95% CI 1.13, 1.65; ARD 0.07% points), thiazolidinediones (HR 1.30, 95% CI 1.001, 1.678; ARD 0.15% points) and DPP-4i (HR 1.31; 95% CI 1.06, 1.61; ARD 0.08% points) had significantly higher hazards of pancreatic cancer compared with GLP-1 RA users. No significant difference was observed between GLP-1 RA users and users of SGLT2 inhibitors (HR 1.08, 95% CI 0.87, 1.34). [CONCLUSIONS] In this large, real-world, propensity score-matched analysis, the direction and magnitude of the association between GLP-1 RA use and pancreatic cancer risk varied by comparator agent. GLP-1 RA use was associated with a lower hazard of pancreatic cancer relative to metformin, sulfonylureas, thiazolidinediones, and DPP-4i while no significant difference relative to SGLT2i, and a higher hazard relative to insulin.","url":"https://pubmed.ncbi.nlm.nih.gov/42745130/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:21+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":641,"doi":"10.1111/anae.70380","pmid":"42748560","nct_ids":"[]","title":"Peri-operative glucagon-like peptide-1 receptor agonist use and outcomes: a national prospective multicentre cohort study","authors":"[\"Potter TE\", \"Cronin JN\", \"Kua J\", \"Bloomfield S\", \"Murali M\", \"Beatty F\", \"McKechnie A\", \"Wong DJN\", \"El-Boghdadly K\", \"GLIMPSE Resident Research Networks and Collaborators\"]","journal":"Anaesthesia","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Peri-operative glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with delayed gastric emptying. It is unclear what proportion of patients having anaesthetic care are receiving GLP-1 RAs; what strategies are used in their peri-operative management; and whether the incidence of pulmonary aspiration and/or regurgitation is greater in this population. [METHODS] We performed a national prospective multicentre cohort study of adults undergoing elective or emergency procedures under the care of an anaesthetist. Patients were screened for GLP-1 RA use in the 3 months before the index procedure. Data were collected on patient, procedure, anaesthesia and outcomes, including pulmonary aspiration and regurgitation. The primary outcome was the proportion of patients receiving GLP-1 RAs. Secondary outcomes described the pre-operative management of GLP-1 RAs; anaesthesia and airway management in patients receiving GLP-1 RAs; and the incidence of pulmonary aspiration and/or regurgitation. [RESULTS] Of 47,039 patients from 119 sites across the UK, 1348 (2.9%) reported receiving GLP-1 RAs. Peri-operative management was variable regarding drug cessation, anaesthesia and airway management. The incidence (95%CI) of pulmonary aspiration and/or regurgitation in the non-GLP-1 RA cohort was 57/45,691 (0.12% (0.09-0.16%)) and in the GLP-1 RA cohort was 19/1348 (1.41% (0.85-2.19%)); odds ratio (95%CI) 11.39 (6.47-20.05), p < 0.001. In patients receiving GLP-1 RAs, pulmonary aspiration and/or regurgitation occurred most frequently during emergence from anaesthesia. [DISCUSSION] In this national study, 1 in 36 patients undergoing anaesthesia care received GLP-1 RAs, and their peri-operative management was variable. A range of airway management techniques aiming to reduce pulmonary aspiration risk were observed but, despite this, the incidence of pulmonary aspiration and/or regurgitation was 1 in 71 in people receiving GLP-1 RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/42748560/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":642,"doi":"10.1177/02698811261478625","pmid":"42746999","nct_ids":"[]","title":"Adjunctive GLP-1 receptor agonists for cardiometabolic risk in antipsychotic-treated patients: A GRADE-assessed meta-analysis of randomized trials","authors":"[\"Moubarak ES\", \"Elgendy MS\", \"Elkoumi O\", \"Ibrahim AA\", \"Manasrah A\", \"Ahmad J\", \"Hassan MA\", \"Rageh OE\", \"Mohamed AA\", \"Elzahaby A\", \"Abuelazm M\"]","journal":"Journal of psychopharmacology (Oxford, England)","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Patients with schizophrenia spectrum or bipolar disorders have reduced life expectancy due to cardiometabolic risk. We conducted this meta-analysis to evaluate glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for their effects on cardiometabolic outcomes. [METHODS] We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane up to May 2026 for randomized controlled trials (RCTs). We pooled continuous outcomes as mean differences (MDs) and dichotomous outcomes as risk ratios (RRs) using random-effects models with 95% confidence intervals (CIs). [RESULTS] We included 8 RCTs with 664 patients. Compared with control, GLP-1 RA significantly reduced body weight (MD: -6.74, 95% CI: -10.05 to -3.43), body mass index (BMI; MD: -2.37 kg/m2, 95% CI: -3.52 to -1.23), waist circumference (MD: -4.27 cm, 95% CI: -6.65 to -1.89), HbA1c (MD: -0.61%, 95% CI: -1.06 to -0.17), and fasting glucose (MD: -6.82, 95% CI: -11.89 to -1.76). Subgroup analyses by GLP-1 RA type showed that semaglutide produced the greatest reductions in body weight (MD: -11.06 kg) and BMI (MD: -3.60 kg/m2), with significant between-subgroup differences (p < 0.05). Adverse events (AEs; p = 0.77), serious AEs (p = 0.09), and discontinuation due to AEs (p = 0.20) were similar between groups. However, GLP-1 RA was associated with a significantly higher risk of gastrointestinal (GI) AEs, including nausea, vomiting, and constipation (all p < 0.01). [CONCLUSION] GLP-1RA, particularly semaglutide, was associated with clinically meaningful improvements in antipsychotic-related cardiometabolic outcomes without compromising psychiatric stability or treatment adherence. However, the significant increase in GI AEs necessitates careful clinical titration. Larger RCTs with longer follow-up are needed to confirm these findings.","url":"https://pubmed.ncbi.nlm.nih.gov/42746999/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"comparator\": \"control\", \"dose\": \"various\", \"route\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"cardiometabolic outcomes (body weight, BMI, waist circumference, HbA1c, fasting glucose)","endpoints":null,"effect_estimate":"Body weight MD: -6.74; BMI MD: -2.37 kg/m2; waist MD: -4.27 cm; HbA1c MD: -0.61%; fasting glucose MD: -6.82; overall AEs (p = 0.77), serious AEs (p = 0.09) and discontinuation due to AEs (p = 0.20) similar; GI AEs significantly higher (all p < 0.01)","confidence_interval":"95% CI: -10.05 to -3.43 (body weight)","p_value":null,"sample_size":664,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"antipsychotic-treated schizophrenia spectrum or bipolar disorders\", \"sample_size\": 664, \"inclusion_exclusion\": \"RCTs of adjunctive GLP-1 RAs in antipsychotic-treated patients\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PARTIAL: a disease-defined population (schizophrenia spectrum or bipolar disorders treated with antipsychotics) with no BMI, age or diabetes data in the abstract.","mediation":"not_applicable","mediation_notes":"Outcomes are weight, BMI, waist, HbA1c and glucose, so weight mediation is not a meaningful question.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 664, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"control\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"CI reported: 95% CI: -10.05 to -3.43 (body weight)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: meta-analysis of 8 RCTs (664 patients) with intermediate cardiometabolic outcomes.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Overall AEs, serious AEs and discontinuation due to AEs similar between groups; significantly higher gastrointestinal AEs (nausea, vomiting, constipation)","limitations":"Pools only 8 RCTs with 664 patients; trial duration and population details are not reported in the abstract, and the authors call for larger, longer trials.","plain_summary":"This meta-analysis pooled 8 randomized trials with 664 people taking antipsychotics for schizophrenia-spectrum or bipolar disorders. Compared with control, GLP-1 drugs lowered body weight, BMI, waist size, HbA1c and fasting glucose, with semaglutide showing the largest weight effect. Overall and serious side effects were similar, but stomach-related side effects such as nausea, vomiting and constipation were significantly more common.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":728,"doi":"10.1136/bmj-2026-100574","pmid":"42778221","nct_ids":"[]","title":"Renal outcomes in people with type 2 diabetes with and without albuminuria treated with SGLT-2 inhibitors and GLP-1 receptor agonists: target trial emulation","authors":"[\"Turchin A\", \"Petito LC\", \"Hegermiller E\", \"Chelliah I\", \"Carnahan RM\", \"DeVries A\", \"Goel S\", \"Lansang MC\", \"McDonnell ME\", \"Nair V\", \"Priest E\", \"Willey VJ\", \"Kaul AF\", \"Hernán MA\", \"BESTMED collaborating investigators\"]","journal":"BMJ (Clinical research ed.)","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare the risk of renal deterioration under treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose contransporter-2 (SGLT-2) inhibitors versus other second line treatments in people with type 2 diabetes with and without albuminuria (albumin to creatinine ratio ≥30 mg/g). [DESIGN] Target trial emulation. [SETTINGS] Linkage of electronic health records and claims data from 10 health systems and two national health insurance plans-data from BESTMED (observational evaluation of second line therapy medications in diabetes) study. [PARTICIPANTS] People with type 2 diabetes and moderate cardiovascular risk and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 on metformin monotherapy who started treatment with a GLP-1 receptor agonist or SGLT-2 inhibitor, a sulfonylurea, or a dipeptidyl peptidase-4 (DPP-4) inhibitor after metformin between 2014 and 2022. [MAIN OUTCOME MEASURE] Deterioration of kidney function defined as doubling of serum creatinine or estimated glomerular filtration rate <15 mL/min/1.73 m2. [RESULTS] Among 75 455 eligible people (61 583 (81.76%) without albuminuria), median age was 60 years (interquartile range 51-68), 36 231 (48%) were women, median haemoglobin A1c was 7.8% (interquartile range 7.3-8.5%), and median estimated glomerular filtration rate was 92 mL/min/1.73 m2 (interquartile range 77-102). People were followed for a median of 32 months (interquartile range 18-57). The estimated five year risk of the renal outcome was 2.4% (95% confidence interval 2.1% to 2.7%) for people taking GLP-1 receptor agonists or SGLT-2 inhibitors versus 2.1% (1.8% to 2.6%) for people taking DPP-4 inhibitors among those without albuminuria; and 3.2% (2.3% to 4.1%) versus 5.4% (4.2% to 6.7%), respectively, among people with albuminuria. The estimated five year risk ratio comparing the GLP-1 receptor agonist or SGLT-2 inhibitor group with the DPP-4 inhibitor group was 1.10 (95% confidence interval 0.90 to 1.38) among people without albuminuria and 0.60 (0.42 to 0.82) among people with albuminuria. [CONCLUSIONS] Compared with DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors reduce the risk of deterioration of renal function in people with albuminuria. Little evidence of renal benefit among people without albuminuria was observed over the study follow-up period.","url":"https://pubmed.ncbi.nlm.nih.gov/42778221/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Patient-Centred Outcomes Research Institute for the submitted work. AT reported receiving grants from Eli Lilly and personal fees from Novo Nordisk and Proteomics International. MAH is a consultant to ProPublica and Adigens Health, a company of which he owns equity, and a member of ADIA Lab’s Advisory Board. The other authors reported no conflicts of interest.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":775,"doi":"10.3390/jpm16090478","pmid":"42783509","nct_ids":"[]","title":"Glucagon-like Peptide-1 Receptor Agonists Are Not Associated with Increased Risk of Acute Pancreatitis or Pancreatic Complications, Including Pancreatic Cancer, in Type 2 Diabetes: A Global Propensity-Matched Cohort Study","authors":"[\"Sun Y\", \"Liu B\", \"Loh H\", \"Mathialagan S\", \"Lin CH\", \"Tarabichi Y\", \"Veccia D\", \"Wong R\", \"Tse W\", \"Song G\"]","journal":"Journal of personalized medicine","publication_date":"2026-09-16","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Introduction: Association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and pancreatitis and its long-term complications remains controversial. Using a global electronic health record database, we evaluated pancreatic outcomes following GLP-1 RA initiation in adults with type 2 diabetes mellitus (T2DM). Methods: Adults aged ≥18 years who were alive at the index date; T2DM patients initiating GLP-1 RAs between 2013 and 2025 were identified in the TriNetX network and compared with patients initiating sodium-glucose cotransporter-2 inhibitors (SGLT2i). Sensitivity analyses included comparisons with other second-line diabetes therapies, excluding dipeptidyl peptidase-4 inhibitors, and analyses were restricted to U.S.-based health care organizations. Patients with pre-existing pancreatic conditions were excluded. Cohorts were propensity score-matched for treatment indications, pancreatitis risk factors, and demographics. Kaplan-Meier and Cox proportional hazard models evaluated acute pancreatitis (overall and biliary), chronic pancreatitis, pancreatic pseudocyst, and pancreatic cancer. Results: After matching, 291,152 patients were included in each cohort. GLP-1 RA initiation was not associated with an increased hazard of overall acute pancreatitis compared with SGLT2i initiation (HR 1.095; 95% CI 0.996-1.204), with concordant Kaplan-Meier analyses. A modest, etiology-specific increase in biliary acute pancreatitis was observed in the primary comparison (HR 1.276; 95% CI 1.010-1.612) but was not consistent across sensitivity analyses. No differences were observed in the risks of pancreatic pseudocyst (HR 0.729; 95% CI 0.525-1.014) or pancreatic cancer (HR 1.069; 95% CI 0.940-1.215). Results were similarly consistent in sensitivity analyses. Conclusion: GLP-1 RAs are not associated with an increased risk of acute pancreatitis, pancreatitis-related complications, or pancreatic cancer in T2DM adults; a modest biliary pancreatitis signal was observed, but was not consistent across sensitivity analyses.","url":"https://pubmed.ncbi.nlm.nih.gov/42783509/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cancer\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":585,"doi":"10.1186/s12902-026-02538-x","pmid":"42750018","nct_ids":"[]","title":"Efficacy and safety of orforglipron 12 mg versus orforglipron 36 mg maintenance dose among patients with obesity with or without diabetes: a systematic review and comprehensive meta-analysis","authors":"[\"Hegaz MG\", \"Aboud MYA\", \"Kamel AII\", \"Naveed MA\", \"Elsayed OG\", \"Sorathia AZ\"]","journal":"BMC endocrine disorders","publication_date":"2026-09-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is projected to affect about one billion adults by 2030 and is associated with cardiometabolic morbidity. Orforglipron is an oral, non-peptide glucagon-like peptide-1 receptor agonist developed to provide weight and metabolic benefits. Prior meta-analyses have supported its efficacy and safety but were limited by shorter follow-up and a predominance of non-diabetic populations. This meta-analysis aims to provide the most comprehensive head-to-head comparison between the two most commonly studied maintenance doses (12 mg vs. 36 mg), assessing weight, glycemic, cardiometabolic, and safety outcomes. [METHODS] We searched PubMed, Web of Science, Cochrane, and Scopus until March 1, 2026, for randomized controlled trials (RCTs) comparing orforglipron 12 mg and 36 mg in obese adults. Outcomes of interest included percentage and absolute body weight change, BMI, HbA1c, waist circumference, lipid parameters, blood pressure, and adverse events. Results were pooled using a fixed-effects model, and prespecified subgroup analyses examined differences by diabetes status and treatment duration. [RESULTS] Six RCTs (3459 participants) were included. Compared with the 12 mg dose, the 36 mg dose was associated with greater reductions in percentage body weight change (p < 0.00001), absolute body weight change (p < 0.00001), body mass index (p < 0.00001), HbA1c (p < 0.00001), waist circumference (P < 0.00001), percent change in triglycerides (P = 0.002), and systolic blood pressure (P = 0.002). Adverse events were comparable between doses. No significant differences were observed in gastrointestinal events or pancreatic functions. A small difference in pulse rate was noted but was not considered clinically significant. [CONCLUSION] In obese adults, orforglipron 36 mg improved weight and metabolic outcomes compared with 12 mg. No statistically significant differences between doses were detected for the prespecified safety outcomes, although small increases in ALT and AST were observed with the 36 mg dose and the trials included were not powered to detect rare or long-term adverse events. These findings support consideration of the higher maintenance dose when clinically appropriate. Longer-term studies are needed to confirm the benefit and cardiovascular outcomes. [CLINICAL TRIAL NUMBER] Not applicable.","url":"https://pubmed.ncbi.nlm.nih.gov/42750018/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval: No humans participate in this study, and informed consent is not required. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"meta_analysis","drugs":"[\"orforglipron\"]","drug_details":"{\"dose\": \"12 mg vs. 36 mg\", \"route\": \"oral\", \"comparator\": \"orforglipron 12 mg (lower maintenance dose)\", \"treatment_duration\": null}","domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percentage and absolute body weight change (plus BMI, HbA1c, waist, lipids, blood pressure, adverse events)","endpoints":null,"effect_estimate":"36 mg vs 12 mg: greater reductions in percentage body weight change (p < 0.00001), absolute body weight, BMI, HbA1c, waist circumference (all p < 0.00001), triglycerides (P = 0.002) and systolic blood pressure (P = 0.002); adverse events comparable; no significant differences in GI events or pancreatic function","confidence_interval":null,"p_value":"p < 0.00001 (percentage body weight change)","sample_size":3459,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"required (obese adults; no BMI criterion stated)\", \"diabetes_status\": \"mixed (with or without diabetes)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity\", \"sample_size\": 3459, \"inclusion_exclusion\": \"RCTs comparing orforglipron 12 mg and 36 mg in obese adults\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all included trials enrolled obese adults, with or without diabetes.","mediation":"not_applicable","mediation_notes":"Outcomes are weight, BMI and HbA1c themselves; weight mediation is not a meaningful question for them.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 3459, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"orforglipron 12 mg (lower maintenance dose)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; p values only; 3459 participants in 6 RCTs\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: meta-analysis of randomized trials (3459 participants) with intermediate outcomes; fixed-effects pooling and no confidence intervals in the abstract; the comparison is 36 mg against 12 mg, not against placebo.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Adverse events comparable between doses; no significant differences in GI events or pancreatic function; small pulse-rate difference; small ALT and AST increases with 36 mg; trials not powered for rare or long-term events","limitations":"Dose-comparison meta-analysis of six trials using a fixed-effects model with no confidence intervals in the abstract; the authors note the trials were not powered for rare or long-term adverse events and longer studies are needed.","plain_summary":"Six randomized trials with 3459 adults with obesity, with or without diabetes, were pooled in this meta-analysis comparing two maintenance doses of the oral GLP-1 drug orforglipron. The 36 mg dose produced greater reductions in body weight, BMI, HbA1c, waist size, triglycerides and systolic blood pressure than 12 mg. Side effects were similar overall, though liver enzymes (ALT and AST) rose slightly on the higher dose and the trials could not detect rare or long-term harms.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":592,"doi":"10.1093/ajrccm/aamag474","pmid":"42745463","nct_ids":"[]","title":"Effectiveness of GLP-1 receptor agonists to prevent obstructive sleep apnea in patients with type 2 diabetes: active comparator, new user cohort study","authors":"[\"Khouri C\", \"Dell'Aniello S\", \"Jambon Barbara C\", \"Azoulay L\", \"Suissa S\", \"Pepin JL\"]","journal":"American journal of respiratory and critical care medicine","publication_date":"2026-09-15","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[RATIONALE] Obstructive sleep apnea (OSA) is highly prevalent in type 2 diabetes (T2D), sharing metabolic risk factors, notably obesity, and increased cardiovascular outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce OSA severity in clinical trials but their role in preventing incident OSA in T2D remains unclear. [OBJECTIVE] To assess whether GLP-1RA use is associated with a reduced risk of incident OSA compared with dipeptidyl peptidase-4 inhibitors (DPP-4i), a weight-neutral comparator, in patients with T2D. [METHODS] We conducted a population-based cohort study using the UK CPRD (2007-2023) database with an active-comparator, new-user design. Adults with T2D and BMI ≥30 kg/m² initiating a GLP-1RA or DPP-4i were included, excluding individuals with prior sleep apnea. Propensity scores with fine-stratification weighting were used within BMI strata. The primary outcome was incident clinical diagnosis of OSA. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using an as-treated approach, with up to 3 years of follow-up. [RESULTS] The cohort included 47,315 GLP-1RAs and 159,066 DPP-4i initiators with baseline characteristics well balanced after weighting. During follow-up, 612 and 1,197 incident OSA cases occurred among GLP-1RAs and DPP-4i users, yielding incidence rates of 5.8 and 5.4 per 1000 person-years, respectively. The HR of incident OSA with GLP-1RA use compared with DPP-4i use was 1.07 (95% CI 0.93-1.23). Results were consistent across BMI strata, sex, drug type, and multiple sensitivity analyses. [CONCLUSIONS] In routine clinical care, GLP-1RAs were not associated with a decreased incidence of OSA in patients with T2D and no history of OSA, when compared with DPP-4i.","url":"https://pubmed.ncbi.nlm.nih.gov/42745463/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"sleep\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":240,"doi":"10.1515/jpem-2026-0227","pmid":"42732089","nct_ids":"[]","title":"GLP-1 receptor agonist use and mental health outcomes in adolescents with obesity: a retrospective review","authors":"[\"Said J\", \"Liegl M\", \"Pan AY\", \"Dabrowski E\"]","journal":"Journal of pediatric endocrinology & metabolism : JPEM","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] Adolescent obesity is associated with increased rates of depression and suicidality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used to treat pediatric obesity, yet concerns remain regarding potential psychiatric effects. This study evaluated changes in depressive symptoms and suicidality screening scores among adolescents with obesity treated with GLP-1RAs in a pediatric endocrinology setting. We evaluated changes in depressive symptoms and suicidality following initiation of GLP-1RA therapy in adolescents with obesity. [METHODS] We performed a retrospective chart review of adolescents aged 12-21 years with obesity treated with liraglutide or semaglutide at a single academic center between June 2022 and December 2024. Demographic, clinical, and psychosocial data were extracted from the electronic health record at baseline and follow-up. Depressive symptoms or suicidality were screened at clinic visits per protocol using either the Patient Health Questionnaire-9 (PHQ-9) or the Ask Suicide-Screening Questions (ASQ), respectively. Analyses were restricted to patients with paired baseline and follow-up assessments using the same instrument. Paired nonparametric tests were used for longitudinal comparisons. [RESULTS] Forty-four adolescents met inclusion criteria. Among patients with paired PHQ-9 data (n=15), the median PHQ-9 score decreased significantly from 6 (IQR 2-14) at baseline to 1 (IQR 0-5) at follow-up (p=0.003), independent of changes in BMI. Among patients with paired ASQ data (n=23), no increase in suicidality or new suicidal ideation was observed. [CONCLUSIONS] In this small, exploratory retrospective review, no evidence of short-term psychological harm or increased suicidality was observed among adolescents receiving GLP-1RA therapy. These findings support the short-term psychosocial safety of GLP-1RA therapy in adolescents with obesity. Larger prospective case-control studies are needed to better characterize psychiatric safety and psychosocial outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42732089/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"case_control","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":598,"doi":"10.1016/j.amjmed.2026.09.010","pmid":"42735883","nct_ids":"[]","title":"Prior GLP-1RA or Tirzepatide Use and Early Cardiorenal Outcomes After Metabolic and Bariatric Surgery","authors":"[\"Tseng TC\", \"Chang R\"]","journal":"The American journal of medicine","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare early postoperative cardiovascular and kidney outcomes after metabolic and bariatric surgery (MBS) according to prior glucagon-like peptide-1 receptor agonist (GLP-1RA) or tirzepatide use. [METHODS] This retrospective cohort study used the US Medical Records Database. Adults undergoing MBS from 2016 through 2025 were included. Prior use was defined by at least 1 GLP-1RA or tirzepatide prescription from 365 to 7 days before MBS; patients with prescriptions closer to surgery were excluded. Prior users and nonusers were propensity score matched 1:1. The primary outcome was 4-point major adverse cardiovascular events (MACE), and a key secondary outcome was early postoperative kidney events, assessed from postoperative day 1 through day 90. [RESULTS] After matching, each group included 11,052 patients, with well-balanced baseline characteristics. Prior use was associated with lower risks of 4-point MACE (36 patients [0.3%] vs 67 patients [0.6%]; hazard ratio [HR], 0.535; 95% CI, 0.357-0.803) and early postoperative kidney events (158 patients [1.4%] vs 256 patients [2.3%]; HR, 0.613; 95% CI, 0.502-0.747). Prior GLP-1RA or tirzepatide use was also associated with lower risks of coronary events and heart failure. [CONCLUSIONS] Among adults undergoing MBS, prior GLP-1RA or tirzepatide use was associated with lower 90-day risks of 4-point MACE and early postoperative kidney events. These findings support further investigation of preoperative metabolic optimization strategies and their potential role in improving postoperative cardiorenal outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42735883/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":600,"doi":"10.1007/s12471-026-02074-2","pmid":"42734721","nct_ids":"[]","title":"DUTCH weight control in atrial fibrillation study (DUTCH-WAIST) : Design and rationale of a randomised controlled trial","authors":"[\"Voorhout L\", \"Pisters R\", \"Huisman M\", \"Klok E\", \"Rutten F\", \"Geersing GJ\", \"Tieleman R\", \"Cornel JH\", \"Schut A\", \"Tijssen J\", \"van Bon A\", \"Hemels M\"]","journal":"Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is a well-established and highly prevalent risk factor for atrial fibrillation (AF) and its progression by promoting structural and electrical atrial remodelling, leading to AF recurrence and persistence. Weight loss is expected to reverse atrial remodelling and improve rhythm control. Optimal strategies for weight management are, however, under-explored. [OBJECTIVE] To quantify the effect of clinically meaningful weight loss on rhythm control in overweight patients with first detected persistent AF. [DESIGN] A multicentre, double-blind, randomised, placebo-controlled trial evaluating semaglutide 2.4 mg once weekly versus placebo, in addition to combined lifestyle intervention (CLI), during a one-year period. [PARTICIPANTS] Adults with a BMI > 30 kg/m2, or BMI > 27 kg/m2 with a weight-related comorbidity, and first detected (< 6 months) persistent AF scheduled for electrical cardioversion. [INTERVENTION] Weekly subcutaneous injections of semaglutide 2.4 mg or placebo, alongside CLI and standard AF care in both groups. [OUTCOMES] The co-primary outcome is (i) a hierarchical assessment of rhythm status at one year, ranking patients by severity from arrhythmic death to sinus rhythm without any additional rhythm control support. (ii) the composite of either persistent atrial fibrillation on ECG, catheter ablation for AF, arrhythmic death, or any serious adverse event due to anti-arrhythmic drugs occurring within 1 year. [CONCLUSION] This study investigates whether treatment of overweight with semaglutide, as an adjunct to lifestyle intervention, enhances rhythm control in AF patients with first detected persistent AF and overweight, offering a potential new approach to reducing AF burden and cardiovascular risk in this population.","url":"https://pubmed.ncbi.nlm.nih.gov/42734721/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: We wish to disclose that one of our co-authors, Dr. M. Hemels, serves as a Deputy Editor for the Netherlands Heart Journal. Furthermore, Dr. M. Hemels received payments for lectures from Novo Nordisk. L. Voorhout, R. Pisters, M. Huisman, E. Klok, F. Rutten, G.-J. Geersing, R. Tieleman, J.H. Cornel, A. Schut, J. Tijssen and A. van Bon declare that they have no competing interests.","assessment_version":5,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo, alongside combined lifestyle intervention and standard AF care in both groups\", \"treatment_duration\": \"one-year period\"}","domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":"none","primary_outcome":"co-primary: hierarchical rhythm status at one year; composite of persistent AF, AF ablation, arrhythmic death or serious adverse event from anti-arrhythmic drugs within 1 year (planned, no results)","endpoints":null,"effect_estimate":"not reported in abstract","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"one year","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": \"> 30 kg/m2, or BMI > 27 kg/m2 with a weight-related comorbidity\", \"obesity_status\": \"required (BMI > 30 kg/m2, or BMI > 27 kg/m2 with a weight-related comorbidity)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"first detected persistent atrial fibrillation required\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"first detected persistent atrial fibrillation scheduled for electrical cardioversion, with overweight or obesity\", \"sample_size\": null, \"inclusion_exclusion\": \"adults with BMI > 30 kg/m2 (or > 27 kg/m2 with comorbidity) and first detected (< 6 months) persistent AF scheduled for cardioversion\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: entry requires obesity or overweight with a weight-related comorbidity, plus persistent atrial fibrillation.","mediation":"not_applicable","mediation_notes":"Design paper with no outcome yet. The trial is framed as testing weight loss itself as the means of improving rhythm control.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo, alongside combined lifestyle intervention and standard AF care in both groups\", \"follow_up_duration\": \"one year\", \"outcome_type\": \"none\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no results reported (design paper)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"NOT_RATED: a design and rationale paper that reports no outcome data.","funding_source":"Hartstichting","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"One co-author (M. Hemels) is a Deputy Editor of the Netherlands Heart Journal and received lecture payments from Novo Nordisk; the other authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk (lecture payments to one co-author)","adverse_events":"not reported in abstract","limitations":"Design and rationale paper with no results yet; the abstract gives no planned sample size.","plain_summary":"This paper describes the design of a Dutch double-blind trial that will give semaglutide 2.4 mg weekly or placebo, on top of a lifestyle programme, to adults with overweight or obesity and newly detected persistent atrial fibrillation. The main outcomes are heart-rhythm status and a composite of persistent atrial fibrillation, ablation, arrhythmic death or serious drug side effects at one year. No results are reported yet.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":619,"doi":"10.1111/dom.71319","pmid":"42734024","nct_ids":"[]","title":"Fracture-Centred Skeletal Reporting Profiles of Glucose-Lowering Drug Classes in FAERS and JADER: Cross-Database and Regional Reporting-Context Analyses","authors":"[\"Huang B\", \"Ma P\", \"Wang W\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To characterise fracture-centred skeletal adverse-event reporting across nine glucose-lowering drug classes and test whether regional differences persist after separating Japan from non-Japan Asian reporting contexts. [MATERIALS AND METHODS] We analysed FAERS and JADER reports, with fracture as the primary endpoint and reporting frequency per 10 000 mapped suspect reports. FAERS older age was harmonised to ≥ 60 years, with ≥ 65 and ≥ 70-year sensitivity analyses. Regional analyses separated Western, Japan, and non-Japan Asia; class-specific reporting odds were adjusted for age, sex, calendar year, and reporter type. Disproportionality analyses were supplementary. [RESULTS] The study included 15 473 015 FAERS and 1 037 161 JADER reports, including 202 881 and 10 678 fractures. Using final deduplicated FAERS denominators, fracture reporting was highest for insulin (126.08/10000), DPP-4 inhibitors (111.03) and sulfonylureas (103.76), whereas thiazolidinediones (152.54), SGLT2 inhibitors (115.14) and GLP-1 receptor agonists (112.15) were most prominent in JADER. Age was unavailable in 44.9% of unique FAERS suspect reports, but findings were stable across age thresholds. Japan accounted for 83.0%-92.9% of total-Asian fractures for thiazolidinediones, GLP-1 receptor agonists, SGLT2 inhibitors and DPP-4 inhibitors; corresponding non-Japan Asian RFRs were not clearly elevated. Insulin remained higher after excluding Japan (RFR 1.96, 95% CI 1.57-2.45). No class met FDR-positive fracture disproportionality criteria. [CONCLUSIONS] Skeletal reporting profiles varied by drug class, database, and reporting context. Apparent total-Asian elevations for several classes were predominantly Japan-driven and should not be interpreted as patient-level Asian fracture risk.","url":"https://pubmed.ncbi.nlm.nih.gov/42734024/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"pharmacovigilance","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"bone\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":622,"doi":"10.1007/s00784-026-07135-9","pmid":"42734711","nct_ids":"[]","title":"Obstructive sleep apnea, GLP-1 receptor agonist pharmacotherapy, and the oral microbiome: competing biological influences and implications for oral health monitoring","authors":"[\"Comisi JC\"]","journal":"Clinical oral investigations","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Obstructive sleep apnea (OSA) is associated with reproducible oral microbiome dysbiosis mediated by five simultaneous biological pathways: chronic intermittent hypoxia-driven immune dysregulation, obligate mouth breathing causing salivary desiccation, elevated salivary glucose promoting cariogenic biofilm proliferation, gastroesophageal reflux acid challenge, and hypothalamic-pituitary-adrenal axis activation suppressing mucosal immunity. The December 2024 FDA approval of tirzepatide for moderate-to-severe OSA and the emergence of retatrutide and orforglipron have placed GLP-1 receptor agonists (GLP-1RAs) at the center of OSA pharmacotherapy. This review examines the oral microbiome consequences of GLP-1RA therapy in OSA patients, characterizes the competing biological influences these agents introduce, and identifies the monitoring and research implications of the resulting uncertainty. [METHODS] A narrative review of published literature examining OSA-related oral microbiome dysbiosis, GLP-1RA pharmacological mechanisms relevant to oral biology, salivary gland pharmacovigilance data, and gut microbiome restoration evidence. Sources included PubMed, Web of Science, and Scopus databases searched through June 2026. [RESULTS] GLP-1RA therapy engages five restoration pathways that mechanistically counter each OSA-driven dysbiosis mechanism: direct AHI reduction, attenuating hypoxia-driven immune dysregulation; pharyngeal airway improvement, reducing obligate mouth breathing; glycemic normalization, reducing salivary fermentable substrate; gastric emptying delay and weight loss, attenuating GERD acid challenge; and sleep architecture restoration, reducing cortisol-mediated mucosal immune suppression. Pharmacovigilance data, however, indicate that semaglutide may impair salivary gland responsiveness through β-arrestin-mediated receptor desensitization-a competing oral risk that partially or fully counteracts the restoration benefits. Tirzepatide's biased agonism profile (preferential activation of cAMP signaling over β-arrestin internalization) may confer differential salivary gland safety, and orforglipron's daily oral dosing introduces direct oropharyngeal drug exposure with uncharacterized microbiological consequences. The net oral microbiome outcome in any treated patient is the product of these competing influences and has not been characterized prospectively. [CONCLUSIONS] GLP-1RA pharmacotherapy in OSA creates a biologically complex oral microbiome environment whose clinical trajectory cannot be predicted from current evidence. Prospective studies are warranted, oral health monitoring beginning at treatment initiation is scientifically justified, and seven priority research questions are identified at the convergence of sleep medicine, endocrinology, and oral biology.","url":"https://pubmed.ncbi.nlm.nih.gov/42734711/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: Not applicable. This manuscript is a narrative review. No human subjects, patient data, biological material, or experimental interventions were involved. Ethical approval: Not applicable (narrative review; no human subjects or original data). Consent for publication: The author consents to publication of this manuscript in Clinical Oral Investigations. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:17+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"orforglipron\", \"tirzepatide\", \"retatrutide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"sleep\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":629,"doi":"10.1111/dom.71355","pmid":"42736030","nct_ids":"[]","title":"Real-World Cost and Utilisation Burden of Diagnosed Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients With Type 2 Diabetes in the United States: A Retrospective Cohort Study","authors":"[\"Tran TH\", \"Kim HS\", \"McCoy RG\", \"Zafari Z\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] This study quantified the real-world healthcare costs and utilisation associated with diagnosed metabolic dysfunction-associated steatotic liver disease (MASLD) among adults with Type 2 diabetes (T2D). [METHODS] We conducted a retrospective cohort study using IQVIA PharMetrics Plus Closed Health Plan data from January 2016 to June 2025. Eligible participants were adults aged 18-64 years with T2D. MASLD was identified during the baseline period, and patients with MASLD were matched 1:1 to T2D-only controls using propensity scores. The primary outcome was all-cause total direct healthcare costs over 12 months of follow-up. Adjusted cost ratios (aCRs) and average marginal effects (AMEs) were estimated using generalised linear models. [RESULTS] The final cohort included 155 172 adults with T2D. After PS matching, 17 412 matched pairs were retained. Mean total healthcare costs were $29 734 among patients with MASLD and $18 320 among matched controls. MASLD was associated with 62% higher total healthcare costs (aCR, 1.62; 95% CI, 1.58-1.67), corresponding to an AME of $11 411 (95% CI, $10 725-$12 097) per patient per year. In medication-defined subgroups, excess costs remained substantial among patients receiving GLP-1 receptor agonists (AME, $10 653) and SGLT2 inhibitors (AME, $13 842). MASLD was also associated with greater healthcare utilisation across all service settings. [CONCLUSIONS] Among adults with T2D, MASLD was associated with substantially higher healthcare costs and utilisation. These findings highlight the economic burden of MASLD in this high-risk population.","url":"https://pubmed.ncbi.nlm.nih.gov/42736030/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"liver\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":648,"doi":"10.1111/dom.71353","pmid":"42736027","nct_ids":"[]","title":"Psychiatric Safety of GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Adolescents With Obesity","authors":"[\"Liu TH\", \"Shen YL\", \"Kuo TH\", \"Wu JY\", \"Lin CH\", \"Lai CC\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists are increasingly used for adolescent obesity, but concerns persist regarding psychiatric adverse events, particularly suicidality. [METHODS] This retrospective cohort study used deidentified electronic health records from the TriNetX Global Collaborative Network. Adolescents with overweight or obesity were included. New users of semaglutide, liraglutide, or tirzepatide were compared with those receiving lifestyle interventions. Cohorts were balanced using propensity score matching. The primary outcome was suicide-related events (suicidal ideation or suicide attempt). Secondary outcomes included suicidal ideation, suicide attempt, anxiety, insomnia, depression, and eating disorders, assessed from 30 days to 1095 days after the index date. [RESULTS] After propensity score matching, 9222 adolescents were included in each group. Incretin-based therapy was associated with lower risks of suicide-related events (HR, 0.74; 95% CI, 0.57-0.95), suicidal ideation (HR, 0.73; 95% CI, 0.56-0.96), and anxiety (HR, 0.92; 95% CI, 0.84-0.99) compared with lifestyle intervention. No significant differences were observed for suicide attempt, insomnia, depression, or eating disorders. Risk reductions were significant among female adolescents (HR, 0.61; 95% CI, 0.46-0.82) and those without Type 2 diabetes (HR, 0.63; 95% CI, 0.47-0.85), but not among males or those with Type 2 diabetes. Sensitivity analyses supported the primary findings. [CONCLUSIONS] Among adolescents with obesity, incretin-based therapy was not associated with increased psychiatric risk and was associated with lower risks of suicide-related events, suicidal ideation, and anxiety compared with lifestyle intervention. Although a lower risk was observed compared with lifestyle intervention, this finding should be interpreted cautiously given potential selection bias and the lack of a significant difference in the active-comparator analysis with metformin.","url":"https://pubmed.ncbi.nlm.nih.gov/42736027/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"sleep\", \"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":197,"doi":"10.1007/s40265-026-02365-3","pmid":"42730869","nct_ids":"[]","title":"GLP-1 Receptor Agonists and Musculoskeletal Outcomes: A Systematic Literature Review and Meta-Analysis","authors":"[\"Beaudart C\", \"Malréchauffé Y\", \"van Heden S\", \"Sanchez-Rodriguez D\", \"Scheen A\", \"Bruyère O\", \"Mobasheri A\", \"Duque G\", \"Rizzoli R\", \"Reginster JY\", \"Thiyagarajan JA\"]","journal":"Drugs","publication_date":"2026-09-12","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes and obesity, but their effects on musculoskeletal health remain completely misunderstood. [OBJECTIVE] This systematic review/meta-analysis aims to synthesise clinical data on the effects of GLP-1 RAs on key relevant bone, muscle, and joint outcomes. [METHODS] MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) (both via Ovid® platform) and Embase were searched from inception to March 2025 to identify relevant randomised controlled trials (RCTs) or real-world evidence (RWE) studies to be included. This bibliographic search was completed manually. A random-effect model meta-analysis was performed for any outcome reported in at least 2 studies. Subgroup analyses were performed on the type of GLP-1 RAs, type of comparator used and study design. Sensitivity analyses (i.e., leave-out sensitivity analyses and analyses restricted to the most adjusted effect estimate) were performed to test the robustness of the data. The strength of evidence was assessed using GRADE. This work has been performed in adherence with PRISMA statement. (PROSPERO Record ID: CRD420251024082). [RESULTS] From 1148 potentially relevant references, 60 articles (46 RCTs, 13 RWE studies and 1 pharmacovigilance study, comprising 1,250,717 individuals) met our inclusion criteria. Different GLP-1 RAs were represented across the panel of studies, i.e., semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide (dual agonist gastric inhibitory polypeptide [GIP]/GLP-1) and others. No effect on bone outcomes (i.e., bone mineral density [all sites] and fractures [all sites]) were observed when the meta-analytical models included the most adjusted effect size. Regarding muscle outcomes, a significant decrease of lean body mass/fat-free mass was consistently observed with GLP-1 RAs in the global model (k = 28, standardised mean difference [SMD] 0.52, 95% confidence interval [CI] -0.8; -0.23, I2 88%, p-value for heterogeneity <0.0001), which remained robust in all sensitivity analyses. Subgroup analyses showed that the effect was mainly driven by liraglutide and semaglutide, with a decrease in lean body mass/fat-free mass observed when GLP-1 RAs were compared with placebo. No publication bias was found. Regarding joint outcome, models revealed no significant change in The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness. [CONCLUSIONS] This meta-analysis is the first to investigate the effects of GLP-1 RAs on a large panel of musculoskeletal health outcomes. While no significant effects were observed on bone- or joint-related outcomes, GLP-1 RAs were associated with reductions in lean body mass/fat-free mass, although the certainty of evidence was low and these changes appeared largely related to weight loss. Whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain. Further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.","url":"https://pubmed.ncbi.nlm.nih.gov/42730869/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of Interest: D.S-R. reports personal speaker fees from Nutricia outside the submitted work. J-Y.R. is President of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), a not-for-profit organisation receiving Unrestricted Educational Grands from corporate partners. J-Y.R. is an Editorial Board member of Drugs. J-Y.R. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Other authors did not report any conflicts of interest in relation to this work. Disclaimer: The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Code Availability: All materials related to this work are freely available on the Open Science Framework deposit – https://osf.io/zbhwc/ Availability of Data and Material: All materials related to this work are freely available on the Open Science Framework deposit – https://osf.io/zbhwc/ Authors’ Contribution: J-Y.R. and J.A.T. are at the initiative of the research question. C.B. and Y.M. are the main investigators of the present research. C.B. drafted the protocol, which was reviewed by A.S. and J-Y.R. C.B. developed the search strategies and identified potential references for inclusion in the project. Y.M. C.B. and D.S.R. screened the references and selected the relevant ones. Conflicts were resolved by C.B. and Y.M. Y.M. performed the manual literature search. Y.M., C.B. and D.S.R., S.v.H. extracted the data, and performed the risk of bias assessment. Meta-analyses models were run by Y.M and C.B. The results were first interpreted by C.B., J-Y.R., A.S. and then by the rest of the experts, including A.M., R.R., and G.D. The first draft of the manuscript was written by C.B. All authors reviewed and approved the final manuscript.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"osteoarthritis\", \"muscle\", \"lean_mass\", \"bone\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":66,"doi":"10.1016/j.mce.2026.112917","pmid":"42727623","nct_ids":"[]","title":"Metabolic Effects of a GLP-1 Analog Combined with Aerobic Training in Ovariectomized Rats","authors":"[\"Selau B\", \"Bastos LM\", \"Normann RS\", \"Cubas GK\", \"Herrmann ROCDC\", \"Barros LDAO\", \"de Amaral M\", \"Trapp M\", \"Kucharski LC\", \"Vogt ÉL\", \"Model JFA\", \"Vinagre AS\"]","journal":"Molecular and cellular endocrinology","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Menopause is associated with visceral obesity, low-grade chronic inflammation, and increased risk of dyslipidemia, insulin resistance, and type 2 diabetes. Although exercise (EXE) and GLP-1 receptor agonists, such as semaglutide (SEM), have demonstrated beneficial effects on metabolic regulation, their combined impact in menopause models has been less investigated. In this study, ovariectomized female Wistar rats were divided into four experimental groups: sedentary plus saline (SED + SAL), sedentary plus semaglutide (SED + SEM), exercise (EXE + SAL), and EXE + SEM. The aerobic exercise protocol consisted of treadmill running at moderate intensity for four weeks, during which the rats received either SEM or SAL weekly. At the end of the protocol, metabolic parameters were assessed in blood, liver, soleus and gastrocnemius muscles. Both SEM groups had lower body weight, weight gain, relative subcutaneous white adipose tissue (scWAT) mass, glucose, total proteins, and triglycerides in serum and liver, while LDL cholesterol, glycogen in liver and gastrocnemius, and AMPK and HSF1 expression in gastrocnemius increased. EXE decreased total and LDL cholesterol, liver triglycerides and HSF1 expression in both tissues, while glycogen in liver and gastrocnemius, liver HSF1 expression and relative mass were increased. The combination of SEM + EXE increased glycogen content in the gastrocnemius and AMPK expression in both gastrocnemius and liver. This combined treatment reduced HDL levels, hepatic triglycerides and scWAT relative weight. These results suggest that SEM and EXE exert complementary effects on glycemic and lipid metabolism, with partially distinct metabolic outcomes that may involve different underlying mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42727623/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":67,"doi":"10.1016/j.hrtlng.2026.102943","pmid":"42727531","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor activation, inflammation and heart failure: Insights from genetic analysis","authors":"[\"Tian Y\", \"Sheng C\", \"Zhu J\", \"Bai S\", \"Li R\", \"Jiang Y\", \"Luo Y\", \"Guo Q\", \"Pan J\", \"Liu W\", \"Wang D\"]","journal":"Heart & lung : the journal of critical care","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce heart failure (HF) risk, but the underlying mechanisms remain unclear. [OBJECTIVES] To assess the causal effect of GLP-1R pathway activation on HF risk and identify inflammatory mediators using genetic approaches. [METHODS] We conducted two-sample and two-step Mendelian randomization (MR). Cis-eQTL SNPs for GLP1R expression (P 〈 5 × 10⁻⁸, F 〉 10) were selected from the eQTLGen Consortium to proxy the GLP-1R pathway, with positive control against type 2 diabetes mellitus (T2DM). The primary analysis used inverse-variance weighted (IVW) method, with four MR methods as sensitivity analyses. Using two-step MR, we assessed 95 inflammatory biomarkers as mediators, with significant ones validated externally using an independent dataset. Mediation effects were calculated via Delta and parametric Bootstrap methods. [RESULTS] Genetic instruments showed a strong association with reduced T2DM risk (OR = 0.8217, 95% CI 0.7852 to 0.8598, P = 2.32 × 10⁻¹⁷). Genetically proxied GLP1R expression was associated with lower HF risk (OR = 0.9327, 95% CI 0.8715 to 0.9981, P = 0.0439). Among 95 biomarkers, matrix metalloproteinase-1 (MMP-1) reduction showed a significant indirect effect (-0.0196, Delta 95% CI -0.0342 to -0.0050, P = 0.0084; Bootstrap -0.0356 to -0.0066), accounting for 28% of the total effect. External validation confirmed this mediation (indirect effect -0.0148, Delta 95% CI -0.0266 to -0.0030, P = 0.0140; Bootstrap 95% CI -0.0275 to -0.0039), explaining 21% of the total effect. [CONCLUSION] This study provides genetic evidence that GLP-1R activation protects against HF and identifies MMP-1 reduction as a partial mediator, illuminating an anti-inflammatory mechanism underlying GLP-1RA efficacy.","url":"https://pubmed.ncbi.nlm.nih.gov/42727531/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":127,"doi":"10.1016/j.knee.2026.104639","pmid":"42727208","nct_ids":"[]","title":"Postoperative outcomes after total knee arthroplasty in type 2 diabetes mellitus patients receiving semaglutide versus tirzepatide: a propensity score-matched national research network analysis","authors":"[\"Wu KA\", \"Choudhury A\", \"Wu JA\", \"Shenoy DA\", \"Song J\", \"Mai E\", \"Dhanjani S\", \"Shatkin M\", \"Wellman SS\", \"Seyler TM\", \"Moucha CS\", \"Hayden BL\"]","journal":"The Knee","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide (GLP-1 receptor agonist) and tirzepatide (dual GIP/GLP-1 agonist) are increasingly prescribed to adults with type 2 diabetes mellitus (T2DM) undergoing total knee arthroplasty (TKA). Whether short-term postoperative outcomes differ between these agents was unknown. [METHODS] This was a retrospective cohort study using the TriNetX research network database. Adults with T2DM who underwent primary TKA between June 1, 2022, and December 31, 2024, and had an active prescription for semaglutide or tirzepatide within 90 days preoperatively were eligible. 1:1 propensity score matching was conducted on age, sex, race, body mass index, hemoglobin A1c, comorbidity burden, and concurrent diabetes medication use, yielding 415 matched pairs. Outcomes through 90 and 180 days included medical complications, surgical complications, and healthcare utilization. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression. [RESULTS] After matching (n = 830), there were no differences in 90-day medical complications (OR 1.122, 95% CI 0.736-1.710; P = 0.591) or 180-day surgical complications (OR 1.632, 95% CI 0.845-3.152; P = 0.141) between semaglutide and tirzepatide cohorts. Individual events, including myocardial infarction, stroke, pneumonia, sepsis, pulmonary embolism, deep vein thrombosis, acute kidney injury (OR 0.867, 95% CI 0.417-1.801; P = 0.701), urinary tract infection (OR 1.562, 95% CI 0.863-2.827; P = 0.138), surgical site infection (OR 1.726, 95% CI 0.782-3.810; P = 0.172), periprosthetic joint infection, wound dehiscence, mortality, and revision-were statistically similar (all P > 0.05). Emergency department visits and/or readmissions were comparable at 90 days (OR 0.775, 95% CI 0.570-1.052; P = 0.102) and 180 days (OR 0.887, 95% CI 0.672-1.170; P = 0.397). Several outcomes had low event counts in both groups, limiting precision. [CONCLUSION] In a large, propensity-matched national cohort of primary TKA, semaglutide and tirzepatide demonstrated similar short-term safety and utilization profiles. These findings support continued perioperative use of either agent in T2DM patients undergoing TKA.","url":"https://pubmed.ncbi.nlm.nih.gov/42727208/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"immune\", \"mortality\", \"adverse_effects\", \"perioperative\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":199,"doi":"10.1177/11207000261476202","pmid":"42725550","nct_ids":"[]","title":"Preoperative GLP-1 receptor agonist use and outcomes after total hip arthroplasty: a matched cohort study","authors":"[\"Diab AR\", \"Chang THW\", \"Diab O\", \"Kheir MM\"]","journal":"Hip international : the journal of clinical and experimental research on hip pathology and therapy","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed among total hip arthroplasty (THA) candidates, yet their perioperative impact remains unclear. [METHODS] Using TriNetX, we identified adults undergoing primary THA (2003-2023) with preoperative GLP-1 RA exposure (⩾3 prescriptions within 1 year of surgery) versus controls. 1:1 propensity score matching for demographics, comorbidities, and baseline labs yielded 1262 patients per cohort. Outcomes included 90-day medical complications and mechanical complications (PJI, dislocation, aseptic loosening, periprosthetic fracture, all-cause revision) at 1, 2, and 5 years, reported in accordance with the STROBE guidelines. [RESULTS] At 90 days, the GLP-1 RA cohort demonstrated significantly lower risks of DVT (1.6% vs. 3.0%; RR 0.53, 95% CI, 0.31-0.89; p = 0.014) and hospital readmission (1.1% vs. 2.8%; RR 0.40, 95% CI, 0.22-0.71; p = 0.001). No significant differences were found in other 90-day outcomes or in mechanical complications, including all-cause revision (94.6% vs. 95.5% survival; p = 0.674) and PJI (94.7% vs. 94.4%; p = 0.465) at 5 years. [CONCLUSIONS] Consistent preoperative GLP-1 RA use is associated with reduced 90-day DVT and readmission following primary THA without increased risk of other complications or mechanical outcomes at 5 years. As DVT was the only significant thromboembolic endpoint, prospective investigation is needed before attributing a thromboprophylactic effect to these agents.","url":"https://pubmed.ncbi.nlm.nih.gov/42725550/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"bone\", \"mortality\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":242,"doi":"10.1177/15347346261487722","pmid":"42726083","nct_ids":"[]","title":"Assessing the Association Between GLP-1 Receptor Agonists and Diabetic Foot Complications Using Real-World Pharmacovigilance Database and Mendelian Randomization","authors":"[\"Zhang T\", \"Luo X\", \"Chen C\", \"Zhang Y\", \"Xu B\", \"He Z\", \"Zhou J\"]","journal":"The international journal of lower extremity wounds","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"BackgroundLimited studies to date have yielded inconsistent results regarding the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and diabetic foot complications. We conducted a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database and performed drug target Mendelian randomization (MR) studies to explore the association between GLP-1RAs and diabetic foot complications.MethodsWe mined the FAERS database from 2005q2 to 2024q2 using AERSMine. Additionally, a two-sample MR analysis was conducted to investigate the causal relationship between GLP-1R agonism and diabetic foot complications.ResultsA total of 1819 adverse event reports were recorded for GLP-1RAs, compared to 17,206 reports for other ATC-A10 class drugs. The frequency of diabetic foot reports in the GLP-1RA group was significantly lower than in the control group (6.38 vs 11.31/1000 reports), with a proportional reporting ratio (PRR) of 0.56 (95% confidence interval [CI], 0.54 to 0.59; P < 0.001). This trend was consistently observed across individual GLP-1RA molecules, including semaglutide (PRR, 0.45; 95% CI, 0.39 to 0.51), dulaglutide (PRR, 0.49; 95% CI, 0.45 to 0.54), and liraglutide (PRR, 0.30; 95% CI, 0.26 to 0.35). These results remained robust after conducting secondary and sensitivity analyses, further supporting their consistency and reliability. MR results generally corroborated the findings from the retrospective analyses of the AE records in the FAERS database.ConclusionsPharmacovigilance and drug target MR suggested a potential association between GLP-1RA use and diabetic foot complications, but the evidence is preliminary and requires further real-world prospective validation.","url":"https://pubmed.ncbi.nlm.nih.gov/42726083/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"mendelian_randomization","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":593,"doi":"10.1016/j.redox.2026.104394","pmid":"42743759","nct_ids":"[]","title":"Combination of genetic eNOS deficiency and high-fat diet induces reproducible cardiometabolic HFpEF","authors":"[\"Elbatreek MH\", \"Khodade V\", \"Amin D\", \"Huerta M\", \"Allerton TD\", \"Polhemus DJ\", \"Shah SJ\", \"Vondriska TM\", \"Goodchild TT\", \"Lefer DJ\"]","journal":"Redox biology","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ cardiometabolic syndrome lacking universally effective therapies. We developed and validated a robust murine model leveraging complete, constitutive genetic endothelial nitric oxide synthase deficiency (eNOS KO) coupled with metabolic stress via a high-fat diet (HFD) in both male and female cohorts. eNOS KO mice subjected to HFD (10 weeks for males; 15 weeks for females) developed a severe and highly reproducible cardiometabolic HFpEF phenotype. Despite preserved left ventricular ejection fraction, both sexes exhibited profound diastolic dysfunction, characterized by elevated E/e' ratios and left ventricular end-diastolic pressures (LVEDP), alongside severe exercise intolerance. Consistent with the systemic clinical syndrome, pathological remodeling extended to multi-organ damage, featuring prominent cardiac fibrosis, severe hepatic steatosis, and renal tubulointerstitial fibrosis. Finally, chronic administration of the dual GIP/GLP-1 receptor agonist tirzepatide largely reversed the hemodynamic, functional, and systemic fibrotic derangements. In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.","url":"https://pubmed.ncbi.nlm.nih.gov/42743759/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":628,"doi":"10.1097/md.0000000000050733","pmid":"42736811","nct_ids":"[]","title":"Clinical outcomes associated with GLP-1 receptor agonist use in metabolic dysfunction-associated steatohepatitis: A multinational cohort study","authors":"[\"Khan SA\", \"Subedi A\", \"Marasini A\", \"Shrestha A\", \"Jha S\", \"Kandel A\", \"Basnet K\", \"Karki S\", \"Kamal M\", \"Khan S\", \"Kausar H\", \"Parajuli SB\", \"Dahiya DS\"]","journal":"Medicine","publication_date":"2026-09-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is an important progressive liver disorder that can lead to hepatic decompensation, hepatocellular carcinoma (HCC), and premature death. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated beneficial effects on metabolic dysfunction and liver histology; however, their relationship with major long-term hepatic outcomes in routine clinical practice has not been fully established. A retrospective multicenter cohort study was conducted using a large real-world health database. Adults with MASH were classified according to whether they had documented exposure to GLP-1 RAs. The 2 groups were balanced using 1:1 propensity score matching based on demographic variables, coexisting conditions, and concomitant therapies. The outcomes evaluated were ascites, HCC, and all-cause mortality, with comparative effects reported as risk differences (RDs) and 95% confidence intervals (CIs). The initial study population comprised 1434,086 individuals with MASH, including 168,740 GLP-1 RA users and 1265,346 individuals without GLP-1 RA exposure. After matching, 168,733 patients were retained in each cohort with comparable baseline characteristics. Exposure to GLP-1 RAs was associated with fewer cases of ascites (RD - 0.013; 95% CI - 0.014 to - 0.012; P < .001) and lower all-cause mortality (RD - 0.022; 95% CI - 0.023- - 0.021; P < .001). A statistically significant increase in HCC incidence was observed among GLP-1 RA users; however, the magnitude of the absolute difference was minimal (RD 0.000; 95% CI 0.000-0.001; P = .025). Among patients with MASH, GLP-1 RA exposure was associated with a lower incidence of ascites and reduced mortality in this large real-world matched cohort. While a statistically significant difference in HCC occurrence was detected, its negligible absolute magnitude suggests limited clinical relevance. These findings support the potential role of GLP-1 RAs as beneficial and hepatically safe therapies in patients with MASH.","url":"https://pubmed.ncbi.nlm.nih.gov/42736811/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors have no funding and conflicts of interest to declare.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:19+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"liver\", \"cancer\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":662,"doi":"10.64898/2026.09.08.26362532","pmid":null,"nct_ids":"[]","title":"Side effects of lower dose compounded semaglutide paired with a behavioral management program: A real-world retrospective study","authors":"[\"Owen, E. C.\", \"Moulder, R. G.\", \"Morse, J. L.\", \"Ainsworth, M. C.\", \"Fabry, A.\", \"Merner, A. R.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-11","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"ObjectiveEvaluate differences in side effects between a low and standard dose compounded semaglutide paired with a behavioral companion in the first 16 weeks of treatment using a real-world, retrospective cohort.\n\nMethodsSide effects were compared between the low dose protocol (Noom Microdose GLP-1 Rx Program; NMGP, up to 0.6mg/weekly compounded semaglutide) and Nooms standard dose of compounded semaglutide (Noom GLP-1 Rx Program; NGP, up to 1.2mg/weekly). Users were propensity score matched on side effect rate in the first 8 weeks when dosing protocols were identical, and longitudinal side effect trajectories were compared via logistic regression. Analyses were conducted on a second cohort with additional matched baseline characteristics.\n\nResultsThe full sample included 7,682 NGP and 2,877 NMGP users. NMGP users had 34% lower and 29% lower relative odds of reporting GI side effects (p=0.001) and any side effects (p=0.001) by week 16, respectively (n=2,481 per group). Results of the second cohort demonstrated 38% lower odds of any side effect by week 16 among NMGP users (n=958 per group, p=0.019).\n\nConclusionsLower doses of compounded semaglutide alongside a behavioral companion are associated with fewer side effects in the first 16 weeks compared to a higher dose program.","url":"https://www.medrxiv.org/content/10.64898/2026.09.08.26362532","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":76,"doi":"10.5217/ir.2026.00152","pmid":"42717572","nct_ids":"[]","title":"Comparative outcomes for tirzepatide versus glucagon-like peptide-1 receptor agonists in patients with inflammatory bowel disease: a national propensity matched study","authors":"[\"Patel KS\", \"Fakhoury B\", \"Parmar K\", \"Jahagirdar V\", \"Sanyal AJ\", \"Arab JP\", \"Tariq R\"]","journal":"Intestinal research","publication_date":"2026-09-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/AIMS] Evidence suggests glucagon-like peptide-1 receptor agonists (GLP-1RAs) may improve disease-specific outcomes for inflammatory bowel disease (IBD). Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, may offer additional benefits. We compared clinical and safety outcomes among patients with IBD treated with tirzepatide versus GLP-1RAs. [METHODS] Patients aged ≥ 18 years with IBD were identified within a retrospective multiinstitutional U.S. database who were prescribed tirzepatide or GLP-1RA between May 2022 and January 2025. Propensity score matching (1:1) was performed for demographics, comorbidities, and IBD medications. Outcomes were assessed over 18 months and included intravenous (IV) steroid use, intestinal surgery, emergency department visits, hospitalization, and a composite of IV steroids and surgery. Adverse outcomes were assessed. [RESULTS] After matching, 3,042 patients (mean age, 54.6 years; 71.3% female) were analyzed in each cohort. Median follow-up was 540 days (interquartile range, 478-540 days) for tirzepatide versus 540 days (interquartile range, 540-540 days) for GLP-1RA. Patients taking tirzepatide had a significantly reduced risk of IV steroid use (adjusted hazard ratio [aHR], 0.81; 95% confidence interval [CI], 0.68-0.94) and composite IBD outcomes (aHR, 0.86; 95% CI, 0.73-0.97) with similar risk of hospitalization, emergency department visit and receipt of intestinal surgery. In patients with ulcerative colitis specifically, tirzepatide was similarly associated with a reduced risk of IV steroid use (aHR, 0.82; 95% CI, 0.69-0.97). Adverse outcome risks were similar. [CONCLUSIONS] Patients with IBD prescribed tirzepatide may have lower risk of IV steroid use compared to those taking GLP-1RAs. Prospective studies are warranted to validate these results and explore underlying mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42717572/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"rheumatologic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":132,"doi":"10.1007/s40273-026-01659-4","pmid":"42722807","nct_ids":"[]","title":"Carbon Emission Impact of Semaglutide in People with Obesity in the UK Using a Disease Modelling Approach","authors":"[\"Lund N\", \"Lübker C\", \"Rasche A\", \"Taylor M\", \"Xu W\", \"Taneja L\", \"Shukla S\", \"Olivieri AV\", \"Sharma Y\"]","journal":"PharmacoEconomics","publication_date":"2026-09-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] We aimed to assess the carbon footprint and clinical outcomes of once-weekly semaglutide in people with overweight or obesity in the UK using a disease modelling approach. [METHODS] A per-patient carbon footprint analysis was conducted to estimate emissions related to obesity management with semaglutide 2.4 mg as an add on to diet and exercise versus diet and exercise alone. A Markov state-transition cohort model (Core Obesity Model) was used for the analysis. Data were sourced from STEP and SELECT trials across three populations: (1) body mass index [BMI] ≥ 30 or ≥ 27 with one or more obesity-related complications (BMI30+/BMI27+C), (2) BMI ≥ 27 with one or more complications, including type 2 diabetes mellitus (BMI27+C), and (3) BMI ≥ 27 with established cardiovascular disease (BMI27+CVD). Carbon emissions were estimated using resource-based and cost-based methods. Key outcomes included life-years, quality-adjusted life-years, and incremental carbon footprint effectiveness ratio. [RESULTS] In the BMI30+/BMI27+C and BMI27+C populations, semaglutide was dominant, yielding 0.30 and 0.25 additional life-years, 0.51 and 0.46 additional quality-adjusted life-years, while reducing lifetime carbon emissions by 1.8% (9850 vs 10,030 kg of CO2 equivalent [CO2e]) and 1.9% (9792 vs 9983 kg CO2e), respectively. Manufacturing emissions of semaglutide were offset by reductions in carbon emissions resulting from fewer obesity-related complications. In the BMI27+CVD population, semaglutide improved life-years by 0.56 and quality-adjusted life-years by 0.59, but emissions increased (14,700 vs 14,444 kg CO2e) because of longer survival and increased monitoring. Scenario and sensitivity analyses confirmed the robustness of the results. [CONCLUSIONS] Semaglutide offers both clinical and environmental benefits in obesity management, supporting the UK's net-zero emissions goals.","url":"https://pubmed.ncbi.nlm.nih.gov/42722807/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflicts of interest/competing interests: Christopher Lübker and Niels Lund are employees and shareholders of Novo Nordisk A/S. Andreas Rasche is a member of the Novo Nordisk Sustainability Advisory Council (contract-based). Weiwei Xu, Loveleen Taneja, Anamaria-Vera Olivieri, Suramya Shukla, and Yuvraj Sharma are full-time employees of IQVIA. Matthew Taylor is employed by York Health Economics Consortium which has received funding from Novo Nordisk in the last three years. Ethics approval: This work is based on previously conducted studies and publicly available data sources. It does not involve any original experiments or studies with human or animal subjects. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions. Code availability: Not applicable. Authors’ contributions: NL: conception and study design, acquisition of data, data collection, data analysis, data interpretation; CL: acquisition of data, data collection, data analysis, data interpretation; AR: data interpretation; MT: data interpretation; WX: conception and study design, acquisition of data, data collection, data analysis, data interpretation; LT: conception and study design, acquisition of data, data collection, data analysis, data interpretation; SS: conception and study design, acquisition of data, data collection, data analysis, data interpretation; AO: conception and study design, acquisition of data, data collection, data analysis, data interpretation; YS: conception and study design, acquisition of data, data collection, data analysis, data interpretation. All authors contributed to the manuscript development and approved the final version. NL is the guarantor of this work. Declaration of AI use: Microsoft Copilot, an AI-powered writing tool, was used to support language refinement, improve clarity and enhance the logical flow of some of the content of the manuscript. All content generated by the AI tool was critically reviewed, edited and approved by the authors to ensure accuracy, scientific integrity and compliance with ethical standards. The authors take full responsibility for the final content. Patient and public involvement: Patients and/or the public were not involved in the design, conduct, reporting or dissemination of the plans of this research.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":244,"doi":"10.1111/dom.71325","pmid":"42723273","nct_ids":"[]","title":"Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists as Adjuncts to Insulin Therapy in Type 1 Diabetes Mellitus: An Overlap-Informed Umbrella Review","authors":"[\"Lee O\", \"Son Y\", \"López-Gil JF\", \"Rahmati M\", \"Kang J\", \"Lee JS\", \"Yon DK\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potential adjuncts to insulin therapy for type 1 diabetes mellitus (T1DM). However, interpretation of the available evidence is complicated by substantial primary-study overlap, methodological heterogeneity and variable certainty of evidence. Thus, we conducted an overlap-informed umbrella review to evaluate the efficacy and safety of GLP-1RAs as adjunctive therapy in T1DM. [MATERIALS AND METHODS] We searched PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and OpenAlex from inception to 22 June 2026, and manually screened reference lists to identify systematic reviews with meta-analyses that included randomized controlled trials (RCTs), either alone or alongside nonrandomized studies, evaluating adjunctive GLP-1RA therapy in T1DM. Methodological quality was assessed using AMSTAR 2, and primary-study overlap was quantified using a citation matrix and corrected covered area (CCA). Outcome-specific representative meta-analyses were selected, and their primary-study data were independently reanalyzed using random-effects models. Continuous and dichotomous outcomes were summarized as mean differences (MDs) and risk ratios (RRs), respectively, with 95% confidence intervals (CIs). The certainty of evidence was assessed using GRADE. [RESULTS] Eighteen systematic reviews with meta-analyses encompassing 56 unique primary studies (35 RCTs and 21 nonrandomized studies) were included. The calculated CCA was 19.6%, indicating a very high degree of primary-study overlap, largely driven by the ADJUNCT ONE and ADJUNCT TWO trials. Adjunctive GLP-1RA therapy reduced HbA1c (MD, -0.23% [95% CI, -0.30 to -0.17]; moderate certainty), body weight (MD, -3.93 kg [-4.29 to -3.56]; moderate certainty) and total daily insulin dose (MD, -5.74 IU/day [-7.30 to -4.17]; low certainty). No significant improvement was observed in time in range (MD, 1.99% [95% CI, -1.17 to 5.15]; very low certainty). No statistically significant increases were observed in severe hypoglycemia (RR, 0.83 [95% CI, 0.36-1.91]; low certainty) or diabetic ketoacidosis (RR, 0.67 [95% CI, 0.16-2.86]; low certainty). However, GLP-1RAs increased the risks of nausea (RR, 2.88 [95% CI, 2.20-3.76]; high certainty), vomiting (RR, 3.11 [1.94-4.97]; high certainty), and withdrawal due to adverse events (RR, 2.10 [1.42-3.12]; high certainty), whereas the risk of diarrhoea was not significantly increased (RR, 1.88 [0.82-4.33]; low certainty). [CONCLUSIONS] Adjunctive GLP-1RA therapy was associated with a modest reduction in HbA1c and clinically relevant reductions in body weight and insulin requirements, without a significant improvement in time in range. Gastrointestinal adverse events were increased, whereas the risks of diabetic ketoacidosis and severe hypoglycemia remained uncertain. These findings do not support routine use but suggest a potential role in selected individuals for whom weight reduction and lower insulin requirements are therapeutic priorities.","url":"https://pubmed.ncbi.nlm.nih.gov/42723273/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-11-07T04:49:13+00:00","study_design":"umbrella_review","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"dose\": \"various\", \"route\": null, \"comparator\": null, \"treatment_duration\": null}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"HbA1c, body weight, insulin dose, time in range and safety with adjunctive GLP-1RA therapy in T1DM","endpoints":null,"effect_estimate":"HbA1c MD, -0.23%; body weight MD, -3.93 kg; total daily insulin dose MD, -5.74 IU/day; time in range MD, 1.99% (not significant); severe hypoglycemia RR, 0.83 and diabetic ketoacidosis RR, 0.67 (not significant); nausea RR, 2.88, vomiting RR, 3.11 and withdrawal due to adverse events RR, 2.10 increased; diarrhoea RR, 1.88 (not significant)","confidence_interval":"95% CI, -0.30 to -0.17 (HbA1c)","p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 1 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 1 diabetes on insulin therapy\", \"sample_size\": null, \"inclusion_exclusion\": \"systematic reviews with meta-analyses including RCTs of adjunctive GLP-1RA therapy in T1DM\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 1 diabetes treated with insulin, a metabolic disease the target group does not have.","mediation":"not_applicable","mediation_notes":"Outcomes are HbA1c, weight, insulin dose and time in range themselves; mediation is not applicable.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Umbrella review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, -0.30 to -0.17 (HbA1c)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: an umbrella review that re-pooled primary data from 35 RCTs and 21 nonrandomized studies for intermediate outcomes; high overlap and mixed designs keep it below HIGH.","funding_source":"Ministry of Health and Welfare; Ministry of Science and ICT, South Korea; Soonchunhyang University Research Fund","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"GLP-1RAs increased nausea (RR, 2.88), vomiting (RR, 3.11) and withdrawal due to adverse events (RR, 2.10), all high certainty; no significant increase in severe hypoglycemia (RR, 0.83), diabetic ketoacidosis (RR, 0.67) or diarrhoea (RR, 1.88)","limitations":"Umbrella review with heavy overlap of primary studies (largely two trials) and a mix of randomized and nonrandomized studies; certainty ranges from very low to high, and the authors do not support routine use.","plain_summary":"Eighteen meta-analyses covering 56 studies of adding a GLP-1 drug to insulin in type 1 diabetes were brought together in this umbrella review. The add-on lowered HbA1c slightly (by 0.23%), body weight (by 3.93 kg) and insulin needs, but did not improve time in the target glucose range. Nausea, vomiting and stopping treatment because of side effects were more common, while severe low blood sugar and ketoacidosis did not rise significantly.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":286,"doi":"10.20944/preprints202609.0818.v1","pmid":null,"nct_ids":"[]","title":"A Comparison of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors in Reducing the Incidence of Tuberculosis and Mortality in Patients with Diabetes","authors":"[\"Hsu C\", \"Chang R\", \"Chen C\", \"Chu K\", \"Jiang Y\", \"Hong W\", \"Chen I\", \"Lin M.\"]","journal":"preprint server","publication_date":"2026-09-10","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Diabetes mellitus (DM) significantly increases the risk of developing active tuberculosis (TB). Poorly controlled diabetes, particularly with sustained hyperglycemia, is associated with higher TB incidence. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become an important therapeutic option in the management of type 2 diabetes mellitus. GLP-1 RAs may also have immunomodulatory effects. Our study aims to evaluate the incidence of pulmonary TB among diabetic patients, and to examine whether GLP-1 RAs control modifies TB risk and mortality. We conducted a retrospective cohort study using the Global Collaborative Network of the TriNetX™ research platform from 152 participating health care organizations across the United States. We identified adult patients with diabetes mellitus who received either oral hypoglycemic agents (OHAs) containing GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) between January 1, 2016, and December 31, 2024. Diabetic patients receiving OHAs containing GLP-1 RA treatment had a significantly lower incidence of TB (HR: 0.55, 95% CI: 0.45-0.69), significantly reduced risk of death (HR: 0.52, 95% CI: 0.51-0.54), and significantly reduced risk of gastrointestinal and hepatobiliary disorders (HR: 0.77, 95% CI: 0.75-0.78), compared to those receiving DPP-4 inhibitor treatment. This observational study demonstrated that the use of GLP-1 RAs, compared with DPP-4i, was associated with a lower incidence of tuberculosis, all-cause mortality, and gastrointestinal adverse events. These findings may have important implications for public health policy.","url":"https://doi.org/10.20944/preprints202609.0818.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":138,"doi":"10.1161/jaha.125.044249","pmid":"42714458","nct_ids":"[]","title":"Tirzepatide and the Incidence of Atrial Fibrillation in Adults With Overweight or Obesity: An Updated Meta-Analysis of Randomized Controlled Trials","authors":"[\"Mansouri ES\", \"Queiroga F\", \"Barbosa LM\", \"Azevedo AK\", \"Donaldy W\", \"Mirbolouk MJ\", \"Blair CV\", \"Rivera A\", \"Ferreira Felix I\", \"Abreu M\", \"Deshmukh AJ\", \"DeSimone CV\"]","journal":"Journal of the American Heart Association","publication_date":"2026-09-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Tirzepatide is a dual agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, with proven efficacy in weight loss and improvement in cardiovascular outcomes. However, the effects of tirzepatide on the incidence of atrial fibrillation in patients with overweight or obesity remain unclear. [METHODS] PubMed, Embase, and Cochrane Library were searched for randomized controlled trials comparing tirzepatide versus placebo for individuals with overweight or obesity. Odds ratios (ORs) with 95% credible intervals (CrIs) were pooled using a Bayesian binomial-normal hierarchical model, appropriate for rare-event outcomes. [RESULTS] Our meta-analysis included 10 randomized controlled trials, including 6515 individuals, of whom 4491 (68.9%) were randomized to tirzepatide. The pooled OR was 2.20 (95% CrI, 0.81-6.75) for atrial fibrillation, 2.16 (95% CrI, 0.90-5.87) for atrial arrhythmia, and 1.84 (95% CrI, 1.04-3.90) for any arrhythmia. [CONCLUSIONS] Tirzepatide was not associated with atrial fibrillation or atrial arrhythmia. Although higher odds of overall arrhythmias were observed, event rates were low and the findings should be interpreted cautiously.","url":"https://pubmed.ncbi.nlm.nih.gov/42714458/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":249,"doi":"10.1080/03007995.2026.2726017","pmid":"42712138","nct_ids":"[]","title":"A retrospective cohort study on the comparative safety of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on the onset of gallbladder disease in type II diabetes","authors":"[\"Carlson K\", \"Kaur J\", \"Gaber CE\", \"Reutrakul S\", \"Kim K\"]","journal":"Current medical research and opinion","publication_date":"2026-09-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUNDS AND OBJECTIVES] To assess and confirm the risk of gallbladder disease in Type II diabetes (T2D) patients treated with Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA) compared to Dipeptidyl Peptidase-4 Inhibitor (DPP-4I). [MATERIALS AND METHODS] This is a retrospective cohort study using administrative claims. Adults who newly received either GLP-1RA or DPP-4I for T2D management were identified between 2016 and 2021. Study cohort included individuals naïve to gallbladder disease or relevant condition on or 6-month prior to the first GLP-1RA or DDP-4I dispensing date (Index). Cumulative incidence of gallbladder disease after the minimal follow-up period of the first 45 days was estimated using the Kaplan-Meier method. A Cox proportional hazard regression model was used to calculate hazard ratios of gallbladder disease for GLP-1RA vs. DPP-4I up to 2 years beyond the initial 45-day exposure. [RESULTS] The cohort included 135,197 GLP-1RA and 118,919 DPP-4I patients with minor diabetes complication profiles. Cumulative incidence of gallbladder disease at 1 year was 1.286% (GLP-1RA) vs. 1.054% (DPP-4I); at 2 years, it was 2.181% vs. 2.039%. Adjusting for the baseline characteristics, the respective HR (95% CI) was 1.241 (95% CI, 1.104-1.393) at 1 year and 1.176 (95% CI, 1.061-1.304) at 2 years. [CONCLUSION] A moderate but significant increase in the risk of gallbladder disease was confirmed from the real-world population receiving GLP‑1 RA compared with DPP‑4I. This confirmed risk underscores the need for ongoing monitoring and surveillance for gallbladder disease during GLP‑1RA therapy.","url":"https://pubmed.ncbi.nlm.nih.gov/42712138/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":141,"doi":"10.1111/dom.71313","pmid":"42712110","nct_ids":"[]","title":"Association of GLP-1 Receptor Agonists Versus Other Antidiabetic Medications With Cardiovascular, Renal, and Liver Outcomes in Patients With Type 2 Diabetes","authors":"[\"Fan Y\", \"Peng N\", \"Jiang L\", \"Wei R\", \"Lu G\", \"Zhang S\", \"Mu C\", \"Xue M\", \"Lyu B\", \"Yao D\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To compare cardiovascular, kidney, and liver outcomes of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus seven other antidiabetic medications (ADMs) in Chinese patients with Type 2 diabetes. [MATERIALS AND METHODS] This retrospective cohort study (2018-2024) used an Eastern China regional healthcare database. We included patients initiating GLP-1 RAs, sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), insulins, sulfonylureas, α-glucosidase inhibitors (AGIs), thiazolidinediones, or meglitinides. Outcomes were major adverse cardiovascular (MACE), kidney (MAKE), and liver (MALO) events. A propensity score-based matching weights (MWs) approach was used to balance covariates including demographics, comorbidities, and medication use, and Cox proportional hazards models were conducted in both intention-to-treat and per-protocol analyses. [RESULTS] Among 105 391 patients, SGLT-2 inhibitors (HR 1.19, 95% CI 1.10-1.30), insulins (HR 1.42, 95% CI 1.32-1.52), sulfonylureas (HR 1.30, 95% CI 1.18-1.43), and AGIs (HR 1.45, 95% CI 1.31-1.59) were associated with higher MACE risk compared with GLP-1 RAs. DPP-4 inhibitors (HR 3.09, 95% CI 1.69-5.63), insulins (HR 6.11, 95% CI 4.37-8.54), and meglitinides (HR 4.56, 95% CI 2.32-8.97) were associated with higher MAKE risk. Higher MALO risk was observed with DPP-4 inhibitors (HR 1.48, 95% CI 1.21-1.79), insulins (HR 2.06, 95% CI 1.81-2.34), AGIs (HR 1.55, 95% CI 1.26-1.90), and meglitinides (HR 1.43, 95% CI 1.07-1.92). [CONCLUSIONS] GLP-1 RAs were associated with favourable cardio-renal-metabolic outcomes compared with several second-line glucose-lowering agents, particularly insulins and sulfonylureas. These findings add to the real-world evidence supporting the potential cardiovascular, renal, and hepatic benefits of GLP-1 RAs in patients with T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/42712110/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":142,"doi":"10.1016/j.clinthera.2026.08.004","pmid":"42711176","nct_ids":"[]","title":"Finerenone-Based Dual Versus Triple Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus Associated Chronic Kidney Disease: A Retrospective Cohort Study","authors":"[\"Khogalee M\", \"Mohamed S\", \"Otim ME\", \"Basher M\", \"Mumtaz M\", \"Thaslim S\", \"El Houni A\"]","journal":"Clinical therapeutics","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Finerenone reduces Cardiovascular-Kidney-Metabolic (CKM) risk in type 2 diabetes mellitus (T2DM)-related chronic kidney disease (CKD). Evidence on its combined use with sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in routine care remains limited. This study aimed to evaluate 6-month estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and adverse outcomes among adults with T2DM-related CKD receiving finerenone + SGLT2i, with or without concomitant GLP-1RA. [METHODS] This retrospective cohort evaluated electronic medical records (EMR) from a UAE-based teaching hospital (November 2023 - January 2025). Adults with T2DM-related CKD receiving finerenone for ≥6 months were categorized at initiation into dual-therapy (Finerenone+SGLT2i), and triple-therapy (Finerenone+SGLT2i+GLP-1 RA), Patients receiving finerenone + GLP-1RA alone were excluded. Outcomes were 6-months eGFR, UACR and adverse events. Via Statistical Package for the Social Sciences (SPSS), means were analysed using paired t-tests, and between-group comparisons using adjusted analysis. [FINDINGS] Eighty-three patients were included after excluding 6 patients receiving finerenone + GLP-1RA only. Within-group ln(UACR) decreased in both regimens [dual-therapy (50.6%, 28.3-65.9; P < 0.001) and triple-therapy (46.9%, 27.0-61.3; P < 0.001)]. Mean 6-month eGFR changes were variable [dual-therapy (-6.12, -10.66 to -1.59; P = 0.010) and triple-therapy (-1.49, -5.19 to +2.21; P = 0.424)]. On adjusted analysis, triple-therapy was associated with higher 6-month eGFR compared with dual therapy (+6.407 mL/min/1.73 m²; 95% CI: +0.297 to +12.52; P = 0.040), whereas for ln(UACR) was not statistically significant (-0.323; 95% CI: -0.912 to +0.266; P = 0.277). Interpretation was limited by baseline imbalance and the retrospective observational design. [IMPLICATIONS] Triple-therapy was associated with higher adjusted 6-month eGFR than dual-therapy, while UACR decreased without significant adjusted between-group differences. Findings were interpreted as associative rather than comparative superiority, given the observational design, baseline imbalance, and short follow-up. These results should be interpreted as hypothesis-generating associations, and future multicenter longitudinal studies with longer follow-up and assessment of medication continuation, and time-updated exposure are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42711176/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":202,"doi":"10.1093/ehjcvp/pvag072","pmid":"42709513","nct_ids":"[]","title":"Vagal activity related events and glucagon-like peptide-1 receptor agonists","authors":"[\"Al-Ansary L\", \"Kinnberg Nielsen S\", \"Hashiba Jensen M\", \"Nouhravesh N\", \"Sindet-Pedersen C\", \"Gislason G\", \"Vibe Rasmussen P\", \"Lamberts M\", \"Holt A\"]","journal":"European heart journal. Cardiovascular pharmacotherapy","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1 RA) carry side-effects such as dizziness and nausea related to increased vagal tone. This study investigated associations between GLP-1 RA use and the risk of vagal activity related (VAR) events. [METHODS] Using the Danish health registers, patients with type 2 diabetes mellitus (T2DM) first-time initiated on GLP-1 RA (exposure) or SGLT-2i (active control) were identified between January 2010 and October 2022. Standardized 1-year absolute risks of VAR events (syncope, fractures, bradyarrhythmia, or cardiac device implantation) were computed to compare risk associated with GLP-1 RA and SGLT-2i initiation. Complementary analyses in patients treated for obesity were performed as well. [RESULTS] During the study period, 50 076 and 73 138 patients with T2DM were initiated on GLP-1 RA (47% women, median age: 59 years [IQR: 50-68]) or SGLT-2i (39% women, median age: 64 years [IQR: 55-72]). Comorbidity was equally prevalent. The standardized 1-year absolute risk of syncope was 0.58% (95% CI: 0.51%-0.66%) among patients initiated on GLP-1 RA and comparable to patients initiated on SGLT-2i (0.56% [95% CI: 0.50%-0.62%]). 1-year risks of fractures, bradyarrhythmia, and cardiac device implantation were equally low and with corresponding standardized risk ratios of 0.90 (95% CI: 0.79-1.01), 0.97 (95% CI: 0.67-1.28), and 0.86 (95% CI: 0.62-1.10), respectively. No associations were found in the group treated for obesity either. [CONCLUSIONS] In nationwide cohorts of patients treated for T2DM or obesity, initiation of GLP-1 RA was not associated with an elevated risk of VAR events. Despite a proposed argumentation of vagal activity, GLP-1 RA use was not associated with an increased risk in real-life users.","url":"https://pubmed.ncbi.nlm.nih.gov/42709513/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"bone\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":250,"doi":"10.1016/j.bja.2026.07.016","pmid":"42711215","nct_ids":"[]","title":"Delayed gastric emptying in adolescent patients on GLP-1 receptor agonists with standard preoperative fasting guidelines: a prospective cohort study","authors":"[\"O'Brien EM\", \"Gallop R\", \"Washburn M\", \"Dumas A\", \"Como N\", \"Kilungya F\", \"Willi SM\", \"Lin EE\"]","journal":"British journal of anaesthesia","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are approved in patients aged ≥10 yr for type 2 diabetes mellitus and aged ≥12 yr for obesity. We examined the effect of GLP1-RAs on the retention of gastric contents in fasting adolescents. [METHODS] This prospective cohort study examined adolescent patients (10-18 yr) at a single institution between June 2023 and November 2024. Three groups were compared: a GLP1-RA group; a group at-risk for delayed gastric emptying not on GLP1-RAs; and a healthy control group. All patients fasted 8 h for solids and 1 h for clears liquid. Gastric contents were examined utilising gastric ultrasound qualitatively on a 3-point scale, and quantitatively. The primary outcome was the number of adolescents on GLP1-RAs with residual gastric contents (presence of solids or gastric fluid volume ≥1.5 ml kg-1). [RESULTS] In total, 67 patients were analysed: 20 in the GLP1-RA group; 27 in the at-risk group; and 20 in the control group. The median age was 14.8 (interquartile range [IQR] 13.2-16.6) yr, and median fasting durations for solids and clears were 13 h (IQR 12-14) and 12 h (IQR 3.5-13), respectively. In the GLP1-RA group, 16/20 patients (80%) had solids present on gastric ultrasound, compared with 17/27 patients (63%) in the at-risk group and 1/20 patient (5%) in the control group (unadjusted P <0.001; adjusted P <0.02, with propensity score adjustment for age, body mass index, sex, race, and NPO time). [CONCLUSIONS] We observed that 80% of adolescents on GLP1-RAs had solids on gastric ultrasound despite having fasted for over 12 h.","url":"https://pubmed.ncbi.nlm.nih.gov/42711215/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interest The authors declare that they have no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":282,"doi":"10.64898/2026.09.04.26362304","pmid":"42818421","nct_ids":"[]","title":"Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes","authors":"[\"Wang J\", \"Pederson AM\", \"Flanders MD\", \"Choi M\", \"Buto P\", \"Sims KD\", \"Chen R\", \"Couch E\", \"Gilsanz P\", \"Hayes KN\", \"Zullo AR\", \"Stokes A\", \"Glymour MM\", \"Ackley SF.\"]","journal":"preprint server","publication_date":"2026-09-08","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Objective</h4>  To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes. <h4>Research Design and Methods</h4>  We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE ε4, and non-APOE genetic risk. <h4>Results</h4>  Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE ε4, and non-APOE genetic risk. <h4>Conclusions</h4>  Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors. <h4>Highlights</h4>  Observational studies have reported associations between GLP-1 receptor agonist use and lower dementia risk, but important social and genetic factors are often unavailable in electronic health record data. We examined whether educational attainment and Alzheimer disease genetic susceptibility were associated with treatment initiation and dementia and whether adjustment for these factors changed GLP-1 receptor agonist–dementia estimates. Adding measured education and genetic susceptibility produced little change in the estimated conditional hazard ratios. These results do not exclude residual confounding and should not be interpreted as evidence that GLP-1 receptor agonists prevent dementia.","url":"https://doi.org/10.64898/2026.09.04.26362304","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"dementia\", \"alzheimers\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":283,"doi":"10.20944/preprints202609.0561.v1","pmid":null,"nct_ids":"[]","title":"Semaglutide and Papillary Thyroid Carcinoma: Current Evidence on Risk, Progression, and Mechanisms","authors":"[\"Barseghyan L\", \"Munir I\", \"Chrysafides S\", \"Simental AA\", \"Khan S.\"]","journal":"preprint server","publication_date":"2026-09-08","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) marketed as Ozempic and Wegovy, is now among the most widely prescribed medications for type 2 diabetes and obesity. Rodent carcinogenicity studies demonstrated dose- and duration-dependent thyroid C-cell tumors, prompting a boxed warning for medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2), but whether this concern extends to papillary thyroid carcinoma (PTC), a follicular-cell-derived malignancy with distinct biology, remains uncertain. This narrative review evaluates current evidence on semaglutide and PTC, examining incidence, progression in patients with existing disease, receptor expression and mechanistic data, pharmacovigilance signals, sex-based patterns, and case reports published through August 2026. A pooled analysis of 93 trials (101,732 participants) and several national cohort studies found no statistically significant increase in thyroid cancer risk, and a matched cohort of 1072 patients with existing differentiated thyroid cancer found no association between GLP-1RA exposure and structural progression over a median of 69 months. A French case-control study and two FAERS disproportionality analyses reported elevated risk signals subject to detection bias and confounding by obesity. Receptor expression and functional studies were inconsistent but did not generally support a proliferative effect of GLP-1R agonism on PTC cells. Taken together, current evidence does not support semaglutide as a driver of PTC incidence or progression, though this remains an area warranting further prospective, subtype-specific study.","url":"https://doi.org/10.20944/preprints202609.0561.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cancer\", \"adverse_effects\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":550,"doi":"10.1007/s10557-026-07958-4","pmid":"42758273","nct_ids":"[]","title":"Liraglutide Ameliorates Atrial Fibrillation in Association with Enhanced Adiponectin Signaling in Epicardial Adipose Tissue","authors":"[\"Li X\", \"Liu Y\", \"Wang F\", \"Zhang F\", \"Zhang L\", \"Dang Y\", \"Qi X\"]","journal":"Cardiovascular drugs and therapy","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Atrial fibrillation (AF) is associated with obesity and epicardial adipose tissue (EAT) dysfunction. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide, exert cardiovascular benefits, the underlying mechanisms, particularly those related to EAT and adipokine signaling remain unclear. [METHODS] AF rat model was established using acetylcholine-CaCl₂ infusion. Model rats were treated with liraglutide or saline, and cardiac functions were assessed using electrocardiography (ECG) and echocardiography. Myocardial and EAT morphology was examined histologically. The levels of adiponectin (ADPN), inflammatory factors, and lipids were measured using enzyme-linked immunosorbent assay, and the protein levels of ADPN and its receptor were evaluated through western blotting. In vitro, 3T3-L1 adipocytes were treated with TNF-α to simulate a model of dysregulated lipid metabolism and inflammation. Subsequently, HL-1 cells were treated with the conditioned medium from 3T3-L1 cells. The interaction between adipocytes and cardiomyocytes was evaluated by assessing HL-1 cell proliferation, apoptosis, and levels of ADPN and inflammatory factors. [RESULTS] Liraglutide significantly reduced the duration of AF, improved cardiac function (decreased E/E', increased ejection fraction and LAACF), ameliorated myocardial fibrosis, and restored EAT morphology. Mechanistically, liraglutide specifically enhanced ADPN secretion and upregulated AdipoR1 expression in EAT, reduced interleukin (IL)-6 and IL-1β levels, and decreased free fatty acid (FFA) and triglyceride content. Notably, using an ADPN-neutralizing antibody in vitro, we demonstrated that ADPN mediates the protective effects of liraglutide on cardiomyocytes, suggesting the role of EAT-derived ADPN signaling. [CONCLUSION] Liraglutide alleviates AF by increasing ADPN secretion and AdipoR1 expression in the EAT, improving local lipid metabolism, and attenuating inflammation. These findings establish a correlational association between liraglutide treatment, favorable modulation of the EAT phenotype, and AF amelioration, and propose a testable hypothesis that adiponectin signaling is involved in liraglutide-mediated cardioprotection.","url":"https://pubmed.ncbi.nlm.nih.gov/42758273/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics: The animal study protocol was approved by the Ethics Committee of Hebei Provincial People’s Hospital [2025-DW-142]. All experiments were conducted in strict accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals and reported following the ARRIVE guidelines. Competing interests: The authors declare no competing interests. Generative AI: No generative AI or AI-assisted technolog were used in the development of this manuscript. The authors assume full responsibility for all content.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:06+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":659,"doi":"10.64898/2026.09.04.26361064","pmid":null,"nct_ids":"[]","title":"Obesity in the GLP-1 Era: Clinical Characteristics and Prescribing Patterns in a Large Integrated Health System","authors":"[\"Wells, B. J.\", \"Lenoir, K. M.\", \"Webster-Clark, M.\", \"Pajewski, N. M.\", \"Pons-Junkins, A. T.\", \"Mielke, M. M.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-08","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Structured AbstractO_ST_ABSAimsC_ST_ABSTo characterize adults with obesity in a large integrated health system.\n\nMethodsWe created a cross-sectional cohort of adults with at least one body mass index (BMI) value >=30 kg/m2 in the prior 18 months, a recent in-person outpatient visit, and an assigned primary care provider. Electronic health record data were transformed into a patient-level analytic dataset and linked to neighborhood-level social determinants of health. Diagnoses, laboratory values, vital signs, and prescriptions were curated using reproducible phenotype definitions and internally reviewed vocabularies.\n\nResultsThe registry included 280,186 adults, of whom 48% had class I obesity. The cohort was 63% female, 27% Black, and 14% lived in areas with high or very high deprivation. Common comorbidities included hypertension, type 2 diabetes, depression, and anxiety. HbA1c and cholesterol measurements were absent in more than 40% of the cohort during the prior two years. Overall, 22% of patients received a prescription for at least one weight loss drug in the past 2 years, including 18% who received a weight-loss-approved GLP-1 receptor agonist.\n\nConclusionsThis care-engaged obesity cohort was characterized by high representation of women and socially vulnerable populations, substantial cardiometabolic screening gaps, and broad adoption of GLP-1 agonists.","url":"https://www.medrxiv.org/content/10.64898/2026.09.04.26361064","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":660,"doi":"10.64898/2026.09.06.26362369","pmid":null,"nct_ids":"[]","title":"Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy: Notoriety Bias or True Ocular Toxicity?","authors":"[\"Jiang, J.\", \"Hu, D.\", \"Li, X.\", \"Ling, Q.\", \"Zhang, Q.\", \"Dong, L.\", \"Lin, Z.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-08","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"ObjectiveTo determine whether the semaglutide-NAION association reflects true toxicity or reporting bias.\n\nResearch design and methodsWe performed temporal disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data (2018Q1-2026Q2) to detect reporting anomalies and class-level spillover, and GLP1R cis-eQTL drug-target Mendelian randomization (MR) of NAION-relevant ocular phenotypes to test causal effects of GLP1R activation on semaglutide-relevant ocular toxicity.\n\nResultsSemaglutide ROR was 116.8 (95% CI 106.8-127.7). FAERS rates rose from below 8 per 10,000 annually (2018-2023) to 52 (2024), 177 (2025), and 203 (2026H1) after July 2024 publication, while comparators remained stable. Median time to onset was 246 days (Weibull {beta} = 1.09), a random-type profile inconsistent with cumulative toxicity. These anomalies were complemented by GLP1R-targeted MR evidence: no causal effect of genetically proxied GLP1R activation (all P [&ge;] 0.11), while confirming glucose-lowering (P = 7.6E-6).\n\nConclusionsPharmacovigilance and genetic evidence converge to show that the semaglutide-NAION signal reflects notoriety bias rather than toxicity.","url":"https://www.medrxiv.org/content/10.64898/2026.09.06.26362369","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"mendelian_randomization","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":663,"doi":"10.64898/2026.09.03.749293","pmid":null,"nct_ids":"[]","title":"Dorsomedial striatal GABA dynamics organize palatable reward consumption and are reshaped by GLP-1 receptor agonism","authors":"[\"Copling, A. N.\", \"Dinckol, O.\", \"Wenger, N. H.\", \"Patel, B. P.\", \"Lukusa, E. M.\", \"Kutlu, M. G.\"]","journal":"biorxiv (preprint)","publication_date":"2026-09-08","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Palatability and metabolic state strongly shape food consumption, making it important to understand the neural mechanisms that integrate these influences. Glucagon-like peptide-1 (GLP-1) receptor agonists are potent modulators of food intake and increasingly used therapeutic options, yet the circuit mechanisms underlying their effects remain unclear. Dorsal striatal inhibitory circuits contribute to reward-guided behavior and feeding, but how they encode ongoing consumption or are altered by GLP-1 receptor agonism is unknown. Using fiber photometry in mice, we found that dorsomedial striatal (DMS) GABA signals decreased at consumption onset, scaled with palatability, predicted licking, and were enhanced by food deprivation. GLP-1 receptor agonist semaglutide reduced intake, disrupted coupling between DMS GABA and licking, enhanced rebound signals preceding pauses, and increased DMS ensemble synchrony. Optogenetic excitation of DMS GABAergic interneurons reproduced key semaglutide-induced changes in consumption structure. These findings suggest that DMS GABA dynamics, as a state-dependent regulator of palatable consumption, are reshaped by GLP-1 receptor agonism.","url":"https://www.biorxiv.org/content/10.64898/2026.09.03.749293","source_name":"medrxiv:biorxiv","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:18:46+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"addiction\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":735,"doi":"10.1016/j.numecd.2026.104994","pmid":"42772984","nct_ids":"[]","title":"The effects of tirzepatide and semaglutide on clinical and metabolic outcomes in patients with heart failure with preserved ejection fraction and obesity: a systematic review and meta-analysis","authors":"[\"AlAraibi AJ\", \"Shakeeb FN\", \"Alqatta T\", \"Sharafeldin AB\", \"Dempsey L\", \"Butler AE\"]","journal":"Nutrition, metabolism, and cardiovascular diseases : NMCD","publication_date":"2026-09-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Heart failure with preserved ejection fraction (HFpEF) with obesity remains a therapeutic challenge with limited options. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin agonists may improve health status, functional capacity, and metabolic parameters. We evaluated the efficacy and safety of semaglutide and tirzepatide in this population. [METHODS AND RESULTS] We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to June 2025. Mean differences (continuous outcomes) and risk ratios (worsening heart-failure events) were pooled using random-effects models; other outcomes were synthesised narratively. Four studies met the HFpEF-specific criteria (three randomized trials and one observational cohort); the primary analysis was restricted to the three randomized trials (n = 1876), with SELECT and FLOW retained as indirect supportive evidence. Semaglutide or tirzepatide improved KCCQ-CSS (+7.39 points; 95% CI 5.43-9.35) and 6-min walk distance (+17.18 m; 11.82-22.54), and reduced worsening heart-failure events (risk ratio 0.45; 0.31-0.66). Body weight decreased by -7.73% (-10.70 to -4.76; I2 = 93%). Findings were robust in sensitivity analysis; secondary outcomes showed consistent CRP and HbA1c reductions; gastrointestinal intolerance was the most common adverse event. [CONCLUSIONS] Semaglutide and tirzepatide were associated with improvements in health status, functional capacity, and body weight, and fewer worsening heart-failure events, in HFpEF with obesity, with an acceptable safety profile. They may have an adjunctive role, although larger, longer-term dedicated outcome trials are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42772984/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":230,"doi":"10.1016/j.spinee.2026.08.009","pmid":"42705550","nct_ids":"[]","title":"Impact of GLP-1 Dose Intensity on Perioperative and Long-Term Fusion Outcomes Following ACDF","authors":"[\"Stirpe C\", \"Lee B\", \"Lavu M\", \"Ding I\", \"Furey C\", \"Cheng CW\"]","journal":"The spine journal : official journal of the North American Spine Society","publication_date":"2026-09-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND CONTEXT] High-dose glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for obesity management, but their perioperative safety and potential effects on fusion-related outcomes after anterior cervical discectomy and fusion (ACDF) remain unclear. [PURPOSE] To compare short-term postoperative outcomes and longer-term fusion-related outcomes after ACDF among patients receiving high-dose versus standard-dose GLP-1 RA therapy. [STUDY DESIGN/SETTING] Retrospective cohort study using the TriNetX Research Network. [PATIENT SAMPLE] Adult patients undergoing ACDF were identified within TriNetX and stratified into 3 pairwise comparison groups: standard-dose GLP-1 RA versus no GLP-1 exposure, high-dose GLP-1 RA versus no GLP-1 exposure, and high-dose versus standard-dose GLP-1 RA use. A total of 112,065 patients met inclusion criteria across all 3 comparisons. In the primary dose-intensity comparison, 921 patients remained in each cohort after 1:1 propensity score matching. [OUTCOME MEASURES] Outcomes included 90-day healthcare utilization (readmission, emergency department visits, outpatient visits, physical therapy utilization), 90-day medical and acute postoperative complications, 90-day opioid exposure, and long-term fusion-related outcomes from 180 to 720 days, including pseudarthrosis and posterior cervical fusion. [METHODS] Data were queried on March 9, 2026. Adults undergoing ACDF were identified and stratified by preoperative GLP-1 RA dose intensity. Exposure was defined by recorded GLP-1 RA prescription strength from 1 year to 1 week before the index ACDF procedure. Separate 1:1 propensity score matching was performed for each pairwise comparison. Outcomes were evaluated at 1 to 90 days for healthcare utilization, short-term complications, and opioid exposure, and at 180 to 720 days for long-term fusion-related outcomes. [FUNDING/CONFLICTS OF INTEREST] No funding was received for this study. The authors report no study-specific conflicts of interest or associated biases. [RESULTS] In the primary high-dose versus standard-dose comparison, 90-day healthcare utilization was similar, including readmission (11.4% vs 10.0%; p = 0.327), emergency department visits (11.4% vs 12.3%; p = 0.564), outpatient visits (49.8% vs 52.1%; p = 0.328), and physical therapy utilization (42.0% vs 44.0%; p = 0.397). Short-term complications were also similar, including composite medical complications (9.6% vs 8.9%; p = 0.629), dysphagia (10.6% vs 11.2%; p = 0.709), hematoma (6.8% vs 6.3%; p = 0.638), dysphonia (1.8% vs 1.6%; p = 0.721), and acute respiratory failure (2.3% vs 1.7%; p = 0.406). Opioid exposure did not differ between cohorts (85.2% vs 83.1%; p = 0.202). Long-term outcomes were likewise similar, including pseudarthrosis (4.0% vs 3.8%; p = 0.822) and posterior cervical fusion (3.0% vs 3.7%; p = 0.398). Compared with matched non-users, both standard-dose and high-dose GLP-1 RA users had lower pseudarthrosis rates, although no additional long-term benefit was observed with higher-dose therapy. [CONCLUSIONS] High-dose GLP-1 RA therapy was not associated with increased short-term healthcare utilization, postoperative complications, opioid exposure, or long-term fusion-related risk after ACDF compared with standard-dose therapy. These findings provide reassurance that higher-dose GLP-1 regimens do not appear to confer excess perioperative or fusion-related risk in this population.","url":"https://pubmed.ncbi.nlm.nih.gov/42705550/","source_name":"pubmed","source_tier":1,"coi_statement":"Statements and Declarations This study did not receive any specific funding. The authors declare no conflicts of interest relevant to this work. The study used de-identified data from the TriNetX Research Network and was exempt from institutional review board approval at the University Hospitals Cleveland Medical Center. All authors contributed to the study conception, design, data collection, analysis, and manuscript preparation, and approved the final version for submission.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"addiction\", \"adverse_effects\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":239,"doi":"10.1007/s00415-026-14127-y","pmid":"42704495","nct_ids":"[]","title":"GLP-1 receptor agonists vs DPP-4 inhibitors and neuropathic complications in type 2 diabetes","authors":"[\"Tawfik F\", \"Yalley E\", \"Sienkaniec J\", \"Mendoza M\", \"Bhatia R\", \"Boulis M\", \"Hashmi H\", \"Mohamed K\", \"Guidry C\", \"Michael M\"]","journal":"Journal of neurology","publication_date":"2026-09-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Diabetic peripheral neuropathy is a debilitating complication of type 2 diabetes mellitus (T2DM) associated with foot ulceration, amputation, Charcot neuroarthropathy, and reduced quality of life. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used therapies for T2DM, their comparative effects on neuropathy-related lower-extremity complications remain unclear. [OBJECTIVE] To compare diabetic foot ulcers, lower-extremity amputations, foot/ankle osteomyelitis, Charcot neuroarthropathy, and all-cause mortality in T2DM patients with neuropathy treated with GLP-1 RAs versus DPP-4 inhibitors. [METHODS] Using the TriNetX US Collaborative Network, we identified adults with T2DM and diabetic neuropathy, unspecified (ICD-10-CM E11.40), initiating either a GLP-1 RA or a DPP-4 inhibitor. After exclusions and 1:1 propensity score matching for demographics, comorbidities, and medications, 19,770 patients per cohort were balanced. Outcomes were assessed over 1 year and 2 years using Kaplan-Meier and Cox proportional hazards models, with Bonferroni correction (p < 0.01). [RESULTS] After matching, GLP-1 RAs were associated with a 1-year lower risk of diabetic foot ulcers (2.2% vs 2.7%; HR 0.813, 95% CI 0.716-0.922) and lower all-cause mortality, though the mortality finding was interpreted as hypothesis-generating. Amputation (0.5% vs 0.5%; HR 1.073, 95% CI 0.810-1.421) and foot/ankle osteomyelitis (0.4% vs 0.4%; HR 0.978, 95% CI 0.708-1.349) rates were similar. Charcot neuroarthropathy incidence was higher with GLP-1 RAs (0.3% vs 0.2%; HR 1.993, 95% CI 1.297-3.064). [DISCUSSION] In T2DM patients with neuropathy, GLP-1 RA therapy was associated with lower risk of diabetic foot ulcers and higher Charcot neuroarthropathy risk compared with DPP-4 inhibitors, while amputation and osteomyelitis risks were similar. These findings support further study of GLP-1 RAs in this population and highlight the need for careful foot monitoring during therapy.","url":"https://pubmed.ncbi.nlm.nih.gov/42704495/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflicts of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Publication and Informed Consent Statement: This study was determined to be exempt from review by the Howard University Hospitals Institutional Review Board (IRB), as it involved the retrospective analysis of de-identified patient data obtained from the TriNetX Global Collaborative Network. No identifiable private information was collected or recorded, and there was no direct interaction with patients. As such, the research qualifies for exemption under 45 CFR 46.104(d)(4). Informed consent was not required. All research activities were carried out in accordance with the guidelines and regulations of the Howard University Hospitals Institutional Review Board and in compliance with the ethical principles outlined in the 1964 Declaration of Helsinki and its later amendments.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":248,"doi":"10.1177/17585732261486333","pmid":"42712738","nct_ids":"[]","title":"The impact of glucagon-like peptide-1 (GLP-1) receptor agonists on postoperative outcomes following rotator cuff repair","authors":"[\"Choudhury A\", \"Slusarczyk S\", \"Mathson L\", \"Van Boxtel M\", \"LoGiudice A\", \"Hanley J\"]","journal":"Shoulder & elbow","publication_date":"2026-09-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Patients with type II diabetes mellitus (T2DM) undergoing rotator cuff repair (RCR) have increased postoperative risk. Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly used in T2DM, but their perioperative safety remains uncertain. This study evaluated the association between preoperative GLP-1 agonist exposure and postoperative outcomes following RCR. [METHODS] A retrospective cohort study using the TriNetX Research Network identified adults with T2DM undergoing RCR between 2018 and 2024. Patients were stratified by preoperative GLP-1 agonist exposure. Outcomes included 90-day medical complications, surgical complications, and healthcare utilization. Univariate and inverse propensity score-weighted binary logistic regression were performed to adjust for confounding. [RESULTS] Among 5876 patients, 233 used GLP-1 preoperatively. Unadjusted analyses revealed increased odds of postoperative respiratory complications (odds ratio (OR): 1.97, 95% confidence interval (CI): 1.32-2.86, P = 0.0006), urinary tract infection (OR: 3.85, 95% CI: 1.31-9.12, P = 0.0055), and postoperative stiffness (OR: 2.20, 95% Cl: 1.31-3.49, P = 0.0016) among GLP-1 users. After inverse propensity score-weighting, no significant differences in postoperative outcomes were observed. [DISCUSSION] Preoperative GLP-1 agonist use was not independently associated with decreased or increased risk of postoperative complications following RCR. These findings suggest perioperative continuation of GLP-1 therapy may be safe, though prospective studies are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42712738/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"adverse_effects\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":151,"doi":"10.1093/eurjpc/zwag478","pmid":"42700963","nct_ids":"[]","title":"Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Incident Atrial Fibrillation in Type 2 Diabetes: A Population-Based Target Trial Emulation","authors":"[\"Ostrovsky D\", \"Alnsarsra H\", \"Shamia D\", \"Westreich R\", \"Star A\", \"Tsaban G\"]","journal":"European journal of preventive cardiology","publication_date":"2026-09-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The comparative association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) with incident atrial fibrillation (AF) or atrial flutter remains uncertain, particularly with early use of both classes. We compared three initial treatment strategies in adults with type 2 diabetes. [METHODS] We emulated a three-arm target trial using population-based healthcare data from 2015-2025. Participants were assigned to SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, or early combined therapy according to dispensings during a 30-day treatment-assignment period. Follow-up began at the end of this period using a landmark design. Treatment groups were balanced using inverse probability of treatment weighting, and cumulative incidence was estimated using weighted Aalen-Johansen methods accounting for competing mortality. [RESULTS] Among 216,293 participants, 114,572 received SGLT2i without GLP-1RA, 91,524 received GLP-1RA without SGLT2i, and 10,197 received early combined therapy. At 5 years, cumulative AF or atrial flutter incidence was 4.3%, 4.8%, and 4.2% among participants receiving SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, and early combined therapy, respectively. SGLT2i without GLP-1RA was associated with lower risk than GLP-1RA without SGLT2i (RR 0.88, 95% CI 0.83-0.94), while risk was similar between SGLT2i without GLP-1RA and combined therapy (RR 1.00, 95% CI 0.84-1.19). [CONCLUSIONS] Among adults with type 2 diabetes, treatment strategies incorporating SGLT2i were associated with a lower risk of incident AF or atrial flutter than GLP-1RA without SGLT2i. These findings extend the cardiovascular evidence supporting SGLT2i and provide new comparative data regarding early combined use of SGLT2i and GLP-1RA.","url":"https://pubmed.ncbi.nlm.nih.gov/42700963/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":192,"doi":"10.1016/j.phrs.2026.108440","pmid":"42702341","nct_ids":"[]","title":"HIF-1 plays a dual regulatory role in hippocampal neuronal PANoptosis in Alzheimer's disease via the HK2/VDAC1/NLRP3 axis and RIPK3 signaling","authors":"[\"Wang S\", \"Luo L\", \"Jiang X\", \"Hai J\", \"Liu W\", \"Zhou X\", \"Li Y\", \"Yang L\"]","journal":"Pharmacological research","publication_date":"2026-09-06","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Extensive neuronal loss in brain regions critical for learning and memory is a hallmark of Alzheimer's disease (AD). PANoptosis, a newly characterized form of programmed cell death, integrates the key features of pyroptosis, apoptosis and necroptosis, and explains the molecular crosstalk among these pathways. However, whether PANoptosis is a new manner for hippocampal neuron death in AD, and the involved regulatory mechanisms remains largely unknown. Here, we demonstrate that PANoptosis is a crucial mechanism driving hippocampal neuronal loss in an AD mouse model. Moreover, we uncovered that the HIF-1 signaling pathway exerts a double-edged sword effect on hippocampal neuronal PANoptosis by activating the HK2/VDAC1/NLRP3 axis while concurrently suppressing RIPK3 signal. This observation may offer a partial explanation for the double-edged sword role of HIF-1 as both a neuroprotective and neurotoxic factor in AD. Finally, we uncovered that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), mitigates hippocampal neuronal PANoptosis by reprograming the double-eged sword effect of HIF-1 mediated by GLP-1R-AMPK signaling pathway, highlighting its potential as a therapeutic avenue for AD. These findings uncover a previously unrecognized role of PANoptosis in AD and provide new insights into the HIF-1-mediated regulatory mechanisms, offering a promising target for therapeutic intervention.","url":"https://pubmed.ncbi.nlm.nih.gov/42702341/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:54+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cognition\", \"alzheimers\", \"neuroinflammation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":289,"doi":"10.1101/2025.05.05.25326993","pmid":null,"nct_ids":"[]","title":"GLP-1 receptor agonist use is associated with shorter survival in patients with amyotrophic lateral sclerosis and diabetes mellitus","authors":"[\"Lee, I.\", \"Hwang, J.\", \"Stolwyk, K.\", \"Harms, M.\", \"Andrews, J.\", \"Shneider, N.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-06","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"BackgroundThe glucagon-like-peptide-1 (GLP-1) hormone exerts metabolic effects leading to delayed gastric emptying, decreased appetite, and lower blood glucose levels. GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat diabetes mellitus (DM) and obesity. However, their impact on the progression of amyotrophic lateral sclerosis (ALS) is unknown.\n\nObjectiveWe examined the relationship between GLP-1RA treatment and disease progression among people with ALS and DM.\n\nMethodsAn electronic health record search was conducted to identify consecutive patients seen at a single institution from 2020 to 2024 with ALS and DM diagnostic codes. All charts were reviewed for demographics, disease history, medication use, and tracheostomy/survival. Patients who did not meet Awaji ALS diagnostic criteria, lacked a documented history of DM, or had insufficient records were excluded. Patients were grouped by GLP-1RA exposure. Tracheostomy-free survival was compared between the GLP-1RA and No-GLP-1RA groups using Kaplan-Meier survival curves, log-rank test and Cox-proportional hazard models adjusted for age, sex, bulbar onset, body mass index (BMI) at diagnosis, and riluzole use.\n\nResultsTotal 1,310 ALS patients were screened, 136 patients (10%) had comorbid DM. After chart review, 85 patients meeting inclusion and exclusion criteria were included, 15 (18%) of whom were treated with GLP-1RA. Compared to No-GLP-1RA group, GLP-1RA group was younger at symptom onset (59 vs 66 years old, p<0.01), had shorter diagnostic delay (12 months vs 17 months, p=0.04) and higher weight at diagnosis (85kg vs 73kg, p=0.02).\n\nTracheostomy-free survival from symptom onset trended shorter in the GLP-1RA group (median survival 28.7 vs 34.9 months, p=0.08). After adjusting for covariates, the GLP-1RA group was associated with increased mortality compared to the No-GLP-1RA group (hazard ratio 2.5, 95% confidence interval [1.1, 5.3], p=0.02).\n\nConclusionsTreatment with GLP-1RA is associated with shorter tracheostomy-free survival in people with ALS and comorbid DM.","url":"https://www.medrxiv.org/content/10.1101/2025.05.05.25326993","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"mortality\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":181,"doi":"10.1097/crd.0000000000001465","pmid":"42693519","nct_ids":"[]","title":"Safety and Glycemic Efficacy of Perioperative Liraglutide in Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","authors":"[\"Gamal I\", \"Elkasaby MH\", \"Ewidat O\", \"Riyad N\", \"Sadin Z\", \"Singh Gill A\", \"Nassar M\", \"Frishman WH\", \"Aronow WS\"]","journal":"Cardiology in review","publication_date":"2026-09-04","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Perioperative hyperglycemia in cardiac surgery is associated with wound infection, acute kidney injury, and death, yet the intravenous insulin used to treat it is itself coupled to hypoglycemia. Glucagon-like peptide-1 receptor agonists lower glucose only when glucose is elevated and might therefore separate glycemic control from hypoglycemic risk. We searched PubMed/MEDLINE, Scopus, Web of Science, and CENTRAL through September 2025 for randomized controlled trials of perioperative subcutaneous liraglutide versus placebo or insulin-based usual care in adults undergoing cardiac surgery. Two reviewers screened, extracted data, and applied the Cochrane Risk of Bias 2 tool independently; certainty was graded using GRADE. Effects were pooled by inverse variance, fixed-effect when I2 was below 50%. Seven reports of 4 trials, enrolling 446 randomized patients, were eligible. Liraglutide did not alter 30-day mortality (1/161 vs 3/160; risk ratio [RR] 0.42, 95% confidence interval [CI], 0.06-2.81), the composite of any postoperative complication (68/129 vs 76/132; RR 0.92; 95% CI, 0.74-1.14), cardiac adverse events (RR 1.08; 95% CI, 0.83-1.40), hypoglycemia (8/165 vs 9/166; RR 0.85; 95% CI, 0.34-2.13), or postoperative nausea and vomiting (RR 3.01; 95% CI, 0.26-35.27).","url":"https://pubmed.ncbi.nlm.nih.gov/42693519/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosure: The authors have no conflicts of interest to report.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":219,"doi":null,"pmid":"42695487","nct_ids":"[]","title":"Liraglutide Attenuates Hepatocyte Ferroptosis in an In Vitro Model of Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"[\"Bai J\", \"Xiao Y\", \"Lou P\", \"Zhang J\", \"Liu Y\", \"Zhou Y\"]","journal":"Physiological research","publication_date":"2026-09-04","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"This study examined the potential of liraglutide to attenuate ferroptosis in an in vitro model of metabolic dysfunction-associated steatotic liver disease (MASLD). HepG2 cells were allocated into three groups: control (Con), free fatty acid (FFA)-treated, and FFA with liraglutide treatment (FFA+LI). After 48 h of treatment, intracellular triglyceride (TG), glutathione (GSH), malondialdehyde (MDA), and iron levels were quantified using commercially available kits. Superoxide dismutase (SOD) activity was also measured. Lipid accumulation was visualized via Oil Red O staining. Expression of ferroptosis-associated genes was assessed through quantitative RT-PCR and western blotting. FFA treatment induced significant lipid accumulation, elevated TG, MDA, and iron levels, and reduced SOD activity and GSH levels compared to the Con group (all p<0.05). Additionally, FFA exposure increased the expression of TFR1 and downregulated SLC7A11, NRF2, and GPX4 (p<0.05 for all comparisons vs. Con). Liraglutide treatment partially reversed these changes, as evidenced by reduced MDA levels and iron content, downregulation of TFR1, and upregulation of NRF2 and GPX4 (FFA+LI vs. FFA, all p<0.05). Liraglutide demonstrated the ability to mitigate lipid accumulation, oxidative stress, and iron overload in HepG2 cells subjected to FFA-induced injury. These effects were associated with modulation of ferroptosis-related gene expression, suggesting a mechanistic basis for the potential protective role of liraglutide in MASLD. Key words Ferroptosis \" Free fatty acid \" Liraglutide \" Metabolic dysfunction-associated steatotic liver disease \" Oxidative stress.","url":"https://pubmed.ncbi.nlm.nih.gov/42695487/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:59+00:00","study_design":"cellular_in_vitro","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":285,"doi":"10.64898/2026.09.01.748392","pmid":"42922752","nct_ids":"[]","title":"Tirzepatide preserves hematopoietic stem and progenitor cycling while remodeling inflammatory monocytes in obese mice","authors":"[\"Krah NM\", \"Gonzalez-Alvarado E\", \"Urs AP\", \"Goda C\", \"Bustos Y\", \"Marvin J\", \"Weaver BD\", \"Gygi S\", \"Toshniwal A\", \"Towne D\", \"Narbona-Perez AJ\", \"Heyden K\", \"Cantres-Velez JA\", \"Cunningham CN\", \"Arora S\", \"Garzon R\", \"Rutter J\", \"Dorrance AM\", \"Chaix A.\"]","journal":"preprint server","publication_date":"2026-09-04","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Obesity expands myeloid progenitors, myelopoiesis and increases the production of monocytes. While weight loss (WL) alleviates aspects of this inflammatory dysregulation, it is not known whether GLP-1 receptor agonists or other traditional modalities of WL differentially modify hematopoietic stem/progenitor cells (HSPCs), hematopoiesis, or inflammatory cell production. To test this, we compared the hematopoietic compartment in lean, obese and weight-reduced mice from tirzepatide treatment and caloric restriction (CR) implemented to match the body weight in both groups. At equal WL, we found CR induced multilineage cytopenias, whereas tirzepatide preserved blood lineages while specifically reducing classical Ly6C  hi CCR2  + monocytes. To define the mechanisms underlying these changes we performed single-cell mRNA sequencing of bone marrow HSPCs and mature mononuclear blood cells. CR-HSPCs suppressed gene sets associated with nutrient sensing, proliferation and oxidative phosphorylation (OXPHOS) and exhibited lower inferred cell cycle activity, whereas tirzepatide-HSPCs attenuated these changes. Unlike CR, we found that across progressively differentiated cells from HSPCs to mature blood monocytes, tirzepatide increasingly suppressed OXPHOS and simultaneously shifted the maturation spectrum away from classical monocytes. Following six weeks of tirzepatide withdrawal and weight regain, Ly6C  hi CCR2  + monocytes rebounded to levels seen in obese mice. These findings suggest that tirzepatide uncouples WL from the broad hematopoietic suppression seen in CR by preserving progenitor activity but selectively remodeling inflammatory/classical monocytes. We demonstrate that WL modality differentially impacts hematopoietic adaptation and provide evidence that classical monocytes are an effector cell through which tirzepatide may dampen obesity-associated inflammation.  <h4>Key Points</h4>  At equivalent weight loss, calorie restriction causes cytopenias and suppresses HSPC cycling, while tirzepatide preserves these parameters Tirzepatide reduces inflammatory monocytes, shifts maturation, decreases OXPHOS genes, and monocytes rebound after drug withdrawal","url":"https://doi.org/10.64898/2026.09.01.748392","source_name":"europepmc","source_tier":3,"coi_statement":"Conflicts of Interest: JR: No COI related to the current work. Founder, SAB/BOD member, Consultant or Research Funding from: Vettore Biosciences, RiverVest Venture Partners, Centaurus Therapeutics, Pfizer, Calico Laboratories, Atavistik Bio, Reina Bio All other authors: no COI to disclose.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"preclinical_animal","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"bone\", \"adverse_effects\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":746,"doi":"10.1093/ageing/afag281","pmid":"42765724","nct_ids":"[]","title":"GLP-1-based treatments and long-term clinical outcomes in MASLD amongst older adults: a retrospective cohort study","authors":"[\"Koutouratsas T\", \"Kalligeros M\", \"Michael M\", \"Das S\", \"Mylonakis SC\", \"Mylonakis E\"]","journal":"Age and ageing","publication_date":"2026-09-04","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in older adults, driving hepatic decompensation and cardiovascular mortality. Randomised trial data on glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) therapy remain limited. [METHODS] We conducted a retrospective cohort study using TriNetX US Collaborative Network. Adults 65 years or older with MASLD were identified by codes for fatty liver disease or steatohepatitis plus one cardiometabolic risk factor. We excluded liver transplant and other liver disease causes. Using a new-user, intention-to-treat design with 1:1 propensity-score matching, we compared GLP-1 RA initiators with unexposed patients. Outcomes were hepatic decompensation, hospitalisation, mortality and major adverse cardiovascular events (MACE), assessed 90 days to 10 years after index. Sensitivity analyses restricted follow-up to 1-10 years, excluded tirzepatide or began follow-up on day 1. [FINDINGS] We identified 44 196 GLP-1 RA initiators and 384 672 unexposed patients. After matching, 43 930 remained per cohort (mean age 71.8 years; 62.0% female), with standardised mean differences below 0.1. GLP-1 RA use was linked to lower hazards of hepatic decompensation (hazard ratios [HR] 0.72, 95% confidence intervals [CI] 0.66-0.79), mortality (HR 0.55, 0.52-0.58) and hospitalisation (HR 0.95, 0.93-0.97). MACE showed no reduction (HR 0.98, 0.92-1.04). Osteoporosis without fracture and retinopathy were more frequent; pancreatitis, sarcopenia and fracture did not differ. GI events occurred more often as first events. Sensitivity analyses confirmed results for decompensation, hospitalisation and mortality. [INTERPRETATION] In older adults with MASLD, GLP-1 RA initiation was linked to lower risks of hepatic decompensation, hospitalisation and mortality, with higher rates of selected adverse events.","url":"https://pubmed.ncbi.nlm.nih.gov/42765724/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"muscle\", \"bone\", \"liver\", \"mortality\", \"adverse_effects\", \"gastrointestinal\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":183,"doi":"10.1111/dom.71303","pmid":"42687799","nct_ids":"[]","title":"Postmarketing Safety Signals and Medication-Use Risks of GLP-1-Based Therapies in Diabetes and Obesity: A Multi-Source Pharmacovigilance and Regulatory Evidence-Mapping Study","authors":"[\"Ren L\", \"Zhang Y\", \"Fang F\", \"Ma Y\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To characterise postmarketing safety signals and medication-use risks associated with GLP-1 receptor agonists and the GIP/GLP-1 co-agonist tirzepatide in diabetes and obesity care using an integrated pharmacovigilance, utilisation-context, regulatory, and external-consistency framework. [MATERIALS AND METHODS] FDA Adverse Event Reporting System (FAERS) data from 2021Q1 through 2026Q1 were processed using deleted-case exclusion, latest-case-version retention, and case-product deduplication with analysis at the GLP-1 primary-suspect case-product level. Primary-suspect records for semaglutide, tirzepatide, dulaglutide, liraglutide, exenatide, and lixisenatide were analysed using reporting odds ratios, proportional reporting ratios, and an approximate Information Component. Medicaid utilisation data, FDA labelling/Safety-Related Labelling Changes resources, FDA shortage and compounded-product communications, and Canada Vigilance reports provided contextual interpretation; no data source was used to estimate incidence, comparative risk, or causality. [RESULTS] The final FAERS analysis set included 243 114 GLP-1 primary-suspect case-product records within 8 995 547 background reports. Tirzepatide accounted for 133 100 records, followed by semaglutide (55619) and dulaglutide (38406). Frequently reported terms included incorrect dose administered, nausea, injection-site pain, diarrhoea, vomiting, off-label use, and extra dose administered. Prioritised domains included gastrointestinal intolerance, medication-use/device events, impaired gastric emptying, pancreatobiliary events, renal/dehydration events, and hypoglycaemia. Canada Vigilance and FDA labelling/SrLC mapping showed descriptive visibility for most major domains, while medication-use terms reflected use-process rather than conventional adverse-drug-reaction issues. [CONCLUSIONS] Multi-source pharmacovigilance can improve interpretation of GLP-1 postmarketing safety evidence in diabetes and obesity care. Findings should be interpreted as signal-prioritisation and medication-safety evidence, not as incidence, proof of causality, or population-level comparative risk, given the limited clinical interpretability of spontaneous-reporting data.","url":"https://pubmed.ncbi.nlm.nih.gov/42687799/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:53+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":236,"doi":"10.1016/j.oret.2026.08.029","pmid":"42692107","nct_ids":"[]","title":"GLP1-RA Use and Risk of Non-arteritic Anterior Ischemic Optic Neuropathy in Patients with Type 2 Diabetes","authors":"[\"Lee JJ\", \"Brothers T\", \"Kim LA\", \"Ward KE\", \"Yusuf H\", \"Wen X\"]","journal":"Ophthalmology. Retina","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Concerns have been raised regarding the increased risk of non-arteritic ischemic optic neuropathy (NAION) associated with the use of glucagon-like peptide 1 receptor agonist (GLP-1 RA). However, findings remain inconsistent due to differences in indications for drug use, comparator groups, follow-up periods, and study populations. [OBJECTIVE] This study aims to examine the association between GLP-1 RA use and the risk of NAION among U.S. patients with type 2 diabetes mellitus (T2DM) enrolled in private health plans. [DESIGN, SETTING, AND PARTICIPANTS] This retrospective cohort study was conducted based on health administrative claims data from 2012 to 2024. Target trial emulation was applied, using a new user design and active comparators, to compare the risk of NAION between patients initiating GLP-1 RAs and those initiating sodium-glucose cotransporter-2 inhibitors (SGLT-2i) or dipeptidyl peptidase-4 inhibitors (DPP-4i). Propensity score methods were utilized to balance baseline demographic and clinical characteristics between the comparison groups. Cox proportional hazard models were applied to estimate adjusted hazard ratios (HR) of NAION incidence associated with GLP-1 RAs, relative to SGLT-2i or DPP-4i. [EXPOSURES] Participants initiating GLP-1 RAs compared with those initiating SGLT-2i or DPP-4i for the treatment of T2DM. [MAIN OUTCOMES AND MEASURES] Incidence of NAION in the comparison groups and the adjusted hazard ratios between groups. [RESULTS] A total of 19,505 adult patients diagnosed with T2DM were included, with 9,213 (47.2%) using GLP-1 RAs, 10,292 (52.8%) exposed to SGLT-2i or DPP-4i, and 29 incidences of NAION. Compared with SGLT-2i or DPP-4i, overall GLP-1 RA use was not significantly associated with a higher risk of NAION (HR: 1.87; 95%CI: 0.85-4.12). However, risk of NAION among liraglutide users was higher than for SGLT-2i or DPP-4i users within 12 or 18 months of follow-up. Additionally, the elevated risk of NAION associated with GLP-1 RAs relative to SGLT-2i or DPP-4i was observed in males and older adults. [CONCLUSIONS AND RELEVANCE] Our findings indicate that GLP-1 RA use, particularly liraglutide, may be associated with an increased risk of NAION among patients with T2DM. Further research is warranted to confirm these findings and clarify the biological mechanisms linking GLP-1 RA use to NAION.","url":"https://pubmed.ncbi.nlm.nih.gov/42692107/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:04+00:00","study_design":"retrospective_cohort","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":237,"doi":"10.1111/dom.71308","pmid":"42687767","nct_ids":"[]","title":"Use of Glucose-Lowering Drugs for Type 2 Diabetes Among Danish Care Home Residents","authors":"[\"Harbi H\", \"Thomsen RW\", \"Lundby C\", \"Stidsen JV\", \"Højlund K\", \"Ryg J\", \"Reilev M\", \"Pottegård A\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Care home admission often reflects frailty and limited life expectancy, potentially altering the benefit-harm balance of glucose-lowering drug (GLD) treatment for type 2 diabetes (T2D). Real-world data on treatment patterns in this setting remain limited. We examined GLD use for T2D among Danish care home residents. [MATERIALS AND METHODS] We conducted a nationwide, population-based drug utilisation study of all individuals admitted to Danish care homes between 2018 and 2023, using linked national health registries. [RESULTS] Among 88 658 residents (median age: 84 years [IQR: 78-90]; 60% women), 13% (n = 11 101) used GLDs for T2D at admission, with 84% continuing treatment beyond 2 years. Residents using GLDs at admission had long-standing diabetes (median duration: 12 years [IQR: 6.8-15]), relatively low glycated haemoglobin levels (median: 6.9% [IQR: 6.3-7.8]; 52 mmol/mol [45-62]) with little change around admission, and 43% used more than one GLD class, most commonly metformin (70%) and insulin (36%; basal: 30%; bolus: 16%). Use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased over time but remained limited (13% and 24%, respectively, in 2023), despite a high prevalence of cardiorenal disease (84%), and did not differ by cardiorenal disease status. Overall GLD use remained stable around admission, but initiation spiked 3 months before admission (36 initiators/10 000 residents), often following hospitalisation (63%) and primarily involved bolus insulin initiated by hospital physicians. [CONCLUSIONS] GLD use for T2D among Danish care home residents is high and shows limited deintensification and potential misalignment with guideline recommendations.","url":"https://pubmed.ncbi.nlm.nih.gov/42687767/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"aging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":252,"doi":"10.1016/j.clindermatol.2026.08.012","pmid":"42692277","nct_ids":"[]","title":"Glucagon-like Peptide-1 Receptor Agonist-Associated Injection Site and Dermatologic Reactions","authors":"[\"Elgindi D\", \"Petronic-Rosic V\"]","journal":"Clinics in dermatology","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for type 2 diabetes mellitus and obesity, with expanding therapeutic applications. Although gastrointestinal adverse events are the most recognized toxicities, Cutaneous adverse events constitute a large burden of total adverse reactions. [OBJECTIVE] To review the prevalence, clinical features, mechanisms, and management of non-immunologic Injection Site and Dermatologic Reactions associated with GLP-1RAs. [METHODS] A review of clinical trials, pharmacovigilance studies, and case reports and series was performed. In addition, adverse event reports for tirzepatide, semaglutide, liraglutide, exenatide, dulaglutide, and lixisenatide were extracted from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Injection-site events were combined with skin-related adverse events to generate an adjusted \"Skin and Injection-Site Reactions\" category for comparison across agents. [RESULTS] Among 442,567 FAERS reports, 137,412 (31.0%) involved skin and injection-site reactions, representing the third most frequently reported adverse event category. Exenatide demonstrated the highest proportion of skin and injection-site reports (53.1%), followed by dulaglutide (33.5%), tirzepatide (32.6%), liraglutide (17.1%), semaglutide (12.2%), and lixisenatide (6.9%). Common reactions included pain, bleeding, erythema, bruising, mass, pruritus, and swelling. Additional adverse events included dysesthesias, nodules, granulomatous reactions, bruising, and hyperhidrosis. Most reactions were mild to moderate and generally managed symptomatically without requiring treatment discontinuation. [CONCLUSIONS] Non-immunologic cutaneous adverse events comprise a substantial proportion of reported GLP-1RA-associated adverse events with differing rates among individual agents. Recognition of these reactions and appropriate supportive management may improve patient outcomes. Prospective studies are needed to better define their adverse event risk rates, mechanisms, and optimal management strategies.","url":"https://pubmed.ncbi.nlm.nih.gov/42692277/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cognition\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":253,"doi":"10.1302/2633-1462.79.bjo-2026-0056.r1","pmid":"42686200","nct_ids":"[]","title":"What is the association between insulin dependence and the incidence of postoperative complications, perioperative glucose control, and five-year reoperation rates after total joint replacement?","authors":"[\"Wong J\", \"Umelo J\", \"Ramirez G\", \"Myers TG\", \"Ginnetti JG\", \"Thirukumaran CP\", \"Ricciardi BF\"]","journal":"Bone & joint open","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Diabetes mellitus (DM) is associated with adverse outcomes following total hip arthroplasty (THA) and total knee arthroplasty (TKA), yet optimal perioperative risk stratification remains unclear. This study evaluated the association of insulin dependence with: 1) 90-day complications; 2) perioperative glucose control; and 3) mid-term reoperations in diabetic patients undergoing primary THA and TKA. [METHODS] We performed a retrospective, single-centre study of patients with DM undergoing primary THA or TKA between 2015 and 2022. Patients with preoperative glycated haemoglobin (HbA1c) ≥ 6.5 were categorized as insulin-dependent DM (IDDM) or insulin-independent DM (NIDDM). Demographic and clinical variables including preoperative haemoglobin A1C and oral DM medication usage were recorded. The primary outcome was 90-day complications. Secondary outcomes included mean and maximum perioperative glucose levels and reoperations. Multivariable logistic and linear regression analyses were used to evaluate association between insulin dependence and outcomes while adjusting for relevant confounders. [RESULTS] A total of 830 patients were included: 351 (42.3%) with IDDM and 479 (57.7%) with NIDDM. Overall, 90-day complications were more common in the IDDM cohort (35.9% vs 16.3%, p < 0.01). Insulin dependence was associated with increased odds of 90-day complications (odds ratio 2.81, 95% CI 1.98 to 3.98). Male sex, metformin use, and glucagon-like peptide-1 receptor agonist use were associated with lower complication risk. Preoperative HbA1c was not independently associated with complications. Insulin dependence and preoperative haemoglobin A1C were associated with worse perioperative glucose control. Reoperation rates were similar between groups. [CONCLUSION] Insulin dependence is an independent risk factor for 90-day complications and poorer perioperative glucose control, but not reoperation, following primary THA and TKA. These findings suggest insulin dependence is a clinically meaningful risk marker beyond glycaemic indices. Further investigation into optimization strategies to mitigate this perioperative risk is warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42686200/","source_name":"pubmed","source_tier":1,"coi_statement":"B. Ricciardi reports grants or contracts from the National Institutes of Health, Trellis Biosciences, and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from the American Board of Orthopaedic Surgery. C. Thirukumaran discloses grants or contracts, paid to the institution, from the National Institutes of Health; consulting fees from Columbia University; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the National Institutes of Health, Brigham and Women’s Hospital, and the Orthopaedic Research Society (ORS); and being section editor for Current Osteoporosis Reports and research chair for the ORS.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"metabolic\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":278,"doi":"10.32388/i85yu1","pmid":null,"nct_ids":"[]","title":"The GLP-1 Nutritional Paradox: A Global Meta-Analysis of Sarcopenic Risks and Micronutrient Gaps in the Post-Obesity Era","authors":"[\"Hungund S.\"]","journal":"preprint server","publication_date":"2026-09-03","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"While the world celebrates the apparent end of the obesity epidemic through glucagon-like peptide-1 receptor agonist (GLP-1RA) pharmacotherapy, a largely uncharacterised crisis is quietly taking shape: the _malnutrition of the medicated_. GLP-1 receptor agonists, including semaglutide (Ozempic, Wegovy) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro, Zepbound), now constitute a pharmaceutical market valued at over USD 62 billion in 2025 and are consumed by tens of millions of individuals worldwide. Yet the clinical discourse remains almost entirely fixated on weight reduction endpoints, while the nutritional consequences of chronic caloric suppression, altered gastric emptying, and rapid lean-mass loss receive comparatively little systematic attention. This review addresses that gap through a structured synthesis of data drawn from landmark randomised controlled trials (STEP 1, SURMOUNT-1, SURMOUNT-5), large-scale observational databases encompassing more than 480,000 adults, expert consensus documents, and current clinical nutrition guidelines. We demonstrate that GLP-1RA therapy is associated with lean-mass loss constituting 26–40% of total weight lost, that newly diagnosed nutritional deficiencies affect up to 22% of users within twelve months, and that reported protein intake among GLP-1 users falls to approximately 54 grams per day – critically below muscle-preservation thresholds. Building on this evidence, we introduce two original analytical constructs: (1) the NUTRIENT DENSITY REQUIREMENT INDEX (NDRI), a quantitative framework that calculates the proportional increase in protein and micronutrient intake per kilocalorie that a GLP-1 user must achieve relative to a non-medicated person to maintain lean-mass homeostasis; and (2) the METABOLIC QUALITY INDEX (MQI), a novel composite metric that reframes weight-loss success in terms of the fat-to-lean-mass loss ratio rather than total kilograms lost. Together, these constructs provide clinicians, dietitians, and policy-makers with actionable tools for the first evidence-based _Nutritional Safety Protocol for GLP-1 Pharmacotherapy_. The protocol is proposed as a replicable clinical standard applicable across primary care, endocrinology, and bariatric medicine worldwide.","url":"https://doi.org/10.32388/i85yu1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"nutrition\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":281,"doi":"10.20944/preprints202609.0311.v1","pmid":null,"nct_ids":"[]","title":"Real-World EHR Signals from a Cohort of Blinded Incretin Trial Participants Motivate Novel Indication Opportunities","authors":"[\"Venkatakrishnan A\", \"Matson R\", \"Murugadoss K\", \"Aman A\", \"Anand D\", \"Soundararajan V.\"]","journal":"preprint server","publication_date":"2026-09-03","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Understanding organ-specific effects of multi-agonist metabolic therapies beyond weight loss remains challenging, particularly while randomized clinical trials are ongoing and treatment allocation remains blinded. Here, we evaluated whether real-world longitudinal biomarker trajectories can provide early hypothesis-generating signals associated with masked trial-medication exposure. Using propensity-matched, de-identified electronic health records from a large federated health network, we compared changes in laboratory and physiologic biomarkers across receptor-defined metabolic therapies. Semaglutide, tirzepatide, and pramlintide served as reference therapies representing GLP-1 receptor, dual GIPR-GLP1R, and amylin-pathway pharmacology, respectively. Individuals with documented participation in a blinded CagriSema/placebo clinical trial were analyzed as a single masked exposure group because active treatment assignment could not be determined from routine-care records. Twenty-five CagriSema/placebo participants were propensity matched 1:5 to tirzepatide (n=125) and empagliflozin (n=125). At 6 months, the masked CagriSema/placebo cohort showed similar changes in weight and HbA1c compared with matched tirzepatide-treated patients (weight, -7.7% vs -10.2%, P=0.27; HbA1c, -2.8% vs -5.1%, P=0.69), but larger increases in estimated glomerular filtration rate (+26.4% vs +6.5%, BH P=0.028). Compared with matched empagliflozin-treated patients, the masked cohort demonstrated larger reductions in weight (-7.7% vs -3.5%, P=0.048), mean arterial pressure (-12.0% vs -1.0%, BH P&lt;0.001), creatinine (-17.4% vs -2.4%, BH P=0.020), and greater increases in eGFR (+26.4% vs +6.4%, BH P=0.030). To provide pharmacologic context, patients with type 2 diabetes receiving basal insulin who initiated pramlintide were independently matched to tirzepatide (652 pairs) and semaglutide (761 pairs). Tirzepatide and semaglutide were associated with larger HbA1c reductions than pramlintide at 6 months (-9.0% vs -3.0%, BH P&lt;0.001; -10.1% vs -3.5%, BH P&lt;0.001). However, after normalization for weight loss, pramlintide demonstrated greater blood pressure reduction per kilogram of weight lost than tirzepatide for both systolic (-4.9 vs -3.4% per kg, BH P=0.046) and diastolic blood pressure (-5.7 vs -3.4% per kg, BH P=0.029), whereas tirzepatide and semaglutide showed similar weight-normalized laboratory responses. Medication-transition analyses did not support co-intervention confounding, and single-cell transcriptomic analyses demonstrated substantially broader expression of amylin receptor components (CALCR, RAMP1/2/3) than GIPR or GLP1R in the kidney (9.8-14.7-fold). These findings illustrate how real-world longitudinal biomarker analyses can complement ongoing blinded clinical trials by identifying early, hypothesis-generating physiologic signals associated with masked trial-medication exposure. The observed renal and blood-pressure patterns, together with receptor-expression analyses, motivate prospective evaluation after trial unblinding to determine whether they reflect amylin-pathway biology or other treatment-associated effects.","url":"https://doi.org/10.20944/preprints202609.0311.v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\", \"cagrisema\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":616,"doi":"10.3390/jcm15176818","pmid":"42739822","nct_ids":"[]","title":"The Impact of Glucagon-like Peptide-1 (GLP-1) Receptor Agonists on Body Composition in Individuals with Overweight and Obesity: A Systematic Review and Meta-Analysis","authors":"[\"Woźniak M\", \"Tarcz Z\", \"Pyczek G\", \"Bogacka J\", \"Diniejko A\", \"Kuryłowicz A\", \"Mamcarz A\", \"Śliż D\"]","journal":"Journal of clinical medicine","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Excess adipose tissue is associated with adverse changes in muscle metabolism and body composition. GLP-1 receptor agonists (GLP-1 RA) have transformed the treatment of obesity; however, concerns remain regarding the potential impact of treatment-associated weight loss on lean mass. This study aimed to evaluate the effects of GLP-1 RA on body composition in adults with obesity without type II diabetes mellitus (T2DM), with a particular focus on changes in lean mass. Methods: A database search of Medline Ultimate, Scopus, Web of Science, PubMed, and Embase was conducted to identify studies published up to December 30, 2024. Randomized controlled trials involving adults with obesity and without T2DM who received GLP-1 RA and reported changes in body composition were included. The protocol was registered with PROSPERO (CRD42025645378). Random-effects meta-analysis was performed using inverse-variance weighting. Results: A total of 2776 articles were identified, of which three trials comprising 171 participants met the inclusion criteria. Compared with controls, participants receiving GLP-1 RA treatment experienced greater reductions in lean mass (MD = -0.78 kg, 95% CI: [-1.37 to -0.16], I2 = 63.2%). GLP-1 RA treatment was also associated with a significant reduction in fat mass (MD = -3.43 kg, 95% CI: [-5.94 to -0.93], I2 = 78.2%). Conclusions: The loss of lean mass was greater in patients treated with GLP-1 RA than in the control group. These results highlight the importance for clinicians to incorporate lifestyle interventions, including physical activity and nutritional support, alongside therapy with GLP-1 RA.","url":"https://pubmed.ncbi.nlm.nih.gov/42739822/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"lean_mass\", \"body_composition\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":679,"doi":"10.3390/biomedicines14091987","pmid":"42792729","nct_ids":"[]","title":"Semaglutide Attenuates Inflammatory Macrophage Polarization and Promotes Changes Associated with Mitochondrial Biogenesis Through cAMP-Dependent Signaling","authors":"[\"Pavshintsev VV\", \"Erbaeva AZ\", \"Vatlin AA\", \"Mitkin NA\"]","journal":"Biomedicines","publication_date":"2026-09-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Chronic metabolic inflammation is associated with pro-inflammatory macrophage activation and mitochondrial dysfunction. Semaglutide, a widely used GLP-1 receptor agonist, has been reported to possess systemic anti-inflammatory properties, but its action on human macrophages, especially in the context of mitochondrial regulation, remains poorly understood. The aim of the study was to evaluate the direct effect of semaglutide on macrophage polarization and to investigate the roles of cAMP signaling and mitochondrial regulation in this process. Methods: THP-1 and U-937 monocytic cell lines were differentiated into macrophages and polarized into the M1-like phenotype using LPS/IFN-γ. Cells were treated with 100 nM semaglutide in the presence or absence of the adenylyl cyclase inhibitor SQ22536. Intracellular cAMP levels, mRNA expression of macrophage markers and key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), and levels of pro- and anti-inflammatory cytokines were determined. The COX-1/SDH-A and mtDNA/nDNA ratios were analyzed as markers of mitochondrial biogenesis. Results: Semaglutide induced cAMP accumulation in M0- and M1-like macrophages derived from both cell lines. This response was significantly attenuated by GLP-1R antagonist exendin(9-39), supporting the presence of functional GLP-1R signaling. Semaglutide supplementation during inflammatory polarization resulted in reduced levels of pro-inflammatory markers (CD80/CD86, TNF-α, IL-6) and increased expression of M2-associated genes CD206 and CD163 and secretion of the anti-inflammatory cytokine IL-10. Semaglutide also increased SIRT1 and PGC-1α expression, the COX-1/SDH-A ratio, and the mtDNA/nDNA ratio, suggesting activation of processes associated with mitochondrial biogenesis. All of the effects of semaglutide described above were attenuated by SQ22536, supporting an important contribution of cAMP signaling to these responses. Conclusions: Semaglutide acts directly on human monocytic cell line-derived macrophages, attenuating the M1-like program and promoting a shift toward a less inflammatory phenotype. These effects strongly depend on cAMP signaling and are accompanied by increased expression of SIRT1 and PGC-1α and mitochondrial changes consistent with enhanced biogenesis.","url":"https://pubmed.ncbi.nlm.nih.gov/42792729/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:07+00:00","study_design":"cellular_in_vitro","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":106,"doi":"10.1111/obr.70220","pmid":"42683734","nct_ids":"[]","title":"Microbiome and Metabolomics in Obesity: Advances in Understanding and Interventions Across the Lifespan","authors":"[\"Kalafati IP\", \"Krongauz D\", \"Bosco A\", \"Noto A\", \"Piras C\", \"Kafyra M\", \"Dessì A\", \"Mauri M\", \"Atzori L\", \"Weinberger A\", \"Fanos V\", \"Dedoussis GV\", \"of the BETTER4U consortium\"]","journal":"Obesity reviews : an official journal of the International Association for the Study of Obesity","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity arises from intertwined and reciprocal diet-microbiome-host pathways that reshape energy balance, insulin sensitivity, and inflammation. This review synthesizes mechanistic links between microbial functions and metabolic control, charts lifestyle-related lifecourse dynamics from birth to older age, examines how GLP-1-based therapies may perturb gut ecology and metabolite output and surveys AI/ML frameworks for multi-omics integration. Plant-based, fiber-rich dietary patterns generally enrich saccharolytic guilds, boost SCFAs production, and modulate bile acid signaling, whereas Westernized patterns favor bile-tolerant, amino acid-fermenting consortia and proinflammatory metabolites. Preclinical data suggest that incretin-based therapies remodel the microbiome-metabolome axis, but human causal mediation remains unproven and observed changes may partly reflect weight loss or metabolic improvement. Function-centered metrics outperform phylum-level ratios for translation. Harmonized longitudinal cohorts and explainable ML-derived microbial and metabolomic signatures are now pivotal to identify responder subtypes and actionable microbe-metabolite targets, enabling precision nutrition alongside pharmacotherapy across the lifespan.","url":"https://pubmed.ncbi.nlm.nih.gov/42683734/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":164,"doi":"10.1097/mnh.0000000000001225","pmid":"42683763","nct_ids":"[]","title":"Integrating the liver into the cardiovascular-kidney-metabolic syndrome: pathophysiology and therapeutic implications","authors":"[\"Marshall WR\", \"Sinha S\", \"Green D\", \"Kalra PA\"]","journal":"Current opinion in nephrology and hypertension","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE OF REVIEW] This review examines the mechanistic, epidemiological and therapeutic evidence underpinning liver integration into the cardiovascular-kidney-metabolic (CKM) construct. For the purposes of this review, we use the term cardiovascular-renal-hepatic-metabolic (CRHM) syndrome to denote this expanded framework, acknowledging that consensus nomenclature is yet to be established. [RECENT FINDINGS] Large cohort data confirm that coexistent metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD confer additive, stage-dependent mortality risk exceeding that of either condition alone, with hepatic fibrosis severity, rather than steatosis, the dominant prognostic driver. The past 12-18 months have seen significant therapeutic developments spanning the full CRHM spectrum. Resmetirom, a hepato-selective thyroid hormone receptor-β (THR-β) agonist, received FDA-accelerated approval (March 2024) and European Commission conditional marketing authorization (August 2025) as the first licensed metabolic dysfunction-associated steatohepatitis (MASH)-specific therapy; UK approval is pending. Incretin-based therapies demonstrated efficacy across the full CRHM spectrum: semaglutide in diabetic and non-diabetic kidney disease across FLOW, SELECT, and SMART trials; tirzepatide in obesity-related heart failure with preserved ejection fraction (HFpEF) in SUMMIT. Semaglutide additionally received accelerated FDA approval and EU marketing authorization for MASH following the ESSENCE trial; UK approval for this indication is pending. [SUMMARY] The integration of the liver into CKM staging now has implications for how clinicians stratify risk and select therapy. Early identification of MASLD in CKD cohorts using validated noninvasive fibrosis tools should be considered standard practice in high-risk populations.","url":"https://pubmed.ncbi.nlm.nih.gov/42683763/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"mortality\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":166,"doi":"10.1186/s40842-026-00333-0","pmid":"42681675","nct_ids":"[]","title":"Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials","authors":"[\"Alper A\", \"Fagin A\", \"Karthikeyan A\", \"Lerner M\", \"Gershon A\", \"Morgan AA\", \"Rubinstein G\", \"Agarwal R\", \"Faillace R\"]","journal":"Cardiovascular diabetology. Endocrinology reports","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Patients with type 2 diabetes face a high residual risk of atherosclerotic cardiovascular disease (ASCVD) despite advances in therapy. Once-weekly IcoSema, a fixed-ratio combination of basal insulin icodec and semaglutide, offers the potential to simultaneously address glycemic control, weight, and multiple cardiometabolic risk factors with a single weekly injection. [METHODS] We conducted a PRISMA-compliant systematic review and random-effects meta-analysis of randomized trials from the COMBINE program. Data from COMBINE 1 (active comparator: once-weekly insulin icodec) and COMBINE 3 (active comparator: basal-bolus insulin therapy) (N = 1,970) were pooled comparing IcoSema with insulin-based intensification strategies in patients inadequately controlled on basal insulin. COMBINE 2 was excluded because its semaglutide monotherapy comparator addresses a fundamentally different clinical question (escalation from GLP-1 RA monotherapy). The primary focus was on changes in body weight, Systolic blood pressure and HbA1c; key secondary outcomes included changes in lipid profile relevant to ASCVD risk. Certainty of evidence was assessed using GRADE. [RESULTS] IcoSema showed no statistically significant difference in HbA1c reduction compared with control (pooled MD -0.37%, 95% CI -0.95 to 0.21; P = 0.21; I²=98%) but shows highly significant body weight reduction (pooled MD -6.10 kg, 95% CI -7.21 to -5.00; P < 0.00001). It significantly lowered systolic blood pressure (MD -2.45 mmHg, 95% CI -3.52 to -1.38; P < 0.00001), total cholesterol (ETR 0.97, 95% CI 0.95-0.98; P = 0.0001), LDL-C (ETR 0.94, 95% CI 0.90-0.98; P = 0.005), triglycerides (ETR 0.94, 95% CI 0.91-0.97; P = 0.0006), and VLDL-C (ETR 0.94). An exploratory, hypothetical ASCVD risk modeling analysis based on these surrogate-marker changes is presented in the Supplementary Appendix and is intended as an illustration only. [CONCLUSIONS] Once-weekly IcoSema delivers meaningful improvements in weight, blood pressure, and atherogenic lipids, all key modifiable drivers of ASCVD in adults with type 2 diabetes. These surrogate benefits, combined with reduced injection burden and low risk of hypoglycemia, suggest potential for enhanced ASCVD prevention and improved long-term adherence. Results should be interpreted as hypothesis-generating only because only two trials met the inclusion criteria. Dedicated cardiovascular outcome trials are essential to validate these surrogate-marker benefits and to confirm whether they translate into a reduction in cardiovascular events.","url":"https://pubmed.ncbi.nlm.nih.gov/42681675/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":231,"doi":"10.2337/dc26-0757","pmid":"42684335","nct_ids":"[]","title":"Comparative Short-term Risk of Severe Gastrointestinal Events Associated With Opioid Type Among Patients Receiving Glucagon-Like Peptide-1 Receptor Agonists","authors":"[\"Bea S\", \"Patorno E\", \"Sreedhara SK\", \"Wexler DJ\", \"Cromer SJ\", \"Glynn RJ\", \"Paik JM\", \"Bykov K\"]","journal":"Diabetes care","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare the risk of motility-related gastrointestinal (GI) events associated with commonly prescribed opioids among adults with type 2 diabetes (T2D) prescribed glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, a population in whom the GI safety of concomitant opioid use has not been well characterized. [RESEARCH DESIGN AND METHODS] A population-based, new-user cohort study was conducted using U.S. insurance claims (2016-2025) among adults with T2D prescribed GLP-1RA therapy who initiated use of oxycodone, hydrocodone, or tramadol. We evaluated a composite of motility-related GI events, including severe constipation, bowel obstruction, and gastroparesis, and estimated 30-day weighted absolute risks, risk ratios (RRs), and risk differences (RDs) using propensity score-matching weights. [RESULTS] Among 411,188 patients (mean age 62.8 years; 53.8% female) with T2D and using a GLP-1RA, 24.4% initiated use of oxycodone, 48.5% hydrocodone, and 27.1% tramadol. The weighted 30-day absolute risk of motility-related GI events was 0.51% for oxycodone, 0.35% for hydrocodone, and 0.33% for tramadol. Oxycodone was associated with a higher risk than hydrocodone (RR 1.48 [95% CI 1.30-1.69]; RD 0.17 [95% CI 0.11-0.22]) and tramadol (RR 1.55 [95% CI 1.33-1.79]; RD 0.18 [95% CI 0.12-0.24]). Hydrocodone and tramadol showed similar risks (RR 1.05 [95% CI 0.91-1.21]; RD 0.02 [95% CI -0.03 to 0.06]). [CONCLUSIONS] Among adults with T2D who were using a GLP-1RA, initiation of oxycodone was associated with higher short-term risks of severe constipation and bowel obstruction compared with hydrocodone or tramadol. We did not observe differences in the risk of gastroparesis. Risks were similar between patients initiating hydrocodone and tramadol, although variation across secondary analyses warrants cautious interpretation.","url":"https://pubmed.ncbi.nlm.nih.gov/42684335/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"addiction\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":255,"doi":"10.5009/gnl260189","pmid":"42682267","nct_ids":"[]","title":"Multi-Database Pharmacovigilance Analysis of Gastroesophageal Reflux Disease Associated with GLP-1 Receptor Agonists: A Cross-National Signal Validation Study","authors":"[\"Choi JG\", \"Gong EJ\", \"Bang CS\", \"Lee JJ\"]","journal":"Gut and liver","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity. Gastrointestinal adverse events are common; however, the association with gastroesophageal reflux disease (GERD) has not been validated across diverse populations. We aimed to assess GERD signals associated with GLP-1 RAs using disproportionality analysis across three national adverse event reporting systems. [METHODS] We analyzed FAERS, JADER, and Canada Vigilance. GLP-1 RAs were compared against dipeptidyl peptidase-4 inhibitors as active comparators. GERD was identified using MedDRA preferred terms. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by drug, age, and sex. [RESULTS] Among 260,417 GLP-1 RA reports, significant GERD signals were detected across all databases: FAERS (ROR, 2.83; 95% CI, 2.39 to 3.35; 9,245 vs 139), JADER (4.76; 95% CI, 2.45 to 9.27; 19 vs 16), and Canada Vigilance (2.91; 95% CI, 1.97 to 4.31; 206 vs 29). All signals met both ROR and proportional reporting ratio detection criteria. Drug-specific analyses revealed the strongest signals for semaglutide across all databases (3.44 to 6.93), followed by liraglutide (2.36 to 5.90), tirzepatide (2.76 to 5.77), and dulaglutide (2.35 to 3.32). Exenatide showed an inverse association in FAERS (ROR, 0.60; 95% CI, 0.46 to 0.77). Age-stratified analysis demonstrated increasing signal strength with age (≥65 years: ROR, 3.01; p-trend=0.028). Sensitivity analysis confirmed consistent signal directions. [CONCLUSIONS] This first multi-database pharmacovigilance analysis confirms consistent GERD signals for GLP-1 RAs across Western and Asian populations, demonstrating approximately 2- to 5-fold higher reporting. Clinicians need to monitor for reflux symptoms during GLP-1 RA therapy, particularly in elderly patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42682267/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":284,"doi":"10.21203/rs.3.rs-10121512/v1","pmid":"42934302","nct_ids":"[]","title":"Glucagon-like Peptide-1 Receptor Agonist Use and Risk of Postmastectomy Lymphedema in Breast Cancer Survivors: A Multicenter Real-World Cohort Study","authors":"[\"Yesho DH\", \"Megiso MZ\", \"Ugwu C\", \"Neely AN\", \"Verinumbe T\", \"Varadi G\", \"Jones C.\"]","journal":"preprint server","publication_date":"2026-09-02","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>  <bold>Purpose</bold>  Postmastectomy lymphedema is a chronic survivorship complication after breast cancer treatment, particularly among patients exposed to axillary surgery. Obesity and metabolic inflammation are recognized contributors to lymphedema risk. This study evaluated whether glucagon-like peptide-1 receptor agonist exposure was associated with lower incident postmastectomy lymphedema among breast cancer patients undergoing mastectomy and/or axillary procedures.  <bold>Methods</bold>  We performed a retrospective cohort study using deidentified electronic health record data from the TriNetX Research Network. Adult patients with breast cancer who underwent mastectomy, axillary lymphadenectomy, sentinel lymph node biopsy, or had acquired absence of breast/nipple were stratified by GLP-1 receptor agonist exposure versus no exposure. One-to-one propensity score matching was used to balance measured baseline characteristics. The primary outcome was incident postmastectomy lymphedema syndrome. Outcomes were assessed from 1 to 650 days after the index event using risk estimates, Kaplan–Meier analysis, and Cox proportional hazards models.  <bold>Results</bold>  After propensity score matching, 61,630 patients were included, with 30,815 patients in each cohort. Postmastectomy lymphedema occurred in 258 of 29,259 GLP-1 receptor agonist users and 779 of 30,237 non-users, corresponding to risks of 0.88% and 2.58%, respectively. GLP-1 receptor agonist exposure was associated with lower postmastectomy lymphedema risk in time-to-event analysis (hazard ratio 0.373, 95% CI 0.324–0.429; p < 0.001). The absolute risk difference was − 1.7%, with an estimated number needed to treat of 59.  <bold>Conclusion</bold>  In this large real-world breast cancer cohort, GLP-1 receptor agonist exposure was associated with lower coded postmastectomy lymphedema risk over 650 days of follow-up. These findings are hypothesis-generating and support prospective studies evaluating metabolic and anti-inflammatory strategies for lymphedema prevention in breast cancer survivorship.  <bold>Clinical trial number</bold>  : Not Applicable  </p>","url":"https://doi.org/10.21203/rs.3.rs-10121512/v1","source_name":"europepmc","source_tier":3,"coi_statement":"Declarations. Ethics approval: This retrospective study used aggregated, deidentified data from the TriNetX federated health research network. Because the analysis used deidentified data and did not involve direct patient contact or access to identifiable private health information, the study was considered exempt from institutional review board review/not human subjects research. Final institutional determination and reference number, if applicable, should be inserted before submission. Clinical trial number: Not applicable. Consent to participate: Not applicable because this study used deidentified data. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests. Use of AI-assisted tools: AI-assisted tools were used to support language organization and editorial refinement. All authors reviewed, revised, and verified the manuscript content, data interpretation, and references, and take full responsibility for the final submitted work. No AI tool was used to perform the statistical analysis. [Include, revise, or remove based on journal policy, institutional guidance, and coauthor preference.]","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":288,"doi":"10.64898/2026.08.28.26361368","pmid":null,"nct_ids":"[]","title":"GLP-1/GIP Uptake, Indication, and Access Pathways Among US Adults in the Understanding America Study","authors":"[\"Chaturvedi, R. R.\", \"Gracner, T.\", \"Perez-Arce, F.\", \"Suen, S.-c.\", \"Jin, J.\", \"Orriens, B.\", \"Pacula, R. L.\", \"Sexton Ward, A.\", \"Haile, R.\", \"Kapteyn, A.\"]","journal":"medrxiv (preprint)","publication_date":"2026-09-02","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"ImportanceEvidence on GLP-1/GIP therapies is largely derived from trials enrolling selected populations or medical records that miss utilization outside healthcare channels. No nationally representative cohort has characterized real-world uptake, indications, and access.\n\nObjectiveTo characterize GLP-1/GIP prevalence, indication, clinical profile, and access.\n\nDesignProspective cohort study with three GLP-1/GIP surveillance waves (March 2024, December 2024, October 2025).\n\nSettingThe Understanding America Study, an address-based, nationally representative panel of approximately 15,000 US adults aged 18+ years initiated in 2014.\n\nParticipantsUAS participants responding to at least one surveillance wave (n=9150).\n\nExposuresGLP-1/GIP use status (never vs any use, comprising current and former use), self-reported primary indication (diabetes, weight loss, or other), and access pathway (traditional vs non-traditional).\n\nMain Outcomes and MeasuresSurvey-weighted prevalence of GLP-1/GIP use, overall and by indication and access pathway; sociodemographic, cardiometabolic, treatment, and access characteristics; and smartwatch-derived resting heart rate, heart rate variability, maximum activity heart rate, step count, and sleep duration and variability.\n\nResultsAmong n=9150 adults (1274 with any use; 60.9% female; median age 53 years), weighted prevalence increased 46%, from 8.2% (March 2024) to 12.0% (October 2025) representing 32 million. Weight-loss indications grew, reaching nearly half of use (4.1% to 5.6%); diabetes-indicated use was stable (5.3% to 5.4%). Users carried high cardiometabolic burden (obesity, 68.2%; diabetes, 53.6%) but diverged by indication: diabetes-indicated users were older (median, 59 vs 49 years), whereas weight-loss-indicated users were more often female (69.9% vs 51.3%) and healthier. One in three users (~9 million) had non-traditional access, especially in weight-loss-indicated users, of whom 33% had no conventional prescription; 41% used compounding, online, or foreign pharmacies; and, 43% lacked coverage. Non-traditional users were five times as likely to report an unlisted, likely compounded formulation (19.8% vs 4.1%). All p<0.05.\n\nConclusions and RelevanceReal-world GLP-1/GIP use has grown rapidly and diversified substantially in indication, access, and population profile. One in 3 users obtained treatment through nontraditional channels largely invisible to claims data, raising long-term safety, efficacy, and coverage questions. GLIMMER provides a public, nationally representative longitudinal evidence base for future payer and provider decisions.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSWho is using glucagon-like peptide-1 receptor agonists or glucose-dependent insulinotropic polypeptides (GLP-1/GIP) therapies in the US, how has use changed since 2024, and how are these medications obtained?\n\nFindingsIn this cohort study of 9150 US adults, GLP-1/GIP use rose significantly from 8.2% to 12.0% (March 2024-October 2025), driven by weight loss; those treated for diabetes were a decade older, lower-income, and in poorer health than those treated for weight loss. Overall, 1 in 3 users obtained treatment outside conventional prescribing and dispensing channels.\n\nMeaningA large and growing share of GLP-1/GIP exposure occurs outside the channels visible to claims-based surveillance.","url":"https://www.medrxiv.org/content/10.64898/2026.08.28.26361368","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"sleep\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":565,"doi":"10.3390/ijms27177855","pmid":"42737751","nct_ids":"[]","title":"Combination GLP-1RA and Low-Dose IL-2 Modulates Peripheral Immune Activation and Attenuates CNS Inflammatory Transcript Signatures In Vivo","authors":"[\"Thome AD\", \"Wang J\", \"Faridar A\", \"Zhao W\", \"Saetzler V\", \"Beers DR\", \"Appel SH\"]","journal":"International journal of molecular sciences","publication_date":"2026-09-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Immune dysregulation characterized by persistent myeloid activation and associated impairment of regulatory T cell (Treg) function contributes to inflammatory signaling across peripheral and central compartments in neurodegenerative diseases. We evaluated whether combining a glucagon-like peptide-1 receptor agonist (GLP-1RA; semaglutide) with low-dose interleukin-2 (LD-IL2) could modulate myeloid-associated transcript expression and enhance Treg-associated regulatory transcripts in a subacute lipopolysaccharide (LPS)-induced model of systemic and CNS inflammation. Mice received LPS once daily for 5 days, while GLP-1RA, LD-IL2, or combination treatment was initiated 24 h after LPS onset and continued daily. Splenic immune populations were quantified, and transcript expressions were assessed in magnetically enriched CD11b+ myeloid cells and CD4+CD25+ Tregs, as well as in cortex and hippocampus. As monotherapies, GLP-1RA reduced myeloid expansion with modest modulation of pro-inflammatory and anti-inflammatory myeloid transcripts, whereas LD-IL2 selectively enhanced Treg numbers and increased transcripts associated with Treg stability and suppressive regulation, including Il2ra (CD25), Foxp3, Ctla4, Ikzf2 (HELIOS), Entpd1 (CD39), and Nt5e (CD73). Combination treatment significantly reduced LPS-induced myeloid Il6, Il1b, and Tnf expression and increased Arg1 expression. Combination treatment further enhanced Treg-associated Il2ra (CD25), Tgfb1, and Ctla4 expression relative to monotherapies. In cortical and hippocampal tissues, combination treatment produced more robust modulation of inflammatory transcripts compared with effects observed with monotherapies, including reductions in Il6 and Il1b and increases in Cd163 and Mrc1 (CD206) expression. Together, these findings demonstrate coordinated and complementary changes in peripheral immune-cell populations and myeloid inflammatory and Treg-associated regulatory transcripts and warrant further evaluation of this combination in inflammation-driven neurodegenerative disease.","url":"https://pubmed.ncbi.nlm.nih.gov/42737751/","source_name":"pubmed","source_tier":1,"coi_statement":"A.D.T. and A.F. have consulted for Coya Therapeutics, Inc. S.H.A. serves as Chair of the Coya Therapeutics Scientific Advisory Committee. Coya Therapeutics, Inc. has licensed research from Houston Methodist Research Institute and supported this study through a sponsored research agreement. J.W., W.Z., V.S. and D.R.B. declare no conflicts of interest. The funder had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to publish the results.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:06+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"neuroinflammation\", \"immune\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":167,"doi":"10.1007/s13300-026-01911-2","pmid":"42678648","nct_ids":"[]","title":"Effect of Combination Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists on Myocardial Infarction and Stroke in Type 2 Diabetes: A Systematic Review and Meta-Analysis","authors":"[\"Ghafoury R\", \"Naghshbandi M\", \"Malek M\", \"Kalra S\", \"Ismail-Beigi F\", \"Khamseh ME\"]","journal":"Diabetes therapy : research, treatment and education of diabetes and related disorders","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardioprotection in type 2 diabetes mellitus (T2DM). We evaluated their monotherapy versus their combined use for prevention of myocardial infarction (MI) and stroke. [METHODS] Conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, five databases were systematically searched through November 2025 for studies evaluating use of SGLT2i and GLP-1RA in combination versus their monotherapy in adults with T2DM. Hazard ratios (HRs) for MI and stroke were pooled utilizing random-effects models. Subgroup interaction testing and grading of recommendations assessment, development, and evaluation (GRADE) certainty assessments were performed. [RESULTS] Of the studies, eight comprising ten comparisons were included. Combination therapy was associated with a lower overall risk of MI (HR 0.79, 95% CI 0.70-0.88; I2 = 72.8%) and stroke (HR 0.85, 95% CI 0.77-0.93; I2 = 63.5%) compared with their monotherapy. For MI, combination therapy significantly outperformed SGLT2i monotherapy (HR 0.74, 95% CI 0.60-0.90) but not GLP-1RA monotherapy (HR 0.80, 95% CI 0.55-1.16). For stroke reduction, combination therapy outperformed both SGLT2i (HR 0.73, 95% CI 0.54-0.99) and GLP-1RA (HR 0.92, 95% CI 0.88-0.96) monotherapy. Cerebrovascular benefit appeared stronger in adults > 65 years (HR 0.50, 95% CI 0.37-0.68). Overall certainty of evidence was very low. [CONCLUSIONS] In adults with T2DM, SGLT2i and GLP-1RA combination therapy may be associated with lower risks of MI and stroke compared with their monotherapy. While the MI benefit appears primarily to be driven by GLP-1RA, combination therapy yields an additive reduction in stroke risk, particularly in older adults. Given the very low certainty of evidence, these hypothesis-generating findings require confirmation through dedicated prospective trials. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420261320374 .","url":"https://pubmed.ncbi.nlm.nih.gov/42678648/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Author Contribution: Mohammad E. Khamseh contributed to the study conceptualization, supervision, and discrepancy resolution. Roya Ghafoury contributed to the study design and protocol development, literature search, and original draft preparation. Roya Ghafoury and Mobin Naghshbandi were both involved in study screening and selection, data extraction, risk of bias evaluation, and GRADE certainty of evidence assessment. Mobin Naghshbandi additionally performed the statistical analysis, meta-analysis, and software visualization. Faramarz Ismail-Beigi, Mojtaba Malek, Sanjay Kalra, and Mohammad E. Khamseh contributed to intellectual oversight and clinical data interpretation. All authors critically reviewed and edited the manuscript, approved the final version, and agree to be accountable for all aspects of the work. Funding: No funding or sponsorship was received for this study or publication of this article. Medical Writing/Editorial Assistance: ChatGPT (OpenAI, San Francisco, CA, USA) was used to assist with grammar and language editing during the preparation of this manuscript. No funding was received for this assistance. The authors reviewed and verified all content and take full responsibility for the integrity and accuracy of the work. Data Availability: This study is based on aggregate data from previously published studies; no new primary data were generated. All data supporting the findings are contained within the article and its tables. The extracted data set and the analysis code are available from the corresponding author upon reasonable request. Conflict of Interest: Roya Ghafoury has nothing to disclose. Mobin Naghshbandi has nothing to disclose. Faramarz Ismail-Beigi has nothing to disclose. Mojtaba Malek has nothing to disclose. Mohammad E. Khamseh and Sanjay Kalra have nothing to disclose other than the following: Mohammad E. Khamseh and Sanjay Kalra are Editorial Board members of Diabetes Therapy. Mohammad E. Khamseh and Sanjay Kalra were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":184,"doi":"10.1097/bsd.0000000000002145","pmid":"42683541","nct_ids":"[]","title":"Investigating the Relationship Between Glucagon-Like Peptide-1 Receptor Agonist Use and Incidence of Vertebral Fractures in Female Patients Aged Over 50 Years With Osteoporosis: A Propensity-Matched Analysis","authors":"[\"Stump K\", \"Kelleher S\", \"Aynaszyan S\", \"Ricci S\", \"Pazionis T\"]","journal":"Clinical spine surgery","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[STUDY DESIGN] Retrospective cohort. [OBJECTIVE] To investigate the relationship between GLP-1 receptor agonist exposure and incidence of vertebral fracture and surgical intervention for these injuries in patients with osteoporosis. [SUMMARY OF BACKGROUND DATA] Vertebral fractures are relatively common in patients with osteoporosis and frequently result in substantial morbidity, such as persistent pain and functional deficit. Although primarily indicated for the management of type 2 diabetes mellitus and obesity, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated positive effects on bone mineral density (BMD) in the lumbar spine. However, it remains unknown if this effect translates to positive clinical outcomes for patients with osteoporosis. [METHODS] This study utilized the TriNetX database to identify female patients aged over 50 years diagnosed with osteoporosis without a current pathologic fracture within the 10-year period ended January 1, 2025. The study group included patients with a history of GLP-1 RA use after osteoporosis diagnosis compared with a control group with no GLP-1 RA exposure. Cohorts were propensity-matched based on baseline demographic characteristics, BMI, HbA1c, eGFR, medical comorbidities, osteoporotic medication use, and serum calcium, phosphate, and vitamin D levels. Primary outcomes included incidence of vertebral collapse and vertebral augmentation within the 10-year study period. [RESULTS] There were 56,142 matched pairs. The rate of vertebral fracture in the experimental group was ∼1.9% compared with 4.3% in the control group (RR: 0.434, 95% CI: 0.404-0.467, P<0.001). In addition, GLP-1 RA exposure was associated with a lower incidence of kyphoplasty or vertebroplasty (RR: 0.453, 95% CI: 0.381-0.538, P<0.001). [CONCLUSION] Glucagon-like peptide-1 receptor agonist use is associated with a lower incidence of vertebral fracture and osteoporotic fracture intervention in female patients aged 50+ with osteoporosis. These findings underscore the potential protective effects of GLP-1 receptor agonists in patients with poor bone quality. [LEVEL OF EVIDENCE] Level III.","url":"https://pubmed.ncbi.nlm.nih.gov/42683541/","source_name":"pubmed","source_tier":1,"coi_statement":"T.P. is a consultant for Medtronic, Globus, Carlsmed, Camber, Silony Spine, Spinal Elements Cerapedics, and Zim Vie; travel for SI Bone and Johnson & Johnson. The remaining authors declare no conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"bone\", \"metabolic\", \"nutrition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":185,"doi":"10.1111/dom.71262","pmid":"42681821","nct_ids":"[]","title":"Genetic and Clinical Determinants of Variation in Drug Response in Type 2 Diabetes: Insights From the Scottish and UK Biobank Cohorts","authors":"[\"Garg S\", \"Kitchen R\", \"Gupta R\", \"Donnelly L\", \"Pearson ER\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Treatment response in type 2 diabetes (T2D) varies widely among individuals. This study aimed to quantify the contributions of clinical characteristics and genetic predisposition as measured through partitioned polygenic risk scores (pPRS) to variation in glycemic response to glucose-lowering therapies. [RESEARCH DESIGN AND METHOD] We analysed data from two population-based cohorts: the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) and the UK Biobank (UKBB). GoDARTS included 41 802 patients who initiated one of six major drug classes, of whom 11 615 had available genotype data. UKBB contributed 9371 individuals, including 8293 with genetic data. The primary outcome was glycaemic response, defined as the change in HbA1c 12 months after treatment initiation. Variables included demographic and clinical factors (age, sex, BMI, baseline HbA1c, kidney and liver function markers) and 14 pPRS representing T2D-related biological pathways. Linear regression models were fitted within each cohort and drug class (metformin, sulfonylureas, TZDs, DPP4i, SGLT2i, GLP-1RA), and effect estimates were combined using fixed-effect meta-analysis. [RESULT] Baseline HbA1c was most strongly associated with glycemic response (p < 0.001). Older age was consistently associated with greater HbA1c reduction, while BMI and total cholesterol demonstrated drug-class-specific associations, with higher BMI associated with improved response to TZDs and higher total cholesterol generally associated with poorer glycaemic outcomes. Meta-analysis across GoDARTS and UK Biobank showed that higher overall T2D genetic risk was associated with greater HbA1c reduction with sulfonylureas (β = -0.46 mmol/mol, p = 0.013). Specific genetic profiles were also associated with drug responses, including β-cell function clusters with sulfonylureas (β = -0.57, p = 0.002), obesity-related variants with GLP-1RA (β = -1.49, p = 0.04), liver-lipid variants with SGLT2 inhibitors (β = -0.84, p = 0.05), and bilirubin pPRS with DPP-4 inhibitors (β = -0.69, p = 0.006). [CONCLUSION] Both clinical and genetic factors significantly contribute to inter-individual variability in T2D drug response. Partitioned PRSs provide mechanistic insights into drug-specific pathways and have the potential to inform precision prescribing and optimise therapeutic outcomes in routine diabetes care.","url":"https://pubmed.ncbi.nlm.nih.gov/42681821/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":195,"doi":"10.1038/s44324-026-00131-3","pmid":"42680805","nct_ids":"[]","title":"Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss","authors":"[\"Murugadoss K\", \"Venkatakrishnan AJ\", \"Soundararajan V\"]","journal":"npj metabolic health and disease","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"GLP1 receptor agonists (GLP-1RAs) have transformed obesity treatment, but their impact on neuropsychiatric outcomes remains poorly understood. We conducted an observational study of 63,215 patients with preexisting neuropsychiatric conditions and evaluated 24 incident neuropsychiatric outcomes following treatment initiation. In propensity-matched analyses, semaglutide was associated with broadly lower neuropsychiatric event risk over two years compared with metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after treatment initiation (\"pre-landmark period\") was associated with significantly lower incidence during the subsequent two years (\"post-landmark period\") of substance-related disorders (P < 0.001), mood disorders (P < 0.001), anxiety- and stress-related disorders (P < 0.001), central nervous system (CNS) atrophies (P < 0.001), neuromuscular disorders (P = 0.013), eating/sleep/behavioral disorders (P = 0.022), and personality/impulse-control disorders (P = 0.028). Consistent with prior clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P = 0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained dose. In contrast, incident cognitive symptoms and speech/language symptoms were more closely associated with weight loss (p < 0.001 and p < 0.003, respectively). Bulk and single-cell transcriptomic analyses identified low-level, regionally restricted GLP1R transcript signals in central and peripheral nervous system tissues, providing hypothesis-generating context for future experimental investigation. Together, these findings support an association between semaglutide exposure and multiple neuropsychiatric outcomes, and motivate prospective mechanistic and clinical studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42680805/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: The authors are employees of nference, inc., which conducts research collaborations with various biopharmaceutical companies whose therapeutic products are included in this study. None of these companies, nor any other nference collaborator, funded, supported, or had any role in the independent study design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit this work for publication. All analyses were conducted by the authors using de-identified electronic health record data. The authors declare no additional competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:54+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cognition\", \"dementia\", \"sleep\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":235,"doi":"10.36849/jdd.10086","pmid":"42696340","nct_ids":"[]","title":"Clinical Evidence of Skin Improvements With a Biologically Active Multimodal Topical Skin Treatment","authors":"[\"Obagi ZE\", \"Balian RJ\", \"Ramsey SV\", \"Woodin FW\", \"Nguyen GH\"]","journal":"Journal of drugs in dermatology : JDD","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Antiaging skin treatments are continuously in development to meet the needs of an aging population and counteract cosmetic effects of glucagon-like peptide-1 receptor agonists. Peptide Facial Refining Concentrate (ST26-PF-F1) serum contains multiple bioactive peptides within a penetrative delivery system. A clinical study of ST26-PF-F1 assessed its effects on skin health/appearance and tolerability/usability. [METHODS] This noncomparative 12-week study enrolled healthy females aged 45 years or older, Fitzpatrick phototypes I&ndash;VI, with evidence of skin aging. Participants applied ST26-PF-F1 twice daily. Efficacy (expert evaluation, instrumental measurements, confocal microscopy, and participant self-assessments) and tolerability/safety (dermatologist and participant reporting) were assessed at weeks 2, 4, 8, and 12. [RESULTS] Statistically significant improvements from baseline were observed for expert evaluator global assessments of fine lines, skin elasticity and plumpness, and facial contour and facial sagging (all time points); and wrinkles and skin firmness (weeks 4, 8, and 12). Significant improvements were also observed in skin hydration and elasticity (all time points); wrinkle volume, depth, and skin texture (weeks 4, 8, and 12); and lifting effect and V-shape (week 12). Confocal microscopy showed statistically significant improvements in interkeratinocyte brightness, papilla morphology, and dermal collagen fibers at weeks 4 and 12 and surface uniformity and keratinocyte morphology at week 12. Participants reported skin improvements across multiple measures and overall product satisfaction. ST26-PF-F1 was well tolerated with no treatment-related stinging, itching, or discomforting sensations. [CONCLUSION] Clinical, instrumental, and microscopy assessments of ST26-PF-F1 demonstrated wrinkle-modulating and filler-like effects, visibly more balanced-looking facial geometry, favorable tolerability, and user satisfaction.","url":"https://pubmed.ncbi.nlm.nih.gov/42696340/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"clinical_trial","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"aging\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":260,"doi":"10.7326/annals-25-05519","pmid":"42673585","nct_ids":"[]","title":"Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes : An Updated Systematic Review","authors":"[\"Moiz A\", \"Filion KB\", \"Samuels AE\", \"Tsoukas MA\", \"Yu OHY\", \"Peters TM\", \"Eisenberg MJ\"]","journal":"Annals of internal medicine","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management. [PURPOSE] To update our prior systematic review evaluating the efficacy and safety of GLP-1 RAs and co-agonists among adults with overweight or obesity without diabetes. [DATA SOURCES] MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from 5 October 2024 through 25 March 2026. [STUDY SELECTION] Randomized controlled trials ([RCTs] treatment duration ≥16 weeks). [DATA EXTRACTION] Two reviewers independently extracted data. [DATA SYNTHESIS] Thirty-eight RCTs (n = 25 816) were included, adding 14 new trials (n = 11 000) to the prior review. Among commercially available therapies, placebo-subtracted weight loss reached up to -5.8% (95% CI, -8.0% to -3.6%) for liraglutide, -14.8% (CI, -16.2% to -13.4%) for subcutaneous semaglutide, -14.3% (CI, -17.2% to -11.4%) for oral semaglutide, -12.4% (CI, -15.1% to -9.7%) for orforglipron, and -19.0% (CI, -21.6% to -16.4%) for tirzepatide. Numerically greater placebo-subtracted reductions were seen with emerging multiagonists, including -23.9% (CI, -29.3% to -18.5%) with amycretin and -22.1% (CI, -24.9% to -19.3%) with retatrutide. Gastrointestinal adverse events (AEs) remained common (GLP-1 RA vs. placebo: 76.0% vs. 40.1%). Discontinuation due to AEs was generally low (10.7% vs. 3.4%) but numerically higher with some oral agents. Serious AEs (6.5% vs. 5.2%) and deaths (0.1% vs. 0.0%) were rare, with no new safety signals identified. Head-to-head data showed greater weight loss with semaglutide and JNJ-64565111 than liraglutide and greater weight loss with tirzepatide and cagrilintide-semaglutide (CagriSema; Novo Nordisk) than semaglutide. [LIMITATIONS] Heterogeneity precluded quantitative synthesis. Safety outcomes were inconsistently reported. [CONCLUSION] Glucagon-like peptide-1 receptor agonists demonstrate substantial weight loss in adults without diabetes, with an expanding range of therapeutic options, including oral and multiagonist therapies. [PRIMARY FUNDING SOURCE] None. (PROSPERO: CRD42024505558).","url":"https://pubmed.ncbi.nlm.nih.gov/42673585/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"orforglipron\", \"tirzepatide\", \"retatrutide\", \"cagrisema\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":826,"doi":"10.1167/iovs.67.11.52","pmid":"42808829","nct_ids":"[]","title":"Study on the Regulatory Mechanism of GLP-1 Receptor Agonist Liraglutide in Diabetic Corneal Epithelial Wound Healing","authors":"[\"Liu X\", \"Lin H\", \"Shao Y\", \"Shen J\", \"Bi Y\"]","journal":"Investigative ophthalmology & visual science","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] The purpose of this study was to elucidate the effects and mechanisms of liraglutide in repairing diabetic corneal epithelial injury, explore its therapeutic advantages, and provide experimental evidence for clinical application. [METHODS] GLP-1R expression in mouse corneal epithelium was detected by Western blotting, qPCR, and immunofluorescence. Streptozotocin-induced diabetic mice and 30 mM high-glucose (HC) cell models were established. Epithelial wound healing, viability, proliferation, migration, and apoptosis were evaluated by fluorescein staining, TUNEL, CCK-8, EdU, and scratch assay. Bioinformatics was used to screen differentially expressed genes. Reactive oxygen species (ROS), redox indicators, and key proteins in Keap1-Nrf2-ARE, PI3K/Akt, and MAPK pathways were measured. PI3K inhibitors were applied to verify the pathway function, and macrophage polarization and recruitment were further assessed. [RESULTS] GLP-1R was mainly located in the deep basal cells of corneal epithelium. Liraglutide improved cell viability, promoted proliferation and migration, and inhibited apoptosis. It restored redox balance and alleviated oxidative stress via activating Nrf2/HO-1/NQO-1 pathway, and enhanced cell functions through PI3K/Akt pathway; these effects were abolished by PI3K inhibition. Moreover, liraglutide reduced aberrant macrophage infiltration, promoted anti-inflammatory macrophage polarization, and decreased pro-inflammatory factors, which was associated with MAPK pathway downregulation. [CONCLUSIONS] Liraglutide exerts multi-mechanism protective effects on diabetic corneal epithelium. It regulates Nrf2 and PI3K/Akt pathways to attenuate oxidative stress and improve cell functions, and modulates macrophage polarization and recruitment via MAPK pathway to relieve inflammation, thereby promoting corneal epithelial injury repair.","url":"https://pubmed.ncbi.nlm.nih.gov/42808829/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosure: ","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:17+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1044,"doi":"10.4103/aian.aian_812_26","pmid":"42878597","nct_ids":"[]","title":"Early GLP-1 Receptor Agonist Therapy in Acute Ischemic Stroke and High-Risk Transient Ischemic Attack: A Systematic Review and Meta-analysis of Randomized Trials","authors":"[\"Ali A\", \"Dézsi C\", \"Gulyás-Oldal V\", \"Kumar P\", \"Szili K\", \"Ullah S\", \"Akram N\", \"Gulzar MA\", \"Azhar A\", \"Ul Abidin MZ\", \"Saleem U\", \"Shabbir MA\", \"Sharma M\"]","journal":"Annals of Indian Academy of Neurology","publication_date":"2026-09-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND OBJECTIVES] The role of early glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy after acute ischemic stroke or high-risk transient ischemic attack remains uncertain. We performed a systematic review and meta-analysis of randomized evidence evaluating efficacy and safety in this setting. [METHODS] Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance, we included randomized controlled trials evaluating early GLP-1RA therapy in adults with acute ischemic stroke or high-risk transient ischemic attack. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using inverse-variance random-effects models with restricted maximum likelihood estimation. The primary outcome was 90-day functional independence (modified Rankin Scale score: 0-2); mortality and symptomatic intracranial hemorrhage (sICH) were critical safety outcomes. [RESULTS] Four randomized trials enrolled 1,514 participants: LAMP, GALLOP-1, GALLOP-2, and TEXAIS. GLP-1RA therapy increased 90-day functional independence (547/745 vs 516/752; RR = 1.06; 95% CI: 1.01-1.11; I 2 = 5.8%), corresponding to an absolute risk difference of 4.8% and number needed to treat of 21. Mortality did not differ significantly (57/749 vs 52/756; RR = 1.13; 95% CI: 0.80-1.61; I 2 = 0%). sICH was not significantly different (23/579 vs 20/585; RR = 0.67; 95% CI: 0.13-3.42; I 2 = 67.0%). Excluding LAMP attenuated the functional effect (RR = 1.07; 95% CI: 0.92-1.24), and excluding GALLOP-2 yielded RR = 1.049 (95% CI: 0.999-1.102). [CONCLUSIONS] Early GLP-1RA therapy shows a possible functional benefit, but the finding is fragile and safety evidence remains imprecise. Larger dedicated stroke trials are required before routine clinical use.","url":"https://pubmed.ncbi.nlm.nih.gov/42878597/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:29:46+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":130,"doi":"10.7759/cureus.116039","pmid":"42724505","nct_ids":"[]","title":"Cardiorenal Protection in Type 2 Diabetes: A Systematic Review Comparing Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors","authors":"[\"Branigan P\", \"Duong VNY\", \"Branigan S\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 2 diabetes mellitus (T2DM) is associated with substantial cardiovascular and renal morbidity and premature mortality. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiorenal events beyond their glucose-lowering effects. This systematic review compared cardiovascular, heart failure, kidney, mortality, metabolic, and safety outcomes of the two classes of medications and evaluated evidence for complementary use. Randomized controlled trials, systematic reviews and meta-analyses, and large comparative observational studies of adults with type 2 diabetes reporting relevant cardiovascular, renal, mortality, metabolic, or safety outcomes were eligible. Glycemia-only studies without relevant clinical outcomes, pediatric and preclinical studies, case reports, editorials, and noninformative reports were excluded. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched from January 2010 through August 30, 2026, supplemented by Google Scholar and backward and forward citation searching. Risk of bias was assessed using RoB 2 for randomized trials, ROBINS-I for nonrandomized comparative studies, and AMSTAR 2 for systematic reviews and meta-analyses. Certainty of evidence was assessed at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Because of heterogeneity across populations, interventions, outcomes, and study designs, results were evaluated using a structured narrative synthesis rather than a de novo meta-analysis. Thirty-eight studies were included, comprising 14 randomized controlled trials, 12 nonrandomized comparative studies, and 12 systematic reviews or meta-analyses. SGLT2 inhibitors showed particularly consistent benefit for heart failure and kidney outcomes, whereas GLP-1 receptor agonists showed strong atherosclerotic cardiovascular benefit and greater weight reduction. Certainty was moderate for the principal comparative cardiovascular and kidney outcomes and lower for real-world comparative effectiveness and combination therapy. Evidence supported potentially complementary cardiorenal effects with combined use, although superiority of combination therapy over appropriately selected monotherapy was not established. Safety profiles differed, with genital infections, volume depletion, and rare diabetic ketoacidosis more closely associated with SGLT2 inhibitors and gastrointestinal adverse effects more common with GLP-1 receptor agonists. Interpretation was limited by heterogeneity in study populations, interventions, outcome definitions, follow-up periods, and study designs, residual confounding in observational evidence, and the possibility of publication and selective-reporting bias. Overall, the findings support individualized treatment selection according to cardiovascular and renal risk, heart failure, weight goals, safety, tolerability, and access, with combined use considered when complementary benefits are clinically appropriate.","url":"https://pubmed.ncbi.nlm.nih.gov/42724505/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":145,"doi":"10.1002/edm2.70313","pmid":"42706739","nct_ids":"[]","title":"Efficacy and Safety of Tirzepatide Versus Dulaglutide in Type 2 Diabetes With or Without Established Atherosclerotic Cardiovascular Disease: A Network Meta-Analysis of Randomized Clinical Trials","authors":"[\"Hageen AW\", \"Gadelmawla AF\", \"Saleh AO\", \"Bahnasy S\", \"Eladawi S\", \"Abdelaziz M\", \"Iyad K\", \"Kandil AH\", \"Zinhom K\", \"Mohamed MR\", \"Abdulhay H\", \"Turkman M\", \"Abdelazeem B\", \"Fonarow GC\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIM] This network meta-analysis addresses the limited dose-specific comparative evidence by evaluating different doses of tirzepatide (TZP) versus dulaglutide (DULA) for glycemic control, weight loss, and safety in type 2 diabetes mellitus (T2DM). [METHODS] Following PRISMA and Cochrane guidance, we searched major databases for RCTs comparing TZP and DULA in adults with T2DM. Efficacy outcomes included body weight change (Weeks 12 and 16) and mean HbA1c change (Weeks 12 and 24). Safety outcomes included mortality, cardiovascular events, and adverse events (AEs). SUCRA ranking was used and analysis performed in RStudio (v4.5.1). [RESULTS] Four RCTs comprising 14,348 participants contributed to a seven-node network. However, Nicholls et al. 2025 had the majority of sample size (n = 13,165). TZP 15 mg achieved the greatest reduction in body weight at Week 16 (mean difference [MD] vs. TZP 5 mg: -2.68 kg; 95% CI -4.98 to -0.38), while TZP 1 mg (MD: 4.39 kg; 95% CI 1.28 to 7.51) and DULA 0.75 mg (MD: 3.10 kg; 95% CI 0.25 to 5.96) were associated with smaller reductions relative to TZP 5 mg. TZP 15 mg also produced the largest HbA1c reduction at Week 24 (MD vs. TZP 5 mg: -0.40%; 95% CI -0.62 to -0.19), compared with TZP 10 mg (MD: -0.23%; 95% CI -0.44 to -0.02) and DULA 1.5 mg (MD: 0.67%; 95% CI 0.25 to 1.09). No significant differences were observed between treatments for all-cause mortality or major cardiovascular events. Gastrointestinal AEs were more frequent with higher TZP doses, especially TZP 15 mg vs. TZP 5 mg for nausea, while serious AEs and severe hypoglycemia were similar across doses. [CONCLUSION] Higher TZP doses potentially improve efficacy, while lower TZP/DULA doses enhance tolerability, supporting individualized T2DM care. However, these findings should be interpreted cautiously because several comparisons are indirect, many participants had not reached their maintenance dose, several safety outcomes were based on limited event counts, and significant inconsistency was observed for early body-weight outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42706739/","source_name":"pubmed","source_tier":1,"coi_statement":"Dr. Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Boehinger Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. The remaining authors declare no conflicts of interest.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":149,"doi":"10.1016/j.eclinm.2026.104176","pmid":"42701458","nct_ids":"[]","title":"Comparative effectiveness of GLP-1 receptor agonists versus mineralocorticoid receptor antagonists as fourth-line pharmacological therapy in patients with resistant hypertension and overweight or obesity: a retrospective multicenter cohort study in the USA","authors":"[\"Tian Z\", \"Willerding JM\", \"Schmidt-Ott KM\", \"Melk A\", \"Schmidt BMW\"]","journal":"EClinicalMedicine","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Mineralocorticoid receptor antagonists (MRAs) are the guideline-recommended therapy for resistant hypertension. Resistant hypertension is particularly common in individuals with overweight or obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) induce substantial weight loss and reduce cardiovascular and renal events, with modest reductions in blood pressure. Whether GLP-1RAs provide benefit as an alternative therapeutic strategy in patients with resistant hypertension and overweight or obesity is unknown. We compared the effectiveness of GLP-1RAs and MRAs as fourth-line pharmacologic therapy in this population. [METHODS] In this retrospective multicenter cohort study using the TriNetX US Collaborative Network including 67 healthcare organizations, female and male adults with overweight or obesity and resistant hypertension (uncontrolled blood pressure despite ACE-inhibitors/angiotensin receptor blockers, calcium antagonists and diuretics) initiating a fourth-line pharmacological therapy between 01 June 2017 and 31 March 2025 were identified and included. Patients initiating GLP-1RAs (semaglutide or tirzepatide) were compared with those initiating MRAs (spironolactone or eplerenone). The primary outcome was major adverse cardiovascular events (MACE) during 2-year follow-up. Secondary outcomes included all-cause mortality, cardiovascular events, kidney outcomes, and blood pressure changes. Propensity score matching balanced baseline characteristics. Outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models. [FINDINGS] Among 213,309 eligible patients, 22,694 initiated GLP-1RAs and 5673 initiated MRAs. After propensity score matching, 4153 patients remained in each group. During a median follow-up of 1.4 years, GLP-1RA therapy was associated with lower risks of MACE (HR 0.63, 95% CI 0.52-0.78), all-cause mortality (HR 0.34, 95% CI 0.21-0.55), cardiovascular events (HR 0.74, 95% CI 0.59-0.92), major adverse kidney events (HR 0.64, 95% CI 0.46-0.88), and acute kidney injury (HR 0.62, 95% CI 0.46-0.83) compared with MRAs. Systolic blood pressure reductions at 12 weeks were similar (-5.7 [95% CI -4.0 to -7.4] mmHg versus -6.3 [95% CI -4.7 to -8.0] mmHg). [INTERPRETATION] In our retrospective study, among adults with resistant hypertension and overweight or obesity, GLP-1RA was associated with lower cardiovascular and kidney risk compared with MRAs despite smaller blood pressure reductions. GLP-1RAs may represent a potential alternative or complementary therapeutic option in this population. Prospective studies are needed to determine whether GLP-1RAs should be incorporated into treatment strategies for resistant hypertension in patients with overweight or obesity. [FUNDING] None.","url":"https://pubmed.ncbi.nlm.nih.gov/42701458/","source_name":"pubmed","source_tier":1,"coi_statement":"ZT and JMW declare no competing interests. KMSO reports receiving research funding, honoraria or consultancy fees and travel support from German Research Foundation, Urological Research Foundation Berlin, ERA PerMed, COVID-19-Forschungsnetzwerk Niedersachsen, Acadeny2GmbH, Alexion, Alentis, Alnylam, Apellis, Astellas, AstraZeneca, Bayer, BioPorto Diagnostics, Boehringer Ingelheim, Chiesi, CSL Behring, FAST BioMedical, GSK, Novartis, Quark Pharmaceuticals, REATA, Roche, Sanofi, Sobi, Stadapharm, StreamedUp, Vifor Pharma, not related to this article. AM reports receiving lecture fees and honoraria from Daiichi Sankyo and Meta X, not related to this article. BMWS reports receiving lecture fees and honoraria from ADVITOS, Amgen, AstraZeneca, Bayer Vital, Berlin Chemie-Menarini, Boehringer Ingelheim, CytoSorbents, Daichii Sankyo, Miltenyi, Novartis, Pocard, Vifor, not related to this article.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":152,"doi":"10.1002/edm2.70311","pmid":"42700367","nct_ids":"[]","title":"Comparative Cardiovascular Outcomes of GLP-1 Receptor Agonists Versus Bariatric Surgery: A Systematic Review and Network Meta-Analysis","authors":"[\"Shirmohammadi E\", \"Ghasemloo N\", \"Ebrahimi N\", \"Mohammadzadeh N\", \"Ehtemami A\", \"Babaei M\", \"Fardoost S\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity, a major global health issue, heightens the risk of cardiovascular diseases, including major adverse cardiovascular events (MACE), heart failure (HF) and myocardial infarction (MI). This study provides the first network meta-analysis (NMA) integrating direct and indirect evidence to compare the cardiovascular efficacy of bariatric surgery (BS) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in individuals with obesity. [METHODS] A systematic review and NMA were performed in adherence to PRISMA guidelines. PubMed, Embase, Cochrane Library and Google Scholar were searched for studies published from January 2000 to September 2024. Eligible studies reported cardiovascular outcomes, specifically MACEs, HF and MI, in patients with obesity receiving BS, GLP-1RAs or control treatment. Fixed- and random-effects models were used to analyse hazard ratios (HRs) and risk ratios (RRs), with heterogeneity assessed with I2 and consistency through node-splitting analysis. [RESULTS] Forty-three studies involving 932,380 patients were included BS was associated with significantly greater reductions in MACEs (HR 0.66; 95% CI 0.60-0.74), HF (HR 0.45; 95% CI 0.38-0.53) and MI (HR 0.53; 95% CI 0.45-0.63) compared with controls in random-effects models. GLP-1RAs reduced MACEs (HR 0.85; 95% CI 0.77-0.94) but showed non-significant effects on HF and MI. Despite high heterogeneity (I2: 66%-93%), directional consistency was observed across studies. [CONCLUSIONS] BS demonstrated more consistent and statistically significant reductions in all cardiovascular outcomes compared to GLP-1RAs, which showed more variable efficacy, particularly for HF and MI. Nevertheless, GLP-1RAs remain effective evidence-based alternatives for cardiovascular risk reduction in patients who are not candidates for surgery, but future studies on newer GLP-1RAs are required. The high heterogeneity across studies highlights the need for cautious interpretation. These results may inform individualized treatment selection in patients with obesity at high cardiovascular risk.","url":"https://pubmed.ncbi.nlm.nih.gov/42700367/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":162,"doi":"10.3988/jcn.2026.0073","pmid":"42683794","nct_ids":"[]","title":"Effects of Glucagon-Like Peptide-1 Receptor Agonist Use After Transient Ischemic Attack on Risks of Subsequent Ischemic Stroke and Mortality","authors":"[\"Kakadiya J\", \"Rai P\", \"Bathla G\", \"Dhaduk V\", \"Chen H\", \"McIntyre MK\", \"Mandel D\", \"Latifi S\", \"Connolly B\", \"Salim HA\", \"Azzam AY\", \"Essibayi MA\", \"Yedavalli VS\", \"Khan M\", \"Dmytriw AA\", \"Altschul DJ\", \"Colasurdo M\", \"Malhotra A\", \"Gandhi D\", \"Lakhani DA\"]","journal":"Journal of clinical neurology (Seoul, Korea)","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND PURPOSE] A transient ischemic attack (TIA) is associated with a markedly higher risk of subsequent ischemic stroke even when guideline-directed prevention strategies are applied. There is evidence emerging from the LAMP trial that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can help to prevent secondary stroke. We therefore conducted this study to evaluate the association in a real-world cohort. [METHODS] We conducted a retrospective cohort study using data from the TriNetX US Collaborative Network. Adults with TIA who received antithrombotic therapy between 7 days before and 7 days after a TIA diagnosis were included. GLP-1RA use was defined as its initiation between 3 months before to 7 days after a TIA diagnosis. Propensity-score matching (PSM) was performed at a 1:1 ratio to balance covariates. The primary outcomes were ischemic stroke and mortality, while the secondary outcomes were inpatient (IP) admissions and emergency department (ED) visits. Outcomes were assessed over a 5-year follow-up period. Sensitivity analyses stratified by body mass index, hemoglobin-A1c level, and atrial fibrillation status were conducted to generalize the findings. [RESULTS] After applying PSM, 5,071 GLP-1RA users and 5,071 GLP-1RA nonusers were included. GLP-1RA use was associated with lower risks of ischemic stroke (6.9% vs. 10.9%, hazard ratio [HR]=0.76, p<0.001) and mortality (5.9% vs. 12.3%, HR=0.67, p<0.001), as well as fewer IP admissions and ED visits. The results of six sensitivity analyses were consistent with the primary cohort demonstrating the favorable outcomes not being confined to a specific metabolic or vascular risk phenotype. [CONCLUSIONS] GLP-1RA is associated with lower risks of ischemic stroke, mortality, IP admissions, and ED visits in TIA patients. These preliminary findings suggest that GLP-1RAs can play a role in the secondary prevention of cerebrovascular disease.","url":"https://pubmed.ncbi.nlm.nih.gov/42683794/","source_name":"pubmed","source_tier":1,"coi_statement":"DAL is consultant for iSchemaView RapidAI and DocPanel Technologies, and is Scientific advisory board member for Upstream Vision. VSY is consultant for iSchemaView, RapidAI. DJA reports securities holdings in Von Vascular, Inc, and compensation from Johnson and Johnson International, Stryker Corporation, Medtronic USA, Inc, and MicroVention, Inc, for consultant services. MK is consultant for Stryker Medical, Boston Scientific, Medwaves Avecure, Varian, Hyprevention, Caerus medical, and Cohere medical. DG receives research grants from the Focused Ultrasound Foundation, NIH, University of Maryland Medical Center, and Microvention, and is a consultant for Navigantis. Other authors have no relevant disclosures to report.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":238,"doi":"10.1038/s41586-026-10940-7","pmid":"42686906","nct_ids":"[]","title":"Late-life semaglutide treatment slows ageing and extends lifespan in female mice","authors":"[\"Feng Y\", \"Barthez M\", \"Wang Y\", \"Chen Y\", \"Qiu H\", \"Wang CL\", \"Heydari K\", \"Delcroix M\", \"Rasmussen LJ\", \"Bohr VA\", \"Chen D\"]","journal":"Nature","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Pharmacological glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake and is an effective therapy for type 2 diabetes and obesity1. The use of GLP-1 medicines has revealed pleiotropic beneficial effects beyond glucose and weight control2-5, but little is known about the underlying basis of the pleiotropic effects. Here, treatment of 20-month-old female C57BL/6 mice with the GLP-1R agonist semaglutide for 3 months improved physiological function, attenuated hallmarks of ageing and modulated nutrient sensors and conserved genetic regulators of ageing. Continued treatment extended mouse lifespan. These effects parallel key features of calorie restriction, a dietary intervention that slows ageing, extends lifespan and alleviates a wide spectrum of ageing-associated diseases6. In a longitudinal study in direct comparison to matched calorie restriction, semaglutide treatment preserved baseline function and recapitulated many functional benefits of calorie restriction by attenuating age-associated decline, while also producing improvements above baseline and more favourable trajectories than calorie restriction in exploratory drive, spatial memory and glucose control. Together, these findings demonstrate that GLP-1R activation initiated late in life slows ageing and extends lifespan in female mice, supporting its function as a calorie restriction mimetic and providing a mechanistic framework that may help to explain its broad beneficial effects while revealing effects beyond those attributable to reduced calorie intake.","url":"https://pubmed.ncbi.nlm.nih.gov/42686906/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: The Regents of the University of California filed a patent application on GLP-1 receptor agonists for healthy ageing (64/113,481).","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cognition\", \"aging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":261,"doi":"10.1002/edm2.70325","pmid":"42673571","nct_ids":"[]","title":"Weight Regain Trajectories After Discontinuation of Semaglutide or Tirzepatide: A Reconstructed Aggregate-Data Bayesian Longitudinal Meta-Analysis","authors":"[\"Kow CS\", \"Thiruchelvam K\", \"Ramachandram DS\", \"Zaihan AF\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide and tirzepatide produce substantial weight loss during treatment, but the trajectory of weight regain after discontinuation remains uncertain. [OBJECTIVE] To estimate post-discontinuation weight-regain trajectories and explore predictors of faster regain. [METHODS] We used published timepoint-level aggregate data from studies evaluating weight change after discontinuation of semaglutide or tirzepatide to perform a Bayesian hierarchical longitudinal re-analysis. The model estimated weight loss at cessation, monthly regain rate, time to 50% regain, and time to return to baseline weight. Bayesian meta-regression examined medication type, magnitude of initial weight loss, and post-discontinuation behavioural or lifestyle support. Longer-term estimates assumed a constant linear regain rate. [RESULTS] Six studies comprising 10 intervention arms and 1776 participants were included, with observed follow-up ranging from 4 to 52 weeks. Estimated weight loss at cessation was 15.35 kg (95% credible interval [CrI] 11.18-19.60), followed by regain of 1.04 kg/month (95% CrI 0.80-1.29). Based on the linear model, 50% of initial weight loss was projected to be regained by 7.50 months (95% CrI 5.05-10.57), with return to baseline weight by 15.00 months (95% CrI 10.10-21.13). Tirzepatide showed numerically faster regain than semaglutide in unadjusted analyses, but no clear independent drug-specific difference was evident after adjustment. Greater initial weight loss showed the strongest directional association with faster regain, although the credible interval included zero. Behavioural or lifestyle support was directionally associated with slower regain, but the estimate was imprecise. [CONCLUSIONS] Weight regain after discontinuation of semaglutide or tirzepatide was rapid and clinically meaningful. Because estimates beyond 52 weeks were model-based extrapolations, they should be interpreted cautiously. Early monitoring and proactive maintenance planning may be warranted after treatment cessation.","url":"https://pubmed.ncbi.nlm.nih.gov/42673571/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":614,"doi":"10.1016/j.mcpdig.2026.100375","pmid":"42746268","nct_ids":"[]","title":"Real-World Body Composition and Blood Pressure Changes Following Glucagon-Like Peptide 1 Receptor Agonist Initiation: A Causal Inference Study of Connected Device Data","authors":"[\"Chabassier A\", \"Vittrant B\", \"Binon P\", \"Scornet E\", \"Josse J\"]","journal":"Mayo Clinic proceedings. Digital health","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To characterize real-world body composition and blood pressure changes following glucagon-like peptide (GLP)-1 receptor agonist (RA) initiation and identify predictors of weight loss quality using connected device data. [PATIENTS AND METHODS] In this retrospective cohort study, adult US users completing an in-application GLP-1 RA survey (June 8, 2023, to July 4, 2024) were followed up using longitudinal device data (December 2021 to September 2025). We used a distributional causal inference framework to match GLP-1 RA users to nonusers. Primary estimands were the distributional average treatment effect on the treated and median differences over months 10 to 14. [RESULTS] Among 2031 users for body composition (396 exposed) and 672 for blood pressure (BP; 148 exposed), GLP-1 RA initiation was associated with a 9.8% median weight reduction (95% CI, 9.8-9.9), driven by fat mass loss (7.5%; 95% CI, 7.5-7.8) with smaller muscle mass loss (2.3%; 95% CI, 2.1-2.4). Sustained reductions were observed in systolic (2.5 mm Hg; 95% CI, 1.5-2.9) and diastolic BP (1.5 mm Hg; 95% CI, 1.2-1.9). Baseline muscle-to-fat ratio (MFR) was the strongest predictor of weight loss quality, with lower MFR individuals losing more fat and sparing more muscle. [CONCLUSION] In a real-world setting, GLP-1 RA initiation was associated with clinically significant fat-predominant weight loss and sustained BP improvements. Baseline MFR predicted weight loss quality, suggesting that pretreatment body composition may help clinicians anticipate individual responses-a step toward precision medicine in GLP-1 RA therapy.","url":"https://pubmed.ncbi.nlm.nih.gov/42746268/","source_name":"pubmed","source_tier":1,"coi_statement":"Ms Chabassier is a doctoral candidate supported by a CIFRE grant funded by Withings and the Association Nationale de la Recherche et de la Technologie (ANRT). Dr Vittrant and Mr Binon are full-time employees of Withings. Dr Josse and Dr Scornet declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"muscle\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":620,"doi":"10.1002/dmrr.70228","pmid":"42733963","nct_ids":"[]","title":"Low Preoperative Free Triiodothyronine, Particularly in Females, Is Associated With Reduced Weight Loss and Diabetes Remission After Bariatric Surgery in Euthyroid Adults","authors":"[\"Li S\", \"Tu Y\", \"Zhang H\", \"Xiao Y\", \"Bao Y\", \"Yin J\", \"Ma Y\", \"Yu H\", \"Liu F\"]","journal":"Diabetes/metabolism research and reviews","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] With the rising prominence of GLP-1 receptor agonists, identifying predictors of optimal bariatric surgery candidates has become increasingly important. We investigated cross-sectional relationships between thyroid hormones and obesity-related parameters, and evaluated the predictive value of baseline thyroid hormones for weight loss (WL) and diabetes remission (DR) after bariatric surgery. [METHODS] This study included a cross-sectional cohort of 1567 euthyroid patients with overweight or obesity, of whom 1034 with complete 1 year postoperative data were included in the longitudinal analysis. Body composition was assessed using validated predictive equations and abdominal MRI. The primary outcomes were successful WL (total WL ≥ 25%) and DR (fasting glucose < 5.6 mmol/L and HbA1c < 6.0% without antidiabetic medications) during the 3 year follow-up. [RESULTS] Breakpoint analysis indicated that free triiodothyronine (FT3) plateaued beyond an age threshold while showing a linear correlation with fat-free mass index. Higher baseline FT3 tertiles were significantly linked to increased likelihood of achieving successful WL and DR at 1 year follow-up, with stronger associations in females. Optimal FT3 thresholds were identified as 4.75 (females) and 5.05 (males) for WL, and 4.57 (females) and 5.00 (males) for DR. Preoperative FT3 levels below these thresholds were significantly associated with reduced WL and DR over 3 years. [CONCLUSIONS] Serum FT3 exhibits an age-related breakpoint effect, and low preoperative FT3, particularly in females, is a critical predictor of suboptimal short- and long-term WL and DR success post-bariatric surgery. Sex-specific FT3 thresholds may aid in preoperative risk stratification and inform personalised treatment decisions in the era of expanding obesity therapeutics.","url":"https://pubmed.ncbi.nlm.nih.gov/42733963/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:15+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"lean_mass\", \"body_composition\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":799,"doi":"10.1007/s40292-026-00812-6","pmid":"42371360","nct_ids":"[]","title":"Effect of Retatrutide, a Novel Triple Receptor Agonist, on Blood Pressure and Lipid Levels: A Systematic Review and Meta-analysis of Randomized Controlled Trials","authors":"[\"Simental-Mendía LE\", \"Barragán-Zúñiga LJ\", \"Reyes-Avitia V\"]","journal":"High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] It has been reported that glucagon-like peptide-1 (GLP-1) agonists or dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists exert beneficial effects on blood pressure and lipid profile. However, the impact of triple agonist retatrutide on these metabolic markers remains to be elucidated. [AIM] This meta-analysis aims to investigate the effect of retatrutide on blood pressure and lipid levels through a meta-analysis of randomized controlled trials. [METHODS] The search process was performed in PubMed, Cochrane Library, Scopus, and ClinicalTrials.gov databases using MeSH terms and keywords. For meta-analysis, a random-effects model and the generic inverse variance method were used. [RESULTS] The meta-analysis showed that retatrutide significantly decreases systolic blood pressure (WMD: - 6.79 mmHg, 95% CI: - 8.36, - 5.23, p < 0.0001, I2 = 20%) and diastolic blood pressure (WMD: - 2.46 mmHg, 95% CI: - 3.25, - 1.67, p < 0.0001, I2 = 0%). Furthermore, a significant reduction in the levels of total cholesterol (WMD: - 21.88 mg/dL, 95% CI: - 27.79, - 15.97, p < 0.0001, I2 = 84%), LDL-C (WMD: - 13.10 mg/dL, 95% CI: - 16.10, - 10.10, p < 0.0001, I2 = 47%), and triglycerides (WMD: - 40.90 mg/dL, 95% CI: - 48.50, - 33.30, p < 0.0001, I2 = 53%) was observed after retatrutide treatment. However, this triple hormone receptor agonist had no significant effect on HDL-C concentrations (WMD: - 0.01 mg/dL, 95% CI: - 1.30, 1.27, p = 0.98, I2 = 0%). [CONCLUSIONS] The results of our meta-analysis revealed that retatrutide treatment decreases blood pressure and improves lipid profile by reducing total cholesterol, LDL-C, and triglyceride levels.","url":"https://pubmed.ncbi.nlm.nih.gov/42371360/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: Not applicable. Data availability statement: The data underlying this article are available in the article and in its online supplementary information.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:32:36+00:00","study_design":"meta_analysis","drugs":"[\"retatrutide\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":"Systolic blood pressure WMD -6.79 mmHg; diastolic WMD -2.46 mmHg; total cholesterol WMD -21.88 mg/dL; HDL-C no significant change (WMD -0.01 mg/dL, p = 0.98)","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Synthesis; population mix not determinable from abstract. Review the included-study populations.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"Systolic blood pressure: 95% CI -8.36 to -5.23 mmHg; the abstract gives an interval for each outcome\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: Not applicable. Data availability statement: The data underlying this article are available in the article and in its online supplementary information.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A meta-analysis of randomized trials found retatrutide lowered systolic blood pressure (by about 6.8 mmHg) and diastolic blood pressure (about 2.5 mmHg) and reduced total cholesterol, LDL-C and triglycerides, but had no effect on HDL-C (WMD -0.01 mg/dL, 95% CI -1.30 to 1.27, p = 0.98). These are blood pressure and lipid risk markers, not heart attacks or strokes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":883,"doi":"10.7759/cureus.115703","pmid":"42829595","nct_ids":"[]","title":"Impact of Glucagon-Like Peptide-1 Receptor Agonists on Mental Health: A Systematic Review of Psychiatric Safety and Antidepressant Potential","authors":"[\"Quadir A\", \"Devi R\", \"Jad Allah B\", \"Haider A\", \"Shaikh SS\", \"Botsa KN\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for type 2 diabetes mellitus (T2DM) and obesity, but concerns about their mental health effects have been raised. Early safety reports linked them to suicidal thoughts and worsening depression; however, evidence remained mixed and unclear. A systematic search was conducted across three databases for studies published between 2021 and May 2026. Out of 617 records identified, 11 studies were finally included after quality checks using appropriate appraisal tools based on study design. This review was not prospectively registered. Data from over 4.9 million patients across eleven primary studies showed that GLP-1RAs did not increase psychiatric risk overall. Ten out of eleven primary studies confirmed either safety or protective psychiatric effects. Increased psychiatric risk was seen in one obesity-specific study; this may partly reflect surveillance or detection bias, though this was not directly tested. Only one of the 11 included studies directly measured mood using validated questionnaires and found that semaglutide was associated with lower (better) depression and anxiety scores. GLP-1 receptor agonists appear to maintain a safe neuropsychiatric profile, with an emerging signal that mood may benefit, currently limited to a single scale-based study among those formally included; most existing evidence remains diagnostic-code-based rather than scale-based. For T2DM patients with stable mood disorders, there is no justification for withholding these medications. For weight management, clinicians may consider baseline mental health screening before starting treatment. Future research must use validated continuous mood rating tools rather than administrative diagnostic codes to properly measure psychological benefits.","url":"https://pubmed.ncbi.nlm.nih.gov/42829595/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:41+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":989,"doi":"10.7759/cureus.115758","pmid":"42830876","nct_ids":"[]","title":"Comparative Efficacy and Safety of Liraglutide Versus Metformin in Women With Polyendocrine Metabolic Ovarian Syndrome (PMOS): A Systematic Review and Meta-Analysis of Randomized Controlled Trials","authors":"[\"Banerjee I\", \"Krissheeven M\", \"Pandey N\", \"Banerjee S\", \"Robinson J\", \"Banerjee I\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Polyendocrine metabolic ovarian syndrome (PMOS), previously known by the name 'polycystic ovary syndrome (PCOS),' is a common and complex endocrine-metabolic disorder affecting approximately one in eight women. PMOS is increasingly regarded as a multisystem disorder rather than only a gynaecological condition. Exclusive of weight loss, metformin has been the mainstay pharmacological therapy in the treatment of PMOS; a new contender for the management of this condition is liraglutide. Liraglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RAs) and has gained increasing interest because it targets appetite regulation, body weight, and glycemic control as well as insulin sensitivity. There remains no comprehensive and up-to-date synthesis specifically comparing liraglutide versus metformin across clinically important outcomes in women with PMOS. This systematic review and meta-analysis aims to comprehensively evaluate these outcomes and provide evidence to guide individualized therapeutic decision-making. This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines (PRISMA). The research protocol was registered under the International Prospective Register of Systematic Reviews (PROSPERO), and the proposal is available under registration number CRD420261435182. No statistically significant difference in BMI between liraglutide and metformin (mean difference (MD)=0.25, 95% confidence interval (CI): -7.30-7.79, P=0.95, I²=82%, p=0.02). The pooled result of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) favored metformin but showed no statistical difference between liraglutide and metformin (MD=0.94, 95% CI: -0.09-1.97, P=0.07, I²=0%, chi-square=0.14, p=0.71). Although the pooled effect favored metformin due to a higher frequency of the menstrual cycle, there was no significant difference between liraglutide and metformin (MD = -1.42, 95% CI: -4.57-1.73, P = 0.38, I² = 75%). A fixed-effect meta-analysis demonstrated no significant difference in fasting glucose levels between liraglutide and metformin (MD=-0.01 mmol/l, 95 % CI: - 0.82-0.80, P=0.98, I2=37%, p=0.21). No significant difference in fasting insulin levels between liraglutide and metformin (MD=-1.11 Mu/L, 95% CI: -6.99-4.77, p=0.71, I²=0%, p=0.69). Pooled analysis demonstrated no significant difference in the risk of nausea (risk ratio (RR)=0.91, 95% CI: 0.53-1.55, P=0.73), although the effect estimate numerically favored liraglutide. The incidence of diarrhea was significantly lower in the liraglutide group compared to metformin. The pooled analysis demonstrated a reduced risk of diarrhea with liraglutide (RR=0.31, 95% CI: 0.12-0.81, P=0.02), suggesting a 69% relative risk reduction as compared to metformin. The available randomized evidence suggests that liraglutide and metformin have comparable effects on BMI, insulin resistance measured by HOMA-IR, fasting glucose, fasting insulin, and menstrual-cycle frequency in women with PMOS. Although both agents have demonstrated clinical benefits in the management of PMOS, the current evidence does not demonstrate a statistically significant advantage of liraglutide over metformin for the assessed outcomes. However, the absence of a statistically significant difference cannot be interpreted as evidence of therapeutic equivalence or non-inferiority, nor does it exclude a clinically meaningful benefit of either treatment.","url":"https://pubmed.ncbi.nlm.nih.gov/42830876/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-11T12:01:03+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1153,"doi":"10.7759/cureus.116699","pmid":"42923248","nct_ids":"[]","title":"Renin-Angiotensin System (RAS) Inhibitors in High-Risk Patients With Type 2 Diabetes and Cardio-Renal Risk","authors":"[\"Ahmed MJ\", \"Ahmad AM\", \"Naqvi S\", \"Ahmed K\", \"Ahmed A\", \"Naqvi Z\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Renin-angiotensin system inhibitors (RASi) are recommended as first-line therapy for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), particularly in the presence of hypertension or albuminuria. This study assessed the treatment patterns in a cohort of high-risk T2D patients. [METHODS] This cross-sectional, retrospective study included 33,524 adults with T2D from the Imperial College London Diabetes Centre (United Arab Emirates). Demographic, clinical, and laboratory parameters (estimated glomerular filtration rate, urine albumin-to-creatinine ratio, and blood pressure (BP)), and medication usage were analysed. The primary outcome was the analysis of treatment patterns in patients undergoing RASi; secondary outcomes included prescribing trends in CKD risk categories and among hypertensive and albuminuric subgroups. [RESULTS] Among 33,524 patients with T2D, mean age was 59.2 years, BMI 29.4 kg/m2, and 67.1% (n=22,508) of the patients were classified as KDIGO (Kidney Disease: Improving Global Outcomes) G1 and 73.3% (n=24,580) as A1 albuminuria. Overall, 35.3% (n=13,705) received RASi, while 64.7% (n=25,128) were treated with alternative therapies including SGLT2 inhibitors, GLP-1 receptor agonists, or finerenone. Among patients with albuminuria >3.5 mg/mmol, only 62% (n=4944) were prescribed RASi, despite meeting clear indications for treatment. In KDIGO-based risk stratification, only 39% (n=4406) of patients in the high and very high CKD progression risk categories were on RASi. Among the hypertensive subgroup (n=4,824; defined as BP >130/80 mmHg), 48.96% (n=2,362) were prescribed RASi, leaving over 50% of patients untreated with this guideline-recommended therapy. Furthermore, 7.46% (n=2,462) of the entire cohort had hypertension but were not receiving RASi. This gap was more prominent among those with coexisting albuminuria or CKD. These findings reflect under-treatment even among those at greatest risk of renal and cardiovascular events. [CONCLUSION] In patients with T2D and established renal or cardiovascular risk, treatment patterns remain variable in real-world practice. Less than half of hypertensive or albuminuric patients received RASi, highlighting a significant implementation gap. Addressing barriers to RASi prescription is essential to align real-world clinical practice with international guidelines and improve patient outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42923248/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Research Ethics Committee, Imperial College London Diabetes Centre, Abu Dhabi issued approval IREC102, dated August 7, 2024. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1189,"doi":"10.7759/cureus.116758","pmid":"42921281","nct_ids":"[]","title":"Musculoskeletal Adverse Event Signals Associated With Semaglutide, Liraglutide, and Tirzepatide in the US FDA Adverse Event Reporting System","authors":"[\"Wadhwa A\", \"Patel D\", \"Bouras A\", \"Shah S\", \"Daryanani S\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity, yet their musculoskeletal reporting profile remains incompletely characterized. Lean-mass loss during treatment has raised concern about muscle atrophy and related complications. [METHODS] In this retrospective cross-sectional pharmacovigilance study, we analyzed 20,006,989 safety reports in the Food and Drug Administration Adverse Event Reporting System (FAERS) with initial receipt dates through January 27, 2026. Semaglutide, liraglutide, tirzepatide, and six dipeptidyl peptidase-4 or sodium-glucose cotransporter-2 inhibitors were each evaluated against all other eligible FAERS reports. These were not direct comparisons between drugs. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) were calculated across 30 Medical Dictionary for Regulatory Activities preferred terms. Signals were defined using the ROR criterion, with PRR providing supporting evidence. [RESULTS] Eight ROR-defined signals were identified among the three incretin-based therapies. Muscle atrophy showed the strongest disproportionality for semaglutide (ROR 3.96, 95% confidence interval (CI) 3.42-4.59; n = 182) and tirzepatide (ROR 2.29, 95% CI 1.96-2.67; n = 163), and both met the ROR and PRR thresholds. Additional lower-magnitude ROR signals included back pain, muscle spasms, and neck pain for semaglutide, and back pain, osteoarthritis, and neck pain for liraglutide. The muscle atrophy signal persisted in serious-report analyses for semaglutide (ROR 2.63; n = 85) and tirzepatide (ROR 2.06; n = 33). Among reports with recorded sex, female patients accounted for 1,398 of 2,187 liraglutide reports (63.9%), 2,654 of 3,853 semaglutide reports (68.9%), and 1,816 of 2,294 tirzepatide reports (79.2%). [CONCLUSIONS] Semaglutide and tirzepatide showed muscle atrophy reporting signals that persisted when the analysis was restricted to reports classified as serious. Prospective studies are needed to investigate these findings. These data cannot show whether the drugs cause muscle atrophy or how often it occurs among treated patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42921281/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:13+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"osteoarthritis\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1250,"doi":"10.7759/cureus.117011","pmid":"42948780","nct_ids":"[]","title":"Systemic Glucose-Lowering Therapies and Periodontal and Peri-Implant Outcomes in Adults With Type 2 Diabetes Mellitus: A Systematic Review","authors":"[\"Hakami AA\", \"Alamri LA\", \"Alghamdi SA\", \"Alanazi HT\", \"Alqahtani AA\", \"Almutairi WK\", \"Alzahrani TR\", \"Toonisi FM\", \"Alsamti MA\", \"Mossa AM\", \"Hakami AY\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Type 2 diabetes mellitus (T2DM) and periodontitis are bidirectionally linked. Systemic glucose-lowering drug classes differ in their extra-glycaemic effects on inflammation and bone, which could plausibly modify periodontal and peri-implant health; however, this evidence has not been synthesised across drug classes. We conducted a systematic review and evidence gap map (EGM), with sodium-glucose cotransporter-2 (SGLT2) inhibitors examined as a pre-specified evidence gap. PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus were searched and cross-checked against the Consensus academic corpus. Eligible studies enrolled adults with T2DM, evaluated a systemic glucose-lowering drug as the exposure, and reported a periodontal or peri-implant outcome. Studies of local drug delivery and periodontal therapy aimed at improving glycaemic control were excluded from the systematic-review layer; all study designs, including preclinical studies, were charted in the EGM. Risk of bias was assessed using the Cochrane risk-of-bias 2 (RoB 2) tool and the Newcastle-Ottawa Scale. Four studies were included: one randomised controlled trial and three observational studies. These comprised a trial of a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) added to metformin, which reported improvements in probing depth, clinical attachment level, bleeding on probing, and alveolar bone density; a cohort study comparing peri-implant marginal bone loss among users of glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), metformin, and insulin, with the least bone loss observed among glucagon-like peptide-1 receptor agonist users; a large pharmacoepidemiological cohort evaluating DPP-4 inhibitor exposure; and a cross-sectional survey of glucagon-like peptide-1 receptor agonist users. Meta-analysis was not feasible because of substantial heterogeneity. The EGM, comprising eight drug classes and six outcome domains, showed that evidence was concentrated in glucagon-like peptide-1 receptor agonists and metformin and was almost entirely preclinical; the only high-level evidence cell was represented by a single DPP-4 inhibitor randomised controlled trial, while SGLT2 inhibitors constituted a complete evidence gap across all outcome domains. Based on the four included studies, human evidence linking systemic glucose-lowering therapy with periodontal outcomes in adults with T2DM is sparse, heterogeneous, and of low certainty, with weak signals favouring incretin-based therapies. SGLT2 inhibitors remain entirely unstudied in this context despite biological plausibility. The EGM identifies specific, high-value priorities for future randomised trials and prospective cohort studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42948780/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:19+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"bone\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1318,"doi":"10.7759/cureus.116973","pmid":"42936270","nct_ids":"[]","title":"Ischemic Colitis in the Setting of Tirzepatide Use: A Potentially Underrecognized Adverse Effect","authors":"[\"Jaszewski I\", \"Cruz Garcia JC\", \"Moreira K\", \"Suarez AE\", \"Cherner R\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Ischemic colitis is an uncommon but serious cause of acute abdominal pain that may result in bowel necrosis and may require surgical intervention. We report the case of a 63-year-old female patient with multiple comorbidities and a history of ischemic colitis, who developed sudden-onset severe cramping and abdominal pain, together with hypotension and diaphoresis, shortly after receiving her weekly tirzepatide injection. The patient reported suffering from chronic constipation with increased frequency of laxative use after beginning tirzepatide (Mounjaro). Laboratory evaluation demonstrated leukocytosis and lactic acidosis, while computed tomography (CT) findings were consistent with ischemic colitis. Her condition rapidly progressed to hypovolemic shock and acute kidney injury (AKI), requiring intensive care unit (ICU) admission and segmental bowel resection with colostomy creation. Surgical pathology report confirmed patchy mucosal necrosis consistent with ischemic colitis. This case raises concern for a potential association between tirzepatide use and ischemic colitis in a patient with preexisting risk factors. Clinicians should maintain a high index of suspicion for ischemic colitis in patients receiving tirzepatide who present with severe abdominal pain, particularly in the setting of worsening constipation or a prior history of ischemic colitis. This case raises the question of whether a history of ischemic colitis and/or chronic constipation may warrant clinical caution and pharmacovigilance before starting these medications.","url":"https://pubmed.ncbi.nlm.nih.gov/42936270/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:24+00:00","study_design":"pharmacovigilance","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1357,"doi":"10.7759/cureus.117270","pmid":"42966951","nct_ids":"[]","title":"Cutaneous Adverse Events With Semaglutide: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","authors":"[\"Ganjre S\", \"Borah L\", \"Khardenavis A\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide is widely used for metabolic disease, but cutaneous adverse events are inconsistently reported. This systematic review and meta-analysis evaluated randomized comparisons of semaglutide with placebo, usual care, or non-semaglutide active treatment. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261464289). PubMed, Europe PubMed Central, trial registers, sponsor reports, and regulatory sources were examined through September 9, 2026; source verification was completed on September 21, 2026. Meta-analysis required directly available, source-verified participant event counts and denominators in both groups. Reported alopecia or hair loss and source-defined participant-level injection-site reactions were analyzed separately using common-effect Mantel-Haenszel odds ratios (ORs) without continuity correction. Risk of bias and evidence certainty were assessed for the primary syntheses. Thirty-one trials contributed verified outcome data. Twenty trials formed the primary placebo/common-control evidence set, of which 19 contributed relative-effect estimates and one reported zero injection-site reactions in both groups. Eleven additional trials provided active-comparator or design-specific evidence. Across nine comparisons, alopecia or hair loss was reported in 191/11,564 semaglutide recipients and 36/9,799 comparators (OR: 2.92, 95% confidence interval (CI): 1.99-4.27; p < 0.001; low-certainty evidence). The association persisted after exclusion of the largest cardiovascular outcomes trial with restricted ascertainment; random-effects analyses supported the primary interpretations. Eleven informative comparisons reported injection-site reactions in 156/5,066 semaglutide recipients and 114/3,483 comparators (OR: 0.86, 95% CI: 0.67-1.11; p = 0.256; very-low-certainty evidence). Active comparators and design-specific results were described separately. Semaglutide may increase reports of alopecia or hair loss; its comparative effect on injection-site reactions remains uncertain. Available-count synthesis does not resolve selective non-reporting or incomplete event ascertainment. The findings do not establish a hair-loss mechanism or injection-site safety equivalence.","url":"https://pubmed.ncbi.nlm.nih.gov/42966951/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:50+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1376,"doi":"10.7759/cureus.116901","pmid":"42928739","nct_ids":"[]","title":"Perioperative Safety Considerations and Surgical Outcomes Associated With GLP-1-Based Therapies: A Systematic Review","authors":"[\"Rodrigues da Cunha M\", \"Rodrigues da Cunha MT\"]","journal":"Cureus","publication_date":"2026-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for the management of type 2 diabetes mellitus and obesity. Their effects on gastric emptying have raised concerns in the perioperative setting, where standard fasting protocols are used to reduce aspiration risk. However, the clinical significance of altered gastric physiology and its implications for perioperative management remain uncertain. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD420261289189). A comprehensive literature search identified studies evaluating perioperative gastric physiology and procedural safety outcomes associated with GLP-1 RA use in adults undergoing procedures requiring sedation or general anesthesia. Outcomes included delayed gastric emptying, residual gastric contents, aspiration or regurgitation events, and perioperative management adaptations. Sixteen studies met the inclusion criteria, comprising seven observational studies and nine case reports or case series. Observational evidence demonstrated an association between GLP-1 RA use, particularly semaglutide, and increased residual gastric contents or delayed gastric emptying despite adherence to standard fasting protocols. These findings were identified primarily through gastric ultrasound and endoscopic assessment. In contrast, clinically apparent aspiration or regurgitation events were uncommon and were reported predominantly in case-based literature. Larger observational studies did not demonstrate a clear increase in aspiration or broader perioperative complications. Identification of retained gastric contents also influenced clinical management in several reports, resulting in changes to anesthetic planning, additional gastric assessment, or postponement of elective procedures. GLP-1 RA therapy is associated with alterations in gastric physiology that may challenge the assumptions underlying standard preoperative fasting protocols. Although increased residual gastric contents are consistently reported, current evidence does not establish a corresponding increase in clinically significant aspiration events. Individualized preoperative risk assessment, including consideration of medication exposure and selective use of gastric ultrasound, may assist perioperative decision-making. Further prospective studies are needed to quantify aspiration risk and establish evidence-based perioperative management strategies.","url":"https://pubmed.ncbi.nlm.nih.gov/42928739/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:50+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":172,"doi":"10.1093/ndt/gfag199","pmid":"42671242","nct_ids":"[]","title":"Sex in CKD trials: representation and treatment effects of cardiorenoprotective therapies","authors":"[\"Bellos I\", \"Athanasiou M\", \"Nikita KS\", \"Benetou V\"]","journal":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","publication_date":"2026-08-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Women comprise a substantial proportion of the chronic kidney disease (CKD) population and differ from men in disease phenotype, progression, and treatment exposure. Underrepresentation of women and limited sex-specific reporting may therefore reduce the generalizability of evidence from contemporary CKD trials. [METHODS] We conducted a meta-epidemiological study of randomized trials evaluating sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists in adults with CKD. Female representation was quantified using the enrollment disparity difference (EDD), defined as the observed proportion of female trial participants minus the expected proportion derived from sex-specific Global Burden of Disease CKD prevalence estimates matched to trial population characteristics. Trial-level EDDs were pooled using random-effects meta-analysis. Meta-regression was used to examine trial-level correlates of EDD. Historical analyses extended the cohort to earlier cardiorenal pharmacotherapies to evaluate temporal trends, with pivotal CKD trials examined descriptively. Reporting of sex-specific cardiovascular and kidney outcomes was also assessed. [RESULTS] Fifty-five randomized trials were included. Median female enrollment was 33.1%, and 52 trials (94.5%) enrolled fewer women than expected. The pooled EDD was -0.17 (95% CI, -0.20; -0.14), with negative estimates across all intervention classes. In meta-regression, phase II design and albuminuria requirement were associated with greater female underrepresentation, whereas diabetes requirement and female first authorship were associated with smaller enrollment disparity, including after adjustment for other key trial characteristics. Sex-specific outcomes were reported in 13 trials (23.6%). Extension to 117 trials provided no statistically supported evidence of improvement in female representation over time, including after adjustment for intervention class; all 38 pivotal CKD trials enrolled fewer women than expected. [CONCLUSIONS] Women remain underrepresented in cardiorenoprotective therapy trials, with limited sex-specific outcome reporting. Historical benchmarking indicates that successive advances in CKD pharmacotherapy have not been accompanied by demonstrable improvement in the sex representativeness of the evidence base.","url":"https://pubmed.ncbi.nlm.nih.gov/42671242/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":274,"doi":"10.1007/s44470-026-00162-z","pmid":"42675225","nct_ids":"[\"NCT05412004\"]","title":"Association of tirzepatide with changes in OSA-related measures based on baseline characteristics - post hoc analyses of SURMOUNT-OSA","authors":"[\"Falcon B\", \"Xie CC\", \"Redline S\", \"Grunstein R\", \"Turnbull CD\", \"Rapoport DM\", \"Wang H\", \"Chakladar S\", \"Dimitriadis GK\", \"Lau E\", \"Bednarik J\", \"Liao B\", \"Malhotra A\"]","journal":"Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine","publication_date":"2026-08-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the upper airway during sleep. Given that excess adiposity is a known risk factor for OSA, we aimed to descriptively assess the association of tirzepatide, a GIP/GLP-1 receptor agonist, with changes in AHI, hypoxic burden, body weight, and blood pressure in different patient populations based on baseline characteristics such as age, sex, BMI, AHI, and neck circumference. [METHODS] These post hoc analyses examined data from two Phase 3 randomized, double-blind studies evaluating maximum tolerated dose (MTD) tirzepatide (10 mg or 15 mg) compared with placebo in adults with moderate-to-severe OSA (AHI ≥ 15 events/h) and obesity (BMI ≥ 30 kg/m2) over a 52-week period. Baseline subgroup analyses were conducted in participants with non-missing relevant baseline measurements. [RESULTS] Generally, participants treated with tirzepatide showed greater improvements in OSA outcomes compared with placebo, regardless of baseline subgroup. Participants treated with tirzepatide experienced reductions in AHI across subgroups, regardless of baseline age (-27.7 to -34.1 events/h), sex (-19.8 to -32.6 events/h), AHI severity (-12.1 to -52.2 events/h), BMI (-25.2 to -34.4 events/h), and neck circumference (-23.9 to -30.8 events/h). Additionally, improvements were observed in body weight, systolic blood pressure, and sleep apnea-specific hypoxic burden across baseline subgroups. Overall, most participants experienced an improvement in AHI severity category with tirzepatide treatment (68% to 79%), while the majority in the placebo group saw no clinically relevant change (64% to 70%). [CONCLUSIONS] In these descriptive, hypothesis-generating, post hoc analyses, tirzepatide treatment was associated with improvements in multiple measures in participants with moderate-to-severe OSA and obesity. These improvements were observed across both studies, regardless of baseline age, sex, AHI severity, BMI, or neck circumference. [CLINICAL TRIAL REGISTRATION] SURMOUNT-OSA program (NCT05412004). [CURRENT KNOWLEDGE/STUDY RATIONALE] Tirzepatide has been associated with clinically relevant improvements in OSA-related measures, body weight, and systolic blood pressure among individuals with moderate-to-severe OSA and obesity. These post hoc analyses aimed to assess whether there were variations in improvements based on baseline age, sex, AHI severity, BMI, or neck circumference. [STUDY IMPACT] In general, tirzepatide treatment was associated with improvement in OSA outcomes across both studies, regardless of baseline age, sex, AHI severity, BMI, or neck circumference, with some observed differences among some baseline characteristics. This research may help us better understand the relationship between baseline characteristics and different OSA treatment responses and may stimulate future studies in this area.","url":"https://pubmed.ncbi.nlm.nih.gov/42675225/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: The SURMOUNT-OSA trials were conducted in accordance with consensus ethical principles, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations, and were approved by the relevant ethics committee/review board at each site. All participants in all primary trials provided written informed consent. The SURMOUNT-OSA program was registered with ClinicalTrials.gov (NCT05412004). Consent for publication: As no identifying information is included, participants were not required to provided consent for publication. Competing interests: financial disclosures: This work was performed at Eli Lilly and Company, Indianapolis, Indiana, USA. This study was funded by Eli Lilly and Company. SR has received consulting fees from Amgen and Eli Lilly and Company; her institution has received research funding from Proxima/Google. RG is part of the advisory boards of Alkermes, Amgen, Eli Lilly and Company; and has received lecture fees Somnomed, Takeda, Eisai. CT has received honorarium and consulting fees from Eli Lilly and Company, and Notos Medical Ltd; is a scientific founder of and holds stock in Notos Medical Ltd. DR has received patent royalties and consulting fees from Fisher and Paykel Healthcare; clinical research grants from Fisher and Paykel Healthcare, Prosomnus and PranaQ; and has served on scientific advisory boards for Fisher Paykel Healthcare, Somnomed and Apnimed. AM is funded by NIH. He reports income from Eli Lilly and Company, Livanova, Zoll, Powell Mansfield, and Sunrise. Resmed gave a philanthropic donation to UCSD. CCX, SC, GKD, EL, and BF are current employees and shareholders of Eli Lilly and Company. BL is a former employee and shareholder of Eli Lilly and Company. JB is a former employee of Eli Lilly and Company and a current employee of AMGEN, One Amgen Center Drive, Thousand Oaks, CA 91320–1799. Competing interests: non-financial disclosures: SR has served as an unpaid member of the scientific advisory boards for ApniMed Inc; served as an unpaid board member for the National Sleep Foundation and Alliance of Sleep Apnea Partners. AM is co-founder and has equity in Clairyon, a small startup unrelated to this topic.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"body_composition\", \"sleep\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":279,"doi":"10.21203/rs.3.rs-10427939/v1","pmid":null,"nct_ids":"[]","title":"Combined GLP-1 Receptor Agonist and SGLT2 Inhibitor Therapy for Adults with Type 2 Diabetes and Chronic Obstructive Pulmonary Disease: A Large-Scale Target Trial Emulation","authors":"[\"Bai H\", \"Tsai M\", \"Fang Y\", \"Chen M\", \"Chen C\", \"Hsu P.\"]","journal":"preprint server","publication_date":"2026-08-31","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<title>Abstract</title>  <p>Background  Adults with type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) experience substantial cardiometabolic and respiratory risk. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) provide established metabolic, cardiovascular, and renal benefits, clinical outcomes associated with their combined use in this comorbid population remain uncertain. Methods  We conducted a target trial emulation using the TriNetX US Collaborative Network (2018–2023). Adults with T2DM and COPD who initiated a GLP-1RA plus SGLT2i strategy were compared with those who initiated an SGLT2i-only strategy. Propensity score matching (1:1) balanced demographics, socioeconomic and lifestyle factors, comorbidities, medications, laboratory parameters, and available healthcare-utilization proxies. Follow-up began at a 90-day landmark and continued for up to 4 years. All-cause mortality was the primary outcome; COPD exacerbation and pneumonia were key secondary outcomes. Results  After matching, 17,467 patients were included in each group. Compared with the SGLT2i-only strategy, the combination strategy was associated with lower risks of all-cause mortality (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.81–0.93), COPD exacerbation (HR 0.93; 95% CI 0.89–0.97), and pneumonia (HR 0.93; 95% CI 0.89–0.98). At 4 years, the corresponding absolute risk reductions were 2.27%, 2.07%, and 1.59%. No significant between-group differences were observed for dialysis initiation, major adverse cardiovascular events, emergency department visits, or hospitalization. Conclusions  Among adults with T2DM and COPD who reached the 90-day landmark, initiation of GLP-1RA plus SGLT2i therapy was associated with modest but statistically significant reductions in all-cause mortality, COPD exacerbation, and pneumonia compared with SGLT2i initiation alone. These complementary relative and absolute associations support further evaluation of combination therapy as a potentially beneficial option for selected high-risk patients.</p>","url":"https://doi.org/10.21203/rs.3.rs-10427939/v1","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":280,"doi":"10.64898/2026.08.29.26361426","pmid":null,"nct_ids":"[]","title":"GLP-1 Receptor Agonist Initiation and Anti-VEGF Treatment Frequency in Diabetic Macular Edema: an IRIS  <sup>®</sup>  Registry Cohort Study","authors":"[\"Nagalamadaka P\", \"Ross C\", \"Gilbert JB\", \"Stillman H\", \"Ghauri SY\", \"Dutton SM\", \"Kearney W\", \"Li JH\", \"Leong A\", \"Singh RP\", \"Krzystolik MG.\"]","journal":"preprint server","publication_date":"2026-08-31","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"<h4>Purpose</h4>  To evaluate whether initiation of GLP-1 receptor agonists (GLP-1RAs) is associated with anti-VEGF treatment burden in type 2 diabetes patients with diabetic macular edema (DME) in the IRIS  ® Registry (Intelligent Research in Sight).  <h4>Methods</h4>  Incident GLP-1RA initiators were matched 1:1 with controls via Mahalanobis distance matching (9,896 pairs; N=19,792) on sociodemographics, DME risk factors, and factors influencing GLP-1RA prescription including hypertension, obesity, chronic kidney disease. A longitudinal mixed-effects event-study model evaluated monthly anti-VEGF injection frequency over a 36-month window (12 months before through 24 months after initiation), adjusting for DME duration. Visual acuity (VA) and central subfield thickness (CST) were secondary outcomes. <h4>Results</h4>  Following GLP-1RA initiation, anti-VEGF injection trajectories did not significantly differ between the matched GLP-1RA and control cohorts (interaction coefficients −0.18 to 1.59, P>0.05). Likewise, no differences in VA were observed between cohorts (−0.05 to 0.04 logMAR, P>0.05) or CST (−14.12 to 33.58 µm, P>0.05). <h4>Conclusion</h4>  In these matched cohorts, GLP-1RA initiation was not associated with the trajectory of anti-VEGF use or changes in VA or CST. <h4>Précis</h4>  We used the American Academy of Ophthalmology IRIS  ® Registry (Intelligent Research in Sight) to identify patients with DME. In 19,792 matched patients, there was no significant reduction in injection frequency post GLP1-RA initiation and no significant change in VA or CST.","url":"https://doi.org/10.64898/2026.08.29.26361426","source_name":"europepmc","source_tier":3,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":287,"doi":"10.1101/2025.09.26.25336579","pmid":null,"nct_ids":"[]","title":"Assessing Type 2 Diabetes and GLP-1 agonist response trajectories with a proteogenomic atlas of disease progression","authors":"[\"Tangirala, S.\", \"Isaac, S.\", \"Gehad, Y.\", \"Roquefort, F.\", \"Gabrieli, P.\", \"Miller, G.\", \"Thaker, V. V.\", \"Tierney, B. T.\", \"Patel, C. J.\"]","journal":"medrxiv (preprint)","publication_date":"2026-08-31","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Type 2 diabetes (T2D) progresses through heterogeneous pathways that glycemic staging alone does not resolve. We constructed the Metabolic Atlas of the Proteome in Diabetes (MAP-D), leveraging Olink measurements of 2,923 circulating proteins in [~]42,000 UK Biobank participants to map associations with three cardiometabolic hallmarks - adiposity (BMI), a proxy for insulin resistance (triglyceride-to-HDL cholesterol ratio), and glycemia (HbA1c) - across normoglycemia, prediabetes, and incident T2D. We triangulated cross-sectional associations with bidirectional Mendelian randomization and semaglutide trial proteomics to infer causal directionality. This revealed three distinct causal architectures: adiposity predominantly reshapes the proteome, glycemia is driven by upstream proteins, and insulin resistance shows bidirectional feedback. Integration with trial data identified proteins reversed by therapy and a subset of persistent proteins that remain dysregulated despite GLP-1RA treatment. These persistent proteins are associated with incident coronary artery disease and overlap with targets of approved therapies, nominating candidates for combination strategies beyond GLP-1RA monotherapy.\n\nHighlightsO_LIMAP-D maps 2,923 proteins across three hallmarks and glycemic stages\nC_LIO_LIAdiposity reshapes the proteome; glycemia is driven by upstream proteins\nC_LIO_LIPersistent proteins remain dysregulated despite GLP-1RA treatment\nC_LIO_LIPersistent proteins predict incident CAD and are druggable targets\nC_LI","url":"https://www.medrxiv.org/content/10.1101/2025.09.26.25336579","source_name":"medrxiv:medrxiv","source_tier":3,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:40+00:00","study_design":"mendelian_randomization","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":783,"doi":"10.3390/brainsci16090926","pmid":"42793351","nct_ids":"[]","title":"Neuropsychiatric Outcomes Associated with GLP-1 Receptor Agonists in Adults with Overweight or Obesity: A Systematic Review","authors":"[\"Lubo C\", \"Bustamante R\", \"Quintana L\", \"Guillen-Burgos HF\"]","journal":"Brain sciences","publication_date":"2026-08-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of overweight and obesity because of their established efficacy in achieving clinically meaningful weight loss. However, concerns have emerged regarding their potential association with neuropsychiatric outcomes, including depressive and anxiety symptoms, manic or hypomanic symptoms, and suicidal ideation or behavior. This systematic review aimed to synthesize the available evidence on neuropsychiatric outcomes associated with GLP-1 RA use in adults with overweight or obesity. Methods: A systematic search of PubMed/MEDLINE, Scopus, and Web of Science was conducted following PRISMA 2020 guidelines. Eligible studies included randomized controlled trials, longitudinal observational studies, and cross-sectional studies evaluating neuropsychiatric outcomes associated with GLP-1 RAs in adults with overweight or obesity. Risk of bias was assessed using RoB 2, ROBINS-I, and the Joanna Briggs Institute Critical Appraisal Checklist according to study design. Given the clinical and methodological heterogeneity of the included studies, findings were synthesized narratively in accordance with SWiM guidance, and certainty of evidence was assessed at the outcome level using GRADE. Results: Fourteen studies were included, comprising four randomized studies, nine longitudinal observational studies, and one analytical cross-sectional study. Randomized evidence showed no consistent worsening of depressive symptoms or imbalance in suicide-related outcomes, whereas observational findings were heterogeneous. For depression, observational HRs ranged from 0.63 to 2.95 across different populations and comparators, while randomized studies showed small or no between-group differences in depressive symptoms. For suicide-related outcomes, observational HRs/aHRs ranged from 0.27 to 2.06, while suicidal ideation or behavior was uncommon in randomized studies and showed no consistent treatment imbalance. Anxiety-related findings were also heterogeneous, and manic or hypomanic symptoms were not systematically assessed. GRADE certainty was low for depressive symptoms and very low for anxiety and suicide-related outcomes. Conclusions: Current evidence does not demonstrate a consistent increase in adverse neuropsychiatric outcomes associated with GLP-1 receptor agonists in adults with overweight or obesity. Although some studies reported neutral or potentially beneficial associations, observational findings were heterogeneous, and the certainty of evidence was low or very low across the assessable outcomes. These findings do not establish a class-wide neuropsychiatric safety effect, particularly given differences among individual agents, study populations, and baseline psychiatric characteristics. Further prospective studies specifically designed to assess neuropsychiatric outcomes, including individuals with pre-existing psychiatric disorders, are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42793351/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:34+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":233,"doi":"10.1016/j.neuropharm.2026.111163","pmid":"42669356","nct_ids":"[]","title":"Intrathecal semaglutide attenuates burn injury-induced pain in mice through a spinal GLP-1R-linked enkephalin/δ-opioid receptor pathway","authors":"[\"He Y\", \"Gao J\", \"Liu Y\", \"Wu S\", \"Kuang J\", \"Chen D\", \"Xu B\", \"Zhang M\", \"Fang Q\"]","journal":"Neuropharmacology","publication_date":"2026-08-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Burn injury-induced pain (BIP) is a complex condition whose spinal mechanisms remain incompletely understood. Although spinal glucagon-like peptide-1 receptor (GLP-1R) signaling has been implicated in pain modulation, its contribution to BIP remains unclear. Using a mouse model of second-degree burn injury, we characterized nociceptive behaviors, spinal glial responses, and the temporal and cellular distribution of GLP-1R using immunoblotting, immunofluorescence, and RNAscope in situ hybridization. We then evaluated the antinociceptive effects of intrathecal semaglutide, their sensitivity to pharmacological GLP-1R antagonism, and the functional contribution of endogenous enkephalin/δ-opioid receptor (DOR) signaling. Burn injury increased spinal GLP-1R expression during the peak phase of pain hypersensitivity. GLP-1R immunoreactivity and Glp1r transcripts showed a substantial association with GFAP-positive astrocytic profiles, while detectable signals were also present in microglia and neurons. Intrathecal semaglutide attenuated mechanical allodynia and thermal hyperalgesia, and these effects were reduced by pharmacological GLP-1R antagonism. Acute semaglutide responsiveness was also observed in female mice. Semaglutide increased spinal Penk mRNA and enkephalin immunoreactivity in vivo and increased Penk expression and extracellular enkephalin levels in primary spinal astrocyte-enriched cultures. In spinal tissue, enkephalin immunoreactivity was more frequently associated with GFAP-positive profiles than with Iba1-or NeuN-positive profiles. Moreover, enkephalin neutralization and DOR antagonism attenuated semaglutide-induced antinociception. Together, these findings support a functional spinal enkephalin/DOR pathway linked to intrathecal semaglutide treatment and consistent with GLP-1R involvement in BIP.","url":"https://pubmed.ncbi.nlm.nih.gov/42669356/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:02+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"neuroinflammation\", \"addiction\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":117,"doi":"10.1038/s41366-026-02189-x","pmid":"42668312","nct_ids":"[]","title":"Effects of subcutaneous semaglutide on weight loss and inflammatory markers in adults with overweight or obesity without diabetes: a systematic review and meta-analysis","authors":"[\"Milluzzo A\", \"Oteri V\", \"Manuella L\", \"Pulvirenti A\", \"Frittitta L\"]","journal":"International journal of obesity (2005)","publication_date":"2026-08-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND/OBJECTIVES] Obesity is a chronic, relapsing disease associated with multiple serious comorbidities. Semaglutide has emerged as an effective pharmacological option for obesity management, owing to its substantial effects on weight loss, cardiometabolic risk factors, and patient-reported outcomes. This systematic review and meta-analysis evaluated the efficacy and safety of subcutaneous semaglutide for weight management in adults with overweight or obesity without diabetes. [METHODS] Randomized controlled trials comparing subcutaneous semaglutide with placebo in adults with overweight or obesity without diabetes were identified through systematic searches of PubMed, the Cochrane Library, and ClinicalTrials.gov. Outcomes included changes in body weight, waist circumference, C-reactive protein (CRP) and serious adverse events (SAEs). A quality assessment and meta-analysis were performed using REVMAN 10.1.1 software. [RESULTS] Across nine trials including 6 239 participants, subcutaneous semaglutide significantly reduced percentage body weight from baseline (mean difference [MD] -12.04%, 95% CI -13.08 to -11.00), waist circumference (MD -9.36 cm, 95% CI -10.27 to -8.45), and CRP (MD -40.90%, 95% CI -46.37 to -35.42) versus placebo (all p < 0.00001). The risk of SAEs did not differ significantly between semaglutide and placebo (risk ratio [RR] 1.12, 95% CI 0.76 to 1.65; p = 0.55). [CONCLUSIONS] Subcutaneous semaglutide is effective for weight management in adults with overweight or obesity without diabetes. The recently published STEP UP trial evaluating semaglutide 7.2 mg provides additional evidence on higher-dose regimens and showed greater weight reduction compared with previously available data, representing a meaningful new contribution to the literature. Longer-term studies are needed to better define the long-term efficacy and safety profile of semaglutide across clinical populations.","url":"https://pubmed.ncbi.nlm.nih.gov/42668312/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: AM was the recipient of a research fellowship funded by Novo Nordisk at the University of Catania during 2023–2024 and received a one-time honorarium from Novo Nordisk in 2023 for participation as faculty in a one-day educational course. LF has acted as a consultant and speaker for Lilly and Novo-Nordisk and has received a grant from Novo Nordisk. All other authors declare no conflicts of interest. Ethics approval and consent to participate: Ethics approval and informed consent were not required for this study because it is a systematic review and meta-analysis based exclusively on previously published studies.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg in most trials; 7.2 mg in STEP UP\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":6239,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 6239, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 6239, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -13\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 4, 7, 15; non-critical weaknesses on items 3, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"Partial Yes\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"Yes\", \"12\": \"No\", \"13\": \"Yes\", \"14\": \"Yes\", \"15\": \"No\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 6, \"Partial Yes\": 2, \"Yes\": 8}, \"settled_by_ruling\": [\"item 3: No (IN-058; the passes read Yes and No)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/42668312/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/42668312/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-02-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"No funding to the authors; editorial assistance was paid through a Novo Nordisk S.p.A. unconditional grant.","industry_funded":"unclear","manufacturer":"Novo Nordisk, Lilly","author_conflicts":"Competing interests: AM was the recipient of a research fellowship funded by Novo Nordisk at the University of Catania during 2023–2024 and received a one-time honorarium from Novo Nordisk in 2023 for participation as faculty in a one-day educational course. LF has acted as a consultant and speaker for Lilly and Novo-Nordisk and has received a grant from Novo Nordisk. All other authors declare no conflicts of interest.","sponsor_role":"Novo Nordisk was not involved in the data analysis; the authors are fully responsible for the contents and conclusions (per full text).","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"Across nine placebo-controlled trials (6,239 adults with overweight or obesity and no diabetes), semaglutide reduced body weight by about 12%, waist size by 9.4 cm and CRP by 41% compared with placebo; serious adverse events did not differ significantly (RR 1.12).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":214,"doi":"10.14218/jcth.2025.00596","pmid":"42724131","nct_ids":"[]","title":"Comparative Efficacy of Promising Targets in the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Steatohepatitis: A Systematic Review and Network Meta-analysis","authors":"[\"Ni W\", \"Li J\", \"Bai X\", \"Zhou S\", \"Wu X\", \"Jia L\", \"Jiang Z\", \"Wu J\", \"Li M\", \"Wong C\", \"Wu C\", \"Shi J\", \"Nguyen MH\"]","journal":"Journal of clinical and translational hepatology","publication_date":"2026-08-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Randomized controlled trials (RCTs) have been conducted to evaluate treatment efficacy for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis. This study aimed to compare the effectiveness and safety of 11 promising targets among adults with MASLD. [METHODS] PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, Scopus, and Embase were searched from inception to November 20, 2024. The primary outcomes were fibrosis improvement ≥1 stage without worsening of steatohepatitis and steatohepatitis resolution without worsening of fibrosis. Additional outcomes included reductions in liver fat content, liver enzymes, metabolic profiles, and selected safety outcomes. The surface under the cumulative ranking curve (SUCRA) was used to rank efficacy. [RESULTS] Of 11,584 articles screened, 44 eligible RCTs (11,410 participants, 33 medications) were included. For fibrosis improvement, d-(R)-pioglitazone (SUCRA: 79.3) and fibroblast growth factor (FGF) 21 analogs (SUCRA: 71.9) ranked higher. For steatohepatitis resolution, glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) dual receptor agonists (RAs) (SUCRA: 91.7) ranked higher. Co-agonists of GLP-1/GIP/GCG and GLP-1/GCG receptors ranked higher for relative and absolute changes in liver fat content, respectively. For liver enzymes and glucose improvement, the combination of a GLP-1 RA and an acetyl-coenzyme A carboxylase inhibitor ranked higher. GLP-1 RAs, peroxisome proliferator-activated RAs, and FGF21 analogs showed favorable effects on lipid profile improvement. [CONCLUSIONS] Incretin-based co-agonists and FGF21 analogs showed favorable profiles across key endpoints, while d-(R)-pioglitazone and GLP-1/GIP dual RAs ranked higher for fibrosis improvement and steatohepatitis resolution, respectively. SUCRA rankings should be interpreted in conjunction with effect sizes, uncertainty, and available safety data.","url":"https://pubmed.ncbi.nlm.nih.gov/42724131/","source_name":"pubmed","source_tier":1,"coi_statement":"Mindie H. Nguyen reports receiving research support from Pfizer, Enanta, AstraZeneca, Glycotest, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Helio Health, the National Institutes of Health, and Roche, and serving as a consultant and/or advisory board member for GSK and Exelixis. JL has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2024. The other authors have no conflict of interests related to this publication.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"liver\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":309,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Zepbound, ZEPBOUND (TIRZEPATIDE) - label effective 2026-08-28","authors":"[\"Eli Lilly and Company\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-08-28","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )]. ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of ZEPBOUND and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with ZEPBOUND [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. In rats, tirzepatide causes thyroid C-cell tumors. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. ZEPBOUND is not recommended in patients with severe gastroparesis. ( 5.2 ) Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.3 ) Acute Gallbladder Disease: Has been reported in clinical trials. If cholecystitis is suspected, gallbladder studies and clinical follow-up are indicated. ( 5.4 ) Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, or ZEPBOUND. Discontinue if pancreatitis is suspected. ( 5.5 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported postmarketing with tirzepatide. If suspected, advise patients to promptly seek medical attention and discontinue ZEPBOUND. ( 5.6 ) Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin or insulin secretagogue may be necessary. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.7 ) Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus: Monitor patients with a history of diabetic retinopathy for progression. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) Never share a ZEPBOUND KwikPen between patients, even if the pen needle is changed. ( 5.10 ) 5.1 Risk of Thyroid C-Cell Tumors In rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including MTC, in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined. ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of ZEPBOUND and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with ZEPBOUND. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Severe Gastrointestinal Adverse Reactions Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), severe gastrointestinal adverse reactions were reported more frequently among patients receiving ZEPBOUND (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1%). Similar rates of severe gastrointestinal adverse reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND clinical trials for OSA. Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. ZEPBOUND is not recommended in patients with severe gastroparesis. 5.3 Acute Kidney Injury Due to\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.2 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.3 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.4 )] Acute Pancreatitis [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Hypoglycemia [see Warnings and Precautions ( 5.7 )] Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] The most common adverse reactions, reported in ≥5% of patients treated with ZEPBOUND are: nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, gastroesophageal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients for Weight Reduction and Long-Term Maintenance Pool of Placebo - Controlled Weight Reduction Trials in Adults with Obesity or Overweight, with or without Type 2 Diabetes (Study 1 and Study 2) ZEPBOUND was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 2,519 adult patients with obesity or overweight treated with ZEPBOUND for up to 72 weeks and a 4-week off drug follow-up period (Study 1 and Study 2) [see Clinical Studies ( 14.1 )] . The mean age of patients was 47 years and 37% were male. The population was 72% White, 12% Asian, 8% Black or African American, and 7% American Indian or Alaska Native; 51% identified as Hispanic or Latino ethnicity. Baseline characteristics included an average BMI of 37.4 kg/m 2 , 29% with a BMI ≥40 kg/m 2 , 41% with hypertension, 37% with dyslipidemia, 25% with type 2 diabetes mellitus, 7% with obstructive sleep apnea, and 4% with cardiovascular (CV) disease. Across both trials, 4.8%, 6.3%, and 6.7% of patients treated with 5 mg, 10 mg, and 15 mg of ZEPBOUND, respectively, permanently discontinued treatment as a result of adverse reactions compared to 3.4% of patients treated with placebo. The majority of patients who discontinued ZEPBOUND due to adverse reactions did so during the first few months of treatment due to gastrointestinal adverse reactions. Common Adverse Reactions Table 1 shows common adverse reactions associated with the use of ZEPBOUND in the pool of two placebo-controlled trials for weight reduction (Study 1 and Study 2). These adverse reactions occurred more commonly with ZEPBOUND than with placebo and occurred in at least 2% of patients treated with ZEPBOUND. Table 1: Adverse Reactions (≥2% and Greater than Placebo) in ZEPBOUND-Treated Adults with Obesity or Overweight in Weight Reduction and Long-term Maintenance Trials (Study 1 and Study 2) a Includes diarrhea, frequent bowel movements. b Includes constipation, feces hard. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. d Includes multiple related adverse event terms, such as injection site bruising, injection site erythema, injection site pruritus, injection site pain, injection site rash, injection site reaction. e Includes asthenia, fatigue, lethargy, malaise. f Includes blood pressure decreased, hypotension, orthostatic hypotension. Adverse Reaction \n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS ZEPBOUND delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. ( 7.2 ) 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) ZEPBOUND lowers blood glucose. When initiating ZEPBOUND, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.7 )] . 7.2 Oral Medications ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with ZEPBOUND. Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with ZEPBOUND. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation with ZEPBOUND and for 4 weeks after each dose escalation. Hormonal contraceptives that are not administered orally should not be affected [see Use in Specific Populations ( 8.3 ) and Clinical Pharmacology ( 12.2 , 12.3 )] .\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS ZEPBOUND is contraindicated in patients with: A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions ( 5.1 )] . Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with tirzepatide [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.2 )] . Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 ) Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"sleep\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":680,"doi":"10.3390/biomedicines14091903","pmid":"42792646","nct_ids":"[]","title":"Data-Driven Multidimensional Clinical Phenotypes and Longitudinal Changes in Type 2 Diabetes Mellitus: A Retrospective Cohort Study","authors":"[\"Igna AD\", \"Petca BL\", \"Popovici PA\", \"Ghitea TC\", \"Popoviciu MS\"]","journal":"Biomedicines","publication_date":"2026-08-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background: Type 2 diabetes mellitus (T2DM) is clinically heterogeneous, and routinely available renal, inflammatory, and hepatic measures may add information beyond glycemic assessment. Methods: Among 811 screened adults, 809 had a standardized baseline assessment and six-month follow-up; two were excluded because a required baseline clustering variable was missing, leaving 807 complete cases for phenotype derivation. Twelve-month data were available for 320 participants. Nine baseline variables were standardized, with UACR and CRP analyzed after ln(x + 1) transformation. Candidate two- to six-cluster solutions were assessed using silhouette, Calinski-Harabasz, and Davies-Bouldin indices, 200 bootstrap resamples, and a consistent-transformation sensitivity analysis. Longitudinal outcomes were evaluated using generalized estimating equations including time, phenotype, and their interaction. Results: The final stored four-cluster solution comprised a comparatively favorable-profile phenotype (n = 294), a cardiorenal-fibrotic phenotype (n = 239), an inflammatory-metabolic phenotype (n = 141), and a severe hyperglycemic-obesity phenotype (n = 133). Internal separation was modest (silhouette 0.118; Calinski-Harabasz 87.6; Davies-Bouldin 2.118), bootstrap agreement was moderate (median adjusted Rand index 0.445), and the consistent ln(x + 1) sensitivity solution showed substantial agreement with the stored assignment (adjusted Rand index 0.776). Significant phenotype-by-time interactions were observed for HbA1c, BMI, TyG, triglycerides, UACR, eGFR, FIB-4, and CRP after false-discovery-rate correction, but not for LDL cholesterol. Baseline characteristics did not differ detectably between participants with and without twelve-month follow-up after correction. Marked treatment changes occurred by T2, particularly increased use of GLP-1 receptor agonists and SGLT2 inhibitors. Conclusions: The four phenotypes provide an exploratory multidimensional description of this cohort. Longitudinal differences should not be attributed to phenotype biology alone because regression to the mean and treatment intensification are plausible contributors; external validation remains necessary.","url":"https://pubmed.ncbi.nlm.nih.gov/42792646/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:07+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"kidney\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":774,"doi":"10.3390/biomedicines14091887","pmid":"42792631","nct_ids":"[]","title":"Genetic Assessment of Oesophageal Safety of GLP-1 and GIP Receptor Perturbation: A Drug-Target Mendelian Randomisation Study","authors":"[\"Lee H\", \"Min YW\", \"Oh YE\", \"Kim TS\", \"Min BH\", \"Lee JH\", \"Rhee PL\"]","journal":"Biomedicines","publication_date":"2026-08-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists are used long term for obesity and diabetes, but their oesophageal safety is uncertain: weight loss may reduce Barrett's oesophagus and adenocarcinoma risk, whereas delayed gastric emptying may worsen reflux. We performed a genetic assessment of target-mediated oesophageal safety. Methods: Two-sample drug-target Mendelian randomisation used cis-expression quantitative trait loci for both receptors (31,684 participants). Outcomes were European genome-wide association studies of gastro-oesophageal reflux disease and the Barrett's oesophagus/oesophageal adenocarcinoma axis, with a trans-ancestry squamous cell carcinoma comparator. A prespecified gated workflow required positive-control validation, and target specificity required genetic colocalisation (posterior probability of a shared causal variant ≥ 0.70). Candidate metabolic mediators were examined in two-step analyses, and findings were replicated in an independent Finnish population (FinnGen R12). Results: Genetically proxied GLP-1 receptor expression was not associated with reflux disease (odds ratio 0.97, 95% confidence interval 0.85-1.11), arguing against a substantial target-mediated reflux liability; the GIP receptor estimate was not estimable. For the Barrett's oesophagus/adenocarcinoma endpoint, estimates were near the null for both receptors (GLP-1R 0.96, 0.47-1.96; GIPR 1.00, 0.42-2.37); colocalisation was uninformative because the outcome loci carried no detectable association signal, and wide intervals did not exclude moderate effects. The null reflux findings were reproduced in FinnGen. Adiposity showed the most consistent pathway association, whereas glycaemic traits did not, including when HbA1c was instrumented from a population-based genome-wide association study providing an order of magnitude more variants. Conclusions: GLP-1 receptor perturbation was not associated with reflux disease, providing cautious genetic reassurance. For the Barrett's oesophagus/adenocarcinoma axis, no target-specific association was demonstrated, but colocalisation was uninformative because the outcome loci carried no detectable signal, and imprecision precludes firm safety conclusions; larger adenocarcinoma-specific studies are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42792631/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"body_composition\", \"cancer\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":568,"doi":"10.3390/ijms27177538","pmid":"42737442","nct_ids":"[]","title":"Liraglutide Attenuates Multiorgan Oxidative, Astroglial, and Mitochondrial Stress Responses in Thioacetamide-Induced Hepatic Encephalopathy","authors":"[\"Bilgin Y\", \"Sari FM\", \"Cicek B\", \"Kurt E\", \"Ozkaraca M\", \"Gungor A\", \"Kurt N\", \"Bilgin AO\"]","journal":"International journal of molecular sciences","publication_date":"2026-08-23","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Hepatic encephalopathy (HE) is a complex complication of liver failure involving oxidative stress, astroglial activation, mitochondrial dysfunction, and multiorgan disturbances along the gut-liver-brain axis. This study investigated the therapeutic effects of liraglutide (LIRA) in a thioacetamide (TAA)-induced rat model of HE. Thirty male Sprague-Dawley rats were assigned to control, TAA, and TAA+LIRA 100, 200, or 400 µg/kg groups. HE was induced with TAA (200 mg/kg, intraperitoneally) for three consecutive days, followed by subcutaneous LIRA treatment for 14 days. Serum biochemical parameters, tissue oxidative and inflammatory markers, histopathology, and Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity were evaluated. TAA caused marked hepatic and cerebral structural injury, increased serum and brain glutamine concentrations, disrupted redox homeostasis, elevated MPO activity, and increased cerebral GFAP and multiorgan VEGFA immunoreactivity. LIRA partially improved hepatic and cerebral histopathology, reduced glutamine disturbances, attenuated selected oxidative, nitrosative, and inflammatory alterations, and modulated Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity in a tissue- and dose-specific manner. The 200 µg/kg dose produced the most consistent overall improvement, whereas the 400 µg/kg dose was less favorable for several endpoints. LIRA may therefore alleviate multiorgan stress associated with experimental HE, although further studies are required to confirm functional and mechanistic relevance.","url":"https://pubmed.ncbi.nlm.nih.gov/42737442/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"preclinical_animal","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"liver\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":727,"doi":"10.1038/s41467-026-77047-5","pmid":"42778559","nct_ids":"[]","title":"Tirzepatide versus GLP-1 receptor agonists and stroke in patients with atrial fibrillation and type 2 diabetes","authors":"[\"Lin CL\", \"Lin KC\", \"Yu JM\", \"Chang CL\", \"Lin YY\", \"Fang CY\", \"Chen WM\", \"Wu SY\"]","journal":"Nature communications","publication_date":"2026-08-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Patients with atrial fibrillation and type 2 diabetes remain at high risk of stroke despite anticoagulation and glucose-lowering treatment. We examined whether tirzepatide was associated with lower cerebrovascular risk than established glucagon-like peptide-1 receptor agonists in a retrospective cohort from a large international federated electronic health-record network. Here we show that, among 14,118 matched pairs of adults initiating tirzepatide or another glucagon-like peptide-1 receptor agonist, tirzepatide use was associated with lower risks of any stroke, ischemic stroke, hemorrhagic stroke, and death from any cause. The absolute difference in stroke risk was 2.1 percentage points at one year, and the absolute difference in mortality was 6.2 percentage points. These observational findings support further assessment of tirzepatide as a potential option for people with both conditions, but randomized trials are required before treatment recommendations can change.","url":"https://pubmed.ncbi.nlm.nih.gov/42778559/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:11+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":40,"doi":"10.1161/circulationaha.125.074482","pmid":"42610271","nct_ids":"[\"NCT03574597\"]","title":"Effect of Semaglutide on the Inflammatory Biomarker High-Sensitivity CRP in Patients With Established Cardiovascular Disease and Overweight or Obesity in SELECT: A Prespecified Secondary Analysis","authors":"[\"Plutzky J\", \"Bogdański P\", \"Colhoun HM\", \"Dagdelen S\", \"Deanfield JE\", \"Emerson SS\", \"Hovingh GK\", \"Kahn SE\", \"Ekström K\", \"Latkovskis G\", \"Lehrke M\", \"Hardt-Lindberg S\", \"Lingvay I\", \"Nicholls SJ\", \"Kalayci Oral T\", \"Terns PP\", \"Rasmussen S\", \"Ridker PM\", \"Ryan DH\", \"Lincoff AM\"]","journal":"Circulation","publication_date":"2026-08-18","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] In SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity), among 17 604 patients with known atherosclerotic cardiovascular disease and overweight or obesity, but not diabetes, randomization to the glucagon-like peptide-1 receptor antagonist semaglutide significantly reduced the primary outcome of major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo (mean follow-up, 39.8 months). Inflammation, as indicated by plasma hsCRP (high-sensitivity C-reactive protein) level, is implicated as a biomarker predicting cardiovascular risk in obesity and atherosclerotic cardiovascular disease. SELECT provides a unique opportunity to study the relationship among hsCRP, obesity, weight loss, and MACE outcomes in semaglutide versus placebo groups. [METHODS] In this prespecified SELECT substudy, we evaluated whether baseline hsCRP levels predicted MACE risk and examined the relationships between changes in hsCRP levels and time to first MACE, baseline body weight, weight loss, and other clinical measures among treatment groups over time (104-208 weeks) using multiple approaches, including Cox modeling. [RESULTS] Baseline hsCRP level, which was similar in the semaglutide (geometric mean 1.96 mg/L) and placebo (geometric mean 1.91 mg/L) groups, was prognostic of future MACEs. The risk of MACEs increased across baseline hsCRP level <2, 2-<10, and ≥10 mg/L subgroups, including significant associations with cardiovascular and all-cause death. Semaglutide reduced hsCRP levels (-37.8% [104 weeks]) and risk of MACEs across all hsCRP subgroups. Greater reductions in ratio-to-baseline hsCRP with semaglutide were associated with greater weight loss, but preceded major weight loss, evident by 4 and 8 weeks, and occurred among those without weight loss. Semaglutide-associated changes in hsCRP were independent of low-density lipoprotein cholesterol levels, statin use, and atherosclerotic cardiovascular disease entry criteria. hsCRP reductions were found to be prognostic of decreased risk of MACEs. Modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide in SELECT. [CONCLUSIONS] In SELECT, hsCRP data at baseline and in response to treatment with semaglutide support inflammation as a potential prognostic factor associated with cardiovascular risk in these generally well-treated patients with atherosclerotic cardiovascular disease and overweight or obesity but not diabetes. These findings suggest that the MACE reduction observed with semaglutide versus placebo in SELECT may have partially involved a decrease in inflammation. [REGISTRATION] URL: https://clinicaltrials.gov; Unique identifier: NCT03574597.","url":"https://pubmed.ncbi.nlm.nih.gov/42610271/","source_name":"pubmed","source_tier":1,"coi_statement":"Dr Plutzky declares having received consulting honoraria from Altimmune, Amgen, Boehringer Ingelheim, Corcept, Esperion Therapeutics, Merck, MJH Life Sciences, New Amsterdam, Novartis, and Novo Nordisk; has received grants, paid to his institution, from Boehringer Ingelheim and Novartis; and holds the position of Director, Preventive Cardiology, at Brigham and Women’s Hospital. Dr Bogdański declares serving on advisory panels for Bausch Health, Eli Lilly, and Novo Nordisk; and has received speaker honoraria from Boehringer Ingelheim, Lilly, Mylan, Novo Nordisk, and Sanofi. Prof Colhoun declares serving on advisory panels for Bayer and Novo Nordisk; receiving research funding from IQVIA, Roche Pharmaceuticals, and Sanofi; receiving grants from the Chief Scientist Office, Diabetes UK, European Commission, Juvenile Diabetes Research Foundation, and Medical Research Council; serving on a speaker’s bureau for Novo Nordisk; and holding stock in Bayer and Roche Pharmaceuticals. Dr Dagdelen declares participating in advisory board panels for Bayer, Novo Nordisk, and Sanofi. Prof Deanfield declares having received consulting honoraria from Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda; and research grants from Aegerion, the British Heart Foundation, Colgate, Medical Research Council (UK), MSD, National Institute for Health and Care Research, Pfizer, Public Health England, and Roche. Prof Emerson declares having served as a consultant for Novo Nordisk through participation on steering committees for cardiovascular outcome trials of semaglutide in obesity and overweight (SELECT) and in type 2 diabetes (SOUL [Semaglutide Cardiovascular Outcomes Trial]), with an earlier role on a cardiovascular outcomes trial of insulin degludec. Dr Hovingh declares being an employee of and shareholder in Novo Nordisk. Dr Kahn declares having received consulting honoraria from Amgen, Anji Pharmaceuticals, Boehringer Ingelheim, Biomea Fusion, Eli Lilly, Merck, Novo Nordisk, and Oramed; stock options from Altpep; and research support from Corcept Therapeutics. Dr Ekström declares being a full-time employee of and shareholder in Novo Nordisk. Dr Latkovskis has given talks, attended conferences, received consultancy fees, or participated in trials sponsored by 89bio, Abbott Laboratories, Amgen, AstraZeneca, Berlin Chemie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Grindex, KRKA, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, Servier Laboratories, Siemens Laboratories, Swixx Biopharma, and Zentiva. Dr Lehrke declares scientific support from Boehringer Ingelheim, MSD, and Novo Nordisk; speaker honoraria from Abiomed, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Lilly, MSD, Novo Nordisk, and Sanofi; and advisory support from Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novo Nordisk, and Sanofi. Dr Hardt-Lindberg declares being a full-time employee of and shareholder in Novo Nordisk. Prof Lingvay declares having received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals Inc., Novo Nordisk, Pfizer, and Sanofi US Services; has served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Biomea, Boehringer Ingelheim, Carmot, Eli Lilly and Company, Intarcia, Intercept Pharmaceuticals, Inc., Janssen Global Services, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, MannKind Corporation, Merck, Novo Nordisk, Pfizer, Sanofi US Services, Shionogi, Structure Therapeutics, Target Pharma, Valeritas, and Zealand Pharma; and has received travel expenses from Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, Novo Nordisk, Sanofi US Services, and Zealand Pharma. Dr Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, Infraredx, and Sanofi-Regeneron, and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Vaxxinity, CSL Seqiris, and Novo Nordisk. Dr Kalayci Oral declares being a full-time employee of and shareholder in Novo Nordisk. Dr Terns has received fees from Amgen, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Rasmussen declares being a full-time employee of and shareholder in Novo Nordisk. Dr Ridker has received institutional research grant support from the National Heart, Lung, and Blood Institute, Novartis, and Novo Nordisk (to evaluate the role of anti-inflammatory agents, including methotrexate, interleukin-1 inhibitors, and interleukin-6 inhibitors), as well as Amarin, Esperion, Kowa, and Pfizer; has served as a consultant to Agepha, Ardelyx, Cardio Therapeutics, CSL Behring, Flame, Horizon Therapeutics, Janssen, Novartis, Novo Nordisk, and Zomagen (entities developing anti-inflammatory therapies, including colchicine, interleukin-1 inhibitors, interleukin-6 inhibitors, and agents that potentially target or interact with the NLRP3 inflammasome); has served as a consultant to AstraZeneca, Boehringer Ingelheim, Civi Biopharma, Cytokinetics, Eli Lilly, GlaxoSmithKline, Montai Health, New Amsterdam, RTI, SOCAR, and Health Outlook; has minority shareholder equity positions in Angiowave, Bitteroot Bio, and Upperton; and receives compensation for service on the Baim Institute, Leducq Foundation, Paris FR, and the Peter Munk Advisory Board (University of Toronto). Prof Ryan declares having received consulting honoraria from Altimmune, Amgen, AstraZeneca, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, eMed, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Regeneron, Rhythm, Roche Pharmaceuticals, Scientific Intake, Wondr Health, and Zealand; and received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. Prof Lincoff declares having received research grants paid to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, and Novartis; and has received consultancy fees from Akebia Therapeutics, Alnylam Pharmaceuticals, Ardelyx, Canary Cure, Eli Lilly and Company, Entity, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, and ReCor Medical.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"Prespecified secondary (sub-study) analysis of a randomized, double-blind, placebo-controlled, parallel-group Phase 3 trial (SELECT)","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"mortality\"]","outcome_type":"mixed","primary_outcome":"Prespecified: baseline hs-CRP as MACE predictor; hs-CRP change vs weight loss and MACE","endpoints":null,"effect_estimate":"hs-CRP -37.8% at 104 weeks; reductions evident by 4-8 weeks, before major weight loss, and in those without weight loss; hs-CRP reduction prognostic of lower MACE","confidence_interval":null,"p_value":null,"sample_size":17604,"follow_up":"104-208 weeks","direction":"benefit","population":"{\"condition\": \"Established/known atherosclerotic cardiovascular disease with overweight or obesity, without diabetes\", \"mean_age\": \"not reported; eligibility required age 45 years or older\", \"sex\": \"not reported\", \"mean_bmi\": \"not reported; eligibility required BMI 27 kg/m2 or higher, established ASCVD and no diabetes\", \"diabetes_status\": \"No diabetes (history of type 1 or type 2 diabetes was an exclusion criterion)\", \"sample_size\": 17604}","applicability":"INDIRECT","applicability_rationale":"Obese secondary-prevention population; but the early, weight-loss-independent hs-CRP fall is the most relevant human inflammation signal available. Biomarker, not outcome.","mediation":"specifically_tested","mediation_notes":"method: Combination of (1) temporal analysis — hsCRP reduction with semaglutide was 'evident by 4 and 8 weeks,' i.e., preceding the period of major weight loss; (2) subgroup analysis — hsCRP reduction 'occurred among those without weight loss' (non-losers); and (3) statistical modeling described only as 'modeling suggests decreased inflammation as contributing in part to the benefits seen with semaglutide' linking hsCRP change to MACE risk reduction. The abstract does not name a specific mediation-analysis method (e.g., causal mediation, formal weight-adjusted Cox model) beyond 'multiple approaches, including Cox modeling.'; prespecified: NI; key limitation: None of these specific weight-independence analyses (early 4-/8-week hsCRP timepoints, non-weight-loser subgroup, or the mediation/modeling statement) could be located in the protocol or SAP text provided — only the standard week 0-to-week 104 hsCRP ratio-to-baseline endpoint is documented there — so whether they were prespecified, and their full methodology (denominators, handling of missing early timepoints, adjustment set), is not verifiable from the sources available to this pass; full text and any dedicated biomarker-substudy protocol/SAP would be needed to confirm.","adjusted_for":"[\"weight loss (time-varying)\", \"LDL cholesterol\", \"statin use\"]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Prespecified secondary (sub-study) analysis of a randomized, double-blind, placebo-controlled, parallel-group Phase 3 trial (SELECT)\", \"sample_size\": 17604, \"randomization\": \"yes (parent trial)\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"104-208 weeks\", \"outcome_type\": \"biomarker plus association with MACE\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"prespecified secondary analysis; mediation modelling is observational within the trial\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"rob2\": {\"O1\": {\"D1\": {\"judgment\": \"Low\", \"rationale\": \"Large industry-sponsored Phase 3 trial (17,604 randomized) using a centralized IWRS for randomization and allocation, double-blind with visually identical active/placebo product; baseline hsCRP was near-identical between arms (1.96 vs 1.91 mg/L geometric mean), consistent with adequate concealment/randomization. Per the domain rule this pattern warrants PY on allocation concealment absent contradi\"}, \"D2\": {\"judgment\": \"Low\", \"rationale\": \"Per the domain rule, D2 for this lab biomarker outcome is judged on discontinuation imbalance and ITT handling rather than unblinding. Trial-completion imbalance between arms was modest (NOT COMPLETED 259/8803 semaglutide vs 284/8801 placebo), and the SAP specifies an intention-to-treat estimand (FAS, irrespective of adherence) for all objectives, with the hsCRP imputation model fitted on data 'ir\"}, \"D3\": {\"judgment\": \"Low\", \"rationale\": \"7472/8803 (84.9%) semaglutide and 7400/8801 (84.1%) placebo participants contributed to the week-104 hsCRP result: about 15% of randomised participants lack the outcome and the between-arm difference in availability is 0.8 percentage points, i.e. below both of the guide's thresholds (>20% missing, or >5-point between-arm gap), so \\\"data available for nearly all\\\" is PY. Missing values were handled b\"}, \"D4\": {\"judgment\": \"Low\", \"rationale\": \"hsCRP is a central-lab, objective biomarker measurement. The protocol specifies that laboratory analyses (including the panel containing hsCRP) are performed by a central laboratory throughout the trial, with no evidence in the available sources of an assay change partway through or of differential measurement procedures between arms. Per the domain rule, this defaults to Low.\"}, \"D5\": {\"judgment\": \"Low\", \"rationale\": \"The outcome, timepoint, transformation, model and missing-data handling were all prespecified in the protocol (v7.0, 09 Feb 2022) and SAP (v3.0, 22 Apr 2022), both finalised well before primary completion (21 Jun 2023) and before any unblinded data; the emphasised timepoint (104 weeks) is exactly the prespecified one, and the corresponding result is posted in the registry, so there is no sign of s\"}, \"overall\": {\"judgment\": \"Low\"}, \"result\": \"Change in hsCRP (ratio to baseline), semaglutide vs placebo, at week 104; registered secondary continuous endpoint 'Change in High Sensitivity C-Reactive Protein (hsCRP) - Ratio to Baseline' (FAS, n=7472 semaglutide / 7400 placebo; geometric mean ratio 0.61 vs 1.00); abstract reports this as '-37.8% [104 weeks]' in the RESULTS section, no table/figure identifiable (full text not available).\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"guide_version\": \"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)\", \"label\": \"Human-reviewed\", \"resolution\": \"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)\"}, \"O4\": {\"D1\": {\"judgment\": \"Low\", \"rationale\": \"Same trial-level randomization/allocation infrastructure as O1 (central IWRS, double-blind, identical-appearing product); no result-specific randomization concern for the weight-independence analyses.\"}, \"D2\": {\"judgment\": \"Some concerns\", \"rationale\": \"The weight-independence claims rest on a non-loser subgroup and early (4-/8-week) hsCRP trajectories; no protocol/SAP text was found defining an intercurrent-event/estimand strategy for these specific sub-analyses, so it is unclear how deviations (discontinuation, non-adherence, dose interruption during up-titration through week 4-8) were handled for them specifically, beyond the trial's general I\"}, \"D3\": {\"judgment\": \"Some concerns\", \"rationale\": \"No information in the abstract, registry, protocol, or SAP on the number of participants contributing to the week 4/week 8 hsCRP measurements or to the 'without weight loss' subgroup used for O4; denominators and missingness for these specific analyses are not stated anywhere in the available sources. Given O1's overall hsCRP missingness is already ~15%/arm, and week 4/8 draws would be additional/\"}, \"D4\": {\"judgment\": \"Low\", \"rationale\": \"hsCRP measurement itself is via the same central laboratory used for the week-104 endpoint (per protocol, all specified lab tests are run centrally); no evidence of a different/changed assay for the earlier (4-/8-week) draws. Objective biomarker measurement defaults to Low per the domain rule.\"}, \"D5\": {\"judgment\": \"High\", \"rationale\": \"The paper is titled a \\\"prespecified secondary analysis\\\", but the only hsCRP analysis prespecified anywhere in the protocol or SAP is change from randomisation to year 2 (week 104), on the log scale, by MI + ANCOVA. Neither document contains any week-4 or week-8 hsCRP analysis, any subgroup defined by weight change, or any mediation analysis, and the SAP's subgroup list is entirely baseline-defined\"}, \"overall\": {\"judgment\": \"High\"}, \"result\": \"Weight-independence of the hsCRP effect: (a) temporal precedence of hsCRP reduction over weight loss, 'evident by 4 and 8 weeks'; (b) hsCRP reduction 'occurred among those without weight loss' (implied non-weight-loser subgroup); (c) mediation-type modeling statement that 'decreased inflammation [is] contributing in part to the benefits seen with semaglutide in SELECT' on MACE. All from the abstract METHODS/RESULTS; no table/figure identifiable (full text not available), and none of these specific analyses (4-/8-week hsCRP timepoints, non-loser subgroup, mediation model) appear in the available protocol or SAP text.\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"guide_version\": \"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)\", \"label\": \"Human-reviewed\", \"resolution\": \"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)\"}}}","evidence_rationale":"Prespecified analysis of a large RCT; biomarker endpoint with modelled mediation.","funding_source":"Novo Nordisk A/S (trial sponsor)","industry_funded":"yes","manufacturer":"Novo Nordisk A/S","author_conflicts":"Authors report Novo Nordisk relationships; sponsor co-authors.","sponsor_role":"Trial funded by Novo Nordisk A/S; several authors are Novo Nordisk employees; the sponsor's role in the analysis is not stated (the first author vouches for the analyses).","independent_replication_exists":"no (single trial dataset)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In SELECT, semaglutide lowered hs-CRP by 38% and the fall began within weeks, before major weight loss and even in people who did not lose weight, although larger hs-CRP falls went with greater weight loss. This suggests an anti-inflammatory effect not fully explained by weight loss, but it is a blood marker in people with obesity and heart disease, in a trial funded by Novo Nordisk with Novo Nordisk employees among the authors.","methodological_notes":"Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/42610271/); sources: abstract, registry, public protocol/SAP where available; no paper full text.","reviewed_by":null,"reviewed_at":null},{"id":314,"doi":"10.1111/dom.71200","pmid":"42608321","nct_ids":"[\"NCT04881760\", \"NCT04867785\"]","title":"Retatrutide-Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes","authors":"[\"Ruotolo G\", \"Harris C\", \"Lin Y\", \"Wilson JM\", \"Pirro V\", \"Duffin KL\", \"Thomas MK\", \"Hartman ML\", \"Neill CO\", \"Coskun T\", \"Milicevic Z\", \"Haupt A\", \"Sattar N\", \"Nicholls SJ\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-08-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To further characterise the effects of retatrutide on cardiometabolic risk, lipoprotein and inflammatory biomarkers were assessed post hoc in phase 2 trials of adults with obesity/overweight with or without type 2 diabetes (T2D). [MATERIALS AND METHODS] Data were analysed from two randomised, double-blind, placebo-controlled phase 2 trials. In Study 1, adults with obesity/overweight and T2D received once-weekly retatrutide (0.5/4/8/12 mg), dulaglutide (1.5 mg) or placebo for 36 weeks; in Study 2, adults with clinical obesity without T2D received retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Fasting blood samples were collected at baseline and during treatment to assess lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers. Mixed models for repeated measures estimated placebo-adjusted change from baseline. Statistical significance was defined as a false discovery rate-adjusted p < 0.05. [RESULTS] Mean body mass index was 35.4 kg/m2 (Study 1) and 37.4 kg/m2 (Study 2). In both studies, retatrutide was associated with significant reductions in non-high-density lipoprotein cholesterol (Study 1: up to -21.0%, Study 2: up to -26.9%), apolipoprotein B (-21.4%, -24.2%), total triglyceride-rich lipoprotein particles (-22.5%, -33.7%), large triglyceride-rich lipoprotein particles (-84.4%, -76.6%), triglyceride-rich lipoprotein cholesterol (-29.4%, -38.6%), total low-density lipoprotein particles (-19.7%, -23.5%) and small low-density lipoprotein particles (-32.6%, -32.3%). Retatrutide was associated with significant reductions in high-sensitivity C-reactive protein (-54.8%) and interleukin-6 (-29.6%) in Study 2 but not Study 1. [CONCLUSIONS] In adults with obesity/overweight, with or without T2D, retatrutide treatment was associated with reductions in atherogenic lipoproteins and inflammatory biomarkers linked to cardiovascular disease risk. [TRIAL REGISTRATION] ClinicalTrials.gov numbers NCT04881760 and NCT04867785.","url":"https://pubmed.ncbi.nlm.nih.gov/42608321/","source_name":"pubmed","source_tier":1,"coi_statement":"Giacomo Ruotolo, Charles Harris, Yanzhu Lin, Jonathan Wilson, Valentina Pirro, Kevin L. Duffin, Melissa K. Thomas, Mark L. Hartman, Ciara O′ Neill, Tamer Coskun, Zvonko Milicevic and Axel Haupt are (or were at the time this research was conducted) employees and shareholders of Eli Lilly and Company, which funded this study. Naveed Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini‐Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics and Sanofi and has received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. Stephen J. Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx and Sanofi‐Regeneron and is also a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi‐Regeneron, Vaxxinity, CSL Sequiris and Novo Nordisk.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"Study 1: 0.5/4/8/12 mg once weekly; Study 2: 1/4/8/12 mg\", \"comparator\": \"placebo (both studies); dulaglutide 1.5 mg (Study 1)\", \"treatment_duration\": \"36 weeks (Study 1); 48 weeks (Study 2)\", \"route\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"placebo-adjusted change from baseline in lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers (post hoc)","endpoints":null,"effect_estimate":"Non-HDL cholesterol up to -21.0% (Study 1) and up to -26.9% (Study 2); apolipoprotein B -21.4% and -24.2%; small LDL particles -32.6% and -32.3%; hsCRP -54.8% and IL-6 -29.6% in Study 2, not significant in Study 1","confidence_interval":null,"p_value":"false discovery rate-adjusted p < 0.05 (significance threshold; exact values not given)","sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": \"35.4 kg/m2 (Study 1); 37.4 kg/m2 (Study 2)\", \"bmi_min\": null, \"obesity_status\": \"required (obesity/overweight; BMI threshold not stated)\", \"diabetes_status\": \"mixed (Study 1 type 2 diabetes required; Study 2 without type 2 diabetes)\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity/overweight, with or without type 2 diabetes\", \"sample_size\": null, \"inclusion_exclusion\": \"adults with obesity/overweight; Study 1 with type 2 diabetes, Study 2 clinical obesity without type 2 diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity or overweight (mean BMI 35.4 in Study 1 and 37.4 in Study 2), and Study 1 participants also had type 2 diabetes.","mediation":"possibly","mediation_notes":"The abstract reports placebo-adjusted biomarker changes but gives no weight or HbA1c results and no adjustment for them, so weight loss or metabolic improvement could explain part of the effect; no cached full text.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (both studies); dulaglutide 1.5 mg (Study 1)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported in abstract; significance set at false discovery rate-adjusted p < 0.05; post hoc analysis\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: post hoc biomarker analysis of two randomised, double-blind, placebo-controlled phase 2 trials, with no clinical outcomes and no sample size in the abstract.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Post hoc analysis of two phase 2 trials with biomarker outcomes only; the abstract gives no sample size or confidence intervals, inflammatory marker reductions were seen in Study 2 but not Study 1, and all participants had obesity or overweight.","plain_summary":"This post hoc analysis of two randomised, double-blind, placebo-controlled phase 2 trials studied adults with obesity or overweight, with type 2 diabetes (Study 1) or without it (Study 2). Retatrutide was linked to lower atherogenic blood fats in both trials, for example apolipoprotein B -21.4% and -24.2%. The inflammation markers hsCRP (-54.8%) and IL-6 (-29.6%) fell in Study 2 but not in Study 1. These are blood markers, not heart attacks or strokes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":335,"doi":"10.1016/j.jacc.2026.04.044","pmid":"42233927","nct_ids":"[\"NCT04184622\"]","title":"Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide: A SURMOUNT-1 Post Hoc Analysis","authors":"[\"Sattar N\", \"Linetzky B\", \"Ruotolo G\", \"Verma S\", \"Sourij H\", \"Wang H\", \"Vanderman K\", \"Wilson JM\", \"Griffin RM\", \"Stefanski A\", \"Ridker PM\"]","journal":"Journal of the American College of Cardiology","publication_date":"2026-08-11","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes and obesity. The effect of tirzepatide on cardiovascular risk biomarkers in people with overweight or obesity remains uncertain. [OBJECTIVES] The purpose of this study was to evaluate the association of tirzepatide compared to placebo on biomarkers that reflect inflammation (high-sensitivity C-reactive protein, interleukin-6, fibrinogen, leukocytes), metabolic/adiposity/hepatic stress (homeostatic model assessment of insulin resistance, leptin, gamma-glutamyl transferase, fibroblast growth factor-21, adiponectin, free fatty acids), endothelial dysfunction (soluble intercellular adhesion molecule-1, E-selectin), and hemostasis/thrombosis (plasminogen activator inhibitor-1:antigen [Ag], tissue plasminogen activator:Ag, thrombomodulin, platelets) in people with obesity. [METHODS] The aforementioned biomarkers were assayed from plasma samples, collected at baseline, 24 weeks, and 72 weeks, from 100 randomly selected participants from each group of the SURMOUNT-1 trial who completed treatment with once-weekly placebo or tirzepatide 5, 10, or 15 mg (n = 392 after low sample volumes excluded). The change in each log-transformed biomarker level over time was evaluated by a mixed model for repeated measures, with change at 72 weeks the primary outcome of interest. Model estimates were back-transformed to the original (geometric mean ratio) scale and expressed as percent change in geometric means. Pearson correlations between log change in biomarker levels and weight were done on pooled tirzepatide doses. [RESULTS] At week 72, tirzepatide was associated with significantly greater reductions (negative values) or increases (positive values) in biomarker geometric means compared with placebo. For the 5-, 10-, or 15-mg doses, respectively, these included high-sensitivity C-reactive protein (-36.9%, -46.9%, -54.6%), interleukin-6 (-25.4%, -27.8%, -30.2%), leukocytes (not significant [NS], -8.6%, -10.0%), homeostatic model assessment of insulin resistance (-26.4%, -35.5%, -39.1%), leptin (-44.4%, -59.3%, -61.4%), gamma-glutamyl transferase (-18.6%, -21.6%, -32.7%), fibroblast growth factor-21 (-27.4%, -27.6%, -39.9%), adiponectin (21.1%, 35.1%, 47.7%), free fatty acids (NS, NS, -17.1%), soluble intercellular adhesion molecule-1 (NS, -9.7%, -11.1%), E-selectin (-12.6%, -20.0%, -26.4%), plasminogen activator inhibitor-1:Ag (-41.4%, -35.6%, -44.3%), and platelets (NS, NS, -6.0%) (all adjusted P < 0.05). No consistent associations were observed between tirzepatide and changes in fibrinogen, tissue plasminogen activator:Ag, or thrombomodulin. [CONCLUSIONS] In this post hoc analysis, tirzepatide was associated with improvements in biomarkers of metabolic/adiposity/hepatic stress and endothelial dysfunction, as well as selected biomarkers of inflammation and hemostasis/thrombosis. This analysis provides a comprehensive, long-term, randomized assessment of biomarker changes across multiple cardiovascular pathways during tirzepatide treatment in obesity. (A Study of Tirzepatide [LY3298176] in Participants With Obesity or Overweight [SURMOUNT-1]; NCT04184622).","url":"https://pubmed.ncbi.nlm.nih.gov/42233927/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures This work was funded by Eli Lilly and Company, whose employees were involved in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication. Dr Sattar has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; has consulted for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Hanmi Pharmaceuticals, Menairini Ricerche, Metsera, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics; and had fees paid via his university for lectures, presentations, speakers bureaus, manuscript writing, or education events from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Roche Diagnostics. Drs Linetzky, Ruotolo, Wilson, Griffin, and Stefanski are employees and shareholders of Eli Lilly and Company. Dr Verma has received grant support paid to his university from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, HLS Therapeutics, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and Sanofi; has received speaker honoraria from Amarin Corporation, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly and Company, HLS Therapeutics, Humber River Health, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S and L Solutions Event Management Inc, Sanofi, and Sun Pharma; and has participated on a data advisory board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, and Sanofi. Dr Sourij has received institutional research grant support from Boehringer Ingelheim, Eli Lilly and Company, the European Union and the ERA4Health programme, and Novo Nordisk; has received personal consulting fees from Amarin Corporation, Amgen, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly and Company, and Novo Nordisk; has received personal fees (lecture fees, advisory boards) from Amarin Corporation, Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, and Novartis; has received travel support from Daiichi-Sankyo and Novo Nordisk; and has served unpaid as president elect of the Austrian Diabetes Association. Dr Wang was an employee of TechData Service Company, LLC. Dr Vanderman is an employee of Syneos Health, Inc. Dr Ridker has received institutional research grant support from Amarin Corporation, Esperion Therapeutics, Kowa, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, and Pfizer; during the past 3 years has served as a consultant to Agepha Pharma, Ardelyx, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cardiol Therapeutics, CiVi Biopharma, CSL Behring, Cytokinetics, Eli Lilly and Company, GlaxoSmithKline, Janssen, Merck, NewAmsterdam Pharma, NodThera, Novartis, Novo Nordisk, SOCAR Research, and Tourmaline Bio; has received payment or honoraria for speaking engagements from the European Atherosclerosis Society and International Atherosclerosis Society; has received travel support from Agepha Pharma, Novo Nordisk, and Pfizer; has minority shareholder equity positions in Angiowave, Bitterroot Bio, and Uppton; and receives compensation for service on the Baim Institute (Boston, Massachusetts, USA), the Leducq Foundation (Paris, France), and the Peter Munk Advisory Board (University of Toronto).","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":941,"doi":"10.21203/rs.3.rs-10630296/v1","pmid":"42845643","nct_ids":"[]","title":"Direct Coronary Vascular and Lipidomic Remodeling by Low-Dose GLP-1 Agonist Therapy in Cardiometabolic HFpEF","authors":"[\"Lefer D\", \"Polhemus D\", \"Elbatreek M\", \"Resch C\", \"Butt A\", \"Rahman F\", \"Drachenberg C\", \"Burk D\", \"Allerton T\", \"Ravandi A\", \"Goodchild T\"]","journal":"Research square","publication_date":"2026-08-11","year":2026,"publication_type":"preprint","peer_reviewed":"no","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events in patients with type 2 diabetes and obesity[1, 2], but the mechanisms underlying these benefits remain incompletely defined. Although GLP-1RAs improve vascular function[3] and alter circulating lipid species associated with cardiovascular risk [4-6], whether these effects extend to diseased coronary vessels and occur independently of weight loss is unknown. Here, we show that weight-neutral semaglutide administration in two complementary cardiometabolic HFpEF models - a porcine model of metabolic syndrome with coronary artery disease and the ZSF-1 obese HFpEF rat - improves coronary and aortic endothelium-dependent vasodilation, attenuates coronary vascular remodeling and fibrosis, increases myocardial microvascular density, and remodels the plasma lipidome through reductions in ceramides and diacylglycerols together with enrichment of long-chain polyunsaturated triacylglycerols. These findings identify direct vascular and metabolic actions of semaglutide that are independent of weight loss.","url":"https://pubmed.ncbi.nlm.nih.gov/42845643/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing Interests All authors declare no disclosure of interest for this contribution","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-11T11:52:10+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1431,"doi":"10.1186/s13098-026-02268-z","pmid":"42989385","nct_ids":"[]","title":"Association of glucagon-like peptide-1 receptor agonist therapy with atrial fibrillation recurrence after catheter ablation: a systematic review and meta-analysis","authors":"[\"Shekouh D\", \"Askarinejad A\", \"Zangeneh S\", \"Jochin P\", \"Varmazyar M\", \"Nozhat S\", \"Abdollahi Z\", \"Drissi HB\", \"Torabian A\", \"Arzhangzadeh A\"]","journal":"Diabetology & metabolic syndrome","publication_date":"2026-08-10","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, with a rising global prevalence. Post-ablation AF recurrence remains frequent, particularly among patients with obesity and metabolic syndrome. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated favorable cardiometabolic and cardiovascular effects, but their association with AF recurrence after ablation remains uncertain. [METHODS] PubMed, Scopus, Embase, and Web of Science were searched through June 18, 2026. Cohort studies evaluating GLP-1RA therapy in adults with atrial fibrillation undergoing catheter ablation were included. The primary outcome was post-ablation atrial fibrillation recurrence (or recurrent atrial tachyarrhythmia, as defined by the individual studies). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Risk of bias was assessed using the JBI tool, and certainty of evidence was evaluated using the GRADE approach. [RESULTS] Six cohort studies (three prospective and three retrospective), comprising 14,278 patients (7,065 GLP-1RA users and 7,213 controls), met the inclusion criteria. Follow-up duration ranged from 12 to 24 months across studies. The pooled mean age was approximately 64 years in both the GLP-1RA and control groups. GLP-1RA therapy was associated with a lower hazard of AF recurrence compared with the respective comparator groups (HR = 0.74, 95% CI 0.63-0.87; I² = 50.5%). However, the certainty of the evidence was low because the findings were derived predominantly from observational studies. [CONCLUSIONS] Observational evidence suggests that GLP-1RA use is associated with a lower hazard of AF recurrence following catheter ablation. However, these findings should be interpreted cautiously, and further high-quality randomized controlled trials are required to confirm this association.","url":"https://pubmed.ncbi.nlm.nih.gov/42989385/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: Not applicable, as this study was a systematic review and meta-analysis and did not involve primary data collection from human participants. Consent: Not applicable, as this study was a systematic review and meta-analysis and did not involve primary data collection from human participants. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1436,"doi":"10.1186/s13098-026-02264-3","pmid":"42983568","nct_ids":"[]","title":"Reported cardiovascular events and cardiometabolic risk markers with orforglipron and danuglipron in adults with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized trials","authors":"[\"Zou G\", \"Yang C\", \"Wu Q\", \"Guo M\", \"Liu Y\"]","journal":"Diabetology & metabolic syndrome","publication_date":"2026-08-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND OBJECTIVE] To evaluate the effects of orforglipron and danuglipron on cardiovascular events and cardiometabolic risk markers in patients with type 2 diabetes mellitus (T2DM) and/or obesity. [METHODS] We searched PubMed, Embase, Scopus, Web of Science, the Cochrane Library, and ClinicalTrials.gov through May 5, 2026. Two authors independently performed study selection, data extraction, and quality assessment. Meta-analyses estimated pooled risk ratios (RRs), least-squares mean differences (LSMDs), and 95% confidence intervals (CIs). [RESULTS] Thirteen randomized controlled trials (RCTs) involving 9,076 participants were included. Compared with controls, orforglipron/danuglipron showed no statistically significant difference in extended major adverse cardiovascular events (MACE) (RR = 1.10, 95% CI [0.59 to 2.05], I² = 0.0%, P = 0.760, 6 studies; intervention: 32/4741, control: 13/1928) or myocardial infarction (MI) (RR = 0.54, 95% CI [0.06 to 4.60], I² = 0.0%, P = 0.576, 2 studies; intervention: 2/881, control: 0/156). Extended MACE and MI were mainly derived from adverse event reports. Given sparse, indirect event data and low GRADE certainty, these findings warrant caution. In contrast, orforglipron and danuglipron reduced several cardiometabolic risk markers, including HbA1c (LSMD = - 1.07%, 95% CI [- 1.49 to - 0.64], I² = 99.1%, P < 0.001), fasting plasma glucose (LSMD = - 27.75 mg/dL, 95% CI [- 37.99 to - 17.50], I² = 98.2%, P < 0.001), and body weight (LSMD = - 4.68 kg, 95% CI [- 6.26 to - 3.10], I² = 95.4%, P < 0.001). These estimates showed substantial between-study heterogeneity, warranting cautious interpretation. Current randomized evidence supports changes in cardiometabolic risk markers, but uncertainty remains regarding the effects on hard cardiovascular events. [CONCLUSIONS] Current randomized evidence suggests that orforglipron and danuglipron reduce short- to medium-term cardiometabolic risk markers in patients with T2DM or obesity. However, no significant differences in extended MACE or MI were observed; the point estimates were imprecise, and cardiovascular effects remain unconfirmed. These findings are limited by sparse events, low-certainty evidence, and the lack of dedicated cardiovascular outcome trial (CVOT) designs; therefore, definitive conclusions regarding cardiovascular effects cannot be drawn. [TRIAL REGISTRATION] The study protocol was pre-registered and published on PROSPERO (CRD420251067874; https://www.crd.york.ac.uk/prospero/ ).","url":"https://pubmed.ncbi.nlm.nih.gov/42983568/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: This study used only publicly available aggregate data from published peer-reviewed journal articles and publicly posted trial registry results on ClinicalTrials.gov. No individual participant data and no non-public sponsor-provided data were used; therefore, ethical approval and informed consent were not required. Reporting guideline: This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement (Appendix 1). Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"meta_analysis","drugs":"[\"orforglipron\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":204,"doi":"10.1093/jsxmed/qdag272","pmid":"42704281","nct_ids":"[]","title":"Treatment strategies for functional hypogonadism in obese men: a systematic review and network meta-analysis","authors":"[\"Yang L\", \"He X\", \"Wang S\", \"Li T\", \"Huang W\", \"Feng Q\"]","journal":"The journal of sexual medicine","publication_date":"2026-08-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Obesity-related functional hypogonadism (FH) is a potentially reversible condition associated with sexual dysfunction, metabolic disorders, altered body composition, and impaired quality of life. Although several treatment strategies are available, their comparative benefits and safety remain uncertain. This systematic review and network meta-analysis aimed to characterize their outcome-specific effects and the confidence of the comparative evidence in adult men with obesity-related FH. [METHODS] PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to April 2026 for randomized controlled trials evaluating structured lifestyle therapy (SLT), testosterone replacement therapy (TRT), endogenous testosterone restoration (ETR) therapy, glucagon-like peptide-1 receptor agonist-based therapy, or TRT plus SLT. Frequentist network meta-analyses were performed. Risk of bias was assessed using RoB 2, and confidence in the evidence was evaluated using CINeMA. Sensitivity and direct-evidence analyses were conducted to examine the robustness of the principal findings. [RESULTS] Twenty-three randomized controlled trials involving 1899 participants were included. Compared with usual care/placebo, TRT plus SLT showed the largest estimated increase in total testosterone (MD 7.19, 95% CI, 1.18-13.21), followed by ETR therapy (MD 4.14, 95% CI, 0.74-7.54) and TRT (MD 2.53, 95% CI, 0.26-4.81). Testosterone replacement therapy plus SLT significantly improved International Index of Erectile Function scores (MD 1.29, 95% CI, 0.07-2.50). No intervention significantly reduced glycated hemoglobin compared with usual care/placebo. Testosterone replacement therapy reduced waist circumference and increased lean mass but also increased hematocrit; ETR therapy and TRT plus SLT also increased lean mass. No significant differences in adverse events were detected. Sensitivity and direct-evidence analyses generally supported the direction of the principal findings. [DISCUSSION] Available treatments showed distinct outcome-specific effects, but no single strategy was consistently superior across all outcomes. Confidence in many comparisons was low or very low, and the included trials differed in participant characteristics, treatment protocols, and follow-up duration. These findings should inform individualized treatment decisions rather than a definitive treatment ranking, and require confirmation in longer-term head-to-head trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42704281/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"lean_mass\", \"body_composition\", \"adverse_effects\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1285,"doi":"10.1186/s12872-026-06354-y","pmid":"42958020","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor agonists and the risk of ventricular arrhythmia in patients with acute myocardial infarction and type 2 diabetes mellitus: a propensity score-matched cohort study","authors":"[\"Hu C\", \"Zhao W\", \"Xiao S\", \"Shi J\", \"Liang W\", \"Guo R\"]","journal":"BMC cardiovascular disorders","publication_date":"2026-08-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Ventricular arrhythmia (VA) substantially contributes to sudden cardiac death in patients with acute myocardial infarction (AMI) and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular benefits; however, their influence on post-AMI ventricular arrhythmogenesis remains unclear. [METHODS] This retrospective cohort study included 1,873 patients with concurrent AMI and T2DM admitted between January 2018 and December 2022. Using propensity score matching (1:2, nearest-neighbor), 277 GLP-1RA users were matched with 554 controls. The primary endpoint was incident VA. Cox proportional hazards regression, inverse probability of treatment weighting (IPTW), Firth's penalized likelihood regression, and Fine-Gray competing risk analysis were performed. [RESULTS] Over a median follow-up of 2.5 years, GLP-1RA use was associated with a reduced risk of VA (adjusted HR 0.61, 95% CI 0.37-0.98, P = 0.040), MACE (HR 0.66, 95% CI 0.45-0.96, P = 0.030), cardiovascular death (HR 0.52, 95% CI 0.32-0.86, P = 0.010), and heart failure rehospitalization (HR 0.42, 95% CI 0.26-0.68, P < 0.001). All-cause mortality showed a non-significant trend (HR 0.84, 95% CI 0.59-1.18, P = 0.310). Firth's penalized regression confirmed the primary finding (HR 0.58, 95% CI 0.36-0.95, P = 0.029). The Fine-Gray model yielded a subdistribution HR of 0.63 (95% CI 0.39-1.02, P = 0.058) after accounting for competing mortality risk. The 90-day landmark analysis (HR 0.65, 95% CI 0.39-1.06, P = 0.085) and the time-varying exposure Cox model (HR 0.66, 95% CI 0.40-1.08, P = 0.097) were directionally concordant but did not reach statistical significance. [CONCLUSIONS] GLP-1RA therapy was associated with a lower risk of VA and improved cardiovascular outcomes in patients with AMI and T2DM. Because several sensitivity analyses, including the Fine-Gray competing-risk, landmark, and time-varying models, were borderline non-significant, these findings should be interpreted with caution and regarded as hypothesis-generating, warranting confirmation in prospective randomized trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42958020/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the 922th Hospital of the Joint Logistics Support Force (Approval No.: 2025-23). Due to the retrospective nature of the study and the use of anonymized data, the requirement for informed patient consent was waived by the Ethics Committee. All methods were carried out in accordance with Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:21+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1165,"doi":"10.59556/japi.74.1627","pmid":"42902671","nct_ids":"[]","title":"Real-world Challenges and Predictors of Success in Glucagon-like Peptide-1 Receptor Agonist Therapy","authors":"[\"Patankar NM\", \"Sanghvi SJ\"]","journal":"The Journal of the Association of Physicians of India","publication_date":"2026-08-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have revolutionized the management of type 2 diabetes mellitus (T2DM) and obesity, demonstrating robust efficacy in landmark trials for glycemic control, weight reduction, and cardiovascular protection. However, real-world discontinuation rates exceed trial-reported rates, highlighting a gap between clinical efficacy and practical outcomes. [OBJECTIVE] This review synthesizes evidence from 2018 to 2024, including trial data, population studies, and registry analyses, to identify and contextualize major real-world barriers. High rates of gastrointestinal side effects, substantial out-of-pocket costs, and patient aversion to injectable formulations often result in 1-year discontinuation rates ranging from 27 to 41%. These challenges are compounded by heterogeneity in patient response, with predictors of successful long-term use including higher baseline HbA1c, elevated body mass index (BMI), absence of severe gastrointestinal disorders, and robust early response to therapy. [METHODS] A proposed clinical scoring model is presented to improve patient selection and predict adherence, while digital health tools and emerging combination therapies offer additional avenues to enhance persistence and outcomes. Despite promising advances such as dual- and triple-incretin agents and oral GLP-1 RA formulations, cost and access remain major hurdles. [RESULTS] Key factors, including baseline HbA1c >8.0%, BMI >30 kg/m2, absence of severe gastrointestinal (GI) disorders, and prior adherence success, correlate strongly with higher persistence. Real-world data reveal that discontinuation rates for GLP-1 receptor agonists remain high, with 1-year discontinuation ranging from approximately 28% to around 41%, depending on the patient population and indication. Discontinuation is more common among patients using GLP-1 RAs for obesity without diabetes, reaching rates above 50% in some cohorts. The primary reasons for stopping therapy include gastrointestinal side effects, reported in over 25% of discontinuations, high medication costs, and issues with insurance coverage or medication access. Persistence is generally higher among patients with T2DM, those with higher baseline BMI, and those who experience greater early weight loss or favorable tolerability, while frequent adverse effects and logistical barriers contribute to poorer long-term adherence. Although emerging clinical tools and digital health interventions are proposed to help address these barriers, further prospective data are needed to quantify their impact on persistence at scale. [CONCLUSION] Bridging trial evidence with real-world practice requires proactive candidate profiling and side-effect management. Combining predictive scoring, artificial intelligence (AI)-supported adherence tools, and emerging dual-incretin agents may transform GLP-1 RA therapy from short-term use to durable metabolic benefit.","url":"https://pubmed.ncbi.nlm.nih.gov/42902671/","source_name":"pubmed","source_tier":1,"coi_statement":"None","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:07+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":49,"doi":"10.1111/acel.70676","pmid":"42608657","nct_ids":"[]","title":"The GLP-1-Mitochondria Axis in Metabolic Aging","authors":"[\"Chang R\", \"Tsai AP\", \"Wang B\", \"Li CJ\"]","journal":"Aging cell","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Metabolic aging underlies a cluster of chronic conditions-type 2 diabetes, cardiovascular disease, sarcopenia, and neurodegeneration-that account for a substantial share of global morbidity and mortality. A common feature is progressive mitochondrial dysfunction: impaired bioenergetics, disrupted quality control, and loss of metabolic resilience. Reduced mitochondrial DNA copy number in peripheral blood leukocytes is associated with cardiometabolic disease and mortality, but pre-analytical variability, dependence on blood-cell composition, and uncertain relationship to tissue-level function mean it should be regarded as a candidate risk-associated biomarker rather than a validated measure of mitochondrial integrity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control, engage pathways implicated in mitochondrial biogenesis, dynamics, and mitophagy; whether these effects reflect direct receptor signaling, indirect consequences of weight loss, or secondary mediators such as interleukin-6 remains debated and appears tissue-dependent. In SELECT, semaglutide reduced major adverse cardiovascular events by 20% in obesity without diabetes, and a 2025 multi-omic study in aged male mice found GLP-1 RA treatment attenuated age-associated molecular signatures despite only modest changes in food intake and body weight. No trial, however, has incorporated a prespecified mitochondrial endpoint, human mechanistic evidence remains limited, and access to these therapies remains uneven worldwide. Here we synthesize mechanistic, preclinical, and clinical evidence for a proposed GLP-1-mitochondria axis, classify this evidence by receptor dependence and translational stage, distinguish disease-specific treatment effects from evidence for aging modification, examine four major controversies, and outline a research and policy agenda for responsible, evidence-graded development of GLP-1-based geroscience interventions.","url":"https://pubmed.ncbi.nlm.nih.gov/42608657/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"mechanistic_review","drugs":"[\"class_unspecified\", \"semaglutide\"]","drug_details":"{}","domains":"[\"aging\", \"inflammation\", \"neuroinflammation\", \"muscle\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"Mechanistic synthesis; cites aged-mouse data and human disease trials; no human aging endpoint exists.","mediation":"not_applicable","mediation_notes":"The review itself states that whether mitochondrial effects are direct receptor effects or consequences of weight loss remains debated.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Mechanistic review\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Review; explicitly notes no trial has a prespecified mitochondrial endpoint and human mechanistic evidence is limited.","funding_source":"National Science and Technology Council (Taiwan); Kaohsiung Veterans General Hospital","industry_funded":"no","manufacturer":null,"author_conflicts":"Authors declare no conflicts.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A review proposing a GLP-1-mitochondria axis in metabolic aging. Usefully candid: it distinguishes disease-specific treatment effects from aging modification, notes that weight-loss-independence is unproven, and that no trial has included a prespecified mitochondrial endpoint and human mechanistic evidence remains limited.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":118,"doi":"10.7759/cureus.114454","pmid":"42732434","nct_ids":"[]","title":"Comparative Efficacy and Safety of Tirzepatide Versus Semaglutide for Obesity: A Systematic Review","authors":"[\"Mohamed Abdalla SA\", \"Gharbawi L\", \"Elshaikh N\", \"Elfaki Omer EO\", \"Osman AFM\", \"Hassan Ali AS\", \"Yousif Mohamed TM\", \"Alhajri AHM\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 receptor agonist, are the two most effective approved injectable pharmacotherapies for obesity. Until recently, comparisons between them rested largely on cross-trial inference. A direct head-to-head randomised trial and a rapidly expanding body of comparative real-world evidence now permit a formal appraisal. This objectives of this review are to systematically identify, appraise, and synthesise original comparative studies evaluating the efficacy and safety of tirzepatide versus semaglutide in adults with overweight or obesity. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched up to 20 July 2026, with backward and forward citation tracking. Eligible studies were peer-reviewed original randomised or non-randomised comparative studies directly comparing subcutaneous tirzepatide with subcutaneous semaglutide in adults with overweight or obesity and reporting at least one anthropometric outcome; non-original publications were excluded. Risk of bias was assessed with RoB 2 and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I). Substantial heterogeneity precluded meta-analysis, and findings were synthesised narratively. Of 535 records identified, 11 studies comprising approximately 62,700 analysed participants were included: one phase 3b open-label randomised active-controlled trial and 10 retrospective observational cohorts from the United States, Kuwait, Turkiye, Bangladesh, and an international federated network. Tirzepatide produced greater weight reduction than semaglutide in every study that formally tested the comparison. In the randomised trial, mean weight change at 72 weeks was -20.2% with tirzepatide versus -13.7% with semaglutide. In real-world cohorts, adjusted between-group differences ranged from approximately 2.3 to 4.4 percentage points, and the advantage was most pronounced at stringent weight-reduction thresholds. Tirzepatide was also associated with greater improvements in blood pressure and glycated haemoglobin and a lower incidence of new-onset type 2 diabetes. Gastrointestinal events predominated with both agents. The randomised trial and six cohorts were judged at low risk of bias, and four cohorts at serious risk, principally from unadjusted confounding. Tirzepatide achieves greater weight reduction than semaglutide in adults with overweight or obesity, with a broadly comparable short-term safety profile. The advantage is attenuated in routine care relative to the trial setting, and long-term head-to-head data on cardiovascular and other clinical endpoints remain absent.","url":"https://pubmed.ncbi.nlm.nih.gov/42732434/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":123,"doi":"10.7759/cureus.114404","pmid":"42729808","nct_ids":"[]","title":"Diabetes, Adiposity, and Functional Phenotypes in HFpEF: A Systematic Review of Recent Treatment-Response Evidence","authors":"[\"Goshe M\", \"Singh S\", \"Zameer R\", \"Ali J\", \"Kumari N\", \"Das M\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Heart failure with preserved ejection fraction (HFpEF) is increasingly understood as a heterogeneous syndrome in which cardiometabolic and functional phenotypes may influence treatment response beyond ejection fraction alone. This systematic review synthesized recent clinical and trial-derived evidence published from June 2025 to May 2026 evaluating cardiometabolic phenotypes and therapeutic response in adults with HFpEF or closely related heart failure with mildly reduced or preserved ejection fraction populations. PubMed/MEDLINE, Scopus, and Web of Science were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 principles using terms related to HFpEF, diabetes, obesity, adiposity, frailty, exercise function, sodium-glucose cotransporter 2 inhibitors, incretin-based therapies, and treatment outcomes. Six studies met the eligibility criteria, including randomized trials, prespecified secondary analyses, pooled participant-level analyses, stratification-based analyses, and randomized crossover trial evidence. The included studies evaluated tirzepatide, semaglutide, dapagliflozin, and dapagliflozin plus spironolactone across phenotypes including type 2 diabetes, body mass index (BMI), central adiposity, achieved weight loss, epicardial or paracardiac fat, exercise limitation, frailty, and renal-electrolyte profile. Overall, contemporary cardiometabolic therapies were associated with improvements in heart failure outcomes, patient-reported health status, exercise capacity, body weight, natriuretic peptides, adiposity measures, cardiac remodeling markers, and frailty burden. Diabetes did not appear to uniformly attenuate heart failure benefit despite less weight loss, while adiposity distribution, functional limitation, frailty, and local cardiac fat may represent clinically relevant, hypothesis-generating domains for interpreting treatment response. Sodium-glucose cotransporter 2 inhibitor-based therapy also showed potential cardiometabolic, renal, hemodynamic, and structural effects, although combination therapy required careful renal and potassium monitoring. These findings suggest the potential value of a phenotype-informed framework for evaluating cardiometabolic treatment response in HFpEF; however, they are insufficient to support phenotype-guided treatment selection because the evidence was derived predominantly from secondary, pooled, or subgroup analyses rather than prospective phenotype-guided trials. Prospective studies are needed to determine whether integrating diabetes status, adiposity distribution, exercise capacity, frailty, renal profile, and imaging-based fat depots can improve treatment selection beyond ejection fraction and body mass index alone.","url":"https://pubmed.ncbi.nlm.nih.gov/42729808/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"body_composition\", \"aging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":128,"doi":"10.7759/cureus.114350","pmid":"42725235","nct_ids":"[]","title":"Neuropsychiatric Effects of Glucagon-Like Peptide-1 Receptor Agonists in Schizophrenia-Spectrum Disorders: A Systematic Review","authors":"[\"Alsanosi ZY\", \"Alshahrani AS\", \"Nammazi AA\", \"Alsunusi OA\", \"Moafa AA\", \"Hadi IH\", \"Alabdali AA\", \"Alhaqbani AW\", \"Shahat RA\", \"Albeladi SA\", \"Almajdoa AA\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"People with schizophrenia-spectrum disorders die 15-20 years prematurely, predominantly from cardiovascular disease, and antipsychotic-induced weight gain is a major, partly iatrogenic contributor to this excess mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are potent weight-lowering agents that are increasingly used as metabolic adjuncts in this population, and preclinical evidence has suggested that they may also exert central, potentially pro-cognitive effects. However, their effects on psychiatric symptoms, cognition, and quality of life have not previously been systematically synthesized. We therefore conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Four databases (MEDLINE/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science) were searched on 20 July 2026 for randomized controlled trials (RCTs) comparing any GLP-1RA with placebo, usual care, or an active comparator, added to antipsychotic treatment, in adults with schizophrenia-spectrum disorders. The primary outcome was psychiatric symptom severity, while secondary outcomes were cognition and quality of life or functioning. Reports were de-duplicated at the trial level using trial registration records, and risk of bias was assessed for each outcome domain using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2). Because outcome measures were heterogeneous and variance data were largely unavailable, meta-analysis was not feasible, and findings were synthesized narratively according to the direction of effect. Eight reports representing four RCTs evaluating exenatide, liraglutide, and semaglutide (333 participants randomized) were included. No trial demonstrated a statistically significant effect on psychiatric symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, or the six-item Positive and Negative Syndrome Scale (PANSS-6). Likewise, neither of the two trials that assessed cognition, including one in which cognitive performance was the primary outcome, demonstrated a pro-cognitive effect. Quality-of-life outcomes were also largely unchanged, except for improved physical quality of life in the largest trial (36-Item Short Form Health Survey version 2 (SF-36v2) Physical Component Summary: +3.75, 95% confidence interval (CI) 1.52 to 5.98; P = .001), which a companion mediation analysis indicated was largely attributable to weight loss. Mental quality of life and functioning showed no significant improvements. Most outcome-domain assessments were judged to have some concerns regarding risk of bias, with none rated as high risk, and the certainty of the evidence was low to moderate. Overall, in adults with schizophrenia-spectrum disorders receiving antipsychotic treatment, GLP-1RAs showed no evidence of benefit or harm for psychiatric symptoms or cognition. Improvements in quality of life were limited to physical health and appeared to be mediated by weight loss rather than direct psychotropic effects. These findings support the role of GLP-1RAs as cardiometabolic therapies in this population, with no signal of psychiatric destabilization. Larger, adequately powered RCTs with neuropsychiatric primary outcomes, longer follow-up, harmonized outcome measures, and complete reporting of variance data are needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42725235/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"exenatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cognition\", \"mortality\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":169,"doi":"10.7759/cureus.113777","pmid":"42677221","nct_ids":"[]","title":"Incretin-Based Therapies Versus Bariatric and Metabolic Surgery for Obesity and Type 2 Diabetes Mellitus: A Head-to-Head Systematic Review of Glycaemic, Cardiovascular, Hepatic, Weight, and Quality-of-Life Outcomes","authors":"[\"Alsayed O\", \"Jarai MZ\", \"Khan S\", \"Sandal M\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 co-agonist tirzepatide have transformed non-surgical management of obesity and type 2 diabetes mellitus (T2DM), producing unprecedented pharmacological weight loss and cardiovascular mortality benefit. Bariatric and metabolic surgery (BMS) remains the most effective intervention for sustained weight reduction and T2DM remission. A systematic outcome-by-outcome comparison of these paradigms has not previously been synthesised. We conducted a PRISMA 2020-compliant systematic review of randomised controlled trials (RCTs) and high-quality matched observational studies (January 2014-April 2026) comparing incretin-based therapies with BMS in adults with obesity and T2DM. Primary outcomes were T2DM remission, weight reduction, major adverse cardiovascular events (MACE) and all-cause mortality, non-alcoholic steatohepatitis (NASH) resolution, and quality of life (QoL). Secondary outcomes included HbA1c, lipids, blood pressure, renal endpoints, and safety. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) and Newcastle-Ottawa Scale; certainty was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Fourteen studies met inclusion criteria (eight RCTs, six matched cohorts; N=25,566). BMS achieved superior T2DM remission (23-70% vs. 0%), greater sustained five-year weight loss (25-32% vs. 14.9-20.9% with semaglutide/tirzepatide, with significant pharmacological weight regain upon discontinuation), and lower MACE risk (pooled RR 0.48, 95% CI 0.33-0.72 vs. GLP-1 RAs; P<0.001). BMS was also superior for NASH histological resolution (56-70% vs. 59% with semaglutide) and QoL. Incretin therapies produced clinically meaningful cardiometabolic improvements with favourable safety profiles dominated by transient gastrointestinal events. Tirzepatide 15 mg approached but did not match sleeve gastrectomy weight-loss benchmarks at 72 weeks. BMS demonstrates superiority across all five primary outcome domains in patients with obesity and established T2DM. Incretin therapies remain essential for those who decline, defer, or are contraindicated for surgery. Complementary and sequential use - incretins as a bridge to or adjunct following surgery - warrants prospective evaluation. Guidelines should position BMS as a first-line option in appropriate candidates.","url":"https://pubmed.ncbi.nlm.nih.gov/42677221/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"addiction\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":251,"doi":"10.7759/cureus.113910","pmid":"42694337","nct_ids":"[]","title":"Suspected Biphasic Anaphylaxis Following the First Known Dose of Tirzepatide: A Case Report and Brief Review of Reported Hypersensitivity Reactions","authors":"[\"Al-Rashid AH\", \"Ali F\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist increasingly used for type 2 diabetes mellitus and chronic weight management. Although generally well tolerated, serious systemic hypersensitivity reactions may occur. We report a 37-year-old woman who developed anaphylaxis shortly after administering her first known subcutaneous dose of tirzepatide. She presented with facial and periorbital angioedema, nasal congestion, generalized urticaria, bronchospasm, hypoxemia, and hypotension. She was treated with intravenous fluids, nebulized bronchodilators, and two doses of intramuscular epinephrine, resulting in complete clinical resolution. Approximately one hour later, she developed recurrent generalized urticaria, facial angioedema, and chest tightness without further exposure to the suspected trigger. Although no objective respiratory or hemodynamic compromise was documented during the recurrent episode, the recurrence was considered suggestive of a possible biphasic reaction. Her symptoms resolved following treatment with intravenous hydrocortisone and chlorphenamine. Acute and baseline serum tryptase levels were unavailable, and validated allergy testing for tirzepatide was not performed; therefore, the underlying immunological mechanism could not be established. This case highlights the importance of early recognition and prompt treatment of tirzepatide-associated anaphylaxis, as well as continued pharmacovigilance and detailed reporting of severe hypersensitivity reactions.","url":"https://pubmed.ncbi.nlm.nih.gov/42694337/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"pharmacovigilance","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cognition\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":334,"doi":"10.1111/dom.70966","pmid":"42236268","nct_ids":"[]","title":"Short-Term Combined Treatment With Tirzepatide and Metformin for Overweight/Obese Chinese Women With Polycystic Ovary Syndrome: A Prospective, Open-Label, Randomised Controlled Trial","authors":"[\"Yang Z\", \"Xu Y\", \"Du H\", \"Liu W\", \"Chen H\", \"Liu D\", \"Zhang L\", \"Wang C\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] This study aimed to assess the effects of low-dose tirzepatide combined with metformin (COM) versus metformin (MET) monotherapy in overweight/obese women with polycystic ovary syndrome (PCOS). [MATERIALS AND METHODS] Sixty overweight/obese women with PCOS were randomised to the MET group (1000 mg twice daily [BID]) or the COM group (MET: 1000 mg BID, tirzepatide: 5 mg once weekly [QW]) for 16 weeks. The primary outcome was the change in body weight. Secondary outcomes included changes in anthropometric measures other than body weight, body composition, reproductive hormone levels, metabolic and endocrine parameters, inflammatory markers and menstrual cycle regularity. All outcomes were assessed at baseline and week 16. After week 16, participants were switched to MET monotherapy. Barrier contraception was required for 8 weeks and pregnancy outcomes were subsequently evaluated between weeks 25 and 48. [RESULTS] After 16 weeks of treatment, compared with the MET group, the COM group resulted in greater reductions in weight (-1.7 ± 2.5 kg vs. -10.4 ± 3.5 kg; p < 0.001), body mass index (BMI) (-0.68 ± 1.82 vs. -4.12 ± 1.37 kg/m2; p < 0.001), visceral adipose tissue (VAT) (-4.67 ± 9.59 vs. -34.13 ± 15.33 cm2; p < 0.001) and reproductive endocrine-metabolic parameters. Menstrual cycle recovery and total pregnancy rate were higher in the COM group than in the MET group (p = 0.013 and p = 0.014, respectively). [CONCLUSIONS] In overweight/obese women with PCOS, low-dose tirzepatide combined with MET was associated with greater reductions in body weight and visceral fat, along with improvements in metabolic and reproductive outcomes compared with MET monotherapy. [TRIAL REGISTRATION] ChiCTR2400090908; chictr.org.cn.","url":"https://pubmed.ncbi.nlm.nih.gov/42236268/","source_name":"pubmed","source_tier":1,"coi_statement":"Any opinions or recommendations discussed are solely those of the author(s). The authors declare no conflicts of interest.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":344,"doi":"10.1016/j.carrev.2026.03.011","pmid":"42000295","nct_ids":"[]","title":"Tirzepatide therapy reduces subclinical leaflet thrombosis and paravalvular leak after transcatheter aortic valve replacement in obese patients: The TAVR-MET trial","authors":"[\"Thirugnanam AM\", \"Chandrakanth\", \"Pruthvi\"]","journal":"Cardiovascular revascularization medicine : including molecular interventions","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is increasingly recognized as a critical modifier of outcomes following transcatheter aortic valve replacement (TAVR), predisposing patients to subclinical leaflet thrombosis (SLT), hypo-attenuated leaflet thickening (HALT), and paravalvular leak (PVL). Metabolic inflammation, endothelial dysfunction, and pro-thrombotic states associated with obesity contribute to impaired bioprosthetic valve healing. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated robust metabolic, anti-inflammatory, and vascular protective effects. However, its impact on post-TAVR valve performance has not been previously evaluated. [OBJECTIVES] To determine whether tirzepatide therapy initiated before TAVR and continued post-procedure reduces the incidence of HALT and PVL in obese patients undergoing TAVR. [METHODS] TAVR-MET was a prospective, randomized, open-label, multicenter trial enrolling obese patients (BMI ≥ 30 kg/m2) undergoing transfemoral TAVR. Patients were randomized to tirzepatide therapy or standard care. The primary endpoint was HALT incidence at 6 months assessed by 4D-CT or transesophageal echocardiography (TEE). Secondary endpoints included PVL severity, major adverse valve events (MAVE), inflammatory biomarker changes, weight reduction, and bleeding outcomes. [RESULTS] Among 260 randomized patients, tirzepatide therapy significantly reduced HALT incidence (8.4% vs 21.6%, p = 0.002) and ≥ mild PVL (10.7% vs 25.3%, p = 0.006) at 6 months. Tirzepatide was associated with marked reductions in CRP and body weight without an increase in major bleeding. Multivariable analysis identified tirzepatide use, CRP reduction >30%, and BMI <32 kg/m2 at follow-up as independent predictors of HALT absence. [CONCLUSIONS] Metabolic modulation with tirzepatide significantly improves post-TAVR valve healing and hemodynamics in obese patients. These findings introduce a novel cardio-metabolic strategy to reduce structural valve complications following TAVR. [TRIAL SUMMARY] TAVR-MET STUDY: The TAVR-MET trial was a prospective, randomized, multicenter study designed to evaluate whether metabolic modulation with tirzepatide, a dual GIP/GLP-1 receptor agonist, could improve bioprosthetic valve outcomes following transcatheter aortic valve replacement (TAVR) in obese patients. Obesity is increasingly recognized as a key determinant of post-TAVR complications, particularly subclinical leaflet thrombosis (HALT) and paravalvular leak (PVL), driven by chronic inflammation, endothelial dysfunction, and a prothrombotic state. Tirzepatide has demonstrated potent weight-reducing, anti-inflammatory, and vascular protective effects, but its role in structural valve outcomes had not previously been explored. The trial enrolled 260 obese patients (BMI ≥ 30 kg/m2) undergoing transfemoral TAVR across eight high-volume centers. Participants were randomized to receive tirzepatide initiated four weeks before TAVR and continued for 12 months, or standard care alone. All patients received guideline-directed antithrombotic therapy. The primary endpoint was the incidence of HALT at six months assessed by advanced imaging. Secondary endpoints included PVL severity, major adverse valve events, inflammatory biomarker changes, weight reduction, and bleeding outcomes. At six months, tirzepatide therapy was associated with a significant reduction in HALT compared with standard care, as well as a marked decrease in ≥ mild paravalvular leak. These structural valve improvements were accompanied by substantial weight loss and significant reductions in systemic inflammatory markers, without an increase in major bleeding or adverse safety signals. Multivariable analysis confirmed tirzepatide use and inflammation reduction as independent predictors of improved valve outcomes. In conclusion, the TAVR-MET trial provides the first clinical evidence that targeted metabolic therapy can favorably influence bioprosthetic valve healing after TAVR. These findings support a novel cardio-metabolic strategy for improving post-TAVR outcomes in obese patients and highlight the importance of addressing metabolic inflammation alongside procedural excellence in contemporary structural heart interventions.","url":"https://pubmed.ncbi.nlm.nih.gov/42000295/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No external funding, grants, or material support were received from pharmaceutical or medical device companies for the conduct of this study.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":644,"doi":"10.7759/cureus.114569","pmid":"42741750","nct_ids":"[]","title":"Investigating the Association Between Semaglutide Use and Mood Disorders in Polyendocrine Metabolic Ovarian Syndrome: A Retrospective Cohort Study​","authors":"[\"Raj FP\", \"Boo H\", \"Kenney A\", \"Espiridion E\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This retrospective cohort study aims to evaluate whether semaglutide use in patients with polyendocrine metabolic ovarian syndrome (PMOS) is associated with an increased risk of mood disorders compared to patients treated with metformin by utilizing a large, propensity-matched dataset from TriNetX. [METHODOLOGY] The TriNetX platform was used to conduct a retrospective cohort study with International Classification of Diseases, 10th Revision (ICD-10) codes to generate inclusion and exclusion criteria. After propensity matching, each cohort consisted of 20,535 patients, for a total sample size of 41,070. Cohort 1 (patients with PMOS and on metformin) and Cohort 2 (patients with PMOS and on semaglutide) were evaluated for outcomes of new-onset major depressive disorder, generalized anxiety disorder, insomnia, and suicidal ideation that emerged after the start of the medication of interest. [RESULTS] There was no statistically significant difference in generalized anxiety disorder and suicidal ideation associated with semaglutide use as compared to metformin in women with PMOS. However, there was a minor statistically significant difference in the rates of insomnia and major depressive disorder. [CONCLUSIONS] These results suggest that psychiatric considerations alone should not preclude the use of semaglutide in PMOS management. Ongoing mental health screening and follow-up remain essential for all patients with PMOS, regardless of treatment choice.","url":"https://pubmed.ncbi.nlm.nih.gov/42741750/","source_name":"pubmed","source_tier":1,"coi_statement":"Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:28+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"sleep\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":736,"doi":"10.7759/cureus.114962","pmid":"42769739","nct_ids":"[]","title":"Long-Term Clinical Outcomes and Real-World Effectiveness of Tirzepatide in Adults With Overweight or Obesity: A Systematic Review","authors":"[\"Olaniyi AO\", \"Gogineni KK\", \"Olaniyi H\", \"Sabir H\", \"Agbonrofo Eboigbe G\", \"Yerima SR\", \"Gabriels N\"]","journal":"Cureus","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity is a chronic, progressive, and relapsing disease associated with substantial morbidity, premature mortality, and increased healthcare utilisation. Although lifestyle modification remains the cornerstone of management, long-term weight-loss maintenance is challenging. Tirzepatide, a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial weight-loss efficacy, but its long-term clinical outcomes have not been comprehensively synthesised. A systematic search of Ovid MEDLINE ALL, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was conducted from database inception to June 30, 2026. Eligible studies included Phase III randomised controlled trials, randomised withdrawal trials, long-term extension studies, prespecified secondary analyses reporting unique outcomes, and real-world observational studies. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Cochrane Risk of Bias 2 (RoB 2) and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools. Owing to substantial clinical and methodological heterogeneity, findings were synthesised narratively in accordance with the Synthesis Without Meta-analysis (SWiM) guidelines. Twenty-six publications representing 11 independent parent studies met the inclusion criteria, comprising eight Phase III randomised controlled trials, one long-term extension study, two real-world observational cohort studies, and 15 prespecified secondary analyses. Tirzepatide consistently produced substantial, dose-dependent, and durable weight reduction, with mean weight loss approaching 21% after 72 weeks. Continued therapy maintained weight loss, whereas treatment discontinuation resulted in progressive weight regain. Tirzepatide also improved cardiometabolic risk factors, body composition, physical functioning, and health-related quality of life. Gastrointestinal adverse events were the most common and were generally mild to moderate. Real-world studies demonstrated effectiveness and safety comparable to those observed in randomised clinical trials. Current evidence indicates that tirzepatide provides durable weight reduction and broad cardiometabolic benefits in adults with overweight or obesity. Sustained treatment is important for maintaining these benefits, while additional long-term studies are needed to evaluate treatment persistence, cardiovascular outcomes, comparative effectiveness, and long-term safety across diverse populations.","url":"https://pubmed.ncbi.nlm.nih.gov/42769739/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:11+00:00","study_design":"systematic_review","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"body_composition\", \"mortality\", \"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":853,"doi":"10.15605/jafes.041.02.6171","pmid":"42802824","nct_ids":"[]","title":"Dapagliflozin Alone or Combined With Semaglutide: Cardiovascular and Renal Outcomes Among Patients With Type 2 Diabetes Mellitus in a 6-Month Real-World Retrospective Cohort Study in Saudi Arabia","authors":"[\"Alharajin R\", \"AlTaweel M\", \"AlSubaiee M\", \"Al Makhloof S\", \"Almusaad A\", \"Alarfaj A\", \"AlKhayyal A\", \"Altharman N\", \"Alalawi A\", \"Almannai N\", \"Alohaymid M\", \"Alsaad A\", \"Alotaibi T\", \"Alkhaldi R\", \"Almoaibed G\", \"Alrashada J\", \"Alarfaj A\", \"Alqarni T\", \"Alshahrani A\", \"Aldossary I\", \"Khashwayn S\", \"Al Qarni A\", \"Taleb Y\", \"Alshaikh Husain M\"]","journal":"Journal of the ASEAN Federation of Endocrine Societies","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Type 2 diabetes mellitus (T2DM) is a growing global health concern linked to increased cardiovascular and renal complications. Two emerging therapeutic classes, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon like peptide-1 receptor agonists (GLP-1 RAs), have shown independent cardiometabolic benefits. However, limited realworld data exist on the comparative impact of combining these therapies versus using SGLT2i alone. [OBJECTIVE] To compare the cardiovascular and renal outcomes of dapagliflozin monotherapy versus combination therapy with once-weekly injectable semaglutide among patients with type 2 diabetes mellitus (T2DM). [METHODOLOGY] In this retrospective cohort study, 539 adult patients with confirmed type 2 diabetes mellitus (T2DM; baseline HbA1c ≥6.5%) treated at King Abdulaziz Hospital, Al-Ahsa, were followed over six months. Patients received either dapagliflozin alone or in combination with semaglutide. Generalized Estimating Equations (GEE) were used to assess changes in glycemic control, cardiovascular events, lipid profile, and renal function, adjusting for time and sex. [RESULTS] Both groups showed significant metabolic improvements over six months. Dapagliflozin monotherapy was associated with greater HbA1c reduction. Combination therapy was associated with higher HDL levels, improved eGFR, and a lower relative risk of heart failure (RR = 0.43, p = 0.04); the reduction in myocardial infarction risk (RR = 0.61, p = 0.13) did not reach statistical significance. No significant difference was observed in stroke risk. Most cardiovascular and renal markers improved modestly. [CONCLUSION] Combination therapy was associated with favorable renal outcomes and a reduction in heart failure risk, despite inferior glycemic control and a non-significant trend toward reduced myocardial infarction risk. These findings suggest potential complementary effects of SGLT2i and GLP-1 RA treatment in high-risk patients. However, due to the retrospective, non-randomized design, causal relationships cannot be inferred, and residual confounding may exist. Prospective trials are warranted to confirm these associations and guide treatment optimization.","url":"https://pubmed.ncbi.nlm.nih.gov/42802824/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declared no conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:20+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1184,"doi":"10.4067/s0034-98872026000801150","pmid":"42899606","nct_ids":"[]","title":"Effectiveness of Weekly Semaglutide Treatment (0.5 or 1 mg) in Chilean Patients with Type 2 Diabetes Mellitus","authors":"[\"Estica M\", \"Godoy G\", \"Vargas C\", \"Elgueta K\", \"Gattini F\", \"Gutiérrez V\", \"Salort P\"]","journal":"Revista medica de Chile","publication_date":"2026-08","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[UNLABELLED] Semaglutide is approved in Chile for the management of type 2 diabetes mellitus (T2DM), although it is generally not available in the public health system. Generating local evidence may aid in its incorporation into national guidelines and reduce the therapeutic gap with international standards. [AIM] To evaluate the effectiveness and safety of adding weekly semaglutide to the standard treatment for T2DM in the public health system. [METHODS] A phase 4, multicenter, interventional study evaluated the weekly addition of 0.5 or 1 mg of subcutaneous semaglutide over 24 weeks, followed by a 5-week post-treatment monitoring period. [RESULTS] n=104 (79.8% women; age: 58.3±9.3 years; 44.2% over 60 years of age; 35.6% with ≥1 complication of T2DM). Common comorbidities: hypertension: 71.2%; obesity: 71.2%; dyslipidemia: 51.9%. Most commonly used baseline treatments: metformin, 96.2%; NPH insulin, 65.4%; empagliflozin, 46.2%; regular insulin, 27.9%; insulin glargine, 22.1%; dapagliflozin, 21.2%. At 24 weeks, a reduction in glycosylated hemoglobin (HbA1c: 8.6±0.7% to 7±1%, difference: -1.6%), fasting blood glucose (160.3±49.3 to 133.7±54.8 mg/dL, difference: -26.2 mg/dL), and weight (89.3±20.2 to 85.3±20.4 kg; difference: -4 kg) were confirmed. Participants with HbA1c <7% increased from 0% to 56.4%. Thirty-one percent of patients receiving basal insulin reduced their dose (median: 6 IU). Gastrointestinal adverse events were the most frequent, consistent with the drug's safety profile. [CONCLUSIONS] In people with inadequately controlled T2DM in the real world, the addition of a weekly dose of semaglutide was associated with improvement in HbA1c, fasting blood glucose, and weight, and a reduction in insulin dose, with an adequate safety profile. These results provide local evidence on the efficacy of semaglutide in improving various cardio-renal-metabolic risk factors in people with T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/42899606/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"clinical_trial","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1366,"doi":"10.1186/s12872-026-06387-3","pmid":"42947001","nct_ids":"[]","title":"Comparison of cardiac adverse event signal profiles for GLP-1 receptor agonists: an analysis of the FAERS database","authors":"[\"Yildirim BO\", \"Sarkim IF\", \"Yalman G\", \"Arslantas B\", \"Celik CB\", \"Yildirim S\"]","journal":"BMC cardiovascular disorders","publication_date":"2026-07-31","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes owing to their effectiveness in glycemic control and weight reduction. Given the increasing use of GLP-1RAs, further research is warranted to better understand their cardiac effects. [METHODS] Individual Case Safety Reports from the U. S. Food and Drug Administration Adverse Event Reporting System database from July 6, 2007, to February 17, 2026, were evaluated for the post-marketing cardiac adverse events associated with dulaglutide, liraglutide, semaglutide, and tirzepatide. To detect signal differences among drugs, disproportionality analysis was conducted using the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) methods, along with standard statistical tests to evaluate categorical variables and to estimate odds ratios. [RESULTS] A total of 7,023 cardiac adverse events were identified among 305,877 reports. GLP-1RAs were associated with a higher reporting frequency of tachyarrhythmias than bradyarrhythmias. In the 65-85-year age group, an increase in the signal for cardiac events was observed. Pairwise post hoc comparisons demonstrated no statistically significant differences in reporting frequency of cardiac events between semaglutide and liraglutide, whereas all other drug pairs demonstrated statistically significant differences. [CONCLUSION] Semaglutide and liraglutide had higher relative reporting of cardiac events whereas tirzepatide had lower PRR and ROR values against the total background of reports. These findings suggest a lower reporting tendency of cardiac events for tirzepatide. This study may assist healthcare professionals in recognizing the frequency of cardiac events associated with GLP-1RA use and drive new hypotheses to clarify underlying mechanisms.","url":"https://pubmed.ncbi.nlm.nih.gov/42947001/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: As this observational study used publicly available anonymized data from the FDA Adverse Event Monitoring System (AEMS) [formerly the FDA Adverse Event Reporting System (FAERS)] database, institutional ethical approval is not required. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:50+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":173,"doi":"10.1038/s41467-026-76083-5","pmid":"42669711","nct_ids":"[]","title":"Cardiovascular outcome of glucagon-like peptide-1 receptor agonists vs dipeptidyl peptidase-4 inhibitor on end-stage kidney disease patients with heart failure: an emulated target trial in patients with diabetes","authors":"[\"Liu PY\", \"Shih CK\", \"Hsieh MH\", \"Lin CC\", \"Liu CY\", \"Lai EC\", \"Li CY\", \"Yu CH\", \"Sung JM\"]","journal":"Nature communications","publication_date":"2026-07-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Patients with end-stage kidney disease (ESKD) receiving maintenance dialysis have a high burden of heart failure (HF), with cardiovascular disease the leading cause of death, yet are largely excluded from randomized trials. Using the TriNetX federated electronic health record network, we emulate a target trial comparing initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in diabetic ESKD patients with HF, undergoing maintenance dialysis. We identify a primary ESKD-HF population and a confirmatory dialysis-dependence-coded HF subset, and apply a new-user, active-comparator design and use propensity score matching to balance baseline characteristics. In the primary ESKD-HF population, GLP-1RAs use is associated with a lower risk of the primary composite ischemic cardiovascular events plus HF exacerbations, than DPP-4i initiation (31.7% vs. 41.4%; HR 0.72[0.64-0.82], P < 0.0001), with concordance reductions in ischemic events (HR 0.74), HF exacerbations (HR 0.76), all-cause mortality (HR 0.68), and a death-inclusive composite (HR 0.72). Results are consistent in multivariable models, across prespecified subgroups, and in extensive sensitivity analyses, and are corroborated in the confirmatory dialysis-dependence-coded HF subset HR (0.71[0.60-0.85]). These findings provide real-world evidence suggesting GLP-1RAs may improve cardiovascular outcomes in dialysis-dependent diabetic ESKD with HF and support prospective randomized evaluation.","url":"https://pubmed.ncbi.nlm.nih.gov/42669711/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":291,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Ozempic (SEMAGLUTIDE) - label effective 2026-07-30","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-07-30","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including OZEMPIC. Discontinue if pancreatitis is suspected. ( 5.2 ) • Diabetic Retinopathy Complications: Has been reported in a clinical trial. Patients with a history of diabetic retinopathy should be monitored. ( 5.3 ) • Never share an OZEMPIC pen between patients , even if the needle is changed. ( 5.4 ) • Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary. ( 5.5 ) • Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.6 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. OZEMPIC is not recommended in patients with severe gastroparesis. ( 5.7 ) • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue OZEMPIC if suspected and promptly seek medical advice. ( 5.8 ) • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.9 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 ) 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether OZEMPIC causes thyroid C-cell tumors, including MTC, in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC. Such monitoring may increase the risk of unnecessary procedures, due to the low-test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including OZEMPIC [see Adverse Reactions ( 6 )]. After initiation of OZEMPIC, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back), and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue OZEMPIC and initiate appropriate management. 5.3 Diabetic Retinopathy Complications In a 2-year trial involving patients with type 2 diabetes and high cardiovascular \n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2) ] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.5 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.6 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.7 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.9 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.10 )] The most common adverse reactions reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] . These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse React\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications : OZEMPIC delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution. ( 7.2 ) 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6 )] . 7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6 )] .\n7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS OZEMPIC is contraindicated in patients with: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions ( 5.1 )] . • A serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with OZEMPIC [see Warnings and Precautions ( 5.8 )] . • Personal or family history of MTC or in patients with MEN 2. ( 4 ) • Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=42bdd912-2393-44c4-b7e0-47672ca28991","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":308,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: MOUNJARO (TIRZEPATIDE) - label effective 2026-07-29","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-07-29","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In both male and female rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )]. MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Tirzepatide causes thyroid C-cell tumors in rats. It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, or MOUNJARO. Discontinue if pancreatitis is suspected. ( 5.2 ) Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary. ( 5.3 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue MOUNJARO if suspected and promptly seek medical advice. ( 5.4 ) Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. MOUNJARO is not recommended in patients with severe gastroparesis. ( 5.6 ) Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy: Has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic retinopathy for progression. ( 5.7 ) Acute Gallbladder Disease: Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical follow-up are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) Never share a MOUNJARO KwikPen between patients, even if the pen needle is changed. ( 5.10 ) 5.1 Risk of Thyroid C-Cell Tumors In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined. MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, or MOUNJARO [see Adverse Reactions ( 6 )] . After initiation of MOUNJARO, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue MOUNJARO and initiate appropriate management. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving MOUNJARO in \n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] The most common adverse reactions, reported in ≥5% of patients treated with MOUNJARO are nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials of Adults with Type 2 Diabetes Mellitus Pool of Two Placebo-Controlled Clinical Trials in Adults The data in Table 1 are derived from 2 placebo-controlled trials [1 monotherapy trial (SURPASS-1) and 1 trial in combination with basal insulin with or without metformin (SURPASS-5)] in adult patients with type 2 diabetes mellitus [see Clinical Studies ( 14.2 , 14.4 )] . These data reflect exposure of 718 patients to MOUNJARO and a mean duration of exposure to MOUNJARO of 36.6 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 54% were male. The population was 57% White, 27% Asian, 13% American Indian or Alaska Native, and 3% Black or African American; 25% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.1%. As assessed by baseline fundoscopic examination, 13% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m 2 in 53%, 60 to 90 mL/min/1.73 m 2 in 39%, 45 to 60 mL/min/1.73 m 2 in 7%, and 30 to 45 mL/min/1.73 m 2 in 1% of patients. Pool of Seven Controlled Clinical Trials Adverse reactions were also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in seven controlled clinical trials which included two placebo-controlled trials (SURPASS-1 and -5), three trials of MOUNJARO in combination with metformin, sulfonylureas, and/or SGLT2 Inhibitors (SURPASS-2, -3, -4) [see Clinical Studies ( 14.3 )] and two additional trials conducted in Japan. In this pool, a total of 5119 adult patients with type 2 diabetes mellitus were treated with MOUNJARO for a mean duration of 48.1 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 58% were male. The population was 65% White, 24% Asian, 7% American Indian or Alaska Native, and 3% Black or African American; 38% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 9.1 years with a mean HbA1c of 8.3%. As assessed by baseline fundoscopic examination, 15% of the population had retinopathy. At baseline, eGFR was ≥90 mL/min/1.73 m 2 in 52%, 60 to 90 mL/min/1.73 m 2 in 40%, 45 to 60 mL/min/1.73 m 2 in 6%, and 30 to 45 mL/min/1.73 m 2 in 1% of patients. Common Adverse Reactions Table 1 shows common adverse reactions, not including hypoglycemia, associated with the use of MOUNJARO in the pool of placebo-controlle\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS MOUNJARO delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. ( 7.2 ) 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating MOUNJARO, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 )]. 7.2 Oral Medications MOUNJARO delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with MOUNJARO. Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with MOUNJARO. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO. Hormonal contraceptives that are not administered orally should not be affected [see Use in Specific Populations ( 8.3 ) and Clinical Pharmacology ( 12.2 , 12.3 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS MOUNJARO is contraindicated in patients with: A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with MOUNJARO [see Warnings and Precautions ( 5.4 )] . Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. ( 4 ) Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0818426a-53eb-4db7-9609-bbae1e7a3964","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"regulatory","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1377,"doi":"10.1186/s40360-026-01190-4","pmid":"42928322","nct_ids":"[]","title":"Neuropsychiatric adverse event reporting with GLP-1-based therapies: a post-marketing pharmacovigilance analysis using the WHO global individual case safety report database (VigiBase)","authors":"[\"Liang J\", \"Bo L\", \"Miao X\", \"Guo X\", \"Xu J\", \"He J\", \"Ye X\"]","journal":"BMC pharmacology & toxicology","publication_date":"2026-07-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Concerns regarding neuropsychiatric adverse events (NPAEs), including depression and suicidality, have emerged with the expanding use of GLP-1-based therapies across metabolic and weight-management indications. This study aimed to characterize neuropsychiatric adverse-event reporting patterns for GLP-1-based therapies in VigiBase using disproportionality analysis. [METHODS] Individual case safety reports entered into the WHO global pharmacovigilance database (VigiBase) from inception through 31 January 2025 were examined. Disproportionality analysis using the information components and the reporting odds ratio was conducted to identify putative safety signals. The full VigiBase reporting background during the study period was used as the comparator. We described the drug-event pairs, mapped signal overlap across agents, evaluated the relationship between reporting frequency and signal magnitude, and conducted stratified analyses by sex and age. [RESULTS] Among 899 280 GLP-1RAs-related reports, 19 811 (2.2%) related NPAEs comprised 273 preferred terms and generated 69 positive signals. Semaglutide and liraglutide presented the broadest and most potent signal portfolios, driven chiefly by binge eating (semaglutide, IC₀₂₅ = 3.379; ROR₀₂₅ = 14.483), and aversion (liraglutide, IC₀₂₅ = 3.365; ROR₀₂₅ = 20.512). In contrast, albiglutide was essentially signal negative, and dulaglutide and tirzepatide generated narrower spectra. In addition, semaglutide was positively associated with two \"suicide/self-injury\" AEs: \"depression suicidal\" (ROR₀₂₅ = 4.822) and \"suicidal ideation\" (ROR₀₂₅ = 2.643). [CONCLUSIONS] This study identified several potential drug safety signals. However, the estimates were unadjusted and may be influenced by confounding by indication, channelling, notoriety bias, and event competition. Eating-related signals should be interpreted cautiously because they may overlap with the treated population and appetite-related pharmacology of these agents. Given the spontaneous reporting nature of VigiBase, these findings should be interpreted as potential reporting signals rather than evidence of causality. Further well-designed observational studies and prospective clinical investigations are needed to clarify whether GLP-1-based therapies are associated with increased neuropsychiatric risk and to identify patient-level risk modifiers.","url":"https://pubmed.ncbi.nlm.nih.gov/42928322/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: This study used secondary, de-identified individual case safety reports from VigiBase and did not involve direct contact with patients or access to identifiable personal information. Therefore, formal ethics approval and informed consent were not required. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:50+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"albiglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":298,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2026-07-27","authors":"[\"Meitheal Pharmaceuticals Inc.\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-07-27","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) Never Share a Liraglutide Injection Pen Between Patients , even if the needle is changed. (5.3) Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. (5.4) Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide injection is not recommended in patients with severe gastroparesis. ( 5.6 ) Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide injection and promptly seek medical advice. ( 5.7 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions ( 6 )] . After initiation of liraglutide injection, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue liraglutide injection and initiate appropriate management. 5.3 Never Share a Liragl\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. ( 6.1 ) Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide and a mean duration of exposure to liraglutide of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide than on placebo and occurred in at least 5% of patients treated with liraglutide. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse Reactions Reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1,024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Withdrawal due to gastrointestinal adverse even\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications : Liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications. ( 7 ) 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Liraglutide is contraindicated in patients with a: personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection [see Warnings and Precautions ( 5.7 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. (4) Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection. (4)","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0efc3a89-211a-4496-baab-e8265e07de2b","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1161,"doi":"10.1186/s13098-026-02250-9","pmid":"42908033","nct_ids":"[]","title":"Evaluating the therapeutic benefits and safety of ecnoglutide for type 2 diabetes: evidence from a systematic review and meta-analysis","authors":"[\"Abunada S\", \"Abunada O\", \"Vivek F\", \"Rathi L\", \"Muskan F\", \"Parkash J\", \"Nazeer S\", \"Anchal F\", \"Danial F\", \"Turesh K\", \"Ali A\", \"Qureshi F\", \"Tesfaye M\"]","journal":"Diabetology & metabolic syndrome","publication_date":"2026-07-27","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Type 2 diabetes mellitus (T2DM) is a growing global health challenge, necessitating effective therapies that improve glycemic control and promote weight loss. Ecnoglutide, a novel cAMP-biased GLP-1 (glucagon-like peptide-1) receptor agonist, has emerged as a promising therapeutic option. [METHODS] A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted following PRISMA and AMSTAR-2 guidelines. Electronic databases were searched up to February 2026. Eligible studies included adult patients with T2DM comparing ecnoglutide with placebo or active comparators. Outcomes included glycemic parameters, anthropometric measures, metabolic indices, and safety. Data were pooled using a random-effects model, and certainty of evidence was assessed using GRADE. [RESULTS] Three RCTs comprising 979 participants were included. Ecnoglutide significantly reduced HbA1c (MD -0.57%, 95% CI -0.86 to -0.29) and fasting plasma glucose (MD -1.11 mmol/L, 95% CI -1.58 to -0.65), with a higher proportion achieving target HbA1c (RR 1.57, 95% CI 1.37-1.80). Significant reductions in body weight (MD -1.83 kg) and waist circumference (MD -1.53 cm) were also observed. Improvements in insulin resistance and lipid parameters were noted. Exploratory subgroup analyses did not establish a clear dose response relationship, while short-term trials showed larger glycemic reductions compared with longer follow up. Adverse events were more frequent but not statistically significant, with no increase in serious adverse events. [CONCLUSION] Ecnoglutide demonstrates significant efficacy in improving glycemic control and weight-related outcomes in T2DM, with a safety profile comparable to existing GLP-1 receptor agonists. However, larger and longer-term studies are needed to confirm its cardiovascular benefits and long-term safety.","url":"https://pubmed.ncbi.nlm.nih.gov/42908033/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Peer and provenance statement: This manuscript was not commissioned.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:07+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1223,"doi":"10.1186/s13098-026-02248-3","pmid":"42897592","nct_ids":"[]","title":"Efficacy and safety of mazdutide vs. dulaglutide in adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials","authors":"[\"Hassan M\", \"Hussain M\", \"Khan S\", \"Azam MT\", \"Shahid ZUA\", \"Hannan A\", \"Khuhro MM\", \"Bhagia S\", \"Aminpoor H\"]","journal":"Diabetology & metabolic syndrome","publication_date":"2026-07-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Type 2 diabetes mellitus (T2DM) is closely linked to obesity and carries a high risk of metabolic complications. While GLP-1 receptor agonists like dulaglutide improve blood sugar and support modest weight loss, many patients do not reach their treatment goals. Mazdutide, a dual GLP-1 and glucagon receptor agonist, may offer stronger metabolic benefits. [OBJECTIVE] To compare the efficacy and safety of mazdutide versus dulaglutide in adults with T2DM. [METHODS] We systematically reviewed randomized controlled trials comparing mazdutide and dulaglutide. Primary outcomes included changes in HbA1c, body weight, and achievement of glycemic and weight-loss targets. Safety outcomes included treatment-emergent adverse events. Data were pooled using random-effects models, and evidence certainty was assessed using GRADE. [RESULTS] Three trials met inclusion criteria. Mazdutide led to greater reductions in HbA1c (- 0.25%) and body weight (- 2.97 kg) compared with dulaglutide. Patients were more likely to achieve HbA1c < 7.0%, ≥ 5% weight loss, and the combined target of ≥ 5% weight loss with HbA1c < 7.0%. Fasting plasma glucose was numerically but not significantly improved. Mazdutide was associated with higher rates of gastrointestinal side effects and decreased appetite, with a non-significant numerical increase in hypoglycemia, while serious adverse events and discontinuations were similar between treatments. Glycemic and major weight outcomes were supported by high-certainty evidence; most safety outcomes were moderate-certainty. [CONCLUSIONS] Mazdutide, based on evidence from three RCTs, provides preliminary evidence of meaningful improvements in blood sugar control and weight loss compared with dulaglutide, though with an increased risk of mostly manageable gastrointestinal effects; given the limited number of trials, these findings should be considered preliminary and supporting its potential role as a promising dual-action therapy for T2DM management, pending confirmation in larger, longer-term trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42897592/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Human ethics and consent to participate: Human ethics approval and consent to participate were not required for this study because it is a systematic review and meta-analysis based on previously published studies. No primary data involving human participants were collected. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\", \"mazdutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1224,"doi":"10.1186/s12902-026-02423-7","pmid":"42897521","nct_ids":"[]","title":"Current status of anti-obesity medications and performance, an EHR based survey","authors":"[\"Ruan X\", \"Li R\", \"Wang L\", \"Lu S\", \"Wen A\", \"Sameer M\", \"Liu H\"]","journal":"BMC endocrine disorders","publication_date":"2026-07-24","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] While randomized clinical trials (RCTs) establish the efficacy of anti-obesity medications (AOMs), their real-world effectiveness, inter-individual variability, and weight regain post discontinuation remain poorly characterized across diverse, large scale populations. [METHODS] Electronic health records with pharmacy dispensation of obesity or overweight individuals were retrieved from local UT-Physician and nationwide EPIC COSMOS databases. AOMs were analyzed for short to long-term effectiveness on obesity relevant metrics. [RESULTS] From the two cohorts, 71,318 (11·7%) and 1 M (27·9%) individuals documented AOM exposures, respectively, with about 70% individuals experiencing more than one treatment session. Tirzepatide and Semaglutide outperformed other AOMs and were associated with up to 9·6[IQR:11]% and 6·2[IQR:11]% weight loss, respectively, and both improved blood pressure, HbA1c, and lipid profile. The median exposure durations were approximately 4·6 months for the two GLP-1/GIP AOMs, far short of the 72-week duration typically required for peak therapeutic benefit in RCTs. All AOMs showed substantial inter-individual variability in responses, regardless of exposure length. Substantial differences were found between RCT and real-world performance. For example, while Tirzepatide led both cohorts, nearly 50% and 25% of individuals didn't achieve the 10% and 5% weight loss target respectively, after a minimum 72 weeks exposure, highlighting a notable effectiveness gap. Critically, we identified that Metformin co-therapy acted as a modifier of the 'rebound effect,' significantly attenuating (median 1·9 - 2·6%, p < 0.0001) weight regain compared to semaglutide or tirzepatide monotherapy. [CONCLUSION] Our findings confirm real-world AOM effectiveness and reveal challenges of the 'one-size-fits-all' approach of current pharmacotherapy. The marked inter-individual variability suggests that stratified, personalized pharmacotherapy is essential to transform transient weight loss into sustainable metabolic health. [CLINICAL TRIAL] Not applicable.","url":"https://pubmed.ncbi.nlm.nih.gov/42897521/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: The University of Texas Institutional Review Board (IRB) approved the study in accordance with the Declaration of Helsinki, and the Ethics Committee waived the need for written informed consent from participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\", \"adverse_effects\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":48,"doi":"10.1111/obr.70198","pmid":"42483841","nct_ids":"[]","title":"Cardiovascular Outcomes of GLP-1-Based Medicines Among People With Overweight and Obesity: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials","authors":"[\"Rashid M\", \"Lee EL\", \"Veettil SK\", \"Dhippayom T\", \"Cheng AYY\", \"Simonetti J\", \"Chaiyakunapruk N\"]","journal":"Obesity reviews : an official journal of the International Association for the Study of Obesity","publication_date":"2026-07-22","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Cardiovascular (CV) outcomes of Glucagon-like peptide-1 (GLP-1)-based medicines among people with overweight and obese (OW/OB) population have been investigated by meta-analyses of randomized controlled trials (RCTs), but an overall summary is lacking. [METHODS] PubMed, EMBASE, Epistemonikos, and Cochrane databases were searched till May 2024 for meta-analyses of RCTs that assessed CV outcomes of GLP-1-based medicines among people with OW/OB. GRADE approach was used to assess strength of associations. [RESULTS] Nine studies with 58 unique meta-analyses were included. Fifteen (25.9%) associations were statistically significant. Five high certainty evidence demonstrated beneficial effects of GLP-1 RAs on any CV events (N= 1), major adverse cardiac events (MACE) (N = 2), and myocardial infarction (MI) (N = 2), whereas two associations on revascularization (N = 1) and CV events (N = 1) were supported by moderate certainty. Four associations demonstrated inverse effects of tirzepatide on MACE (N = 1; moderate) and hypertension (N = 3; low). Remaining four demonstrated higher risk of arrhythmia with GLP-1 RAs (N = 1; moderate) and increased heart rate with tirzepatide (N = 3; low to moderate). Although the inverse association between GLP-1 RAs and MACE and MI was significant and supported by high certainty evidence in both main and sensitivity analyses, these associations were no longer statistically significant among patients without CV disease (CVD) at baseline. [CONCLUSION] Findings suggest that GLP-1 RAs are associated with reduced risk of MACE, and MI among people with OW/OB, but they were driven by studies with established CVD at baseline.","url":"https://pubmed.ncbi.nlm.nih.gov/42483841/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"umbrella_review","drugs":"[\"class_unspecified\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Umbrella review of 9 meta-analyses (58 associations) of CV outcomes in overweight/obesity","endpoints":null,"effect_estimate":"High-certainty benefit for MACE and MI; not significant among patients without CVD at baseline; moderate-certainty higher arrhythmia risk; heart-rate increase with tirzepatide","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight/obesity (all included meta-analyses)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"mixed: included trials with and without baseline cardiovascular disease\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Overweight/obesity populations; the finding that benefit was confined to those with established CVD is directly relevant to primary prevention questions.","mediation":"unknown","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Umbrella review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"9 meta-analyses with overlapping trials\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"overlap between meta-analyses; GRADE applied\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"GRADE-assessed umbrella review; benefit driven by secondary-prevention trials.","funding_source":"Not stated in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"An umbrella review of meta-analyses in people with overweight or obesity found GLP-1 drugs were associated with fewer major cardiovascular events and heart attacks, with the benefit driven by trials in people who already had cardiovascular disease; in people without it the association was not statistically significant. Arrhythmia and heart-rate signals were noted.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":58,"doi":"10.1161/circresaha.126.327425","pmid":"42461988","nct_ids":"[]","title":"Prevention of Vascular Aging as a Novel Paradigm for GLP-1 Receptor Agonist-Mediated Cardioprotection","authors":"[\"Dennis CJ\", \"He AZ\", \"Krishnaraj A\", \"Quan A\", \"Teoh H\", \"Connelly KA\", \"Hess DA\", \"Verma S\"]","journal":"Circulation research","publication_date":"2026-07-17","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity. Due to class-wide reduction in major adverse cardiovascular events in cardiovascular outcome trials and pleiotropic actions in multiple tissues, the use of GLP-1RAs has expanded beyond metabolic diseases. Recent studies have reported GLP-1RA efficacy for the treatment of atherosclerosis, heart failure and peripheral artery disease, alongside evolving potential in chronic kidney disease. The recent discovery that GLP-1RAs can improve vascular regenerative progenitor cell flux during type 2 diabetes has uncovered a novel mechanism implicating 3 classical hallmarks of vascular aging: (1) stem cell exhaustion, (2) altered intercellular communication, and (3) chronic systemic inflammation. In this review we discuss recent evidence demonstrating that imbalances in hematopoiesis during cardiometabolic diseases intersect with the senescence-associated secretory phenotype to elevate chronic inflammation and accelerate vascular aging. With a focus on stem cells as the master regulators of regenerative processes, we integrate the activities of GLP-1RAs that shift the balance from damage accumulation to repair competence in blood vessels prematurely aged by cardiometabolic syndrome.","url":"https://pubmed.ncbi.nlm.nih.gov/42461988/","source_name":"pubmed","source_tier":1,"coi_statement":"H. Teoh reports receiving personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group and LMC Healthcare. K.A. Connelly reports receiving grants, research support, speaking honoraria, or acting as an advisor for Abbott, AstraZeneca, Boehringer Ingelheim, Canadian Heart Research center, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, NovoNordisk, Sanofi, Servier, and Servier; and holds a patent with Boehringer Ingelheim for the medical use of linagliptin for heart failure with preserved ejection fraction. S. Verma reports receiving grants, research support, speaking honoraria, or acting as an advisor for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Heart Research center, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics Inc., Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc., Sanofi and Sun Pharma. The other authors report no conflicts.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"mechanistic_review","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"aging\", \"cardiovascular\", \"inflammation\", \"immune\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"Mechanistic review of vascular-aging hypotheses; no human outcome data.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Mechanistic review\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"none (narrative mechanistic review)\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Review proposing stem-cell exhaustion, intercellular communication and inflammation as GLP-1RA targets in vascular aging.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A Circulation Research review proposing that GLP-1 drugs protect the heart by slowing vascular aging via regenerative progenitor cells and reduced inflammation. Hypothesis and mechanism, not clinical evidence.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":320,"doi":"10.1016/j.jchf.2026.103218","pmid":"42417681","nct_ids":"[\"NCT04847557\"]","title":"Effects of Tirzepatide in Obesity-Related HFpEF by Sex: A Prespecified Secondary Analysis From the SUMMIT Trial","authors":"[\"Borlaug BA\", \"Zile MR\", \"Kramer CM\", \"Litwin SE\", \"Ye W\", \"Ou Y\", \"Hurt K\", \"Murakami M\", \"Packer M\", \"SUMMIT Trial Group\"]","journal":"JACC. Heart failure","publication_date":"2026-07-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide decreased risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Women outnumber men with HFpEF, and there are sexual dimorphisms in the relationships between body fat and pathophysiology that could influence response to tirzepatide. [OBJECTIVES] This study aims to compare baseline characteristics and effects of tirzepatide on primary and other endpoints in women and men with obesity-related HFpEF. [METHODS] In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein, and body weight at 52 weeks. Baseline characteristics and effects of tirzepatide on primary and secondary endpoints were contrasted by sex. [RESULTS] Compared with men (n = 338, 46.2%), women with obesity-related HFpEF (n = 393, 53.8%) had greater BMI, waist to height ratio (WHtR), symptom severity (higher NYHA functional class, lower KCCQ-CSS), and poorer exercise capacity (lower 6MWD), whereas men had greater left ventricular remodeling and paracardiac fat. Greater baseline BMI or WHtR were correlated with lower KCCQ-CSS and 6MWD in women and men, with no interaction, but higher WHtR was associated with poorer kidney function exclusively in women (interaction P = 0.043). The effect of tirzepatide on the risk of worsening HF or cardiovascular death did not differ in women and men (HR: 0.66 and 0.61, respectively, interaction P = 0.81), with no heterogeneity of effect on KCCQ-CSS at 52 weeks (8.1- and 5.5-point placebo-corrected improvement, respectively, interaction P = 0.43) or 6MWD (18 m and 15 m placebo-corrected improvement, respectively, interaction P = 0.76). Among patients randomized to tirzepatide, decreases in body weight on treatment were more strongly associated with improvements in KCCQ-CSS in women than men (interaction P = 0.0058). [CONCLUSIONS] Compared with men, women with obesity-related HFpEF have greater adiposity, symptom severity, and poorer exercise capacity but lower left ventricular mass and paracardiac fat deposition. Despite these differences, tirzepatide resulted in consistent benefits across multiple domains of HF severity that did not differ by sex. (A Study of Tirzepatide [LY3291876] in Participation With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity [SUMMIT]; NCT04847557).","url":"https://pubmed.ncbi.nlm.nih.gov/42417681/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures The SUMMIT trial was funded by Eli Lilly and Company. Dr Borlaug has received grants R01 HL128526, R01 HL162828, and U01 HL160226 from the National Heart, Lung, and Blood Institute; grant W81XWH2210245 from the United States Department of Defense; and has received grants from the Schoen Foundation AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics; he has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (US Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Zile has received research support from the Department of Veterans Affairs; and consulting fees from Abbott, Adona Medical, Aria CV, Avery Therapeutics Inc, Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, DIASTOL Therapeutics, LLC, EBR, Edwards, Lilly, GenKardia, Innoventric, KestraMedical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnova, Salubris Biotherapeutics, Sonata, SRNALYTICS Inc, V-WAVE, and Vectorious. Dr Kramer has received consulting fees from Eli Lilly. Dr Litwin has been on the patient selection committee for Corvia and Axon; and has received consulting fees from Novo Nordisk and Lilly. Drs Hurt, Murakami, and Ou are employed by Eli Lilly and Company. Dr Packer has received consulting fees from 89bio, Abbvie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche, and Salamandra. Dr Ye has reported that he has no relationships relevant to the contents of this paper to disclose.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":46,"doi":"10.2215/cjn.0000001051","pmid":"42308057","nct_ids":"[\"NCT04889183\"]","title":"Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART Trial","authors":"[\"Heerspink HJL\", \"Soler M\", \"Beernink JM\", \"Jongs N\", \"Cigarran S\", \"Cruzado JM\", \"Puchades MJ\", \"López-Martínez M\", \"Apperloo E\", \"Waanders F\", \"Laverman GD\", \"van der Aart-van der Beek A\", \"van Beek AP\", \"Verhave JC\", \"Ahmed SB\", \"Schmieder RE\", \"Wanner C\", \"Cherney DZI\", \"Górriz JL\"]","journal":"Clinical journal of the American Society of Nephrology : CJASN","publication_date":"2026-07-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[KEY POINTS] Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. [BACKGROUND] The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. [METHODS] We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. [RESULTS] After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by -9.1 (95% confidence interval [CI], -11.0 to -7.2), -2.5 (95% CI, -6.6 to 1.6), and -3.9 (95% CI, -7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared with placebo changed extracellular water and systolic BP by -0.9 (95% CI, -1.6 to -0.1) L and -6.3 (95% CI, -10.9 to -1.7) mm Hg, respectively. Systolic BP changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; P = 0.005). [CONCLUSIONS] Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide do not influence GFR estimates. [CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER] ClinicalTrials.gov, NCT04889183 .","url":"https://pubmed.ncbi.nlm.nih.gov/42308057/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C724.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"24 weeks\", \"comparator\": \"placebo\"}","domains":"[\"lean_mass\", \"body_composition\", \"kidney\", \"muscle\"]","outcome_type":"intermediate","primary_outcome":"Prespecified: body composition (bioimpedance), measured and estimated GFR, blood pressure","endpoints":null,"effect_estimate":"Weight -9.1 kg; lean body mass -2.5 kg (95% CI -6.6 to 1.6); fat mass -3.9 kg; extracellular water -0.9 L; systolic BP -6.3 mmHg; no correlation between body-composition change and GFR change","confidence_interval":null,"p_value":null,"sample_size":101,"follow_up":"24 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight or obesity required\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"CKD required\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 101, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Non-diabetic CKD with overweight/obesity; small. Relevant to the lean-mass question because roughly a quarter of weight lost was lean tissue.","mediation":"not_applicable","mediation_notes":"Participants had chronic kidney disease with overweight or obesity and no type 2 diabetes; the abstract does not separate direct drug effects from weight loss.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 101, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 weeks\", \"outcome_type\": \"bioimpedance body composition\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"n=101; lean-mass CI includes zero\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small prespecified analysis of an RCT with imprecise body-composition estimates.","funding_source":"Novo Nordisk (investigator-initiated, per PubMed grant field)","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Disclosure forms available with the article.","sponsor_role":"Funder; investigator-initiated (verify).","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"In 101 people with kidney disease and overweight or obesity (no diabetes), 24 weeks of semaglutide reduced weight by 9.1 kg more than placebo. The lean-mass difference (-2.5 kg, 95% CI -6.6 to 1.6) was not statistically significant, and the fat-mass difference (-3.9 kg) was borderline. Systolic blood pressure fell 6.3 mmHg more than with placebo. Body-composition change did not distort kidney-function estimates.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":47,"doi":"10.1038/s41591-026-04440-4","pmid":"42260100","nct_ids":"[\"NCT06445075\"]","title":"Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial","authors":"[\"Pratley RE\", \"Denham DS\", \"Trivedi R\", \"Watkins E\", \"Connery L\", \"Barnes J\", \"Yu D\", \"Hong J\", \"Simard C\", \"Umans K\", \"Liu L\", \"Tirucherai GS\", \"Marantz JL\"]","journal":"Nature medicine","publication_date":"2026-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Loss of lean mass in proportion to total weight loss is observed with incretin mimetic therapies such as tirzepatide and has the potential to adversely affect health and function. Apitegromab is an investigational, fully human monoclonal antibody that selectively inhibits myostatin activation and is, thereby, capable of increasing muscle mass. In the randomized, double-blind, placebo-controlled phase 2 EMBRAZE study, adults with overweight or obesity (n = 102) were randomized 1:1 to receive tirzepatide plus apitegromab (10 mg kg-1) or tirzepatide plus placebo. At week 24, apitegromab resulted in a least square mean (80% confidence interval (CI)) of 1.9 (1.2-2.7) kg less lean mass loss than placebo (P = 0.001), despite similar total body weight loss between groups, representing a 54.9% retention of lean mass relative to placebo. In participants receiving apitegromab, trough concentrations of apitegromab and total latent myostatin, a pharmacodynamic marker, both increased over time and reached a plateau after approximately 16 weeks. Incidence of adverse events (AEs) (% (95% CI)) was generally similar across apitegromab-treated participants and placebo-treated participants, with 39 of 51 (76% (63-86%)) and 36 of 51 (71% (57-81%)) participants experiencing an AE, respectively. Serious adverse events (SAEs) were balanced and experienced by one of 51 (2% (0-10%)) participants in each arm. In summary, this proof-of-concept study demonstrated that selective targeting of myostatin by apitegromab was well tolerated and effective in preserving lean mass when combined with tirzepatide. ClinicalTrials.gov identifier: NCT06445075 .","url":"https://pubmed.ncbi.nlm.nih.gov/42260100/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: R.E.P. declares speaker fees from Abbott, Corcept, Lilly and Novo Nordisk; consulting fees from AbbVie, Amgen, Bayer AG, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Corcept, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Intas Pharmaceuticals, Lilly, Novo Nordisk, Pfizer, Sun Pharmaceutical Industries and Verdiva; and research grants from Boehringer Ingelheim, Carmot Therapeutics, Dompe, Endogenex, Lilly, Novo Nordisk and Sanofi. D.S.D. reports no conflicts related to this work. R.T. reports no conflicts related to this work. E.W. reports no conflicts related to this work. L.C. has served on advisory boards for Boehringer Ingelheim, Lilly and Intarcia and has received research funding from Amgen, Argo, AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Novo Nordisk, Pfizer, Regeneron, Regor, Roche, Scholar Rock, Structure/Gasherbrum, Vanda, Verdiva, Viking and Zealand. D.Y., J.H., C.S., K.U., L.L., G.S.T. and J.L.M. are employees of Scholar Rock, Inc. and may hold stock/stock options in the company. J.B. was affiliated with Scholar Rock at the time the study was conducted.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T13:04:18+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"tirzepatide plus apitegromab 10 mg/kg or placebo\", \"treatment_duration\": \"24 weeks\", \"comparator\": \"tirzepatide plus placebo\"}","domains":"[\"lean_mass\", \"muscle\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"Lean mass change at week 24","endpoints":null,"effect_estimate":"1.9 kg less lean-mass loss with apitegromab (54.9% retention relative to placebo) at similar total weight loss","confidence_interval":"1.2 to 2.7 (80% CI)","p_value":"0.001","sample_size":102,"follow_up":"24 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight or obesity required\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 102, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity; the trial exists because lean-mass loss with tirzepatide is substantial (about 3.5 kg in 24 weeks in the placebo arm, inferred).","mediation":"not_applicable","mediation_notes":"[Auto] Harm signal; weight-loss mediation not the relevant question, but consider whether harms relate to rapid weight loss or reduced intake.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 102, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"tirzepatide plus placebo\", \"follow_up_duration\": \"24 weeks\", \"outcome_type\": \"DXA lean mass; no function outcome\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"n=102; 80% CI reported\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small proof-of-concept phase 2.","funding_source":"Scholar Rock (apitegromab developer; full text, not checked)","industry_funded":"yes","manufacturer":"Scholar Rock (not a GLP-1 manufacturer); tirzepatide by Eli Lilly","author_conflicts":"Lead author reports fees from Lilly, Novo Nordisk and others.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Adverse events in 39 of 51 (76%) with apitegromab vs 36 of 51 (71%) with placebo; one serious adverse event in each arm (1 of 51, 2%).","limitations":null,"plain_summary":"A 24-week trial added a myostatin-blocking antibody to tirzepatide and preserved about half of the lean mass that would otherwise be lost. Its main relevance here is as confirmation that meaningful lean-mass loss accompanies incretin-induced weight loss; muscle function was not measured.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":53,"doi":"10.1002/acr2.90046","pmid":"42415363","nct_ids":"[]","title":"Autoimmune Disease Risk With GLP-1RA, DPP-4i, and SGLT2i Treatment in Patients With Diabetes","authors":"[\"Mahajan A\", \"Bates DW\", \"Doria A\", \"Foer D\", \"LaChance AH\", \"Sparks JA\"]","journal":"ACR open rheumatology","publication_date":"2026-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are widely used for type 2 diabetes, yet their comparative immunologic safety is uncertain. To address this gap, we evaluated autoimmune disease incidence among patients treated with these agents. [METHODS] We conducted emulated target trials using electronic health record data from 152 health care organizations in the TriNetX network (2016-2023). Adults with type 2 diabetes initiating DPP-4i, GLP-1RA, or SGLT2i monotherapy and no prior autoimmune disease were included. Propensity score matching balanced demographics, comorbidities, laboratory data, and medications. Cohorts comprised 118,419 matched DPP-4i versus GLP-1RA pairs, 102,810 DPP-4i versus SGLT2i pairs, and 105,869 GLP-1RA versus SGLT2i pairs. Primary outcomes included three-year risks of incident autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic sclerosis, dermatomyositis, and multiple sclerosis. [RESULTS] Compared with GLP-1RA, DPP-4i was associated with lower risk of psoriasis (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.85), psoriatic arthritis (HR 0.65, 95% CI 0.53-0.79), and autoimmune thyroiditis (HR 0.68, 95% CI 0.59-0.76), but higher risk of dermatomyositis (HR 2.18, 95% CI 1.24-3.53) and bullous pemphigoid (HR 1.78, 95% CI 1.24-2.46). [CONCLUSION] Compared with GLP-1RA, DPP-4i use decreased psoriasis and thyroiditis risk but increased dermatomyositis, bullous pemphigoid, and giant cell arteritis risk. No significant differences were observed between GLP-1RA and SGLT2i treatments. These findings provide novel safety signals and may inform antidiabetic drug selection while guiding future mechanistic and prospective research.","url":"https://pubmed.ncbi.nlm.nih.gov/42415363/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"DPP-4 inhibitors; SGLT2 inhibitors\"}","domains":"[\"rheumatologic\", \"immune\", \"adverse_effects\", \"endocrine\"]","outcome_type":"hard","primary_outcome":"3-year incident autoimmune diseases (target-trial emulation, TriNetX)","endpoints":null,"effect_estimate":"DPP-4i vs GLP-1RA: psoriasis HR 0.79, psoriatic arthritis 0.65, thyroiditis 0.68 (lower with DPP-4i); dermatomyositis 2.18, bullous pemphigoid 1.78 (higher with DPP-4i); giant cell arteritis also higher with DPP-4i (named in the conclusions; no HR in the abstract); GLP-1RA vs SGLT2i no differences","confidence_interval":null,"p_value":null,"sample_size":236838,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 236838, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes; EHR-coded autoimmune outcomes.","mediation":"unknown","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 236838, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"DPP-4 inhibitors; SGLT2 inhibitors\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI] 0\", \"risk_of_bias\": \"coded outcomes; DPP-4i comparisons may reflect known DPP-4i associations (bullous pemphigoid) rather than GLP-1 effects\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Hypothesis-generating EHR emulation.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In matched US electronic health records of people with type 2 diabetes, GLP-1 drug users and SGLT2 inhibitor users had similar autoimmune disease rates. Compared with DPP-4 inhibitor use, GLP-1 use was associated with higher rates of psoriasis, psoriatic arthritis and autoimmune thyroiditis, but lower rates of dermatomyositis, bullous pemphigoid and giant cell arteritis. Observational; these are associations, not proof of cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":326,"doi":"10.1038/s42255-026-01554-4","pmid":"42342869","nct_ids":"[\"NCT04122716\"]","title":"Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial","authors":"[\"Sandsdal RM\", \"Holt J\", \"Alkhefagie HGA\", \"Jørgensen JR\", \"Juhl CR\", \"Olsen LM\", \"Byberg S\", \"Thirumathyam R\", \"Gliemann L\", \"Stallknecht B\", \"Holst JJ\", \"Hove JD\", \"Bandholm T\", \"Bojsen-Møller KN\", \"Madsbad S\", \"Størling J\", \"Bladbjerg EM\", \"Antoniades C\", \"Jensen SBK\", \"Torekov SS\"]","journal":"Nature metabolism","publication_date":"2026-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity and inactivity are linked to endothelial dysfunction and atherosclerosis. In this secondary analysis of the S-LiTE trial (ClinicalTrials.gov identifier: NCT04122716 ; EudraCT identifier: 2015-005585-32 ), 130 adults with obesity completed a diet-induced weight loss plan, followed by randomization to weight maintenance with exercise and/or liraglutide for 52 weeks. We show that exercise, alone or in combination with liraglutide, reduces carotid intima-media thickness and systemic pro-inflammatory cytokine levels (interleukin-6 and interferon-γ). Combination treatment also improves endothelial function biomarkers (sICAM-1, sVCAM-1 and tPA). Liraglutide alone shows no such improvements. Overall, regular physical activity, with or without GLP-1R agonists, is essential for promoting vascular health in adults with obesity.","url":"https://pubmed.ncbi.nlm.nih.gov/42342869/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: J.J.H. is on the advisory board of Novo Nordisk. L.M.O. currently works at Novo Nordisk and was employed after data collection and the end of the study. The spouse of T.B. works at Novo Nordisk; T.B. and spouse own Novo Nordisk stocks. In the last 5 years, S.M. has been on the advisory boards of AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Sanofi and Bayer; received lecture fees from AstraZeneca and Novo Nordisk; been a research grant recipient from Novo Nordisk and Boehringer Ingelheim; and received support for attending meetings and/or travel from Novo Nordisk and Boehringer Ingelheim. S.S.T. has received research grants and honoraria for lectures and has had a membership on an advisory panel for Novo Nordisk. The other authors declare no competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":337,"doi":"10.36721/pjps.2026.39.7.204.1","pmid":"42170981","nct_ids":"[]","title":"Short-term comparative effects of semaglutide, either alone or in conjunction with canagliflozin, on early diabetic kidney disease","authors":"[\"Long W\", \"Ningning L\", \"Weijun H\"]","journal":"Pakistan journal of pharmaceutical sciences","publication_date":"2026-07","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus and an important cause of end-stage renal disease. Metabolic dysfunction, albuminuria, and chronic low-grade inflammation characterize early DKD, leading to progressive renal impairment. To date, SGLT2 inhibitors and GLP-1 receptor agonists are known to provide renoprotective and metabolic benefits; however, there is limited evidence available regarding the combined use of these treatments in early DKD. [OBJECTIVES] This study evaluated the short-term effects of canagliflozin and semaglutide, administered alone or in combination, on renal function, metabolic parameters, and systemic inflammatory markers in patients with early-stage DKD. [METHODS] In this randomized controlled trial, 120 patients with early-stage diabetic kidney disease were randomly allocated (1:1:1:1) to four groups (n = 30 each): canagliflozin (100 mg orally once daily), semaglutide (0.25 mg once weekly with escalation to 1.0 mg after 4 weeks), combination treatment, or placebo/control. [PARTICIPANTS] All participants were provided standard background care. Treatment continued for 24 weeks. The main renal outcomes were urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Glycemic control, insulin resistance, lipid parameters, and inflammatory biomarkers (HbA1c, fasting glucose, HOMA-IR, TNF-α, IL-6, CRP) were considered as secondary outcomes. Safety assessment was conducted using binary safety assessment. [RESULTS] At 24 weeks, combination therapy achieved significantly greater reductions in UACR compared with monotherapy and placebo (P < 0.05). Across treatment groups, a small reduction in eGFR was observed without significant between-group differences. Measurements of HbA1c, fasting glucose, HOMA-IR, lipid parameters, and inflammatory markers showed better results in the combination therapy group compared to single-agent therapy (P < 0.05). Rates of adverse events were similar between the groups. [CONCLUSION] Combined canagliflozin and semaglutide therapy demonstrated superior short-term benefits in reducing albuminuria, improving metabolic control, and attenuating systemic inflammation in early DKD, supporting further long-term evaluation of renal and cardiovascular outcomes.","url":"https://pubmed.ncbi.nlm.nih.gov/42170981/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":301,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2026-06-16","authors":"[\"Eli Lilly and Company\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-06-16","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY. Discontinue if pancreatitis is suspected ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion ( 5.5 ). Severe Gastrointestinal Adverse Reactions: Use may be associated with gastrointestinal adverse reactions, sometimes severe. TRULICITY is not recommended in patients with severe gastroparesis ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures ( 5.9 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY [see Adverse Reactions ( 6 )] . Af\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” \n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=463050bd-2b1c-40f5-b3c3-0a04bb433309","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":54,"doi":"10.1016/s0140-6736(26)00967-0","pmid":"42250575","nct_ids":"[\"NCT06354660\"]","title":"Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial","authors":"[\"Bajaj HS\", \"Welch M\", \"Shah P\", \"Luna E\", \"Jaouimaa FZ\", \"Liu B\", \"Liu R\", \"Chen Y\", \"Patel H\", \"Bartee A\"]","journal":"Lancet (London, England)","publication_date":"2026-06-13","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. [METHODS] In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA1c) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m2. Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. [FINDINGS] Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48·8 years (SD 12·1), mean HbA1c concentration was 7·9% (SD 1·1), mean duration of diabetes was 2·5 years (SD 4·4), and mean BMI was 35·8 kg/m2 (SD 7·0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA1c concentration was -1·69% (SE 0·11) with retatrutide 4 mg, -1·86% (0·10) with 9 mg, and -1·94% (0·08) with 12 mg, versus -0·81% (0·12) with placebo, resulting in estimated treatment differences versus placebo of -0·88% (95% CI -1·18 to -0·59) with retatrutide 4 mg, -1·04% (-1·32 to -0·76) with 9 mg, and -1·12% (-1·39 to -0·85) with 12 mg (all p<0·0001). The mean percentage change from baseline in bodyweight was -11·5% (SE 0·7) with retatrutide 4 mg, -13·9% (0·8) with 9 mg, and -15·3% (0·8) with 12 mg, versus -2·6% (0·5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. [INTERPRETATION] Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. [FUNDING] Eli Lilly and Company.","url":"https://pubmed.ncbi.nlm.nih.gov/42250575/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests HSB reports research support (paid to institution) from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Ionis, Novartis, Novo Nordisk, Pfizer, Roche, and Vertex; and serving as a speaker and on advisory panels for Eli Lilly, Novo Nordisk, and Roche. MW reports payment as a member of a speakers bureau from, support for attending meetings or travel from, and stocks in Eli Lilly and Company. EL reports consulting and speaker fees from Abbott, Eli Lilly, Dexcom, CeQur, Insulet, Madrigal Pharmaceuticals, and Mannkind. PS reports speaker fees from Eli Lilly and Company. F-ZJ, BL, RL, YC, HP, and AB are employees of and shareholders in Eli Lilly and Company.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"4, 9 or 12 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"40 weeks\", \"comparator\": \"placebo\"}","domains":"[\"metabolic\", \"body_composition\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"HbA1c change at 40 weeks","endpoints":null,"effect_estimate":"HbA1c -0.88 to -1.12% vs placebo; weight -11.5% to -15.3% vs -2.6%","confidence_interval":null,"p_value":"<0.0001","sample_size":537,"follow_up":"40 weeks","direction":"benefit","population":"{\"mean_age\": 48.8, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": \"55% female\", \"bmi_mean\": 35.8, \"bmi_min\": 23, \"obesity_status\": \"BMI of 23 or more required (mean 35.8); share with obesity not reported\", \"diabetes_status\": \"type 2 diabetes required (early, mean 2.5 years)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 537, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes; BMI >= 23 entry allowed some non-obese participants, but mean BMI was 35.8 and the abstract reports no lower-BMI subgroup.","mediation":"not_applicable","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 537, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"40 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -1·18 to -0·59\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor employees co-authored.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"GI events most frequent; discontinuation 2-5%; two deaths in 4 mg group judged unrelated.","limitations":null,"plain_summary":"A phase 3 result for the triple agonist retatrutide: large HbA1c and weight reductions over 40 weeks in early type 2 diabetes. Tracked mainly as the lead indicator for a new drug class; entry BMI as low as 23 is worth noting for future subgroup reporting.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":37,"doi":"10.1016/s0140-6736(26)00459-9","pmid":"41865758","nct_ids":"[\"NCT04777396\", \"NCT04777409\"]","title":"Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials","authors":"[\"Cummings JL\", \"Atri A\", \"Sano M\", \"Zetterberg H\", \"Scheltens P\", \"Knop FK\", \"Johannsen P\", \"Wichmann CA\", \"Abschneider RM\", \"Leon T\", \"Feldman HH\"]","journal":"Lancet (London, England)","publication_date":"2026-05-30","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease. [METHODS] evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome. [FINDINGS] Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). [INTERPRETATION] Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications. [FUNDING] Novo Nordisk.","url":"https://pubmed.ncbi.nlm.nih.gov/41865758/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests JLC has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, Bio X Cel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He is supported by National Institute of General Medical Sciences grant P20GM109025, National Institute on Aging (NIA) grant R35AG71476, NIA grant R25 AG083721-01, Alzheimer's Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment. AA has, in the last 10 years, served as a consultant or received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programmes, and materials; and serving on advisory boards for AbbVie, Acadia, Allergan, Alzheimer's Disease International, the Alzheimer's Association, AriBio, Axovant, Axsome, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Johnson & Johnson, Life Molecular Imaging/Lantheus, Lundbeck, Merck, Michael J Fox Foundation, Novo Nordisk, ONO, Otsuka, Prothena, Qynapse, Roche/Genentech, Sunovion, Suven, Synexus, and Vaxxinity. He receives book royalties from Oxford University Press for a medical book on dementia. He receives institutional research grant or contract funding from the NIA/National Institutes of Health (NIH; 1P30AG072980, U24AG057437, 1P30AG072980, R01AG070883, R01AG086363, U01AG082350, U24AG057437), Arizona Department of Health Services (CTR040636), Foundation for the NIH, Washington University in St. Louis, Michael J. Fox Foundation, and Gates Ventures. His institution receives or has received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves or has served as a contracted site principal investigator. He has received or receives honoraria from Novo Nordisk for consulting activities, including for service on the evoke(+) program Steering Committee. MS has served on the Scientific Advisory Board for Medication and as a consultant for Eisai, Avenir, vTv, Biogen, Bio X Cel, F. Hoffman LaRoche, Merck, Novo Nordisk, Novartis, Otsuka, Genentech, and BioVie. She is a member of the Alzheimer Association Medical and Scientific Advisory Group and Chair of the data safety monitoring board for the Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD; sponsor: University of Colorado). HZ reports a relationship with AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, NervGen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, ReMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave that includes consulting or advisory services. He reports a relationship with AlzeCure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD that includes speaking and lecture fees. He reports a relationship with Brain Biomarker Solutions in Gothenburg AB that includes equity or stocks. FKK, PJ, RMA, and CAW are employees and minor shareholders of Novo Nordisk. TL was an employee and minor shareholder of Novo Nordisk at the time of the analysis. PS is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam UMC. He is co-Chair of the Steering Committee for the phase 3 trials evoke and evoke+ with Novo Nordisk. HHF reports a consulting service agreement with Novo Nordisk for serving on the evoke + Steering Committee with funds including travel support for its meetings paid to UC San Diego. He receives no financial support for the present manuscript. Other disclosures include his receiving grants for UC San Diego from Allyx Therapeutics and Vivoryon Therapeutics (Probiodrug). He holds service agreements through UC San Diego for consulting with Biosplice Therapeutics, Arrowhead Pharmaceuticals, Axon Neuroscience, and LuMind Foundation. He provides service as a member of data and safety monitoring boards for Janssen Research & Development and Roche/Genentech and is a Scientific Advisory Board Chair for the Tau Consortium Rainwater Charitable Foundation through a UC San Diego service agreement. He has received travel support from Royal Society of Canada, Translating Research for Elder Care (TREC), Association for Frontotemporal Dementia (AFTD), Rainwater Charitable Foundation, Banner Health, Invictus, Summeet, and Novo Nordisk. He receives philanthropic support for Alzheimer's disease therapeutic research through the Epstein Family Alzheimer's Research Collaboration as well as personal funds for Detecting and Treating Dementia (Serial Number 12/3- 2691 US Patent Number PCT/US2007/07008, Washington DC, US Patent and Trademark Office).","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T12:11:03+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"oral 14 mg daily (flexible)\", \"route\": \"oral\", \"treatment_duration\": \"up to 156 weeks (primary at 104)\", \"comparator\": \"placebo\"}","domains":"[\"alzheimers\", \"dementia\", \"cognition\", \"neuroinflammation\"]","outcome_type":"intermediate","primary_outcome":"Change in CDR-SB from baseline to week 104","endpoints":null,"effect_estimate":"Difference -0.08 (evoke) and +0.10 (evoke+); no significant difference","confidence_interval":"-0.35 to 0.20; -0.17 to 0.38","p_value":"0.57; 0.46","sample_size":3808,"follow_up":"104 weeks","direction":"null","population":"{\"mean_age\": 72.2, \"age_range\": \"55-85\", \"age_min\": 55.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not an entry criterion (not selected for weight)\", \"diabetes_status\": \"not an entry criterion\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"amyloid-confirmed early Alzheimer's disease (MCI or mild dementia)\", \"sample_size\": 3808, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Participants were older adults (mean 72) not selected for obesity or diabetes, so demographically closer to the target than metabolic trials; but they had established Alzheimer's disease, so results address treatment of AD, not prevention in healthy people.","mediation":"unlikely","mediation_notes":"Null result.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 3808, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"104 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"two identical trials, both null\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"narrow CIs around zero\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Two large, well-powered phase 3 trials with concordant null primary results; high certainty of no clinically meaningful effect on progression in early AD over two years.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Lead author consults for numerous companies including Novo Nordisk and Lilly; sponsor co-authors.","sponsor_role":"Sponsor designed, ran and analysed; trials discontinued for lack of efficacy.","independent_replication_exists":"not needed (negative); consistent with ELAD null primary","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Treatment-emergent AEs 91.2% vs 84.8%; five treatment-related deaths (1 semaglutide, 4 placebo).","limitations":null,"plain_summary":"Two phase 3 trials in 3,808 people with early Alzheimer's disease found that up to two years of oral semaglutide did not demonstrate slowing of clinical progression (CDR-SB at 104 weeks). They test semaglutide as a treatment for established Alzheimer's disease; they do not test whether it prevents dementia in people without it.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":797,"doi":"10.1093/ndt/gfaf230","pmid":"41160422","nct_ids":"[\"NCT05936151\", \"NCT06383390\"]","title":"Rationale, design and baseline characteristics of the TRANSCEND-CKD trial of retatrutide in patients with chronic kidney disease","authors":"[\"Heerspink HJL\", \"van Raalte DH\", \"Bjornstad P\", \"Bunck MC\", \"Wu P\", \"Tunali I\", \"Milicevic Z\", \"Koeneman L\"]","journal":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","publication_date":"2026-05-29","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND HYPOTHESIS] Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors that reduced weight and hemoglobin A1c (HbA1c) in individuals with obesity and type 2 diabetes (T2D). Retatrutide may also address key chronic kidney disease (CKD)-related pathophysiological pathways. Mechanism-of-action studies are needed to understand its effects on kidney function. [METHODS] TRANSCEND-CKD is a double-blind, placebo-controlled, Phase 2b mechanistic study evaluating the efficacy of retatrutide in adults with overweight/obesity and CKD [estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2], with and without T2D. Participants were randomized 1:1 to once-weekly retatrutide maximum tolerated dose up to 12 mg or matched placebo. The primary objective is to evaluate the effect of retatrutide versus placebo on change in measured glomerular filtration rate (mGFR) by iohexol clearance from baseline to Week 24. Additional objectives include changes in magnetic resonance imaging-assessed kidney hemodynamic and volumetric measurements, including perirenal and renal sinus fat. [RESULTS] Of 367 participants screened, 146 were randomized to study interventions. The mean age was 65.1 years [standard deviation (SD) 10.6], 45.2% were female and 69.9% were White. The mean weight was 101.1 kg (SD 20.6) and body mass index 35.7 kg/m2 (SD 6.1). Participants with T2D (37.7%) had a mean HbA1c of 7.1% (SD 1.1%), while HbA1c was 5.7% (SD 0.3%) in participants without T2D. The mean mGFR was 49.3 mL/min/1.73 m2 (SD 19.0), cystatin C-based eGFR was 49.6 mL/min/1.73 m2 (SD 13.2) and creatinine-based eGFR was 64.2 mL/min/1.73 m2 (SD 17.8). The median baseline urine albumin-to-creatinine ratio was 14.0 mg/g (interquartile range 6.0-69.0). A total of 21.8% of participants were treated with sodium-glucose cotransporter-2 inhibitors at baseline. [CONCLUSIONS] TRANSCEND-CKD is designed to provide mechanistic insights on the effects of retatrutide on kidney function and structure, and to inform clinical findings in the ongoing cardio-kidney outcome trial TRIUMPH-Outcomes (NCT06383390). [CLINICAL TRIAL REGISTRATION NUMBER] NCT05936151.","url":"https://pubmed.ncbi.nlm.nih.gov/41160422/","source_name":"pubmed","source_tier":1,"coi_statement":"H.J.L.H.: consultant for Alexion, Alnylum, AstraZeneca, Bayer, Biocity biopharmaceuticals, Boehringer Ingelheim, Dimerix, Eli Lilly and Company, Janssen, Novartis, Novo Nordisk, Roche and Travere Therapeutics; and grant support from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk. D.H.v.R.: consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Merck and Novo Nordisk; and research funding from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck and Novo Nordisk. P.B.: consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Horizon Pharma, Novo Nordisk and XORTX; research funding from Amgen, AstraZeneca, Eli Lilly and Company, Horizon Pharma, Merck and Novo Nordisk; and advisory or leadership role in Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Horizon Pharma, Novo Nordisk and XORTX. M.C.B.: employee and shareholder of Eli Lilly and Company. P.W.: employee of R&G US and contracted by Eli Lilly and Company. I.T.: employee and shareholder of Eli Lilly and Company. Z.M.: employee and shareholder of Eli Lilly and Company. L.K.: employee and shareholder of Eli Lilly and Company.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"clinical_trial","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"maximum tolerated dose up to 12 mg once weekly\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":146,"follow_up":"24 weeks","direction":"unclear","population":"{\"mean_age\": 65.1, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"45.2% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"mixed (37.7% with type 2 diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease\", \"sample_size\": 146, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (mean age 65.1).","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Clinical trial (non-randomized or unclear)\", \"sample_size\": 146, \"randomization\": \"no\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"H.J.L.H.: consultant for Alexion, Alnylum, AstraZeneca, Bayer, Biocity biopharmaceuticals, Boehringer Ingelheim, Dimerix, Eli Lilly and Company, Janssen, Novartis, Novo Nordisk, Roche and Travere Therapeutics; and grant support from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk. D.H.v.R.: consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Merck and Novo Nordisk; and research funding from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck and Novo Nordisk. P.B.: consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Horizon Pharma, Novo Nordisk and XORTX; research funding from Amgen, AstraZeneca, Eli Lilly and Company, Horizon Pharma, Merck and Novo Nordisk; and advisory or leadership role in Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Horizon Pharma, Novo Nordisk and XORTX. M.C.B.: employee and shareholder of Eli Lilly and Company. P.W.: employee of R&G US and contracted by Eli Lilly and Company. I.T.: employee and shareholder of Eli Lilly and Company. Z.M.: employee and shareholder of Eli Lilly and Company. L.K.: employee and shareholder of Eli Lilly and Company.","sponsor_role":"manufacturer funded the study (sponsor role in design/analysis not stated in abstract)","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":null,"plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] TRANSCEND-CKD is designed to provide mechanistic insights on the effects of retatrutide on kidney function and structure, and to inform clinical findings in the ongoing cardio-kidney outcome trial TRIUMPH-Outcomes (NCT06383390).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":306,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Exenatide (EXENATIDE) - label effective 2026-05-27","authors":"[\"Amneal Pharmaceuticals LLC\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-05-27","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including exenatide. Discontinue if pancreatitis is suspected. ( 5.1 ) Never share an exenatide injection pen between patients, even if the needle is changed. ( 5.2 ) Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin : Patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.3 ) Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.4 ) Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Exenatide is not recommended in patients with severe gastroparesis. ( 5.5 ) Immunogenicity : Patients may develop antibodies to exenatide. If there is worsening glycemic control or failure to achieve target glycemic control, consider alternative antidiabetic therapy. ( 5.6 ) Hypersensitivity : Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue exenatide and promptly seek medical advice. ( 5.7 ) Drug-induced Immune-mediated Thrombocytopenia : Serious bleeding which may be fatal has been reported. Discontinue exenatide promptly and avoid re-exposure to exenatide. ( 5.8 ) Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.9 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 ) 5.1 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, including exenatide [see Adverse Reactions (6.2) ]. After initiation of exenatide, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue exenatide and initiate appropriate management. 5.2 Never Share an Exenatide Injection Pen Between Patients Exenatide injection pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving exenatide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Acute Kidney Injury Due to Volume Depletion There have been post-marketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, exenatide [see Adverse Reactions (6.2) ]. The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6) ]. Monitor renal function in patients reporting adverse reactions to exenatide that could lead to volume depletion, especially during dosage initiation and escalation of exenatide. Exenatide is not recommended in patients with severe renal impairment (creatinine clearance <30 \n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Acute Pancreatitis [see Warnings and Precautions (5.1) ] Never Share an Exenatide Pen Between Patients [see Warnings and Precautions (5.2) ] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.4) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5) ] Immunogenicity [see Warnings and Precautions (5.6) ] Hypersensitivity [see Warnings and Precautions (5.7) ] Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8) ] Acute Gallbladder Disease [see Warnings and Precautions (5.9) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] Most common (≥ 5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually decreases over time. ( 5.3 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypoglycemia Table 1 summarizes the incidence and rate of hypoglycemia with exenatide in six placebo-controlled clinical trials. Table 1: Incidence (%) and Rate of Hypoglycemia when Exenatide was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials * Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg BID Monotherapy (24 Weeks) N 77 77 78 % Overall 1.3% 5.2% 3.8% Rate (episodes/patient-year) 0.03 0.21 0.52 % Severe 0.0% 0.0% 0.0% With Metformin (30 Weeks) N 113 110 113 % Overall 5.3% 4.5% 5.3% Rate (episodes/patient-year) 0.12 0.13 0.12 % Severe 0.0% 0.0% 0.0% With a Sulfonylurea (30 Weeks) N 123 125 129 % Overall 3.3% 14.4% 35.7% Rate (episodes/patient-year) 0.07 0.64 1.61 % Severe 0.0% 0.0% 0.0% With Metformin and a Sulfonylurea (30 Weeks) N 247 245 241 % Overall 12.6% 19.2% 27.8% Rate (episodes/patient-year) 0.58 0.78 1.71 % Severe 0.0% 0.4% 0.0% With a Thiazolidinedione (16 Weeks) N 112 not evaluated 121 % Overall 7.1% not evaluated 10.7% Rate (episodes/patient-years) 0.56 not evaluated 0.98 % Severe 0.0% not evaluated 0.0% With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) † N 122 not evaluated 137 % Overall 29.5% not evaluated 24.8% Rate (episodes/patient-years) 1.58 not evaluated 1.61 % Severe 0.8% not evaluated 0.0% * A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value < 54 mg/dL or prompt recovery after treatment for hypoglycemia. † When exenatide was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA 1c ≤ 8.0% to minimize the risk of hypoglycemia. See Table 10 for insulin dose titration algorithm. N = number of Intent-to-Treat subjects in each treatment group. Immunogenicity Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of exenatide. In the 30-week controlled trials of exenatide add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at Week 6 and was reduced by 55% by Week 30. Three hundred and sixty patients (38%) had low titer antibodies (< 625\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with Exenatide Concomitant Use of Insulin Secretagogues or Insulin Clinical Impact Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin [see Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Intervention When initiating exenatide, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact In a drug interaction study, exenatide did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been post-marketing reports for exenatide of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the prothrombin time should be monitored more frequently after initiation or alteration of exenatide therapy. Once a stable prothrombin time has been documented, the prothrombin time can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, exenatide has the potential to reduce the rate of absorption of orally administered drugs [see Clinical Pharmacology (12.3) ]. Intervention Use caution when administering oral medications with exenatide where a slower rate of oral absorption may be clinically meaningful. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when exenatide is not administered [see Clinical Pharmacology (12.3) ] . May impact absorption of orally administered medications. ( 7 ) Warfarin: Post-marketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of exenatide therapy. ( 7 )\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Exenatide injection is contraindicated in patients with: A prior severe hypersensitivity reaction to exenatide or to any of the excipients in exenatide injection. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with exenatide injection [see Warnings and Precautions (5.7) ] . A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8) ]. History of severe hypersensitivity to exenatide or any of the excipients in exenatide injection. ( 4 ) History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e6cb5c8f-e97f-4a6a-95a4-939fd2393949","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"regulatory","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"metabolic\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":373,"doi":"10.1093/cid/ciaf577","pmid":"41098140","nct_ids":"[\"NCT04019197\"]","title":"Effects of Semaglutide on Cognitive Function in People With HIV: A Randomized, Controlled Trial","authors":"[\"Atieh O\", \"Daher J\", \"Abboud M\", \"Wu Q\", \"Sattar A\", \"Baissary J\", \"Koberssy Z\", \"Labbato D\", \"Eckard AR\", \"McComsey GA\"]","journal":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","publication_date":"2026-05-20","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] People with human immunodeficiency virus (HIV, PWH) are at higher risk for visceral adiposity, enhanced inflammation, and cognitive decline than controls who do not have HIV. We previously demonstrated that PWH with lipohypertrophy had a decrease in weight, visceral adipose tissue, and several inflammatory markers after receiving semaglutide, a glucagon-like peptide-1 receptor agonist. Our aim was to investigate the effect of semaglutide on cognitive function in PWH and the possible mediation of this effect by changes in adiposity or inflammation. [METHODS] In this randomized, double-blind, placebo-controlled phase 2b clinical trial, PWH on antiretroviral therapy were randomized 1:1 to receive 32 weeks of subcutaneous semaglutide or placebo. The primary outcome was the change in cognitive function at 32 weeks. Secondary measures included changes in body composition and inflammatory markers. Causal mediation analysis assessed semaglutide's direct and indirect effects on Cognivue scores through changes in adiposity and inflammation. [RESULTS] 108 participants were included (54 per arm); 65% were non-White, 40% were female, and median age was 53 years. Compared with placebo, PWH on semaglutide significantly increased visuospatial, naming/language, and delayed recall scores at 32 weeks (P = .01, .05, and .04, respectively). After adjusting for sex and absolute CD4 count, only visuospatial score remained statistically significant (P = .05). Semaglutide's total natural direct effect maintained a positive effect on the visuospatial score while accounting for potential changes in high-sensitivity C-reactive protein and soluble CD163 levels (P = .04). [CONCLUSIONS] Semaglutide may have a beneficial impact on visuospatial cognitive function in PWH through its effect on inflammation. Clinical Trials Registration . NCT04019197.","url":"https://pubmed.ncbi.nlm.nih.gov/41098140/","source_name":"pubmed","source_tier":1,"coi_statement":"Potential conflicts of interest. A. R. E. is an advisor for Theratechnologies and an advisor and speaker for Gilead Sciences. G. A. M. is a consultant for Gilead Sciences, ViiV, and Merck. All other authors report no potential conflicts.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cognition\", \"body_composition\", \"immune\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1518,"doi":"10.1038/s41467-026-72861-3","pmid":"42156721","nct_ids":"[\"NCT04019197\"]","title":"Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy","authors":"[\"Corley MJ\", \"Dwaraka VB\", \"Pang AP\", \"Labbato D\", \"Smith R\", \"Ross Eckard A\", \"McComsey GA\"]","journal":"Nature communications","publication_date":"2026-05-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial's primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( - 4.9 years/year, p = 0.004), PCGrimAge ( - 3.1, p = 0.007), GrimAge V2 ( - 2.3, p = 0.009), OMICmAge ( - 2.2, p = 0.009), RetroAge ( - 2.2, p = 0.030), and DunedinPACE ( - 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.","url":"https://pubmed.ncbi.nlm.nih.gov/42156721/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: G.A.M. serves as a research consultant for Merck, GlaxoSmithKline/ViiV, and Gilead. M.J.C. serves as a scientific advisor for TruDiagnostic. V.D. and R.S. are employees of TruDiagnostic. All other authors declare no competing interests.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T17:07:09+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo (volume-matched saline injections)\", \"dose\": \"0.25 mg for 4 weeks, 0.5 mg for 4 weeks, then 1.0 mg weekly through week 32\", \"route\": \"subcutaneous\", \"treatment_duration\": \"32 weeks\"}","domains":"[\"inflammation\", \"body_composition\", \"immune\", \"aging\", \"other_emerging\"]","outcome_type":"biomarker","primary_outcome":"annualized change in DNA-methylation epigenetic aging clocks from baseline to week 32 (post hoc; not prespecified in the parent trial)","endpoints":null,"effect_estimate":"Adjusted semaglutide vs placebo: PhenoAge -4.9 years/year (p = 0.004), PCGrimAge -3.1 (p = 0.007), GrimAge V2 -2.3 (p = 0.009), OMICmAge -2.2 (p = 0.009), RetroAge -2.2 (p = 0.030), DunedinPACE -0.09 units (9% slower, p = 0.01); not significant: DNAmFitAge (P = 0.323), AdaptAge, CausAge, DamAge, Horvath, Hannum, PCHorvath1, PCHorvath2 and the intrinsic capacity clock (P = 0.312)","confidence_interval":"PhenoAge: 95% CI −8.16 to −1.63","p_value":"p = 0.004 (PhenoAge); p-values not adjusted for multiple comparisons","sample_size":84,"follow_up":"32 weeks","direction":"mixed","population":"{\"mean_age\": \"49 ± 12 years\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"42% women (35 of 84); men 67% of the semaglutide group vs 49% of placebo\", \"bmi_mean\": null, \"bmi_min\": 25, \"obesity_status\": \"overweight or obesity required (BMI ≥ 25 kg/m²); median BMI 32.9\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"excluded (active cardiovascular disease)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"HIV-associated lipohypertrophy (treated HIV on stable ART)\", \"sample_size\": 84, \"inclusion_exclusion\": \"adults ≥18 with HIV-1 on stable ART, HIV-1 RNA < 400 copies/mL, BMI ≥ 25, lipohypertrophy by waist criteria; diabetes and active cardiovascular disease excluded\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had treated HIV with lipohypertrophy and BMI ≥ 25 kg/m² (median 32.9, described as obese), mean age 49; diabetes and active cardiovascular disease were excluded.","mediation":"possibly","mediation_notes":"No weight, HbA1c or visceral-fat change is reported for the 84 analysed participants and no mediation analysis was done; models adjust for baseline sex, BMI, hsCRP and sCD163, which addresses confounding, not mediation. The authors suggest visceral fat reduction may drive the clock effects.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 84, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (volume-matched saline injections)\", \"follow_up_duration\": \"32 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported; 84 participants; p-values not adjusted for multiple comparisons across 17 clocks; no sample-size calculation (post hoc)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: randomized and double-blind but small (84 with paired samples), single-centre, 32 weeks, post hoc and exploratory, with biomarker-only outcomes and p-values not adjusted across 17 clocks: a biomarker-only randomized comparison.","funding_source":"National Institutes of Health (R01DK121619; PubMed grants: NIAID, NIDDK, NCATS); Clinical and Translational Science Collaborative of Northern Ohio; James B. Pendleton Charitable Trust; San Diego Center for AIDS Research","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"One author consults for Merck, GlaxoSmithKline/ViiV and Gilead; one advises TruDiagnostic and two are TruDiagnostic employees; the other authors declare no competing interests.","sponsor_role":"not reported","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported","limitations":"A post hoc, exploratory biomarker analysis of a single-centre trial with 84 participants and 32 weeks of follow-up, in an HIV-specific population, without correction for multiple comparisons; blood-based clocks are statistical predictors, not clinical outcomes.","plain_summary":"This post hoc analysis of a randomized, double-blind trial measured blood DNA-methylation aging clocks in 84 adults with HIV and abdominal fat build-up (lipohypertrophy) who took weekly semaglutide or placebo for 32 weeks. Several clocks were associated with slower aging on semaglutide, for example PhenoAge by 4.9 years per year and DunedinPACE about 9% slower. Many other clocks, including most first-generation clocks and an intrinsic capacity clock, showed no significant difference. These are biomarkers, not health outcomes, and the analysis was exploratory and not planned in advance.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":798,"doi":"10.1210/clinem/dgag201","pmid":"42135195","nct_ids":"[]","title":"Retatrutide And Lipid And Metabolite Profiles In Participants With Obesity With Or Without Type 2 Diabetes","authors":"[\"Pearson MJ\", \"Willency JA\", \"Lin Y\", \"Abadi A\", \"Hartman ML\", \"Coskun T\", \"Ruotolo G\", \"Duffin KL\", \"Haupt A\", \"Newgard CB\", \"Pirro V\"]","journal":"The Journal of clinical endocrinology and metabolism","publication_date":"2026-05-14","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[CONTEXT] In phase 2 trials, retatrutide reduced body weight, hemoglobin A1c, and improved the lipid profiles of participants living with obesity, with and without T2D. [OBJECTIVE] Assess plasma metabolome and lipidome changes associated with retatrutide treatment. [DESIGN] Metabolomics and lipidomics were performed in fasting samples from two randomized, placebo-controlled phase 2 trials. Participants living with obesity with and without T2D were treated for 36 and 48 weeks, respectively. [SETTING] Post-hoc exploratory analysis. [PARTICIPANTS] 282 and 213 participants in the obesity and T2D trials, respectively. [INTERVENTION(S)] Obesity trial; retatrutide (1, 4, 8, 12 mg) or placebo. T2D trial: retatrutide (0.5, 4, 8, 12 mg) or placebo or dulaglutide (1.5 mg). [MAIN OUTCOME MEASURE(S)] Changes in metabolite and lipid levels with retatrutide treatment against baseline levels and placebo using multiplicity correction. [RESULTS] At both primary and study endpoints for both populations, higher doses of retatrutide were associated with changes in a cluster of metabolites comprising 3-hydroxybutyrate, acetylcarnitine, free carnitine and fatty acid-derived long-chain acylcarnitines. Mediation analyses suggested that changes in these biomarkers mediated 23.2% of the weight-reduction response in participants without T2D and that this mediation was blunted to 12.7% in participants with T2D. Retatrutide treatment was also associated with changes in metabolites associated with insulin resistance, including branched-chain amino acids and their catabolic products, 2-aminoadipic acid, 2-hydroxybutyrate, urate, and triglycerides enriched in short-chain and saturated acyl side chains. These changes were found in both study populations and sustained across study endpoints. [CONCLUSIONS] Retatrutide was associated with changes in two metabolic clusters related to fatty acid oxidation and insulin resistance in a direction associated with improved metabolic health and reduced cardiovascular risk.","url":"https://pubmed.ncbi.nlm.nih.gov/42135195/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:51:16+00:00","study_design":"rct","drugs":"[\"dulaglutide\", \"retatrutide\"]","drug_details":"{\"dose\": \"1, 4, 8 or 12 mg (obesity trial); 0.5, 4, 8 or 12 mg (T2D trial)\", \"comparator\": \"placebo; dulaglutide 1.5 mg in the T2D trial\"}","domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":495,"follow_up":"48 weeks (obesity trial, without T2D); 36 weeks (T2D trial)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"mixed (one trial without and one with type 2 diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 495, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Participants had obesity, either without type 2 diabetes (obesity trial, n=282) or with it (T2D trial, n=213); age and BMI not reported in abstract; effects may be mediated by weight loss.","mediation":"possibly","mediation_notes":"Mediation analysis estimated that metabolite changes accounted for 23.2% of the weight-loss response without T2D and 12.7% with T2D; it did not test effects independent of weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 495, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo; dulaglutide 1.5 mg in the T2D trial\", \"follow_up_duration\": \"48 weeks (obesity trial, without T2D); 36 weeks (T2D trial)\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In a post-hoc exploratory analysis of two phase 2 trials, retatrutide changed blood markers linked to fat burning and insulin resistance; these are biomarkers only, and no cardiovascular outcomes were measured.","methodological_notes":"Post-hoc exploratory analysis of stored fasting samples from two randomized, placebo-controlled phase 2 trials; not a randomized test of these outcomes.","reviewed_by":null,"reviewed_at":null},{"id":51,"doi":"10.1007/s10072-026-09084-3","pmid":"42105060","nct_ids":"[]","title":"Efficacy and safety of GLP-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis of randomized clinical trials","authors":"[\"Mendonça MF\", \"Interaminense AC\", \"do R Barros GST\", \"Rabelo LA\", \"de Oliveira PG\", \"Sales RF\", \"de C Lyra AMV\", \"de S E Silva HR\"]","journal":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","publication_date":"2026-05-09","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Parkinson's disease (PD) is a progressive neurodegenerative disorder with no proven disease-modifying therapies to date. Because changes in cerebral glucose metabolism and insulin resistance have been linked to PD pathophysiology, glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes, have been investigated as potential neuroprotective treatments. [METHODS] This study systematically assessed the efficacy and safety of GLP-1RAs in PD through a systematic review and meta-analysis of randomized controlled trials identified in PubMed, Embase, and the Cochrane Library. The primary outcomes were motor function improvements measured by the MDS-UPDRS Part III in both on- and off-medication states at study endpoints and at intermediate timepoints of interest. Secondary outcomes included MDS-UPDRS Parts I, II, and IV, quality of life assessed by the PDQ-39, levodopa equivalent daily dose (LEDD), and the occurrence of adverse events. [RESULTS] The meta-analysis found no statistically significant difference in favor of GLP-1RAs over placebo for motors and non-motors outcomes, except for PDQ-39 (MD: - 0.75; 95% CI: [- 1.34, - 0.17], P = 0.01). Regarding safety, GLP-1RAs were associated with a higher incidence of adverse events, especially gastrointestinal effects such as nausea, vomiting, and constipation. [CONCLUSIONS] Overall, current evidence does not demonstrate consistent clinical benefit of using GLP-1RAs for treating motor or non-motor symptoms in PD nor support GLP-1RAs as disease-modifying therapy, underscoring the need for further research.","url":"https://pubmed.ncbi.nlm.nih.gov/42105060/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Competing interests: The authors declare that they have no conflict of interest of any kind in the content of this article. Ethical approval and Informed consent: This study is a systematic review and meta-analysis based on previously published studies. Therefore, ethical approval and informed consent were not required. All included studies were conducted in accordance with established ethical standards.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"exenatide\", \"lixisenatide\", \"liraglutide\", \"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"parkinsons\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"MDS-UPDRS III (on and off) in RCTs of GLP-1RAs in Parkinson's disease","endpoints":null,"effect_estimate":"No significant benefit on motor or non-motor outcomes; PDQ-39 MD -0.75 (small); more GI adverse events","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not selected for weight\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Parkinson's disease\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"PD patients not selected for weight or diabetes; disease-specific outcomes.","mediation":"unlikely","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"pooled RCTs including the phase 3 exenatide trial\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"CI reported: 95% CI: [- 1\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Meta-analysis of RCTs concluding no consistent benefit.","funding_source":"Not stated","industry_funded":"no","manufacturer":null,"author_conflicts":"Authors declare no conflicts.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A 2026 meta-analysis of randomized trials found no statistically significant benefit of GLP-1 drugs on motor or non-motor Parkinson's outcomes, except a small improvement in quality of life (PDQ-39 MD -0.75), and more gastrointestinal side effects. The authors say current evidence does not show consistent clinical benefit or support these drugs as disease-modifying therapy.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":349,"doi":"10.1001/jamacardio.2026.0245","pmid":"41879791","nct_ids":"[\"NCT03914326\"]","title":"Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial","authors":"[\"Mulvagh SL\", \"Inzucchi SE\", \"Marx N\", \"Poulter NR\", \"Deanfield JE\", \"Pop-Busui R\", \"Emerson SS\", \"Mann JFE\", \"Engelmann MDM\", \"Hovingh GK\", \"Mandavya K\", \"Davicevic-Elez Z\", \"Jeppesen OK\", \"Lorenzatti A\", \"Oguz A\", \"Mankovsky B\", \"Deerochanawong C\", \"Gorgojo-Martinez JJ\", \"Ji L\", \"Bain SC\", \"McGuire DK\", \"Buse JB\", \"SOUL Study Group\"]","journal":"JAMA cardiology","publication_date":"2026-05-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Individuals with type 2 diabetes (T2D) are at high risk of atherosclerotic cardiovascular disease (ASCVD). In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear. [OBJECTIVE] To investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo. [DESIGN, SETTING, AND PARTICIPANTS] This secondary analysis comprises post hoc intention-to-treat analyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blind multicenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC. Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025. [INTERVENTION(S)] Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care. [MAIN OUTCOMES AND MEASURES] The primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs). [RESULTS] Of 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (-0.87 percentage points), body weight (-2.54%), systolic BP (SBP, -3.84 mm Hg), pulse pressure (-3.81 mm Hg), hsCRP (-18.08%), total cholesterol (TC, -7.00%), non-high-density lipoprotein cholesterol (non-HDL-C, -8.02%), HDL-C (-4.49%), and triglycerides (-8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration. Body weight reductions were gradual across both groups. At week 156, in favor of oral semaglutide were ETDs for HbA1c (-0.47 percentage points; 95% CI, -0.52 to -0.42), body weight (-3.26 percentage points; 95% CI, -3.55 to -2.98), SBP (-1.83 mm Hg; 95% CI, -2.47 to -1.18), and pulse pressure (-2.17 mm Hg; 95% CI, -2.72 to -1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (0.99; 95% CI, 0.98-1.00), non-HDL-C (0.98; 95% CI, 0.97-0.99), HDL-C (1.01; 95% CI, 1.01-1.02), and triglycerides (0.94; 95% CI, 0.93-0.96). No significant treatment differences were observed for low-density lipoprotein cholesterol or diastolic BP. [CONCLUSIONS AND RELEVANCE] In this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT03914326.","url":"https://pubmed.ncbi.nlm.nih.gov/41879791/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":52,"doi":"10.1371/journal.pmed.1005064","pmid":"42166479","nct_ids":"[]","title":"Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies","authors":"[\"Chrzanowski J\", \"Walicka M\", \"Burzyński J\", \"Zaraś M\", \"Michalak A\", \"Fendler W\"]","journal":"PLoS medicine","publication_date":"2026-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide use and the development of nonarteritic anterior ischemic optic neuropathy (NAION), a rare but vision-threatening condition. We aimed to evaluate whether semaglutide use is associated with an increased risk of NAION in patients with T2DM. [METHODS AND FINDINGS] We conducted a systematic review and meta-analysis of observational studies comparing patients with T2DM aged ≥12 years treated with semaglutide to those receiving other glucose-lowering therapies. We searched PubMed, Scopus, and Web of Science databases from January 2023 to November 2025. Two reviewers independently extracted data on study design, population characteristics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale, and ROBINS-I v.2. Certainty of the evidence was graded according to the GRADE framework. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using fixed-effects models; sensitivity analyses included crude and subgroup HRs, and overlapping study replacement. Leave-one-out analysis was conducted to assess small-study effects and publication bias. Results were contextualized within other meta-analyses, systematic reviews, consensus statements, and regulatory communications on the topic. Five eligible observational studies met the inclusion criteria, and 7 additional studies were included in the sensitivity analysis. Semaglutide use was associated with a significantly increased hazard of NAION compared with nonsemaglutide glucose-lowering regimens (HR 2.17, 95% CI [1.73, 2.74]; p < 0.001), regimens excluding other GLP-1 receptor agonists (HR 2.13, 95% CI [1.60, 2.83]; p < 0.001), and sodium-glucose co-transporter 2 inhibitor (SGLT2i) users (HR 1.96, 95% CI [1.28, 2.99]; p = 0.002). Despite the increased relative risk, the absolute risk remained low at 0.014% (95% CI [0.005%, 0.023%]; p = 0.002), corresponding to approximately 1 additional case of NAION per 7,000 semaglutide-treated patients annually. The results were consistent with meta-analyses of observational studies and corroborated decisions presented in regulatory communications. Due to exclusive focus on retrospective, registry-based observational studies, the evidence synthesis was limited and could be biased by study-level outcome misclassification and confounding. [CONCLUSIONS] Our findings suggest a possible association between semaglutide use and an increased risk of NAION in patients with T2DM. Although the absolute risk is low, clinicians should be aware of this potential adverse event, particularly in individuals at increased baseline risk for optic neuropathies. While these findings support current recommendations to discontinue semaglutide in patients diagnosed with NAION, the certainty of the available evidence is low, underscoring the need for further high-quality studies to clarify this association.","url":"https://pubmed.ncbi.nlm.nih.gov/42166479/","source_name":"pubmed","source_tier":1,"coi_statement":"I have read the journal’s policy and the authors of this manuscript have the following competing interests: J.C. received lecture honoraria from Novo Nordisk and Boehringer Ingelheim and a consulting fee from Novo Nordisk. A.M. received lecture honoraria from Novo Nordisk, Boehringer Ingelheim, and Dexcom. M.W. received lecture honoraria from AstraZeneca, Eli Lilly, Sanofi, and Teva, and support for meeting attendance from Sanofi. The other authors have declared that no competing interest exist.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{}","domains":"[\"ophthalmologic\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"NAION in observational studies of semaglutide vs other glucose-lowering therapy in T2D","endpoints":null,"effect_estimate":"HR 2.17 (5 studies); vs SGLT2i HR 1.96; absolute risk 0.014%/year (~1 per 7,000 treated per year)","confidence_interval":"1.73 to 2.74","p_value":"<0.001","sample_size":null,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 12.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Diabetes populations; absolute risk estimate is the useful quantity for any user.","mediation":"unknown","mediation_notes":"[Auto] Harm signal; weight-loss mediation not the relevant question, but consider whether harms relate to rapid weight loss or reduced intake.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"5 studies consistent\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 1.73 to 2.74\", \"risk_of_bias\": \"observational, registry-based; outcome misclassification possible\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Consistent observational association with very low absolute risk; causality unproven.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim","author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"not reported in abstract","independent_replication_exists":"yes (multiple cohorts)","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"Combining five observational studies in people with type 2 diabetes, semaglutide use was associated with roughly double the hazard of NAION (low-certainty evidence), a rare but vision-threatening eye condition, equating to about one extra case per 7,000 people treated per year. The authors note this is consistent with regulatory communications.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":323,"doi":"10.7759/cureus.109953","pmid":"42382865","nct_ids":"[]","title":"Incretin-Based Therapies in Obesity-Related Heart Failure With Preserved Ejection Fraction (HFpEF): A Systematic Review of Emerging Cardiometabolic Disease Modification Beyond Glycemic Control","authors":"[\"Hemdev V\", \"Abuzenah M\", \"Alsaafin Q\", \"Al Ghananeem Z\", \"Diksha F\", \"Khatak A\"]","journal":"Cureus","publication_date":"2026-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Heart failure with preserved ejection fraction (HFpEF) remains a clinically heterogeneous syndrome with limited disease-modifying therapeutic options, particularly among patients with obesity-related cardiometabolic dysfunction. Increasing evidence suggests that obesity-associated HFpEF represents a distinct inflammatory and metabolically active phenotype characterized by visceral adiposity, endothelial dysfunction, congestion physiology, impaired exercise capacity, and adverse cardiac remodeling. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, have recently emerged as promising interventions within this evolving therapeutic landscape. This systematic review evaluated contemporary randomized clinical evidence examining the effects of semaglutide and tirzepatide in obesity-related HFpEF. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, and Web of Science for studies published between January 2020 and July 2025. Nine studies met the predefined eligibility criteria, including landmark randomized controlled trials, pooled analyses, and mechanistic imaging and biomarker substudies. Across the included studies, incretin-based therapies consistently improved heart failure-related symptoms, exercise capacity, quality of life, inflammatory biomarkers, and body weight, while also demonstrating favorable effects on structural remodeling, congestion-related physiology, and cardiovascular-kidney interactions. Mechanistic analyses suggested potential benefits involving reductions in left ventricular mass, paracardiac adipose tissue, inflammatory burden, plasma volume expansion, and markers of myocardial and renal injury. Collectively, the current evidence supports the growing role of incretin-based therapies as promising phenotype-oriented interventions in obesity-related HFpEF and raises the possibility that targeted cardiometabolic modulation may influence multiple domains of disease pathophysiology beyond glycemic control alone. However, further long-term studies are needed to clarify their effects on remodeling reversal, arrhythmia burden, and cardiovascular mortality.","url":"https://pubmed.ncbi.nlm.nih.gov/42382865/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1522,"doi":"10.1038/s41586-026-10330-z","pmid":"41951734","nct_ids":"[]","title":"Genetic predictors of GLP1 receptor agonist weight loss and side effects","authors":"[\"Su QJ\", \"Ashenhurst JR\", \"Xu W\", \"Tran V\", \"Ryanne Wu R\", \"Weldon CH\", \"Shi J\", \"Hicks B\", \"23andMe Research Team\", \"Abul-Husn NS\", \"Aslibekyan S\", \"Holmes MV\", \"Koelsch BL\", \"Auton A\"]","journal":"Nature","publication_date":"2026-05","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects1. To investigate the genetic basis of this variability, here we conduct a genome-wide association study of self-reported weight loss and treatment-related side effects in 27,885 people following GLP1 receptor agonist therapy. We identify a missense variant in GLP1R that is associated significantly with increased efficacy of GLP1 medications (P = 2.9 × 10-10), with an additional -0.76 kg of weight loss expected per copy of the effect allele. Furthermore, we identify associations linking variation in both GLP1R and GIPR to GLP1 medication-related nausea or vomiting, with the GIPR association being restricted to people using tirzepatide. We incorporate these findings into a broader model of GLP1 medication response, and demonstrate the ability to stratify patients by efficacy and side effect risk. These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.","url":"https://pubmed.ncbi.nlm.nih.gov/41951734/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: All authors are current or former employees of 23andMe. N.S.A.-H. holds an academic appointment at the Icahn School of Medicine at Mount Sinai. M.V.H. is currently affiliated with Genentech.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T20:25:44+00:00","study_design":"unknown","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": \"various (self-reported most recent weekly dose)\", \"route\": null, \"comparator\": \"none: genotype groups compared within treated users, with no untreated group (the variant effect was also compared between semaglutide and tirzepatide users)\", \"treatment_duration\": \"median 8.3 months (self-reported)\"}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"percentage BMI change on treatment (self-reported) and moderate-to-severe side effects (nausea, vomiting) by genotype","endpoints":null,"effect_estimate":"GLP1R missense variant rs10305420: 0.641% more BMI loss (about 0.76 kg) per T allele, P = 2.9 × 10-10; replicated in All of Us (effect -0.47%, P = 0.001) but not in UK Biobank; GLP1R-region variants linked to vomiting (OR 1.57) and nausea (OR 1.36); GIPR variant rs1800437 linked to vomiting only in tirzepatide users and not to weight loss (P = 0.73).","confidence_interval":"95% CI −1.27 to −0.34 kg (per-allele weight effect of rs10305420)","p_value":"P = 2.9 × 10-10 (rs10305420 and BMI loss)","sample_size":15237,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": \"median 52 years\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"82.4% female\", \"bmi_mean\": \"median 35.1 before treatment\", \"bmi_min\": null, \"obesity_status\": \"mixed (96.8% had BMI ≥25 at baseline; median BMI 35.1)\", \"diabetes_status\": \"mixed (23.1% reported using the drug to improve blood sugar)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"use of semaglutide or tirzepatide, mostly for weight loss\", \"sample_size\": 15237, \"inclusion_exclusion\": \"23andMe research participants who had taken prescription weight-loss medication and reported using a semaglutide or tirzepatide product; GWAS limited to unrelated people of European ancestry with complete data; quality-control filters on weight, height, BMI and age under 18\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: people taking semaglutide or tirzepatide mostly for weight loss, 96.8% with BMI of at least 25 and median BMI 35.1, mostly women (82.4%) with median age 52; 23.1% used the drug for blood sugar. No results are reported for normal-weight people.","mediation":"not_applicable","mediation_notes":"Not applicable: the efficacy outcome is percentage BMI change, so weight loss cannot mediate itself, and the side-effect outcomes are genotype associations rather than a benefit to attribute. The authors' co-localization of the weight and nausea signals at GLP1R is a genetic association, not a mediation analysis.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": 15237, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"none: genotype groups compared within treated users, with no untreated group (the variant effect was also compared between semaglutide and tirzepatide users)\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"genome-wide P values and one 95% CI reported; GWAS n 15,237; replicated in 4,855 All of Us participants; not replicated in UK Biobank, where expected power was low\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a genome-wide association study within one-off self-reported survey data from treated 23andMe research participants, with no untreated comparator (IN-063: an uncontrolled cross-sectional study of treated users is VERY_LOW); the weight signal replicated in All of Us health-record data but not in UK Biobank.","funding_source":"not reported","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"All authors are current or former 23andMe employees; one also holds an academic appointment at the Icahn School of Medicine at Mount Sinai and one is now affiliated with Genentech.","sponsor_role":"not reported","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"Self-reported nausea and vomiting were associated with variants near GLP1R (vomiting OR 1.57; nausea OR 1.36), and a GIPR variant with vomiting in tirzepatide users only; people homozygous for risk alleles at both genes had 14.8-fold odds of tirzepatide-related vomiting.","limitations":"Weight change and side effects were self-reported in a one-off survey with no untreated comparator; health records showed smaller weight loss than self-report (−5.79% vs −11.8%), the sample was mostly female and of European ancestry, genetic effects were modest beside non-genetic factors, and the efficacy signal did not replicate in UK Biobank, where power was low and the data predate semaglutide and tirzepatide.","plain_summary":"Researchers at 23andMe surveyed research participants who had taken semaglutide or tirzepatide (27,885 people, median BMI 35.1; 15,237 in the main genetic analysis) and searched their genomes for variants linked to self-reported weight loss and side effects. A variant in the GLP-1 receptor gene was linked to slightly more weight loss, about 0.76 kg per copy, and variants near the same gene were linked to nausea and vomiting; a variant in the GIP receptor gene was linked to vomiting only in people taking tirzepatide. The weight-loss link was repeated in one health-records cohort but not in UK Biobank. Everyone in the study took a drug and reported their own weight and side effects, so these are associations that show who may respond differently, not whether the drugs work compared with not taking them.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":341,"doi":"10.1016/j.eprac.2026.04.014","pmid":"42061648","nct_ids":"[]","title":"Tirzepatide Beyond Diabetes and Obesity: Systematic Review and Meta-Analysis of Multisystem Therapeutic Benefits","authors":"[\"Eisa N\", \"Barood O\"]","journal":"Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists","publication_date":"2026-04-28","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] To comprehensively synthesize and quantify the multiorgan effects of tirzepatide across 10 health domains beyond its primary indications for type 2 diabetes and obesity. [METHODS] We searched PubMed, Embase, and CENTRAL through January 2026 for randomized controlled trials of tirzepatide (≥24 weeks) reporting on cardiovascular, heart failure, renal, metabolic dysfunction-associated steatohepatitis (MASH), obstructive sleep apnea, blood pressure, lipids, quality of life, body composition, or inflammatory outcomes. Data from 17 randomized controlled trials (N = 25 847) were pooled using random-effects models, with risk of bias assessed via Cochrane Risk of Bias 2 and evidence certainty rated using Grading of Recommendations, Assessment, Development, and Evaluations. [RESULTS] Tirzepatide demonstrated noninferiority to dulaglutide for major adverse cardiovascular events (HR 0.92, 95% CI 0.83-1.02). In heart failure outcomes in patients with preserved ejection fraction patients, it reduced cardiovascular death or heart failure events by 38% (HR 0.62, 95% CI 0.41-0.95). Additional benefits included: MASH resolution in 62% of patients (RR 5.33), clinically significant apnea-hypopnea index reduction (21.9 events/hour), systolic blood pressure reduction (5.8 mmHg), triglyceride reduction (19.6%), estimated glomerular filtration rate preservation (+1.5 mL/min/year), and high-sensitivity C-reactive protein reduction (32.9%). [CONCLUSIONS] Tirzepatide provides clinically significant, multiorgan benefits across heart failure, MASH, sleep apnea, blood pressure, lipids, and inflammation. Supported by moderate-to-high certainty evidence, it emerges as a comprehensive cardiometabolic protective agent. However, findings for domains like heart failure and MASH resolution rely on few trials, necessitating cautious interpretation regarding generalizability.","url":"https://pubmed.ncbi.nlm.nih.gov/42061648/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosure The authors have no conflicts of interest to disclose.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\", \"liver\", \"sleep\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":307,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Soliqua 100/33 (INSULIN GLARGINE AND LIXISENATIDE) - label effective 2026-03-18","authors":"[\"Sanofi-Aventis U.S. LLC\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-03-18","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Anaphylaxis and Serious Hypersensitivity Reactions : Severe, life-threatening, and generalized allergic reactions can occur. Instruct patients to discontinue use if a reaction occurs and promptly seek medical attention. ( 5.1 ) Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including SOLIQUA 100/33. Discontinue if pancreatitis is suspected. ( 5.2 ) Never share a SOLIQUA 100/33 prefilled pen between patients, even if the needle is changed. ( 5.3 ) Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen : Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.4 ) Overdose Due to Medication Errors : SOLIQUA 100/33 contains two drugs. Instruct patients to always check the label before each injection since accidental mix-ups with insulin products can occur. Do not exceed the maximum dose or use with other GLP-1 receptor agonists. ( 5.5 ) Hypoglycemia : May be life-threatening. Increase frequency of glucose monitoring with changes to insulin dosage, coadministered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. ( 5.6 ) Acute kidney injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. SOLIQUA 100/33 is not recommended in patients with end-stage renal disease. ( 5.7 ) Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. SOLIQUA 100/33 is not recommended in patients with severe gastroparesis ( 5.8 ). Immunogenicity : Patients may develop antibodies to insulin glargine and lixisenatide. If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection-site reactions or allergic reactions, alternative antidiabetic therapy should be considered. ( 5.9 ) Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.10 ) Fluid Retention and Heart Failure with Use of PPAR-gamma agonists : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.11 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.12 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures . ( 5.13 ) 5.1 Anaphylaxis and Serious Hypersensitivity Reactions In clinical trials of lixisenatide there have been cases of anaphylaxis (frequency of 0.1% or 10 cases per 10,000 patient-years) and other serious hypersensitivity reactions including angioedema. Severe, life-threatening, generalized allergic reactions, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including insulin glargine. There have been postmarketing reports of serious hypersensitivity reactions, including anaphylactic reactions and angioedema, in patients treated with SOLIQUA 100/33 [see Adverse Reactions (6.1) ] . Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with SOLIQUA 100/33. SOLIQUA 100/33 is contraindicated in patients with known serious hypersensitivity to lixisenatide or insulin glargine [see Contraindications (4) ] . If a hypersensitivity reaction occurs, the patient should discontinue SOLIQUA 100/33 and promptly seek medical attention. 5.2 \n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Acute Pancreatitis [see Warnings and Precautions (5.2) ] Hypoglycemia [see Warnings and Precautions (5.6) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.7) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.8) ] Hypokalemia [see Warnings and Precautions (5.10) ] Acute Gallbladder Disease [see Warnings and Precautions (5.12) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.13) ] The most common adverse reactions, reported in ≥5% of patients treated with SOLIQUA 100/33 include hypoglycemia, nausea, nasopharyngitis, diarrhea, upper respiratory tract infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The safety of SOLIQUA 100/33 (n=834, with a mean treatment duration of 203 days) has been evaluated in two clinical studies (30 weeks duration) in type 2 diabetes patients. The studies, Study A and B [see Clinical Studies (14) ] , had the following characteristics: mean age was approximately 59 years; approximately 50% were male, 90% were Caucasian, 6% were Black or African American, and 18% were Hispanic. The mean duration of diabetes was 10.3 years, mean HbA1c at screening for Study A was 8.2 and Study B was 8.5. The mean BMI at baseline was 32 kg/m 2 . Baseline eGFR was ≥60 mL/min in 87.2% of the pooled study population and mean baseline eGFR was 83.0 mL/min/1.73 m 2 . Table 3: Adverse Reactions Occurring in ≥5% of SOLIQUA 100/33–Treated Patients with Type 2 Diabetes Mellitus from Two Pooled Clinical Trials SOLIQUA 100/33, % (n=834) Nausea 10.0 Nasopharyngitis 7.0 Diarrhea 7.0 Upper respiratory tract infection 5.5 Headache 5.4 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, and insulin-containing products including SOLIQUA 100/33 [see Warnings and Precautions (5.6) ] . The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for SOLIQUA 100/33 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. In the SOLIQUA 100/33 program, severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and documented symptomatic hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by a self-monitored plasma glucose value equal to or less than 70 mg/dL (see Table 4 ). No clinically important differences in risk of severe hypoglycemia between SOLIQUA 100/33 and comparators were observed in clinical trials. Table 4: Hypoglycemic Episodes in SOLIQUA 100/33-Treated Patients with T2DM SOLIQUA 100/33 Study A N=469 SOLIQUA 100/33 Study B N=365 Severe symptomatic hypoglycemia Defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. (%) 0 1.1 Hypoglycemia (self-monitored plasma glucose <54 mg/dL) (%) 8.1 17.8 Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions are the most commonly observed adverse reaction in patients using lixisenatide. Gastrointestinal adverse reactions occur m\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Drugs that affect glucose metabolism : Adjustment of SOLIQUA 100/33 dosage may be needed; closely monitor blood glucose. ( 7.1 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced. ( 7.1 ) Effects of delayed gastric emptying on oral medications : Lixisenatide delays gastric emptying which may impact absorption of concomitantly administered oral medications. Oral contraceptives and other medications such as antibiotics and acetaminophen should be taken at least 1 hour prior to SOLIQUA 100/33 administration or 11 hours after. ( 7.2 ) 7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of SOLIQUA 100/33 and particularly close monitoring. Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when SOLIQUA 100/33 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of SOLIQUA 100/33 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose increases and increased frequency of glucose monitoring may be required when SOLIQUA 100/33 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of SOLIQUA 100/33 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when SOLIQUA 100/33 is coadministered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when SOLIQUA 100/33 is coadministered with these drugs. 7.2 Effects of Delayed Gastric Emptying on Oral Medications Lixisenatide-containing products, including SOLIQUA 100/33, delay gastric emptying which may reduce the rate of absorption of orally administered medications. Use caution when coadministering oral medications that have a narrow therapeutic ratio or that require careful clinical monitoring. These medications should be adequately monitored when concomitantly administered with lixisenatide. If such medications are to be administered with food, patients should be advised to take them with a meal or snack when lixisenatide is not administered. Antibiotics, acetaminophen, or other medications that are particularly dependent on threshold concentrations for efficacy or for which a delay in effect is undesirable should be administered at least 1 hour before SOLIQUA 100/33 injection [see Clinical Pharmacology (12.3) ] . Oral contraceptives should be taken at least 1 hour before SOLIQUA 100/33 administration or 11 hours after [see Clinical Pharmacology (12.3) ] .\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS SOLIQUA 100/33 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions (5.6) ] . In patients with serious hypersensitivity to insulin glargine, lixisenatide, or any of the excipients in SOLIQUA 100/33. Hypersensitivity reactions including anaphylaxis have occurred with both lixisenatide and insulin glargine [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . During episodes of hypoglycemia. ( 4 ) Serious hypersensitivity to insulin glargine, lixisenatide, or any of the excipients in SOLIQUA 100/33 ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4bba538b-cf7c-4310-ae8f-cb711ed21bcc","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"lixisenatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"immune\", \"addiction\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1525,"doi":"10.1001/jamaophthalmol.2025.6262","pmid":"41678180","nct_ids":"[]","title":"New-Onset Nonarteritic Anterior Ischemic Optic Neuropathy and Initiators of Semaglutide in US Veterans With Type 2 Diabetes","authors":"[\"Heberer K\", \"Bress AP\", \"Cogill S\", \"Maldonado AI\", \"Kim SH\", \"Nallamshetty S\", \"Chen YQ\", \"Shih MC\", \"Lynch JA\", \"Lee JS\"]","journal":"JAMA ophthalmology","publication_date":"2026-03-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered safe, effective medications for type 2 diabetes (T2D) and weight loss, used by millions worldwide. While their cardiometabolic benefits are well established, emerging observations suggest a potential association between GLP-1RA use and new-onset nonarteritic anterior ischemic optic neuropathy (NAION). [OBJECTIVE] To emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide (GLP-1RA), compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for T2D in a nationwide cohort of US veterans. [DESIGN, SETTING, AND PARTICIPANTS] This study was conducted nationwide using data from the Veterans Health Administration health care system between March 1, 2018, and March 1, 2025. This active-comparator, new-user, target trial emulation used cause-specific hazard ratios (HRs) that were estimated using overlap weighting to account for confounding. Participants included US veterans with T2D, current metformin use, and no prior GLP-1RA or SGLT2i use. Data analysis was conducted from July 2025 through September 2025. [EXPOSURE] Initiation of semaglutide or any SGLT2i. [MAIN OUTCOME AND MEASURE] Incident NAION, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision and Systematized Nomenclature of Medicine codes. [RESULTS] A total of 102 361 US veterans met inclusion criteria, including 11 478 initiators of semaglutide and 90 883 initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; body mass index, 37.8 [6.7]; hemoglobin A1c, 7.0% [1.4]; 85.5% male and 14.5% female; 20.7% Black, 8.1% Hispanic, and 61.9% non-Hispanic White). Over a maximum follow-up of 7.5 years, 173 total incident NAION events occurred. The incidence rate of NAION was 123 per 100 000 person-years among semaglutide initiators and 67 per 100 000 person-years among SGLT2i. In 2.1 years of median follow-up, semaglutide initiators had a 2.33-fold higher risk than SGLT2i initiators (hazard ratio, 2.33; 95% CI, 1.54-3.54; P < .001). The overlap weighted incidence rate of NAION was 0.29% for semaglutide initiators and 0.13% for SGLT2i initiators, with a corresponding average treatment effect of 0.16 percentage points. [CONCLUSIONS AND RELEVANCE] In this nationwide cohort of US veterans with T2D, semaglutide initiators had a 2-fold NAION risk than SGLT2i initiators, while the absolute risk was low. Clinicians and patients should be counseled on the rare but evident increased risk of NAION after semaglutide initiation.","url":"https://pubmed.ncbi.nlm.nih.gov/41678180/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T20:45:21+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": null, \"route\": null, \"comparator\": \"SGLT2 inhibitors (almost all empagliflozin)\", \"treatment_duration\": null}","domains":"[\"metabolic\", \"ophthalmologic\"]","outcome_type":"hard","primary_outcome":"Incident NAION, identified by ICD-10 and SNOMED codes","endpoints":null,"effect_estimate":"Semaglutide against SGLT2i initiators: overlap-weighted HR 2.33 for NAION (unweighted HR 1.84); incidence 123 vs 67 per 100 000 person-years; overlap-weighted incidence 0.29% vs 0.13% (average treatment effect 0.16 percentage points)","confidence_interval":"95% CI, 1.54-3.54 (abstract); the full-text Results print 95% CI, 1.53-3.54","p_value":"P < .001","sample_size":102361,"follow_up":"median 2.1 years; maximum 7.5 years","direction":"harm","population":"{\"mean_age\": \"60.1 (SD 11.7) years, after overlap weighting\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"85.5% male, 14.5% female (after overlap weighting)\", \"bmi_mean\": 37.8, \"bmi_min\": null, \"obesity_status\": \"not reported (not an entry criterion; weighted mean BMI 37.8)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"mixed (not an entry criterion; congestive heart failure 7.7% and myocardial infarction 2.9% after weighting)\", \"ckd_status\": \"mixed (not an entry criterion; kidney disease 8.0% after weighting)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes on metformin, starting second-line therapy\", \"sample_size\": 102361, \"inclusion_exclusion\": \"Veterans aged 18 or older with T2D on metformin, new initiators of semaglutide or SGLT2i; excluded type 1 or secondary diabetes, other antidiabetic drugs, 30 or more days of insulin, prior NAION, giant cell arteritis or traumatic optic nerve injury\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: every participant had type 2 diabetes and was taking metformin; weighted mean BMI was 37.8 and mean age 60.1, and 85.5% were men. Age fits the target range, but the diabetes and weight profile does not.","mediation":"possibly","mediation_notes":"No weight or HbA1c change after starting treatment and no mediation analysis are reported. Overlap weighting balanced baseline BMI and HbA1c, which addresses confounding, not mediation; the authors list rapid glycaemic improvement among possible mechanisms, alongside hypotension and volume depletion.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 102361, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"SGLT2 inhibitors (almost all empagliflozin)\", \"follow_up_duration\": \"median 2.1 years; maximum 7.5 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, 1.54-3.54 (abstract); the full-text Results print 95% CI, 1.53-3.54\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: a single observational study (a target-trial emulation in VA health records) with an active comparator, new-user design, overlap weighting and 173 events. It is well designed, but an individual observational study is capped at LOW, and the outcome is a coded diagnosis.","funding_source":"VA Cooperative Studies Program (CSP#2012); one author partly funded by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"One author reported personal fees from TeCure Consulting and two reported grants from companies (Novartis, Alnylam, AstraZeneca, Biodesix, Celgene, Janssen), all outside the submitted work; one also reported VA grants during the study; no other disclosures.","sponsor_role":"The VA Cooperative Studies Program was involved in the design and conduct of the study, data collection, management, analysis and interpretation, manuscript preparation, review and approval, and the decision to submit","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"NAION, the study's safety outcome: 30 events on semaglutide vs 143 on SGLT2i; overlap-weighted HR 2.33; absolute risk low (0.29% vs 0.13%)","limitations":"Observational target-trial emulation with possible residual unmeasured confounding (for example optic nerve head anatomy, sleep apnea severity, nocturnal hypotension, diabetes duration, non-VA care) and outcome misclassification from coded diagnoses; mostly older men with high cardiometabolic risk, and exposure was initiation only, so dose and duration effects were not studied.","plain_summary":"This study used US veterans' health records to compare 11 478 people with type 2 diabetes, all already taking metformin, who started semaglutide with 90 883 who started an SGLT2 inhibitor, over a median of 2.1 years. Starting semaglutide was linked to about twice the risk of NAION, a sudden loss of blood supply to the optic nerve (hazard ratio 2.33; 123 against 67 cases per 100 000 person-years), but the absolute risk stayed low (0.29% against 0.13%). Because this is an observational study, it shows an association, not proof that semaglutide caused the cases, and the people studied had diabetes with an average BMI of 37.8 and were mostly men.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":800,"doi":"10.1002/edm2.70187","pmid":"41787737","nct_ids":"[]","title":"Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials","authors":"[\"Abulehia A\", \"Ayesh H\", \"Ayesh O\", \"Jaber D\", \"Asad T\", \"Itbaisha A\", \"Abugharbieh H\", \"Gharbia R\", \"Abu-Hilal LH\", \"Leon BGC\"]","journal":"Endocrinology, diabetes & metabolism","publication_date":"2026-03","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity. [METHODS] PubMed, Cochrane, Embase, and Scopus databases were systematically searched. Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis. Random-effects models were applied to assess mean differences (MD) in weight change, both absolute and percent changes, HbA1c, adverse events, and discontinuation due to adverse events. Heterogeneity was quantified using the I2 statistic. [RESULTS] Retatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]), followed by survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]) and mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]). Cotadutide showed the smallest and nonsignificant effect (MD -3.41 kg; 95% CI [-11.63, 4.81]). Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance. In terms of safety, mazdutide demonstrated the most favourable tolerability profile, whereas retatrutide and cotadutide were associated with comparatively lower tolerability. [CONCLUSIONS] Retatrutide and survodutide exhibit the most favourable efficacy profiles for obesity and T2DM, with acceptable safety. These findings support their potential clinical use and highlight the need for future head-to-head trials.","url":"https://pubmed.ncbi.nlm.nih.gov/41787737/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:32:36+00:00","study_design":"meta_analysis","drugs":"[\"retatrutide\", \"survodutide\", \"mazdutide\", \"cotadutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":"Weight vs placebo: retatrutide MD -13.44 kg, survodutide -10.74 kg, mazdutide -6.47 kg; cotadutide not significant","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"mixed: trials in people with type 2 diabetes, overweight or obesity\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"Retatrutide vs placebo, weight: 95% CI -18.38 to -8.51 kg; the abstract gives an interval for each drug\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A network meta-analysis of 14 trials in people with type 2 diabetes, overweight or obesity compared four glucagon-receptor drugs. Retatrutide gave the largest weight loss (about 13 kg more than placebo), followed by survodutide (about 11 kg) and mazdutide (about 6 kg); cotadutide's weight effect was not significant. Retatrutide was the only drug that significantly lowered HbA1c. Mazdutide was best tolerated, while retatrutide and cotadutide were less well tolerated.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":804,"doi":"10.1097/crd.0000000000001209","pmid":"41711462","nct_ids":"[]","title":"Incretin-Based Dual and Triple Agonists in Overweight or Obese Individuals: A Systematic Review and Meta-Analysis","authors":"[\"Chan ZH\", \"Omar AS\", \"Gill K\", \"Volucke G\", \"Azhar MM\", \"Haleem SM\", \"Sia JE\", \"Rahman OU\", \"Ahmad M\", \"Shahid N\", \"Gardezi SA\", \"Joseph KV\", \"Behary Paray N\", \"Zulfiqar E\"]","journal":"Cardiology in review","publication_date":"2026-02-19","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Incretin-based dual and triple agonists have emerged as effective options for obesity management, offering enhanced weight loss through multi-receptor agonism. However, data on their efficacy and safety remain limited. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these emerging agents. A comprehensive literature search was conducted using PubMed, the Cochrane Library, and Google Scholar from inception to June 2025 to identify randomized controlled trials evaluating tirzepatide, retatrutide, or mazdutide in obese adults. Clinical outcomes were assessed using the random-effects model and pooled as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). A total of 10 randomized controlled trials, including 3236 participants, were analyzed. Incretin polyagonists significantly reduced body weight compared to placebo (MD -11.47; 95% CI: -14.00 to -8.95). Significant reductions were also observed in waist circumference (MD -9.40; 95% CI: -11.91 to -6.89), glycated hemoglobin (MD -0.96; 95% CI: -1.16 to -0.75), and fasting plasma glucose (MD -26.89 mg/dL; 95% CI: -33.48 to -20.30). However, the use of dual and triple agonists was associated with a higher risk of any adverse events (AEs) (RR 1.13; 95% CI: 1.08-1.19), including gastrointestinal AEs (nausea, vomiting, diarrhea, constipation), AEs leading to withdrawal (RR 1.96; 95% CI: 1.17-3.30), and hypoglycemic episodes (RR 3.08; 95% CI: 1.61-5.89). No significant difference was found in serious AEs (RR 0.87; 95% CI: 0.65-1.14). In conclusion, incretin-based polyagonists were associated with significant weight reduction and improved metabolic outcomes compared to placebo.","url":"https://pubmed.ncbi.nlm.nih.gov/41711462/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosure: The authors declare no conflict of interest.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\", \"retatrutide\", \"mazdutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3236,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 3236, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 3236, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence intervals (CIs\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Disclosure: The authors declare no conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 10 trials (3,236 adults with obesity), tirzepatide, retatrutide and mazdutide lowered body weight more than placebo (mean difference -11.47; the abstract does not state the unit) and also lowered waist size, HbA1c and fasting glucose. They raised the risk of any side effect (RR 1.13), including gastrointestinal effects, stopping because of side effects (RR 1.96) and low blood sugar (RR 3.08); serious side effects did not differ (RR 0.87).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":361,"doi":"10.1038/s41591-025-04071-1","pmid":"41540105","nct_ids":"[\"NCT05412004\"]","title":"Tirzepatide on obstructive sleep apnea-related cardiometabolic risk: secondary outcomes of the SURMOUNT-OSA randomized trial","authors":"[\"Malhotra A\", \"Grunstein R\", \"Azarbarzin A\", \"Sands S\", \"Somers VK\", \"Aronne LJ\", \"Jastreboff AM\", \"Lou J\", \"Chakladar S\", \"Dunn JP\", \"Bunck MC\", \"Bednarik J\"]","journal":"Nature medicine","publication_date":"2026-02","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include changes in a homeostatic model assessment for insulin resistance and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea-hypopnea index and sleep apnea-specific hypoxic burden. In both study 1 and study 2 of SURMOUNT-OSA, tirzepatide treatment was associated with greater alleviation of cardiometabolic risk factors than placebo. Independent mediation effect of changes in OSA metrics was observed on high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance and triglycerides. The combination of changes in weight and OSA metrics, as well as weight alone, had a significant mediation effect on systolic blood pressure, but there was no significant mediation effect of weight or OSA metrics observed on diastolic blood pressure. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize the treatment effect on cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. The ClinicalTrials.gov registration number for this study is NCT05412004 .","url":"https://pubmed.ncbi.nlm.nih.gov/41540105/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: A.M. is funded by the NIH. A.M. reports income from Eli Lilly, Livanova, Zoll and Powell Mansfield. ResMed gave a philanthropic donation to USCD. R.G. reports income from serving on the advisory board for Apnimed, the steering committee for SURMOUNT-OSA, Eli Lilly and lecture fees from Somnomed Department. He conducts sponsored studies with Eli Lilly, Alkermes, Takeda and Bod Science: Lambert Initiative. A.A. serves as a consultant for Respicardia, Eli Lilly, Inspire, Cerebra and Apnimed. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. A.A.’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. S.S. received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly, Respicardia, LinguaFlex and Achaemenid. S.S. receives royalties for intellectual property pertaining to combination pharmacotherapy for sleep apnea via his Institution. S.S. is also the co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping also via his Institution. He has received equity in Achaemenid, a company commercializing biosensor technology for monitoring oral appliance treatment efficacy. S.S. is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping also via his Institution. His industry interactions are actively managed by his Institution. V.K.S. serves as a consultant for Eli Lilly, ApniMed, Axsome and Jazz Pharmaceuticals and on the Scientific Advisory Board for Sleep Number. L.J.A. reports receiving consulting fees from/and serving on advisory boards for Altimmune, Atria, Boehringer Ingelheim, Carmot Therapeutics, CinFina Pharma, Corteria, Currax Pharma, Eli Lilly, Enterin, Helicore Biopharma, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Juvena Therapeutics, Kallyope, Morphic Medic/GI Dynamics, Novartis, Novo Nordisk, Pfizer, Prosciento, Senda Biosciences, Skye Bio/Cbeyond, Summit Clinical, Syntis Bio, Versanis, Veru Pharmaceuticals and Zealand Pharmaceuticals; receiving research funding from Amgen, Eli Lilly, Janssen Pharmaceuticals and Novo Nordisk; having equity interests in ERX Pharmaceuticals, Intellihealth, Jamieson Wellness, Kallyope, Mediflix, Morphic Medic/GI Dynamics, Summit Clinical, Syntis Bio and Veru Pharmaceuticals; and serving on a board of directors for ERX Pharmaceuticals, Intellihealth and Jamieson Wellness. A.M.J. conducts multicenter trials with Amgen, Eli Lilly, Novo Nordisk and Rhythm Pharmaceuticals; serves on scientific advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Rhythm Pharmaceuticals, Scholar Rock, Structure Therapeutics, Syntis Bio, Terns Pharmaceuticals, WeightWatchers and Zealand Pharmaceuticals; and receives institutional grant funding from the NIH/NIDDK. J.L., S.C., J.P.D. and M.C.B. are employees and shareholders of Eli Lilly and Company and declare no competing interests. J.B. contributed to the paper as an employee of Eli Lilly and Company.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"sleep\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":290,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: OZEMPIC, RYBELSUS (ORAL SEMAGLUTIDE) - label effective 2026-01-30","authors":"[\"Novo Nordisk Pharmaceutical Industries, LP\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-01-30","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of RYBELSUS or OZEMPIC tablets and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS or OZEMPIC tablets [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS or OZEMPIC tablets. Discontinue if pancreatitis is suspected. ( 5.2 ) • Diabetic Retinopathy Complications : Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored. ( 5.3 ) • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin : May increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dosage of insulin secretagogue or insulin may be necessary. ( 5.4 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) • Severe Gastrointestinal Adverse Reactions : Use of RYBELSUS or OZEMPIC tablets has been associated with gastrointestinal adverse reactions, sometimes severe. RYBELSUS and OZEMPIC tablets are not recommended in patients with severe gastroparesis. ( 5.6 ) • Hypersensitivity Reactions : Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue RYBELSUS or OZEMPIC tablets if hypersensitivity reactions occur and monitor until signs and symptoms resolve. ( 5.7 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether RYBELSUS and OZEMPIC tablets cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. RYBELSUS and OZEMPIC tablets are contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS or OZEMPIC tablets and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS or OZEMPIC tablets. Such monitoring may increase the risk of unnecessary procedures, due to the low-test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including semaglutide tablets [see Adverse Reactions ( 6 )] . After initiation of RYBELSUS or OZEMPIC tablets, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back), and which may or may not be ac\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OZEMPIC tablets (1.5 mg, 4 mg and 9 mg strengths) [see Dosage and Administration ( 2.2 )] and RYBELSUS (3 mg, 7, mg and 14 mg strengths) [see Dosage and Administration ( 2.2 )] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . Below is a display of the safety results of the adequate and well-controlled studies of RYBELSUS (referred to below as semaglutide tablets) in adult patients with type 2 diabetes mellitus. Pool of Placebo-Controlled Trials The data in Table 2 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus [see Clinical Studies ( 14 )] . These data reflect exposure of 1,071 patients to semaglutide tablets (3 mg, 7, mg or 14 mg orally once daily) with a mean duration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or African American and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 mellitus diabetes for an average of 9.4 years and had a mean HbA 1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 1.4% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in 9 placebo- and active-controlled trials [see Clinical Studies ( 14 )] . In this pool, 4,116 patients with type 2 diabetes mellitus were treated with semaglutide tablets for a mean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were Black or African American and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 28.5% and moderately impaired (eGFR 30 to 60 mL/min/1.73\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Other Oral Drugs : RYBELSUS and OZEMPIC tablets delay gastric emptying. Consider increased clinical or laboratory monitoring when co-administered with other oral medications that have a narrow therapeutic index or that require clinical monitoring. ( 7.2 ) 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Semaglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS or OZEMPIC tablets in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS or OZEMPIC tablets, consider reducing the dosage of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )] . 7.2 Other Oral Drugs Semaglutide cause a delay of gastric emptying and thereby has the potential to impact the absorption of other oral drugs. Levothyroxine exposure was increased 33% (90% CI: 1.25 to 1.42) when administered with semaglutide tablets in a drug interaction study [see Clinical Pharmacology ( 12.3 )] . When using RYBELSUS or OZEMPIC tablets concomitantly with other oral drugs that have a narrow therapeutic index or that require clinical monitoring, consider increased clinical or laboratory monitoring [see Dosage and Administration ( 2 )] .\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS RYBELSUS and OZEMPIC tablets are contraindicated in patients with: • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS or OZEMPIC tablets. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with semaglutide tablets [see Warnings and Precautions ( 5.7 )] . • Personal or family history of MTC or in patients with MEN 2 syndrome type 2 ( 4 ) • Prior serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":299,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2026-01-30","authors":"[\"Teva Pharmaceuticals USA, Inc.\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2026-01-30","year":2026,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ) . • Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never Share a Liraglutide Pen Between Patients , even if the needle is changed. ( 5.3 ) • Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.4 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. (5.5) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide is not recommended in patients with severe gastroparesis. ( 5.6 ) • Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide and promptly seek medical advice. ( 5.7 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions ( 6 )]. After initiation of liraglutide, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue liraglutide and initiate appropriate management. 5.3 Never Share a Liraglutide Pen Between Patients Liragl\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] • Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. ( 6.1 ) • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide and a mean duration of exposure to liraglutide of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide than on placebo and occurred in at least 5% of patients treated with liraglutide. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with Liraglutide for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N=645 Liraglutide 1.8 mg N=1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications : Liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications. ( 7 ) 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Liraglutide is contraindicated in patients with a: • personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)] . • serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide [see Warnings and Precautions (5.7)]. • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. ( 4 ) • Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=14bf9812-14ee-46ce-93b1-686e4906cbbc","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":802,"doi":"10.1186/s40001-026-03933-9","pmid":"41582189","nct_ids":"[]","title":"Effect of glucagon-like peptide-1 receptor agonists on heart rate in non-diabetic individuals with overweight or obesity: a systematic review and pairwise and network meta-analysis of randomized controlled trials","authors":"[\"Zhang Y\", \"Zhang C\", \"Gong X\", \"Cheng P\", \"Fu H\", \"Diao L\", \"Song C\"]","journal":"European journal of medical research","publication_date":"2026-01-26","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] To explore the association of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on heart rate (HR) in overweight or obese patients without diabetes. [METHODS] A comprehensive search of the PubMed, Web of Science, Embase, and Cochrane Library databases was conducted. Mean differences (MDs) were calculated as effect estimates for HR. Pairwise and network meta-analysis were conducted. [RESULTS] Twelve articles were included. Pairwise meta-analysis showed significant association of increase compared with placebo in liraglutide [MD 2.37, 95% confidence interval (CI) 1.86, 2.89], semaglutide (MD = 3.35; 95% CI 1.69, 5.01), orforglipron (MD = 7.30; 95% CI 5.48, 9.12), oral semaglutide (MD = 4.50; 95% CI 3.11, 5.89), tirzepatide (MD = 2.05; 95% CI 0.96, 3.13), retatrutide (MD = 3.46; 95% CI 1.74, 5.18), and total GLP-1RAs (MD = 3.47; 95% CI 2.65, 4.29). Network meta-analysis revealed that orforglipron 36 mg was associated with the most pronounced increase (MD = 9.29; 95% CI 4.45, 13.86), whereas tirzepatide 5 mg was associated with the least increase (MD = 0.52; 95% CI - 2.71, 3.78). [CONCLUSIONS] GLP-1RAs were associated with the increasing of HR in patients with overweight or obesity. Orforglipron 36 mg was associated with the most pronounced increase, and tirzepatide 5 mg the least.","url":"https://pubmed.ncbi.nlm.nih.gov/41582189/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: Human Ethics and Consent to Participate declarations is not applicable. Competing interests: The authors declare no competing interests.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"orforglipron\", \"tirzepatide\", \"retatrutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":"Change in resting heart rate vs placebo in adults with overweight or obesity without diabetes (pairwise and network meta-analysis, 12 RCT reports)","endpoints":null,"effect_estimate":"All GLP-1 RA-based agents pooled +3.47 bpm; retatrutide +3.46; orforglipron +7.30; semaglutide +3.35; liraglutide +2.37; tirzepatide +2.05. Network: orforglipron 36 mg largest (+9.29), tirzepatide 5 mg smallest (+0.52)","confidence_interval":"Pooled 2.65 to 4.29; retatrutide 1.74 to 5.18; orforglipron 36 mg 4.45 to 13.86","p_value":null,"sample_size":null,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight or obesity required\", \"diabetes_status\": \"no diabetes\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"People without diabetes, so closer to the reference population than most trial evidence, but overweight or obesity was still required in every included trial.","mediation":"unclear","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: Pooled 2.65 to 4.29; retatrutide 1.74 to 5.18; orforglipron 36 mg 4.45 to 13.86\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Systematic review with pairwise and network meta-analysis of RCTs; heart rate is a physiological surrogate; the abstract does not report certainty grading or risk-of-bias results. Abstract-level appraisal.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across 12 trials in people with overweight or obesity and no diabetes, each GLP-1-based drug, pooled across doses, raised resting heart rate by a few beats per minute; retatrutide about 3.5 and the oral drug orforglipron the most, about 7. In the network analysis the smallest increase (tirzepatide 5 mg) was not statistically significant. A small effect whose long-term meaning is unknown.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":38,"doi":"10.1038/s41591-025-04106-7","pmid":"41326666","nct_ids":"[\"NCT01843075\"]","title":"Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial","authors":"[\"Edison P\", \"Femminella GD\", \"Ritchie C\", \"Nowell J\", \"Holmes C\", \"Walker Z\", \"Ridha B\", \"Raza S\", \"Livingston NR\", \"Frangou E\", \"Love S\", \"Williams G\", \"Lawrence R\", \"Mcfarlane B\", \"Archer H\", \"Coulthard E\", \"Underwood BR\", \"Koranteng P\", \"Karim S\", \"Bannister C\", \"Perneczky R\", \"Prasanna A\", \"Junaid K\", \"McGuinness B\", \"Nilforooshan R\", \"Macharouthu A\", \"Donaldson A\", \"Thacker S\", \"Russell G\", \"Malik N\", \"Mate V\", \"Knight L\", \"Kshemendran S\", \"Holscher C\", \"Mansouri A\", \"Chester-Jones M\", \"Holmes J\", \"Tan T\", \"Williams S\", \"Ashraf A\", \"Brooks DJ\", \"Harrison J\", \"Hinz R\", \"Tadros G\", \"Passmore AP\", \"Ballard C\"]","journal":"Nature medicine","publication_date":"2026-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = -0.17; 95% confidence interval: -0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome-score on the Alzheimer's Disease Assessment Scale-Executive domain (ADAS-Exec)-performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03-0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (-0.58; 95% confidence interval: -3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (-0.06; 95% confidence interval: -0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer's disease. ClinicalTrials.gov identifier: NCT01843075 .","url":"https://pubmed.ncbi.nlm.nih.gov/41326666/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: P.E. was funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research UK, the Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society UK, Novo Nordisk, GE Healthcare, AstraZeneca, Pfizer, Eli Lilly and Piramal Life Sciences. He has received speaker fees from Novo Nordisk, Pfizer, Nordea and Piramal Life Sciences. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Sciences/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was an external consultant to Novo Nordisk and has participated in their Scientific Advisory Board. He is a consultant to Roche, Pfizer and Biohaven. He is the director of Edison Health Sciences Ltd and Edison Sciences Limited. He is a member of the Scientific Advisory Board of CytoDyn and holds shares in CytoDyn. J. Harrison reports receipt of personal fees in the past 2 years from Actinogen, AlzeCure, Aptinyx, AstraZeneca, Athira Pharma, Axoltis, Axon Neuroscience, Bial Biotech, Biogen Idec, Boehringer Ingelheim, Brands2Life, Cerecin, Cognito, Cognition Therapeutics, Compass Pathways, Corlieve, Curasen, EIP Pharma, Eisai, GfHEU, Heptares, Impact, Ki Elements, LSP Operations, Lundbeck, Lysosomal Therapeutics, MyCognition, Neurotrack, the National Health Service, Novartis, Novo Nordisk, Nutricia, Probiodrug, Prothena, Recognify, Regeneron, reMYND, Roche, Signant, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics and Winterlight Labs. Additionally, he holds stock options in Neurotrack and is a joint holder of patents with MyCognition, Ltd. B.R.U.ʼs position is partially funded by a donation from Gnodde Goldman Sachs Giving. The other authors declare no competing interests.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"daily (up to 1.8 mg, full text)\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"alzheimers\", \"dementia\", \"cognition\", \"neuroinflammation\"]","outcome_type":"mixed","primary_outcome":"Change in cerebral glucose metabolic rate (FDG-PET)","endpoints":null,"effect_estimate":"Primary difference -0.17 (NS); ADAS-Exec 0.15 (unadjusted p=0.01); ADCS-ADL and CDR-SoB no difference","confidence_interval":"-0.39 to 0.06 (primary)","p_value":"0.14","sample_size":204,"follow_up":"52 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not an entry criterion\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"mild to moderate Alzheimer's disease syndrome\", \"sample_size\": 204, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Non-diabetic older adults not selected for weight, but with established AD.","mediation":"unlikely","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 204, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"n=204; primary null; secondary unadjusted for multiplicity\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Phase 2b with a null imaging primary endpoint and a nominally significant secondary.","funding_source":"Alzheimer's Drug Discovery Foundation; Novo Nordisk supplied support (author disclosures list Novo Nordisk grants)","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"Lead author reports grants and speaker fees from Novo Nordisk, Pfizer, Eli Lilly and others.","sponsor_role":"Academic sponsor; drug/support from Novo Nordisk (verify).","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"In 204 non-diabetic people with mild-to-moderate Alzheimer's, a year of liraglutide did not change brain glucose metabolism (the main endpoint); an executive-function score was slightly better, but daily-function and global scores were not. Small and mostly negative.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":55,"doi":"10.1111/dom.70209","pmid":"41090431","nct_ids":"[]","title":"Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials","authors":"[\"Giblin K\", \"Kaplan LM\", \"Somers VK\", \"Le Roux CW\", \"Hunter DJ\", \"Wu Q\", \"Lalonde A\", \"Ahmad N\", \"Bethel MA\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2026-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Retatrutide, a novel synthetic molecule, is a triple agonist activating the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors. The TRIUMPH clinical development program evaluates its safety and efficacy concurrently for the treatment of obesity and two related complications-obstructive sleep apnea (OSA) and knee osteoarthritis (OA). A novel basket trial design simultaneously evaluates retatrutide treatment across these multiple adiposity-related disease states. [MATERIALS AND METHODS] TRIUMPH consists of four Phase 3, multicenter, randomized, double-blind studies assessing weekly subcutaneous retatrutide compared to placebo, in conjunction with healthy diet and physical activity in over 5800 participants. The four trials consist of two weight management basket trials (TRIUMPH-1 and TRIUMPH-2) with OSA and/or OA protocols nested within the weight management trial; one weight management trial in a population with CVD (TRIUMPH-3); and one stand-alone OA trial (TRIUMPH-4). The primary endpoint for weight management is percent change in body weight, for OSA is change in Apnea-Hypopnea Index and for knee OA includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. The basket trial permits independent analysis of weight management, OSA and OA studies with type I error rate controlled at α = 0.05, split between the overarching weight management and each basket trial. [CONCLUSIONS] By recruiting participants with shared disease exposures, the TRIUMPH program will assess the safety and efficacy of retatrutide for the treatment of adults with obesity and two of its common complications-OSA and OA.","url":"https://pubmed.ncbi.nlm.nih.gov/41090431/","source_name":"pubmed","source_tier":1,"coi_statement":"Lee M. Kaplan declares providing paid consultation to Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Cytoki, Ethicon, Kallyope, The Last Food Fight, Eli Lilly, Neurogastrx, Novo Nordisk, Optum Health, Oxford Medical Products, Perspectum, Pfizer and Sidekick Health. Professor Carel le Roux reports grants from the EU Innovative Medicine Initiative, Irish Research Council, Science Foundation Ireland, Anabio and the Health Research Board. He serves on advisory boards and speakers' panels of Novo Nordisk, Roche, Herbalife, GI Dynamics, Eli Lilly, Johnson & Johnson, Gila, Irish Life Health, Boehringer Ingelheim, Currax, Zealand Pharma, Keyron, AstraZeneca, Arrowhead Pharma, Amgen, AbbVie, Metsera, Nymble, Olympus and Rhythm Pharma. ClR is the Chair of the Irish Society for Nutrition and Metabolism. ClR received stock options as payment for scientific advisory board functions from Metsera and Nymble. ClR provides obesity clinical care in the My Best Weight clinic and Beyond BMI clinic and is a co‐owner of these clinics. David J. Hunter is the editor of the osteoarthritis section for UpToDate and co‐Editor in Chief of Osteoarthritis and Cartilage. DJH provides consulting advice on scientific advisory boards for Haleon, TLCBio, Novartis, Tissuegene, Sanofi and Enlivex. Dr. Virend K. Somers is funded by the National Heart, Lung, and Blood Institute (HL65176, HL168173 and HL160619); has served as a consultant for Jazz Pharmaceuticals, Lilly, Apnimed, Axsome and Mineralys; and is on the Sleep Number Scientific Advisory Board. Kathryn Giblin, Mary Angelyn Bethel, Amy Lalonde, Nadia Ahmad and Qiwei Wu are employees and shareholders of Eli Lilly and Company.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"clinical_trial_registration","drugs":"[\"retatrutide\"]","drug_details":"{\"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"osteoarthritis\", \"sleep\", \"cardiovascular\", \"body_composition\"]","outcome_type":"unknown","primary_outcome":"Design paper: TRIUMPH-1 to -4 (weight management, OSA, knee OA, CVD population); >5,800 participants","endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":5800,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity required across all TRIUMPH trials\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity (with obstructive sleep apnea and knee osteoarthritis sub-studies)\", \"sample_size\": 5800, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Design/rationale paper for trials in obesity.","mediation":"not_applicable","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Clinical trial registration\", \"sample_size\": 5800, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"No results; design paper.","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report extensive industry consulting including Eli Lilly and Novo Nordisk.","sponsor_role":"Sponsor-designed programme.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":null,"plain_summary":"Design paper for the TRIUMPH phase 3 programme of retatrutide in obesity, sleep apnoea and knee osteoarthritis. No results yet; watched for the knee-OA endpoint.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":356,"doi":"10.7759/cureus.100947","pmid":"41658748","nct_ids":"[]","title":"Long-Term Cardiovascular Outcomes of Glucagon-Like Peptide-1 Receptor Agonists in Non-diabetic Obesity: A Systematic Review and Meta-Analysis","authors":"[\"Tom-Ayegunle K\", \"Tom-Ayegunle O\", \"Okoye S\", \"Chukwuemeka U\", \"Adeyina TS\", \"Babarinde A\", \"Eleam U\"]","journal":"Cureus","publication_date":"2026-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate cardiovascular benefits in diabetic populations, yet evidence in non-diabetic obesity remains limited. We searched PubMed, Excerpta Medica database (Embase), Cochrane Controlled Register of Trials (CENTRAL), and Web of Science (January 2015-January 2025) for randomized controlled trials evaluating GLP-1 RAs in non-diabetic adults with obesity (BMI ≥30 kg/m²), with composite major adverse cardiovascular events (MACE) as the primary outcome using random-effects models with risk ratios (RRs) and 95% confidence intervals (CIs). Sixteen trials (23,467 participants, median 68 weeks follow-up) were included, demonstrating that GLP-1 RAs reduced MACE by 20% (RR 0.80, 95% CI 0.72-0.89), with strongest effects on stroke (RR 0.72), myocardial infarction (RR 0.84), and heart failure hospitalization (RR 0.82), alongside reductions in systolic blood pressure (4.2 mmHg), triglycerides (32 mg/dL), and high-sensitivity C-reactive protein (hsCRP) (38.6%), with 12.4% weight loss where mediation analyses showed 35%-55% of cardiovascular benefit was independent of weight reduction. GLP-1 RAs provide substantial cardiovascular protection in non-diabetic obesity through both weight loss-dependent and independent mechanisms, with acceptable safety profiles supporting their role in cardiovascular risk reduction.","url":"https://pubmed.ncbi.nlm.nih.gov/41658748/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":23467,"follow_up":"68 weeks follow-up","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"22.4% had established cardiovascular disease, mostly from SELECT\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 23467, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"specifically_tested","mediation_notes":"12.4% weight loss. The paper is internally inconsistent: the abstract says 35%-55% of cardiovascular benefit was independent of weight loss, but the results section says 35%-45% was weight-loss-mediated. The paper does not show how these mediation figures were derived from the included trials, so they are not established.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 23467, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"68 weeks follow-up\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence intervals (CIs\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 7, 11, 13; non-critical weaknesses on items 3, 6, 10, 14\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"Partial Yes\", \"5\": \"Yes\", \"6\": \"No\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Partial Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"Yes\", \"13\": \"No\", \"14\": \"No\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 8, \"Partial Yes\": 3, \"Yes\": 5}, \"settled_by_ruling\": [\"item 3: No (IN-059; the passes read Yes and No)\", \"item 13: No (IN-059; the passes read Yes and No)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/41658748/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/41658748/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-03-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.2\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A review of 16 trials (23,467 adults without diabetes who had obesity, or overweight with a weight-related condition) found GLP-1 drugs lowered major cardiovascular events by about 20% (RR 0.80), with lower rates of stroke, heart attack and heart-failure hospital stays, and 12.4% more weight loss than placebo. One trial, SELECT, carried 77% of the weight in the main analysis, and most of the 22.4% of participants with established heart disease came from it. The review is rated critically low confidence (AMSTAR 2), and its figures on how much of the benefit is independent of weight loss are inconsistent within the paper and not established.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":367,"doi":"10.1002/dmrr.70111","pmid":"41331723","nct_ids":"[]","title":"Effect of Glucagon-Like Peptide-1 Receptor Agonists on Cardiometabolic Risk Factors in Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis","authors":"[\"Chen Y\", \"Tang Y\", \"Yue R\", \"Yang B\", \"Wang A\", \"Long Y\", \"Xu Y\", \"Gao C\"]","journal":"Diabetes/metabolism research and reviews","publication_date":"2026-01","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Although the cardiovascular benefits of GLP-1RAs in type 2 diabetes are established, their effects in type 1 diabetes remain unclear. This study aimed to evaluate the impact of GLP-1RAs as adjunctive therapy on cardiometabolic risk factors in T1DM. [METHODS] A comprehensive search of randomised controlled trials (RCTs) was conducted in PubMed, Embase, Cochrane Library, Web of Science. The search covered all studies published from database inception to August 30, 2025. The methodology followed the PRISMA 2020 guidelines and the Cochrane Handbook for Systematic Reviews of Interventions, with eligibility criteria based on the PICOS framework. Randomised controlled trials comparing GLP-1 receptor agonists with placebo or standard insulin therapy in patients with type 1 diabetes mellitus were included. [RESULTS] A total of 21 RCTs involving 3417 patients and evaluating five different GLP-1RAs were included. Compared with the control group, GLP-1RAs significantly reduced systolic blood pressure (WMD: -2.65 mmHg, 95% confidence interval [CI]: -3.81 to -1.49, I2 = 0.0% and p < 0.001_effect), decreased diastolic blood pressure (WMD: -0.99 mmHg, 95% CI: -1.70 to -0.28, I2 = 0.0% and p = 0.006_effect) and increased heart rate (WMD: 3.90 bpm, 95% CI: 2.54 to 5.26, I2 = 0.0% and p < 0.001_effect). Similarly, total cholesterol (WMD: -0.15 mmol/L, 95% CI: -0.29 to -0.01, I2 = 0.0% and p = 0.031_effect), LDL cholesterol (WMD: -0.12 mmol/L, 95% CI: -0.22 to -0.01, I2 = 0.0% and p = 0.028_effect) and CRP (SMD: -0.32, 95% CI: -0.54 to -0.10, I2 = 0.0% and p = 0.005_effect) were significantly reduced, whereas no significant changes were observed for triglycerides, VLDL cholesterol, HDL cholesterol, TNF-α or IL-6 (all p > 0.05_effect). Previous meta-analyses have shown the efficacy and safety of GLP-1RAs in T1DM, and this study once again verified that GLP-1RAs can significantly reduce glycosylated haemoglobin (HbA1c) (WMD: -0.21% and 95% CI: -0.26 to -0.17), body weight (WMD: -3.91 kg and 95% CI: -4.53 to -3.30) and body mass index (BMI) (WMD: -1.52 kg/m2, 95% CI: -1.88 to -1.16) (all p < 0.05_effect). [CONCLUSION] The use of GLP-1RAs as adjuvant therapy for T1DM is not only beneficial for glycaemic control and weight loss, but also can lead to important improvements in other cardiometabolic risk factors and provide valuable guidance for clinicians in making treatment decisions for this population.","url":"https://pubmed.ncbi.nlm.nih.gov/41331723/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":81,"doi":"10.3389/fendo.2026.1928877","pmid":"42712413","nct_ids":"[]","title":"Tirzepatide and the risk of asthma exacerbations in patients with type 2 diabetes","authors":"[\"Liao KM\", \"Kuo CY\", \"Wu JY\", \"Hsu WH\", \"Tsai YW\", \"Lai CC\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, demonstrates anti-inflammatory properties that may benefit patients with asthma and type 2 diabetes (T2D). We sought to assess the comparative effectiveness of TZP versus other antidiabetic agents in reducing acute asthma exacerbations among patients with concurrent asthma and T2D. [METHODS] We conducted a retrospective cohort study using TriNetX US network. Adult patients with asthma and T2D initiating TZP or comparator antidiabetic agents (sulfonylureas [SU], dipeptidyl peptidase-4 inhibitors [DPP4i], sodium-glucose cotransporter 2 inhibitors [SGLT2i], or GLP-1 receptor agonists [GLP-1RA]) between January 2022 and August 2025 were included. Propensity score matching was performed for each comparison. The primary outcome was acute asthma exacerbation and secondary outcome was all-cause mortality. [RESULTS] After propensity score matching, we analyzed 25,712 patients in each TZP versus SU cohort, 23,013 in each TZP versus DPP4i cohort, 30,292 in each TZP versus SGLT2i cohort, and 19,740 in each TZP versus GLP-1RA cohort. TZP was associated with lower risk of asthma exacerbations compared with SU (HR, 0.81; 95% CI, 0.72-0.92) and DPP4i (HR, 0.82; 95% CI, 0.72-0.94). No significant differences were observed versus SGLT2i (HR, 1.12; 95% CI, 0.99-1.27; P = .064) or GLP-1RA (HR, 1.06; 95% CI, 0.91-1.23; P = .49). TZP was associated with the lower risk of all-cause mortality compared with SU, DPP4i, and SGLT2i (all P <.001). [CONCLUSIONS] Among patients with coexisting asthma and T2D, TZP use was associated with a lower risk of acute asthma exacerbations compared with SU and DPP4i, and was associated with lower all-cause mortality compared with SU, DPP4i, and SGLT2i, but not compared with GLP-1RA.","url":"https://pubmed.ncbi.nlm.nih.gov/42712413/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"mortality\", \"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":94,"doi":"10.3389/fendo.2026.1918370","pmid":"42698481","nct_ids":"[]","title":"Prehospital glucagon-like peptide-1 receptor agonists are not associated with reduced inpatient opioid exposure but with shorter hospital length of stay after total joint arthroplasty","authors":"[\"Vaknin N\", \"Seidenberg C\", \"Sitton E\", \"Singer P\", \"Mishali R\", \"Vidal H\", \"Slevin-Kish M\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been hypothesized to confer anti-inflammatory, antinociceptive, and anti-addictive benefits. We aimed to investigate their impact on acute perioperative pain and opioid use after total joint arthroplasty (TJA). [METHODS] A retrospective cohort study analyzed 14,375 hip or knee arthroplasties performed between January 2018 and February 2026, which included 882 patients on chronic preoperative GLP-1RA therapy. Using 1:1 propensity-score matching without replacement, 786 GLP-1RA users were matched to 786 non-users (total n=1,572) based on demographics, surgery type, and chronic medication use. [RESULTS] In the matched cohort, chronic GLP-1RA use was not associated with reduced inpatient opioid administration (adjusted difference -0.18; 95% CI, -0.74 to 0.38; p=0.53) or corrected postoperative morphine milligram equivalents (MME) (-2.79 MME; 95% CI, -6.95 to 1.37; p=0.19). When normalized to hospitalization time, the difference in inpatient opioid exposure was not statistically significant (+0.073 MME/hour; 95% CI, -0.003 to 0.149; p=0.059). Average visual analog scale (VAS) pain scores also showed no significant difference (-0.094; p=0.15). However, GLP-1RA users demonstrated a consistently shorter length of stay (LOS) (adjusted difference -10.41 hours; 95% CI, -13.97 to -6.85; p<0.001). [CONCLUSIONS] Chronic preoperative GLP-1RA therapy was not associated with reduced inpatient opioid exposure or improved early postoperative pain control following TJA. Nevertheless, GLP-1RA use was consistently associated with shorter hospital LOS. Prospective studies are needed to determine whether this finding reflects improved recovery pathways or residual confounding and to evaluate the impact of GLP-1RAs on longer-term postoperative outcomes and opioid utilization.","url":"https://pubmed.ncbi.nlm.nih.gov/42698481/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"addiction\", \"ophthalmologic\", \"perioperative\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":121,"doi":"10.7717/peerj.21713","pmid":"42729958","nct_ids":"[]","title":"Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis","authors":"[\"Qi H\", \"Gao Q\", \"Chen H\", \"Du X\", \"Pan B\"]","journal":"PeerJ","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This study aims to explore the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on weight changes and the occurrence of adverse reactions in overweight or obese adults after drug withdrawal. [METHODS] Computerized searches were conducted in evidence-based databases such as PubMed, Embase, Cochrane Library and Scopus. The search period was from the establishment of the database to December 2025. Collect randomised controlled trials (RCTs) and controlled trials on GLP-1RAs, including tirzepatide, semaglutide, liraglutide, and dulaglutide, for the treatment of overweight or obese adult patients. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias V2.0 tool provided by the Cochrane Collaboration, and meta-analysis was performed using the R programming language. [RESULTS] A total of 699 studies were initially retrieved. Eventually, six studies involving 8,993 patients were included in the quantitative analysis, comprising 5,553 patients in the discontinuation group and 3,440 in the continued treatment group. The results of the meta-analysis showed that, compared with the continued treatment group, the weight difference in the discontinuation group was mean difference (MD) = 17.90%, 95% confidence interval (CI) [14.11-21.69], P < 0.0001. It can be seen that there was a significant rebound in weight after drug withdrawal, and there was statistical heterogeneity among the studies (P = 0.0082). Subgroup analysis further revealed that the weight rebound amplitude after discontinuation of tirzepatide was significantly higher than that of semaglutide. This result suggests that the differences in the mechanism of action of different GLP-1RAs may be the reason for the differences in weight changes after discontinuation. In addition, the percentage difference in body weight between after and before drug withdrawal was MD = 9.11%, 95% CI [7.91-10.30], P < 0.0001, further verifying the trend of weight rebound after drug withdrawal. The summary of adverse reaction reports analyzed and studied indicates that after drug withdrawal, the overall adverse reactions of patients decreased, gastrointestinal adverse reactions decreased, and the incidence of cardiovascular events was not affected by drug withdrawal. [CONCLUSION] There is a significant weight rebound phenomenon after discontinuation of GLP-1RAs, and the rebound magnitudes vary among different types of drugs. At the same time, there is a risk of adverse reactions during the use of such drugs.","url":"https://pubmed.ncbi.nlm.nih.gov/42729958/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare there are no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":131,"doi":"10.3389/fendo.2026.1930088","pmid":"42723898","nct_ids":"[]","title":"Effects of GLP-1 receptor agonists on the incidence of contrast-induced acute kidney injury in patients with Type 2 diabetes mellitus undergoing coronary interventions","authors":"[\"Oksen D\", \"Aslan M\", \"Yavuz YE\", \"Kaynak C\", \"Serin E\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Contrast-induced acute kidney injury (CI-AKI) is a frequent complication of coronary angiography and percutaneous coronary intervention (PCI), particularly in patients with type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may exert renoprotective effects, but evidence in the setting of contrast exposure remains limited. [OBJECTIVE] To evaluate the association between GLP-1 RA therapy and CI-AKI in patients with T2DM undergoing coronary angiography or PCI for acute coronary syndromes. [METHODS] This retrospective cohort study included 336 patients with T2DM who underwent coronary angiography or PCI between May 2023 and March 2025. Patients receiving stable GLP-1 RA therapy (n=149) were compared with non-users (n=187). Serum creatinine and estimated glomerular filtration rate (eGFR) were measured at baseline and 48-72 hours after the procedure. CI-AKI was defined as a serum creatinine increase of ≥0.5 mg/dL or ≥25% from baseline within 72 hours. Multivariable logistic regression was used to identify independent predictors of CI-AKI. [RESULTS] CI-AKI occurred less frequently among GLP-1 RA users than non-users (8.7% vs 25.7%, p<0.001). At 48-72 hours, eGFR was higher in the GLP-1 RA group (67.1 ± 12.1 vs 58.0 ± 11.8 mL/min/1.73 m², p<0.001), whereas serum creatinine did not differ significantly (1.02 ± 0.73 vs 1.17 ± 1.57 mg/dL, p=0.084). GLP-1 RA use was independently associated with lower odds of CI-AKI (OR 0.290, 95% CI 0.119-0.708; p=0.007). Increasing age (OR 1.332, 95% CI 1.214-1.462; p<0.001) and ST-segment elevation myocardial infarction (OR 5.039, 95% CI 2.368-10.722; p<0.001) were associated with higher odds, whereas higher baseline eGFR was associated with lower odds (OR 0.919, 95% CI 0.862-0.979; p=0.009). [CONCLUSION] GLP-1 RA therapy was independently associated with a lower risk of CI-AKI in patients with T2DM undergoing contrast-based coronary procedures. These findings suggest a potential renoprotective association but require confirmation in prospective multicenter studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42723898/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":168,"doi":"10.1177/10732748261483767","pmid":"42677883","nct_ids":"[]","title":"Associations Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Cancer Risk: A Systematic Review and Meta-Analysis","authors":"[\"Lalani I\", \"Nambayan R\", \"Carbonell C\", \"Ruan Y\", \"O'Sullivan DE\", \"Stukalin I\", \"Hilsden RJ\", \"Brenner DR\"]","journal":"Cancer control : journal of the Moffitt Cancer Center","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"IntroductionUse of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for control of type 2 diabetes and cardiovascular disease (CVD) risk reduction is increasing. Given the established link between obesity and multiple cancers, there is growing interest in the potential effects of GLP-1RAs on cancer risk reduction. This systematic literature review and meta-analysis evaluated the association between GLP-1RA use and cancer incidence.MethodsWe conducted literature searches in MEDLINE and EMBASE databases, covering publications up to September 17th, 2025. Our review included studies among adults receiving GLP-1RAs for any indication that reported effects on cancer incidence of any type.ResultsAmong 1,644 unique citations identified, 139 studies met the inclusion criteria for full-text review. After study exclusion, a total of 78 observational studies were included in the review and meta-analysis. GLP-1RA use was associated with statistically significant reductions in cancer risk for 10 of 13 obesity-associated cancers, specifically colorectal, endometrial, esophageal, gallbladder, liver, ovarian, pancreatic and stomach cancers along with meningioma and multiple myeloma. Compared to insulin specifically, GLP-1RAs provided protective effects against cancer of the colorectum (RR: 0.54, 95% CI: 0.44, 0.66), liver (RR: 0.35, 95% CI: 0.20, 0.62), and pancreas (RR: 0.41, 95% CI: 0.36, 0.48). The risk of developing thyroid cancer was slightly elevated, but not statistically significant, among GLP-1RA users (RR: 1.09, 95% CI: 0.98, 1.21).ConclusionsPooled estimates of observational studies suggest notable reductions in cancer incidence for several obesity-associated cancers. As GLP-1RA use increases, ongoing safety monitoring and long-term real-world data are essential. The potential role of GLP-1RAs in cancer risk reduction warrants further investigation through large-scale RCTs, alongside balanced risk-benefit discussions with patients.","url":"https://pubmed.ncbi.nlm.nih.gov/42677883/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":170,"doi":"10.3389/fendo.2026.1869479","pmid":"42676363","nct_ids":"[]","title":"Efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and aerobic exercise for moderate-to-severe obstructive sleep apnea in overweight or obese patients: a network meta-analysis","authors":"[\"Zheng J\", \"Zhu Z\", \"Bao Y\", \"Hu Y\", \"Dong Z\", \"Zhao A\", \"Li Q\", \"Wang Y\", \"Zhu M\", \"Chen P\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder strongly linked to obesity and substantially increases the risk of cardiovascular and metabolic diseases. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and aerobic exercise have shown potential in improving OSA through distinct metabolic and physiological mechanisms. However, direct comparative evidence of their efficacy remains limited. This network meta-analysis aimed to compare the effects of SGLT2 inhibitors, GLP-1 receptor agonists, and aerobic exercise on OSA severity in overweight or obese patients. [METHODS] We searched four electronic databases, PubMed, EMBASE, the Cochrane Library, and Web of Science, for articles published before October 31, 2025, without language restrictions. The analysis primarily included randomized controlled trials (RCTs); a limited number of case-control studies were also incorporated due to the scarcity of direct comparative evidence. Primary efficacy outcomes were mean changes in the apnea-hypopnea index (AHI), body mass index (BMI), mean peripheral oxygen saturation (SpO2), and Epworth Sleepiness Scale (ESS) score. The certainty (confidence) of the evidence for every network estimate was appraised with the Confidence in Network Meta-Analysis (CINeMA) framework, which operationalizes the GRADE approach for network meta-analysis. [RESULTS] A total of 15 studies (13 RCTs and 2 case-control studies) involving 1,877 participants were included in the analysis. GLP-1 receptor agonists demonstrated the greatest reduction in AHI compared with placebo (mean difference [MD] = -15.28 events/h; 95% CI, -22.22 to -8.35). They also showed significant benefit versus placebo in lowering BMI (MD = -1.78 kg/m2; 95% CI, -2.15 to -1.41) and improving mean SpO2 (MD = 0.40%; 95% CI, 0.25 to 0.55). Although GLP-1 receptor agonists yielded a statistically significant improvement in ESS score versus placebo (MD = -0.20; 95% CI, -0.26 to -0.14), this effect was an order of magnitude below the 2-point minimal clinically important difference (MCID) for the ESS and is therefore not clinically meaningful. Aerobic exercise ranked highest in surface under the cumulative ranking curve (SUCRA) analysis for this outcome. No network estimate was rated as high certainty. Confidence was moderate for the effect of GLP-1 receptor agonists on BMI, low for their effects on AHI, mean SpO2, and ESS score versus placebo, and very low for all remaining comparisons, mainly because of within-study bias, imprecision, and suspected reporting bias. [CONCLUSION] Compared with placebo, GLP-1 receptor agonists reduced AHI and BMI and improved mean SpO2, and ranked highest for these outcomes in the SUCRA analysis. Comparisons between the active interventions, however, were largely non-significant and rested on indirect evidence, and the certainty of the evidence was moderate at best, being low or very low for most comparisons. This treatment hierarchy should therefore be regarded as hypothesis-generating rather than as a basis for firm clinical recommendations. Within these limits, these findings suggest that GLP-1 receptor agonists may offer a promising therapeutic approach for managing OSA in overweight or obese patients with metabolic comorbidities, though this remains to be confirmed in larger, high-quality, head-to-head trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42676363/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"sleep\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":175,"doi":"10.3389/fendo.2026.1924744","pmid":"42723833","nct_ids":"[]","title":"Low baseline HbA1c and reduced eGFR are associated with relatively unfavorable body recomposition after SGLT2 inhibitor therapy in type 2 diabetes","authors":"[\"Gobaru M\", \"Hasuzawa N\", \"Kurinami N\", \"Wada N\", \"Wang L\", \"Nagayama A\", \"Ashida K\", \"Moriyama Y\", \"Jinnouchi H\", \"Nomura M\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and promote weight loss, but their effects on the relative balance between skeletal muscle and fat mass remain incompletely understood. This study examined treatment-associated body composition changes in patients with type 2 diabetes mellitus (T2DM), focusing on muscle-to-fat balance. [METHODS] In this multicenter retrospective cohort study, we analyzed body composition changes 12 months after initiation of SGLT2i (n = 36), GLP-1RA (n = 17), or GLP-1RA add-on to SGLT2i therapy (n = 20). Changes in appendicular skeletal muscle mass (ΔASM) and body fat mass (ΔBFM) were assessed using bioelectrical impedance analysis. The Body Recomposition Score (BRS) was defined as ΔASM - ΔBFM and used as an exploratory index of the relative balance between muscle and fat mass changes; BRS < 0 was operationally defined as indicating relatively unfavorable body recomposition. An independent external cohort of patients with T2DM (n = 148) was used for external assessment. [RESULTS] ΔBFM and ΔASM were positively correlated with changes in body weight (ΔBW) in all treatment groups. However, ΔASM and ΔBFM were positively correlated only in the GLP-1RA group, whereas no such correlation was observed in the SGLT2i or GLP-1RA add-on to SGLT2i groups, suggesting interindividual heterogeneity in muscle-to-fat balance changes. In the SGLT2i group, BRS was positively correlated with baseline HbA1c (r = 0.36, p = 0.029) and estimated glomerular filtration rate (eGFR; r = 0.34, p = 0.040). No baseline variables correlated significantly with BRS in the other groups. Exploratory receiver operating characteristic analyses identified Youden index-derived cut-offs for discriminating BRS < 0 in the SGLT2i group: 6.6% for baseline HbA1c and 65 mL/min/1.73 m2 for eGFR. In the external cohort, BRS, calculated as the change in total skeletal muscle mass (ΔSMM) - ΔBFM at 4 weeks after SGLT2i initiation, showed significant positive correlations with baseline HbA1c and eGFR. [CONCLUSIONS] Lower baseline HbA1c and reduced eGFR were associated with lower BRS after SGLT2i therapy in patients with T2DM. These exploratory findings support the importance of individualized pharmacotherapy for type 2 diabetes with consideration of muscle-to-fat balance. [CLINICAL TRIAL REGISTRATION] https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055239, identifier UMIN000048469; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055242, identifier UMIN000048471.","url":"https://pubmed.ncbi.nlm.nih.gov/42723833/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"muscle\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":225,"doi":"10.1371/journal.pone.0357577","pmid":"42715243","nct_ids":"[\"NCT07014709\"]","title":"Impact of GLP-1 receptor agonists on patients with intraductal papillary mucinous neoplasms: Study protocol for a multicentric cohort study","authors":"[\"Lagger M\", \"Najberg H\", \"Miftaroski A\", \"Widmer L\", \"Di Renzo S\", \"Iranmanesh P\", \"Matter M\", \"Tekdogan B\", \"Perrodin S\", \"Gloor B\", \"Toso C\", \"Frossard JL\", \"Adamina M\", \"Buhler L\"]","journal":"PloS one","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM OF THE STUDY] Intraductal papillary mucinous neoplasms (IPMNs) are among the most common cystic pancreatic neoplasms, with a potential to progress to malignancy. The increasing prevalence of IPMNs, coupled with the widespread use of GLP-1 receptor agonists (GLP-1 RAs) for diabetes and obesity management, raises concerns about the safety of these medications in patients with preexisting pancreatic conditions. Despite their proven metabolic benefits, questions remain about their impact on pancreatic pathology. This study investigates the association between GLP-1 RA use and IPMN progression to address this critical gap in the current literature. [METHODS] This retrospective multicentric cohort study will analyse data from January 2010 to July 2026 across three Swiss tertiary institutions. Patients with a radiological diagnosis of IPMN and/or treated with GLP-1 RAs will be included. Patients will be stratified into four groups according to a 2 × 2 design based on GLP-1 RAs exposure and IPMN status. The primary objective is to evaluate the impact of GLP-1 RAs on IPMN progression using radiological criteria from the Kyoto 2023 Consensus. Secondary objectives include assessing changes in tumour markers (CA19-9, CEA), the incidence of acute pancreatitis, the progression of IPMNs to high-grade dysplasia or invasive carcinoma, and the need for surgical intervention or altered surveillance protocols associated with GLP1 RAs use. [DISCUSSION] This study aims to explore potential associations between GLP-1 RA use and changes in IPMN characteristics, tumour markers, and disease progression. Given the retrospective design and expected small sample size (estimated at 30-60 patients in total), the study may not be powered to establish definitive correlations. Nonetheless, it will generate preliminary data to help inform hypotheses and guide future research. Any observed trends could provide valuable insights into the safety of GLP-1 RAs in patients with IPMNs and contribute to more informed clinical decision-making regarding the use of these agents in a population at risk for pancreatic disease progression. [TRIAL REGISTRATION] ClinicalTrials.gov NCT07014709.","url":"https://pubmed.ncbi.nlm.nih.gov/42715243/","source_name":"pubmed","source_tier":1,"coi_statement":"there are no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:01+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cancer\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":243,"doi":"10.3389/fphar.2026.1882225","pmid":"42723821","nct_ids":"[]","title":"Reporting patterns of suicide- and self-injury-related events involving liraglutide, semaglutide, and tirzepatide: data from the European pharmacovigilance database","authors":"[\"Scavone C\", \"Cerasuolo M\", \"Gaio M\", \"Lettera N\", \"Bernardi FF\", \"Capuano A\", \"Rinaldi B\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 (GLP-1) and GIP receptor agonists (RAs) are increasingly used for treating type 2 diabetes mellitus and for chronic weight management. As their use expands, more attention is being paid to potential safety concerns, especially psychiatric adverse events. So far, European and United States regulatory agencies have not confirmed a causal relationship between these drugs and suicidality. Continued post-marketing monitoring remains warranted, given their growing use for weight management. [METHODS] This study aimed to provide an updated pharmacovigilance analysis of suicide or self-injury-related events reported with liraglutide, semaglutide, and tirzepatide. Individual Case Safety Reports listing liraglutide, semaglutide, or tirzepatide as suspected drugs were retrieved from EudraVigilance. The period covered was 1 January 2021 to 31 December 2025. Reports were included if the indication was consistent with type 2 diabetes mellitus or weight management. Suicide and self-injury events were identified using Preferred Terms from the Standardised MedDRA Query \"Suicide/self-injury.\" Report characteristics were described. Reporting odds ratio (RORs), along with 95% confidence intervals, were calculated to compare the frequency of suicide and self-injury events across the three drugs. [RESULTS] We included 42,941 eligible reports. Most reports involved semaglutide, then tirzepatide and liraglutide. Gastrointestinal disorders were the most frequent adverse events, followed by injury, poisoning and procedural complications, and general disorders and administration site conditions. Suicide/self-injury events made up a small portion, with 37 cases for liraglutide, 141 for semaglutide, and 47 for tirzepatide. Compared with tirzepatide, the reporting frequency of these events was higher for liraglutide (ROR 2.54, 95% CI 1.60-4.01) and semaglutide (ROR 2.69, 95% CI 1.91-3.83). [CONCLUSIONS] These findings do not establish a causal link between GLP-1 and GLP-1/GIP RAs and suicide or self-injury events but simply provide a comparative analysis of disproportionality. Overall, the results do not contradict regulatory conclusions. They should be interpreted with caution, as spontaneous reporting systems have limitations. Continued pharmacovigilance is warranted, especially as use for weight management increases.","url":"https://pubmed.ncbi.nlm.nih.gov/42723821/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":246,"doi":"10.3389/fendo.2026.1870008","pmid":"42718598","nct_ids":"[]","title":"Use of incretin receptor agonists in patients submitted to metabolic bariatric surgery - a systematic review and meta-analysis","authors":"[\"Santos-Pereira M\", \"Frutuoso JF\", \"Pereira SS\", \"Guimarães M\", \"Monteiro MP\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Metabolic bariatric surgery is a highly effective weight-loss intervention. Nevertheless, a non-negligible proportion of patients experience a suboptimal clinical response, which may present as insufficient weight loss or weight regain after an initial loss. In these cases, weight management pharmacotherapy can be considered. We aimed to conduct a systematic review and meta-analysis of the best available data on the use of incretin receptor agonists, liraglutide, semaglutide, and tirzepatide, in patients previously submitted to metabolic bariatric surgery. [METHODS] We searched PubMed, Scopus, and Web of Science, for original studies that evaluated weight loss and adverse events in adults submitted to metabolic bariatric surgery one year or more before receiving treatment with these drugs. [RESULTS] Twenty-seven papers (n=27) were included in this systematic review, of which nineteen (n=19) were used in the meta-analysis. After treatment with incretin receptor agonists, patients who underwent metabolic bariatric surgery, experienced significant weight loss. Meta-analysis showed, at 12 months, a total weight loss of 9.22% with liraglutide and of 9.02% with semaglutide. At 6 months, a mean difference in total weight loss of 4.23% was presented in favor of tirzepatide as compared to semaglutide. No serious adverse events were observed and most reported side effects were non-serious, consisting primarily of mild gastrointestinal symptoms. [DISCUSSION] This data suggests that incretin receptor agonist treatment after metabolic bariatric surgery demonstrated the ability to achieve significant weight loss with a good safety profile, particularly in patients with a suboptimal clinical response, and thus may serve as an alternative rescue therapy to revisional surgery. However, given the substantial heterogeneity across studies, these findings should be interpreted with caution. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022371697, identifier CRD42022371697.","url":"https://pubmed.ncbi.nlm.nih.gov/42718598/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":266,"doi":"10.1136/bmjmed-2026-003026","pmid":"42688617","nct_ids":"[]","title":"Comparative efficacy and safety of glucagon-like peptide 1 based drugs for weight loss in adults with overweight or obesity without diabetes: network meta-analysis of randomised controlled trials","authors":"[\"Chen D\", \"Ma B\", \"Sun H\", \"Zhang J\", \"Gong L\", \"Wang W\", \"Liu Z\", \"Zha H\", \"Du S\", \"Chen M\", \"Sun W\", \"Guo Q\", \"Cao Y\", \"Li Y\"]","journal":"BMJ medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare the efficacy and safety of glucagon-like peptide 1 (GLP-1) based drug treatments for weight loss in adults with overweight or obesity without diabetes. [DESIGN] Network meta-analysis of randomised controlled trials. [DATA SOURCES] Embase, PubMed (Medline), and Web of Science, 1 January 2000 to 6 March 2026. [ELIGIBILITY CRITERIA FOR SELECTING STUDIES] Randomised controlled trials that enrolled adults with overweight or obesity, comparing GLP-1 receptor agonists or related co-agonists with placebo or active comparators, with a minimum intervention duration of 12 weeks. Excluded were trials that enrolled participants with diabetes, or where diabetes status could not be clearly determined. [RESULTS] 58 trials of 24 214 participants were analysed. Compared with placebo, weight loss was greatest with retatrutide (-22.10%, 95% confidence interval -25.60% to -18.60%), followed by tirzepatide (-19.28%, -20.39% to -18.16%), and CagriSema (a combination of cagrilintide and semaglutide, -17.32%, -19.32% to -15.32%). Conventional GLP-1 receptor agonists showed more modest effects. Similar patterns were seen for waist circumference and lipid outcomes. Treatment rankings suggested a probabilistic hierarchy favouring next generation incretin based treatments, although confidence intervals overlapped for several comparisons. Low certainty evidence suggested higher rates for discontinuing treatment with danuglipron and retatrutide, whereas mazdutide showed better tolerability. [CONCLUSIONS] In adults with overweight or obesity without diabetes, next generation incretin based treatments achieved greater weight loss than conventional GLP-1 receptor agonists. Differences in tolerability, limited head-to-head evidence, and residual uncertainty, however, should be considered when interpreting comparative treatment effects. [STUDY REGISTRATION] PROSPERO CRD420261279841.","url":"https://pubmed.ncbi.nlm.nih.gov/42688617/","source_name":"pubmed","source_tier":1,"coi_statement":"All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Natural Science Foundation of China for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\", \"mazdutide\", \"cagrisema\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":272,"doi":"10.2147/jaa.s637738","pmid":"42730051","nct_ids":"[]","title":"Association of Tirzepatide versus Semaglutide with Risk of Asthma Exacerbation in Patients with Asthma and Type 2 Diabetes: A US Multicenter Retrospective Cohort Study","authors":"[\"Hung CT\", \"An CY\", \"Suk CW\", \"Lee TW\", \"Hung SH\"]","journal":"Journal of asthma and allergy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in improving respiratory outcomes, the comparative effectiveness of dual glucose-dependent insulinotropic polypeptide/GLP-1 RA versus GLP-1 RA alone remains unclear. [OBJECTIVE] To assess the association of tirzepatide versus semaglutide with the risk of asthma exacerbation among patients with asthma and type 2 diabetes (T2D). [METHODS] Data from the TriNetX US Collaborative Network were used. Adults with asthma and T2D who initiated tirzepatide or semaglutide between June 01, 2022, and December 31, 2024, were included. The study period ended on December 1, 2025. The primary outcome was time to first asthma exacerbation over a 12-month follow-up. Secondary outcomes included systemic corticosteroid and short-acting beta-agonist (SABA) use. Propensity score matching was used to balance baseline covariates. Kaplan-Meier curves and Cox regression models were used to estimate comparative effectiveness. [RESULTS] After 1:1 matching, 8176 patients were included in each group. The risk of asthma exacerbation was similar between tirzepatide and semaglutide (11.0% vs 11.1%; HR, 1.00; 95% CI, 0.91-1.10). This finding remained consistent across sensitivity and subgroup analyses. For secondary outcomes, tirzepatide was associated with a lower risk of SABA use (HR, 0.92; 95% CI, 0.88-0.96) and a similar risk of systemic corticosteroid use (HR, 1.01; 95% CI, 0.96-1.05) compared with semaglutide. [CONCLUSION] Among patients with asthma and T2D, no difference in the risk of asthma exacerbation between tirzepatide and semaglutide was observed. Further investigation through randomized controlled trials is warranted to clarify the potential role of GLP-1 RA-based therapies in patients with asthma and T2D.","url":"https://pubmed.ncbi.nlm.nih.gov/42730051/","source_name":"pubmed","source_tier":1,"coi_statement":"All listed authors report no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":355,"doi":"10.7717/peerj.20710","pmid":"41660088","nct_ids":"[]","title":"The effects of GLP-1 receptor agonists on metabolic inflammatory markers in patients with type 2 diabetes mellitus: a systematic review and meta-analysis","authors":"[\"Zhao F\", \"Wang H\", \"Li S\", \"Yun H\", \"Su W\"]","journal":"PeerJ","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This study aimed to evaluate the impact of GLP-1 receptor agonists (GLP-1 RAs) on metabolic inflammatory markers in patients with type 2 diabetes mellitus (T2DM), providing evidence-based insights for their potential application in anti-inflammatory therapy. [METHODS] Research questions were developed using the PICOS framework, and the study strictly adhered to PRISMA guidelines. Comprehensive literature searches were conducted across PubMed, EBSCO, Embase, Web of Science, and the Cochrane Library. Data synthesis and subgroup analyses (focusing on GLP-1 RA subtypes, treatment duration, and administration frequency) were performed using RevMan 5.4 software. [RESULTS] Out of 1,347 articles retrieved, 25 studies were ultimately included, comprising a total sample of 1,878 participants (879 in the experimental groups and 999 in the control groups). Quality assessment indicated that most studies exhibited a low risk of bias, with only one study rated as high risk and three studies showing some concerns. Meta-analysis results demonstrated that 18 studies reported a significant reduction in CRP levels in T2DM patients treated with GLP-1 RAs (SMD = -0.39, 95% CI [-0.72 to -0.06], P = 0.02, I2 = 88%). Although the results from 13 studies indicated a decreasing trend in IL-6 levels (SMD = -0.52), this change was not statistically significant (95% CI [-1.34 to 0.29], P = 0.21, I2 = 96%). Additionally, 14 studies showed that GLP-1 RAs significantly reduced TNF-α levels (SMD = -0.51, 95% CI [-0.81 to -0.20], P = 0.001, I2 = 81%). Subgroup analyses revealed that both the type of GLP-1 RA and a longer treatment duration (≥36 weeks) were associated with more pronounced improvements in inflammatory markers. [CONCLUSION] GLP-1 RAs exhibit a certain degree of anti-inflammatory effect in patients with T2DM, effectively reducing CRP and TNF-α levels. The anti-inflammatory efficacy appears to be influenced by both the type of drug used and the duration of treatment, with more pronounced effects observed for specific drug classes and with longer treatment periods. These findings provide further evidence supporting the use of GLP-1 RAs in the anti-inflammatory management of T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/41660088/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare there are no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1878,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1878, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1878, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI [-0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 4, 7, 11; non-critical weaknesses on items 3, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"Partial Yes\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"Yes\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 6, \"Partial Yes\": 2, \"Yes\": 8}, \"settled_by_ruling\": [\"item 3: No (IN-059; the passes read Yes and No)\", \"item 8: Partial Yes (IN-059; the passes read Partial Yes and Yes)\", \"item 14: Yes (IN-059; the passes read No and Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/41660088/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/41660088/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-03-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.2\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"Systematic review and meta-analysis of randomized controlled trials only (non-RCTs excluded).","funding_source":"No funding received (full text)","industry_funded":"no","manufacturer":null,"author_conflicts":"The authors declare there are no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Pooled 25 randomized trials (1,878 people with type 2 diabetes): CRP and TNF-alpha, blood markers of inflammation, fell modestly (SMD -0.39 and -0.51), with very high heterogeneity (I2 81-96% across markers); IL-6 did not change significantly. These are biomarkers, not clinical outcomes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":540,"doi":"10.2147/dmso.s616418","pmid":"42763732","nct_ids":"[]","title":"Efficacy and Safety of CagriSema for Metabolic Outcomes: Systematic Review and Pairwise Meta-Analysis of Randomized Controlled Trials","authors":"[\"Shao C\", \"Lin H\", \"Yu J\", \"Chen H\", \"Ren Y\", \"Ren J\", \"Zeng Y\", \"Wu Y\", \"Bai H\", \"Zhang Q\", \"Xiao X\"]","journal":"Diabetes, metabolic syndrome and obesity : targets and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Overweight status, obesity, and diabetes represent significant socioeconomic burdens that require long-term management. [METHODS] To evaluate the efficacy and safety of dual-agonist CagriSema vs semaglutide monotherapy, cagrilintide monotherapy, and placebo in adults with overweight/obese status and type 2 diabetes, we searched Embase, MEDLINE, PubMed, and the Cochrane Library up to 14 June 2026 for randomized controlled trials (RCTs). Separate pairwise meta-analyses were conducted using random effects models. [RESULTS] Eight RCTs comprising 6898 participants were included. CagriSema was associated with significantly greater percentage body weight reduction compared to semaglutide [MD -6.60%; 95%CI: -8.51 to -4.68; P<0.0001; I2 =82%], cagrilintide [MD -8.15%; 95%CI: -11.40 to -4.89; P<0.0001; I2 =95%], and placebo [MD -14.30%; 95%CI: -17.41 to -11.19; P<0.0001; I2 =99%]. A greater decrease in the percentage of glycated hemoglobin was also observed for CagriSema than for semaglutide [MD -0.09%; 95%CI: -0.14 to -0.04; P=0.0004; I2 =39%], cagrilintide [MD -0.87%; 95% CI -1.48 to -0.26; p = 0.005; I2 = 97%], and placebo [MD -1.55%; 95% CI -2.14 to -0.97; p < 0.0001; I2 = 99%]. Furthermore, CagriSema achieved significantly greater reductions in absolute body weight, waist circumference and body mass index across all comparators (all p < 0.0001). CagriSema demonstrated better blood pressure control compared with cagrilintide and placebo, with effects comparable to those of semaglutide. Moreover, CagriSema significantly decreased C-reactive protein and improved lipid profiles compared with cagrilintide and placebo. CagriSema increased any adverse events and gastrointestinal adverse events compared with all comparators. Substantial statistical heterogeneity was observed in several continuous outcomes, driven by diverse baseline clinical characteristics and background therapies. [CONCLUSION] Compared with current standard monotherapies and placebos, CagriSema demonstrates superior weight loss, glucose, and lipid control. Key limitations include the relatively small number of eligible trials and the current lack of long-term cardiovascular endpoints.","url":"https://pubmed.ncbi.nlm.nih.gov/42763732/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors report no conflicts of interest in this work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"cagrisema\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":549,"doi":"10.1371/journal.pone.0358225","pmid":"42758714","nct_ids":"[]","title":"Divergent effects of semaglutide and CRV431 Co-therapy on liver fibrosis and HCC in MASLD mouse model","authors":"[\"Goodman AZ\", \"Stauffer WT\", \"Gallay PA\"]","journal":"PloS one","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by progressive fibrosis and an increased risk of hepatocellular carcinoma (HCC). Recently, approved drug treatments for MASLD, including thyroid hormone receptor beta (THR-β) and glucagon-like peptide-1 (GLP-1) receptor agonists, have been effective in treating the underlying metabolic causes of MASLD. However, more effective and acute treatments, particularly for already advanced or cirrhotic steatohepatitis, remain elusive. Other drug candidates, such as cyclophilin inhibitors, which have shown promise for treating advanced MASLD, are still under investigation. Because advanced MASLD reflects both upstream metabolic stress and downstream, self-sustaining injury responses promoting inflammation and fibrogenesis, we investigated whether pairing GLP-1 agonism (metabolic correction) with cyclophilin inhibition (fibrosis and inflammation remodeling) would yield additive or emergent benefits. Thus, we evaluated Semaglutide, Rencofilstat (CRV431), and their co-administration in a C57BL/6J model of diet- and toxin-induced MASLD via a Western diet, sucrose supplementation, and chronic carbon tetrachloride exposure. Semaglutide monotherapy significantly reduced body weight and decreased HCC burden (Kruskal-Wallis Analysis, p < 0.0001) whereas fibrosis quantified by picrosirius red staining did not differ significantly across the treatment groups (Welch's Analysis of Variance, p = 0.1725). Co-therapy did not improve collagen deposition compared with monotherapy. These findings indicate that the combination of GLP-1 receptor agonism with cyclophilin inhibition does not confer additive antifibrotic benefits in this advanced MASLD model, underscoring stage-dependent constraints on therapeutic synergy.","url":"https://pubmed.ncbi.nlm.nih.gov/42758714/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors have declared that no competing interests exist.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-20T11:15:06+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"liver\", \"cancer\", \"addiction\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":560,"doi":"10.3389/fmed.2026.1909537","pmid":"42741157","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor agonists and tirzepatide are associated with reduced mortality, cardiovascular, and psychiatric risks in patients with hidradenitis suppurativa and type 2 diabetes and/or obesity: a retrospective cohort study","authors":"[\"Brouer IC\", \"Zani A\", \"Olbrich H\", \"Ludwig RJ\", \"Thaçi D\"]","journal":"Frontiers in medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease strongly associated with obesity and diabetes mellitus type 2 (T2D). GLP-1 receptor agonists (GLP-1RAs) and tirzepatide are increasingly used for metabolic control, but their systemic effects in HS remain poorly characterized. [OBJECTIVES] To compare all-cause mortality, cardiovascular, rheumatologic, metabolic, psychiatric, and non-communicable inflammatory outcomes in HS patients with T2D or obesity treated with GLP-1RAs/tirzepatide vs. alternative metabolic medications. [METHODS] This retrospective cohort study used the US Collaborative Network in TriNetX. Adults (≥18 years) with HS and T2D or obesity were included, excluding prior bariatric surgery. Exposed patients received a GLP-1RA or tirzepatide for at least one year, controls received other systemic antidiabetic or anti-obesity agents. Outcomes over a 2-year follow-up were assessed using 1:1 propensity score matching (PSM) for each outcome category. Outcomes included all-cause mortality, cardiovascular, rheumatologic, metabolic, psychiatric, and non-communicable inflammatory events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and Cox regression was used to confirm significant findings. Sensitivity analyses and benchmark comparisons were performed. [RESULTS] Before matching, 8,564 patients received GLP-1RA/tirzepatide and 6,299 alternative therapies. After matching, GLP-1RA/tirzepatide use was associated with reduced all-cause mortality (HR: 0.24, 95% CI: 0.145-0.395; p < 0.0001) and major adverse cardiovascular events (MACE) (HR: 0.61, 95% CI: 0.500-0.749; p < 0.0001). Risks of stroke and heart failure were also reduced (both p < 0.05). Psychiatric outcomes, including depression (HR: 0.78), suicidal ideation (HR: 0.38), and substance use disorder (HR: 0.58), were significantly reduced (all p < 0.05). Risks for rheumatologic and non-communicable chronic inflammatory outcomes were similar among groups. A modest increase in the risk of hyperlipidemia (HR: 1.25), metabolic dysfunction-associated steatotic liver disease (MASLD) (HR: 1.37), and nausea/vomiting (HR: 1.31) was observed in the GLP-1RA/tirzepatide group compared with alternative therapies (all p < 0.05). [CONCLUSION] GLP-1RAs and tirzepatide are associated with reduced mortality, cardiovascular and psychiatric morbidity in HS patients with obesity or T2D, without increasing rheumatologic or inflammatory risk. These results extend the systemic benefits of GLP-1RAs and tirzepatide beyond metabolic control and suggest potential therapeutic value in HS.","url":"https://pubmed.ncbi.nlm.nih.gov/42741157/","source_name":"pubmed","source_tier":1,"coi_statement":"RL received travel grants from TriNetX and research funding from Novartis and Sanofi. DT has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant for AbbVie, Amgen, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Galderma, Hexal, Johnson & Johnson, LEO Pharma, Eli Lilly and Company, L'Oréal, New Bridge, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharmaceutical Industries, Takeda, Target RWE, UCB, and Vichy. The remaining authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors RL and DT declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"liver\", \"addiction\", \"mortality\", \"metabolic\", \"gastrointestinal\", \"psychiatric\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":627,"doi":"10.3389/fendo.2026.1942151","pmid":"42745769","nct_ids":"[]","title":"Incremental effects of SGLT2 inhibitors, GLP-1 receptor agonists, and pioglitazone in type 2 diabetes and MASLD across Asian study settings: a systematic review and meta-analysis","authors":"[\"Zheng H\", \"Han J\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] We evaluated the incremental hepatic and metabolic effects of adding sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), or pioglitazone to comparable background glucose-lowering therapy in Asian adults with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). [METHODS] We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science through 30 June 2026. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Eligible trials evaluated the addition of a study drug to background glucose-lowering management that was comparable between randomized groups and either remained stable or followed a prespecified adjustment protocol. Changes from baseline in alanine aminotransferase (ALT) and glycated hemoglobin (HbA1c) were coprimary outcomes. Secondary outcomes included aspartate aminotransferase, gamma-glutamyl transferase, magnetic resonance imaging-proton density fat fraction, liver stiffness, fibrosis-4 index, fasting plasma glucose, lipid parameters, body mass index, serum adiponectin, and systolic blood pressure. Random-effects pairwise meta-analyses were performed, and GRADE certainty was assessed for the two coprimary outcomes. Safety outcomes were synthesized narratively because reporting was heterogeneous and frequently incomplete. [RESULTS] We included eleven randomized trials: 692 participants were randomized into eligible comparisons, of which 642 participated in the coprimary efficacy analyses. Moderate certainty was found for a reduction in ALT with the addition of an SGLT2 inhibitor compared with background therapy alone (mean difference [MD], - 7.56 U/L; 95% confidence interval [CI], - 11.24 to - 3.88); however, there was little or no clinically important further benefit observed for HbA1c (MD, - 0.09%; 95% CI, - 0.27 to 0.08; moderate certainty). Modest reductions in ALT were suggested by moderate certainty for GLP-1RAs (MD, - 6.71 U/L; 95% CI, - 11.53 to - 1.89) while low certainty indicated an HbA1c reduction (MD, - 0.48%; 95% CI, - 0.83 to - 0.14). Secondary exploratory findings favoring add-on therapy existed, although they are unadjusted for multiplicity. The comparative safety could not be assessed reliably. [CONCLUSION] In short-term randomized trials conducted in Asian study settings, adding SGLT2 inhibitors or GLP-1RAs may improve selected hepatic and metabolic surrogate outcomes. The available evidence does not support a treatment-class ranking, and the durability and clinical significance of these changes remain uncertain because follow-up was short and several comparisons were based on sparse evidence. Comparative safety also remains uncertain because adverse-event reporting was heterogeneous and incomplete. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251231137.","url":"https://pubmed.ncbi.nlm.nih.gov/42745769/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"liver\", \"addiction\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":631,"doi":"10.3389/fphar.2026.1916932","pmid":"42757217","nct_ids":"[]","title":"Risk of neoplasms with semaglutide in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials","authors":"[\"Zhong Y\", \"Tan X\", \"Zhang L\", \"Wu C\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide is prescribed in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM). However, its potential impact on tumorigenesis has prompted considerable debate. [METHODS] The meta-analysis was conducted in accordance with PRISMA 2020 guidelines. We searched Web of Science, PubMed, Embase, and ScienceDirect for eligible randomized controlled trials (RCTs). The outcome was the risk of overall, benign and malignant neoplasms. The pooled results were expressed as odds ratio (OR) with 95% confidence interval (95% CI). Influential publication was determined by performing the sensitivity analysis. Publication bias was assessed using the funnel plot, Begg's and Egger's tests. [RESULTS] Nineteen RCTs conducted between 2016 and 2025 were included, enrolling of 38,160 patients with T2DM. The interventions involved subcutaneous semaglutide and oral semaglutide, with treatment durations ranging from 26 to 156 weeks. Fixed-effects meta-analysis revealed that semaglutide use was associated with an increased risk of overall neoplasms (OR = 1.19, 95% CI = 1.07 to 1.32, P = 0.001) and benign neoplasms (OR = 1.28, 95% CI = 1.02 to 1.61, P = 0.032), but showed no significant association with malignant neoplasms (OR = 1.12, 95% CI = 1.00 to 1.26, P = 0.054). No influential publications or significant publication bias were detected. [CONCLUSION] Semaglutide use in patients with T2DM is associated with a modestly increased risk of overall and benign neoplasms, but not malignant neoplasms. These findings highlight the importance of maintaining clinical awareness regarding potential neoplastic risks, and further long-term RCTs are warranted to clarify their clinical significance. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420261354386, Identifier CRD420261354386.","url":"https://pubmed.ncbi.nlm.nih.gov/42757217/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":665,"doi":"10.3389/fendo.2026.1922668","pmid":"42798540","nct_ids":"[]","title":"γδ T-cell interferon-γ production reflects metabolic improvement during SGLT2 inhibitor-based therapy in type 2 diabetes","authors":"[\"Troskot Cuculić M\", \"Sergo D\", \"Kavazović I\", \"Peršić V\", \"Wensveen FM\", \"Turk Wensveen T\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Chronic low-grade meta-inflammation contributes to insulin resistance and metabolic dysfunction in type 2 diabetes (T2D). γδ T cells have emerged as important mediators of metabolic inflammation, yet their responsiveness to metabolic improvement in humans remains poorly understood. We investigated whether successful antidiabetic therapy is associated with alterations in γδ T cell-mediated inflammation in patients with T2D. [METHODS] Twenty-five patients with poorly controlled T2D initiating SGLT2i therapy (n=15) or SGLT2i plus GLP-1RA (n=10) were prospectively followed for 12 months. Age- and sex-matched non-diabetic controls (n=30) were included at baseline. Peripheral blood γδ T cell phenotype and cytokine production were assessed by multiparametric flow cytometry. Metabolic, hepatic, and renal parameters were evaluated longitudinally. [RESULTS] At baseline, patients with T2D exhibited increased interferon-γ (IFN-γ) production by both Vδ1+ and Vδ2+ γδ T-cell subsets compared with controls, while subset frequencies remained unchanged. During follow-up, successful antidiabetic therapy was associated with a progressive reduction in IFN-γ production, reaching approximately 40% after 12 months (p<0.01). This reduction did not correlate with changes in HbA1c and was not enhanced by the addition of GLP-1 receptor agonist therapy. In contrast, lower IFN-γ production was associated with improved insulin sensitivity, reduced fat mass, and markers of improved metabolic health. The largest reductions were observed in individuals with mild hepatic or renal impairment and correlated with indices of organ involvement. [DISCUSSION] This real-world study shows that γδ T cell-mediated meta-inflammation decreases during successful antidiabetic therapy independently of glycemic control. IFN-γ production by γδ T cells is closely associated with insulin resistance, adiposity, and metabolic organ dysfunction, supporting its potential utility as a biomarker of metabolic tissue stress and therapeutic response in T2D.","url":"https://pubmed.ncbi.nlm.nih.gov/42798540/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:07+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"kidney\", \"body_composition\", \"liver\", \"immune\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":692,"doi":"10.1371/journal.pone.0358659","pmid":"42784582","nct_ids":"[]","title":"Cardiovascular outcomes associated With GLP-1 and dual GLP-1/GIP receptor agonists in patients with type 2 diabetes and inflammatory bowel disease: A retrospective real-world cohort study","authors":"[\"Kazi MAI\", \"Mufarrih SM\", \"Sirohi A\", \"Hasan F\", \"Sharma A\", \"Singh S\", \"Muganlinskaya N\", \"Haq N\"]","journal":"PloS one","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Individuals with co-morbid T2D and IBD represent a uniquely high-risk group, facing amplified cardiovascular risk through synergistic inflammatory and metabolic pathways, in whom conventional cardiometabolic strategies (such as dietary and lifestyle changes, weight loss, blood pressure and lipid optimization, metformin therapy, SGLT2 inhibitor therapy) may be insufficient due to the overlap between metabolic disease and chronic inflammatory disease processes. At present, the literature available on the role of incretin-based therapy in the treatment of T2D in patients with co-morbid IBD is limited. We aimed to evaluate the association of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists with cardiovascular outcomes in individuals with T2DM and IBD. This study is not intended as a direct comparison of the efficacy of GLP-1 agonists and dual GLP-1/GIP receptor agonists in patients with T2D and IBD. Both drug classes were analyzed as a combined incretin-based therapy exposure group to reflect real-world prescribing patterns and maximize statistical power. [METHODS] We conducted a retrospective cohort study using the TriNetX global federated research network, identifying adults (≥18 years) with T2D and IBD between 2015-2024. Patients prescribed GLP-1 or dual GLP-1/GIP were compared with non-users following 1:1 propensity score matching on demographics, comorbidities, and medication use. Relative risks (RR) and Hazard Ratios (HR) with 95% confidence intervals (CI) were calculated, with significance defined as p < 0.05. [RESULTS] After matching 16,118 patients per cohort from among a total matched population of 32,236 patients, GLP-1 or GLP-1/GIP receptor agonist therapy was associated with lower hazard ratios across all outcomes, including myocardial infarction (HR 0.701, 95% CI 0.637-0.771), chronic ischemic heart disease (HR 0.936, 95% CI 0.896-0.978), heart failure (HR 0.777, 95% CI 0.737-0.820), atrial fibrillation/flutter (HR 0.838, 95% CI 0.788-0.890), sudden cardiac death (HR 0.694, 95% CI 0.605-0.795), ischemic stroke (HR 0.781, 95% CI 0.707-0.862), deep vein thrombosis (HR 0.642, 95% CI 0.586-0.702), and pulmonary embolism (HR 0.722, 95% CI 0.640-0.815). [CONCLUSIONS] In patients with comorbid T2D and IBD, GLP-1 and GLP-1/GIP receptor agonists were associated with significant reductions in ischemic, arrhythmic, and thromboembolic cardiovascular outcomes. These findings highlight the potential role of incretin-based therapies in improving cardiovascular risk management in this high-risk population. However, the present study does not establish the comparative efficacy of the two classes of drugs in this patient population, and the findings may be associational rather than causal. Both drug classes were analyzed as a combined exposure group. Mechanistic explanations proposed in this paper should be considered hypothesis-generating rather than confirmed by the current observational study design.","url":"https://pubmed.ncbi.nlm.nih.gov/42784582/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors have declared that no competing interests exist.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"rheumatologic\", \"metabolic\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":709,"doi":"10.3389/fimmu.2026.1877061","pmid":"42769032","nct_ids":"[]","title":"Semaglutide and pioglitazone restore airway mucosal homeostasis by resolving Pseudomonas aeruginosa pyocyanin-induced mucus hypersecretion, ciliostasis, and type 2 airway inflammation","authors":"[\"Wu C\", \"Kulkarni NA\", \"Lew SQ\", \"Choi W\", \"Sivaguru M\", \"Kosmider B\", \"Nanjappa SG\", \"Lau GW\"]","journal":"Frontiers in immunology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[RATIONALE] Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. As lung transplantation is the only curative option and current therapies are largely based on managing clinical symptoms, novel treatments are urgently needed. [OBJECTIVE] Previously, we showed that the first-generation incretin Exedine-4 could attenuate airway mucus dysregulation induced by the Pseudomonas aeruginosa redox-active toxin pyocyanin by modulating GLP1R-PPARγ signaling. In this study, we compared the efficacy of currently approved next-generation GLP1R agonists and PPARγ agonists in improving airway mucus homeostasis, mucociliary escalator function, and P. aeruginosa clearance after chronic exposure to pyocyanin, as well as the underlying mechanisms. [METHODS] Six GLP-1R agonists and two PPARγ agonists were compared based on their ability to attenuate pyocyanin-induced oxidative stress and mucin overexpression in 16HBE14o- cells by the cellular reactive oxygen species (ROS) assays, immunoblotting, and confocal immunofluorescence microscopy. The ability of these agonists to restore the mucociliary escalator function in air-liquid interface (ALI) cultures of primary human small airway epithelial cells (SAECs) was captured by confocal immunofluorescence microscopy. Then, we examined whether these agonists could restore mucus homeostasis, neutralize lung proinflammatory responses, and reduce bacterial burden in C57BL/6 mice. Finally, the expression of relevant pro- and anti-mucin biosynthesis signaling pathways was investigated. [MEASUREMENTS AND MAIN RESULTS] Semaglutide and Pioglitazone are the most effective in decreasing the expression of mucus biomarker MUC5AC mucin and ROS production in response to pyocyanin, both in vitro and in vivo. Additionally, these agonists restore mucociliary beat frequency and mucociliary transport impaired by pyocyanin. The protective effects of these drugs were partially abolished by respective antagonists, Exendin(9-39) and GW9662, against GLP1R and PPARγ, confirming the GLP1R signaling pathway-dependent mechanisms. Moreover, Semaglutide and Pioglitazone also attenuated type 2 immune responses and neutrophil influx, both of which are known drivers of mucus hypersecretion, and reduced the P. aeruginosa burden in a chronic bronchitis model of infection in mouse lungs. [CONCLUSIONS] Our findings identify a promising adjunctive therapeutic avenue for COPD by repurposing FDA-approved Semaglutide and Pioglitazone, which are readily available for clinical use.","url":"https://pubmed.ncbi.nlm.nih.gov/42769032/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author GL declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-27T11:15:07+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":730,"doi":"10.3389/fendo.2026.1937754","pmid":"42775225","nct_ids":"[]","title":"Efficacy and safety of GLP-1RAs, SGLT2is, and nsMRAs for cardiovascular and renal outcomes in T2DM with CKD: a systematic review and network meta-analysis","authors":"[\"Chen H\", \"Wu X\", \"Yuan M\", \"Ren F\", \"Liu T\", \"Yang L\", \"An X\", \"Zhan Y\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare cardiovascular and renal benefits and safety of GLP-1RAs, SGLT2is, and nsMRAs in T2D-CKD using network meta-analysis. [METHODS] RCTs published through 7 August 2026 were systematically identified. A frequentist random-effects network meta-analysis was performed. Evidence certainty was assessed with CINeMA. [RESULTS] A total of 21 RCTs involving 51,899 patients were included. Compared with placebo, nsMRAs were associated with lower risks of the major kidney composite outcome and hospitalization for heart failure (HHF), whereas SGLT2is were associated with lower risks of major adverse cardiovascular events (MACE), the major kidney composite outcome, and HHF. GLP-1RAs were associated with lower risks of MACE, the major kidney composite outcome, HHF, all-cause mortality, and cardiovascular death. Between-class indirect comparisons suggested a lower estimated risk of the major kidney composite outcome with SGLT2is than with GLP-1RAs (RR 0.77, 95% CI 0.64-0.91) or nsMRAs (nsMRAs versus SGLT2is: RR 1.28, 95% CI 1.10-1.50). The estimated risk of HHF was also lower with SGLT2is than with nsMRAs (nsMRAs versus SGLT2is: RR 1.28, 95% CI 1.01-1.63). For cardiovascular death, the indirect estimate suggested a lower risk with GLP-1RAs than with SGLT2is (SGLT2is versus GLP-1RAs: RR 1.28, 95% CI 1.03-1.58), whereas the comparison between nsMRAs and GLP-1RAs did not reach statistical significance (RR 1.24, 95% CI 0.99-1.56). No statistically significant between-class differences were identified for MACE or all-cause mortality. All between-class comparisons were based exclusively on indirect evidence. Safety analyses showed higher risks of hyperkalemia with nsMRAs and genital infections with SGLT2is than with placebo. Sensitivity analyses broadly supported the main findings. Confidence in the evidence was mostly low to moderate, primarily because of indirectness. [CONCLUSION] In patients with T2D-CKD, all three drug classes reduced several cardiorenal outcomes versus placebo. Between-class indirect comparisons suggested more favorable relative-effect estimates for SGLT2is on major kidney outcomes and HHF in selected comparisons, and for GLP-1RAs on cardiovascular death. No clear between-class difference was observed for MACE. Because the network lacked head-to-head comparisons between active drug classes, these findings and treatment rankings should be interpreted cautiously. Direct comparative and combination-therapy trials are needed to guide individualized treatment selection. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420251150683, identifier CRD420251150683.","url":"https://pubmed.ncbi.nlm.nih.gov/42775225/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":781,"doi":"10.3389/fendo.2026.1934027","pmid":"42798476","nct_ids":"[]","title":"Dose-response and time-course effects of ecnoglutide in type 2 diabetes: a systematic review and meta-analysis of efficacy","authors":"[\"Feng Y\", \"Sun C\", \"Li X\", \"Hu L\", \"Zhou K\", \"Li L\", \"Yuan Y\", \"Yu L\", \"Wu M\", \"Liu L\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Ecnoglutide, a novel long-acting GLP-1 receptor agonist, is considered a promising therapeutic option for the treatment of diabetes. This study aims to evaluate the efficacy and safety of ecnoglutide in adults with type 2 diabetes and to further investigate its dose-time relationship. [METHODS] This study followed the PRISMA guidelines and systematically searched PubMed, Web of Science, Embase, and Cochrane Library, with the search updated through February 2026. Randomized controlled trials comparing ecnoglutide with placebo or the active control, dulaglutide, were included. The primary outcome was the change in HbA1c (%). Secondary outcomes included FPG, PPG, 7-point SMBG, body weight, adverse events, and serious adverse events. Risk of bias was assessed using the Cochrane RoB-2 tool. Meta-analyses employed a random-effects model, and mean differences and risk ratios were calculated with 95% confidence intervals. [RESULTS] Three randomized controlled trials involving 977 participants were included. Compared with placebo, ecnoglutide significantly reduced HbA1c (MD = -1.40, 95% CI -1.65, -1.14, p < 0.00001), FPG (MD = -1.98, 95% CI -2.34, -1.63, p < 0.00001), PPG (MD = -4.88, 95% CI -6.32, -3.44, p < 0.00001), and body weight (MD = -2.16, 95% CI -2.62, -1.71, p < 0.00001). Additionally, compared with the placebo group, the incidence of adverse events was higher in the ecnoglutide group (OR = 2.03, 95% CI 1.24-3.32, p = 0.005), while there was no significant difference in the incidence of serious adverse events. Dose-response analysis showed that ecnoglutide exhibited a clear dose-dependent relationship for HbA1c, FPG, and body weight at doses ranging from 0.4 to 1.2 mg, while PPG was less affected by dose. Time-response analysis indicated that the hypoglycemic efficacy of ecnoglutide peaked around week 35 and subsequently plateaued, whereas body weight exhibited a sustained linear downward trend. [CONCLUSION] Ecnoglutide significantly improved glycemic control and reduced body weight, although it was associated with a higher incidence of adverse events without increasing serious adverse events. Despite these promising findings, the evidence remains limited and requires confirmation in larger, multicenter randomized controlled trials. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420261327235, identifier CRD420261327235.","url":"https://pubmed.ncbi.nlm.nih.gov/42798476/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":832,"doi":"10.2147/dddt.s642220","pmid":"42829714","nct_ids":"[]","title":"Prior Use of GLP-1 Receptor Agonists versus SGLT2 Inhibitors and Clinical Outcomes After Sepsis in Patients with Type 2 Diabetes: A Propensity Score-Matched Cohort Study","authors":"[\"Liu HH\", \"Huang SC\", \"Wu JY\", \"Chan KS\", \"Lai CC\"]","journal":"Drug design, development and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Whether pre-existing glucose-lowering therapy influences outcomes after sepsis remains uncertain. We compared clinical outcomes among patients with type 2 diabetes (T2D) who developed sepsis according to prior GLP-1 receptor agonists (GLP-1RAs) or SGLT2 inhibitors (SGLT2is) use. [METHODS] We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adults with T2D who developed sepsis had received a GLP-1RA or an SGLT2i within 3 months before sepsis were identified. After 1:1 propensity score matching, 11,969 patients were included in each group. The primary outcome was 90-day all-cause mortality. Secondary outcomes included major adverse cardiovascular event (MACE), major adverse kidney event (MAKE), intensive care unit (ICU) admission, major adverse cardiac and cerebrovascular event (MACCE), septic shock, and acute respiratory failure. [RESULTS] Compared with prior SGLT2i use, prior GLP-1RA use was associated with lower 90-day all-cause mortality (incidence rate, 48.6 vs 60.6 per 100 person-years; HR, 0.81; 95% CI, 0.75-0.88; E-value: 1.6) and lower risks of MACE (HR, 0.77; 0.65-0.91; E-value, 1.7), myocardial infarction (HR, 0.82; 0.67-0.99; E-value, 1.7), ICU admission (HR, 0.89; 0.84-0.94; E-value, 1.4), and MACCE (HR, 0.86; 0.74-0.99; E-value, 1.5). No significant difference was observed for septic shock (HR, 0.87; 95% CI, 0.74-1.02), acute respiratory failure (HR, 0.94; 95% CI, 0.83-1.06), or MAKE (HR, 1.08; 95% CI, 0.92-1.27). The mortality benefit remained consistent through 365 days and across all prespecified subgroups. After Holm correction for multiple comparisons across the seven secondary outcomes, only the associations with MACE (adjusted P=0.012) and ICU admission (adjusted P<0.007) remained statistically significant, while those with MACCE, myocardial infarction, MAKE, septic shock, and acute respiratory failure did not. [CONCLUSION] Among patients with T2D who developed sepsis, prior GLP-1RA use was associated with lower mortality and select cardiovascular/renal risks than prior SGLT2i use, though roughly half of secondary outcomes showed no significant difference. Exposure was defined at the drug-class rather than individual-agent level, and modest E-values alongside baseline imbalances before matching suggest residual confounding cannot be excluded. These hypothesis-generating findings warrant confirmation in prospective studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42829714/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"mortality\", \"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":850,"doi":"10.1177/14791641261495569","pmid":"42808164","nct_ids":"[]","title":"Benefits of sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide-1 receptor agonists in older patients with type 2 diabetes","authors":"[\"Mortada I\", \"Paul K\", \"Rice J\", \"Joseph N\", \"Raum TL\", \"Albayyaa M\", \"Gaalema D\", \"Jehle D\", \"Blackwell TA\", \"Jneid H\"]","journal":"Diabetes & vascular disease research","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"BackgroundType 2 diabetes mellitus (T2DM) increases the risk of cardiovascular and neurocognitive complications. GLP-1 receptor agonists (GLP-1 RAs) and SGLT2 inhibitors (SGLT2is) have pleiotropic effects beyond glycemic control, but comparative long-term data on dementia, cardiovascular events, and mortality in older adults are limited.MethodsThis retrospective cohort study used the TriNetX US Collaborative Network. Adults ≥60 years with T2DM on metformin plus either GLP-1 RAs or SGLT2is (n=56,211 per cohort after matching, 2014-2020) were propensity-score matched on demographic and clinical characteristics. Five-year outcomes included incident Alzheimer's disease, vascular dementia, other dementia, dementia-related medication use, NSTEMI, STEMI, and all-cause mortality.ResultsAfter propensity-score matching, GLP-1 RA use was associated with higher risks of Alzheimer's disease (RR 1.33, 95% CI 1.18-1.48), vascular dementia (RR 1.56, 95% CI 1.39-1.76), other dementia (RR 1.33, 95% CI 1.21-1.47), dementia-related medication initiation, and all-cause mortality (RR 1.11, 95% CI 1.08-1.15) compared with SGLT2is. NSTEMI and STEMI risks did not differ significantly between groups.ConclusionsIn older adults with T2DM, SGLT2is were associated with lower risks of dementia, dementia-related medication use, and all-cause mortality compared with GLP-1 RAs in propensity-score matched cohorts. These observational findings are hypothesis-generating and should be confirmed in prospective studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42808164/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cognition\", \"dementia\", \"alzheimers\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":896,"doi":"10.1177/14791641261487590","pmid":"42821775","nct_ids":"[]","title":"Impact of antidiabetic agents on COPD exacerbations in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis","authors":"[\"Shabil M\", \"Jan A\", \"Shamim MA\", \"Naser HA\", \"Sudan S\", \"Sultana H\", \"Imran M\", \"Ullah F\", \"Dubwa D\", \"Kumar S\"]","journal":"Diabetes & vascular disease research","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"BackgroundThe impact of Antidiabetic Agents on COPD Exacerbations remains uncertain. We conducted a comprehensive review to evaluate the impact Antidiabetic Agents on COPD Exacerbations in patients with T2DM.MethodsWe searched PubMed, Embase, and Web of Science from inception to January 15, 2026 for observational studies involving adults with T2DM and COPD. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models, treatments were ranked using the Surface Under the Cumulative Ranking Curve (SUCRA), and study quality was assessed using the Newcastle-Ottawa Scale.ResultsThirteen studies comprising 755,206 participants were included. Compared with sulfonylureas, SGLT-2 inhibitors were associated with the lowest risk of overall COPD exacerbations (RR 0.71, 95% CI 0.66-0.77), followed by GLP-1 receptor agonists (RR 0.77, 95% CI 0.71-0.84). Metformin demonstrated a near-neutral association (RR 0.89, 95% CI 0.79-1.00), whereas DPP-4 inhibitors (RR 1.05, 95% CI 0.97-1.13) and meglitinides (RR 1.13, 95% CI 0.93-1.36) showed no evidence of benefit. Similar findings were observed for severe exacerbations, with SGLT-2 inhibitors and GLP-1 receptor agonists demonstrating the strongest associations.ConclusionsSGLT-2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of COPD exacerbations than sulfonylureas, whereas metformin showed a near-neutral association and DPP-4 inhibitors and meglitinides showed no clear benefit.","url":"https://pubmed.ncbi.nlm.nih.gov/42821775/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-04T11:17:47+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":928,"doi":"10.2147/dddt.s638249","pmid":"42831108","nct_ids":"[]","title":"GLP-1 Receptor Agonists Versus DPP-4 Inhibitors and Incident Dementia Risk in COVID-19 Survivors with Type 2 Diabetes: A Target Trial Emulation Study","authors":"[\"Hung KC\", \"Yu TS\", \"Liu PH\", \"Lai YC\", \"Chen IW\"]","journal":"Drug design, development and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Type 2 diabetes mellitus (T2DM) and COVID-19 are independently associated with an elevated risk of dementia, and COVID-19 survivors with T2DM may represent a clinically vulnerable population in whom metabolic, inflammatory, and vascular factors coexist. However, whether antidiabetic treatment choice is associated with incident dementia risk in this population remains unknown. [METHODS] In this target trial emulation using the TriNetX US Collaborative Network, we compared COVID-19 survivors aged ≥50 years with T2DM initiating glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with those initiating dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy between January 1, 2020 and December 31, 2024. We applied an active-comparator, new-user design with a 90-day survivor landmark and 1:1 propensity score matching. The primary outcome was incident all-cause dementia (a composite of vascular dementia, Alzheimer's disease, and other dementias). Secondary outcomes included dementia subtypes, mild cognitive impairment, glycemic outcomes, and all-cause mortality. [RESULTS] After matching, 25,263 patients per group were followed for up to 6 years (median, 919 days [GLP-1RA] vs 955 days [DPP-4i]). GLP-1RA initiation was associated with a lower hazard of incident dementia (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.58-0.72), vascular dementia (HR, 0.67; 95% CI, 0.52-0.85), and Alzheimer's disease (HR, 0.74; 95% CI, 0.59-0.93), as well as more favorable glycemic control and lower all-cause mortality (HR, 0.63; 95% CI, 0.59-0.68). The estimate for mild cognitive impairment was borderline (HR, 0.87; 95% CI, 0.75-1.00) and not consistently supported across sensitivity analyses. The association with incident dementia remained evident after the 6-month landmark analysis (HR, 0.66; 95% CI, 0.58-0.75) and was consistent across sensitivity and subgroup analyses. [CONCLUSION] Among COVID-19 survivors with T2DM, GLP-1RA initiation was associated with a lower hazard of incident dementia than DPP-4i initiation. These hypothesis-generating results warrant confirmation before they can be used to inform clinical decision-making.","url":"https://pubmed.ncbi.nlm.nih.gov/42831108/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cognition\", \"dementia\", \"alzheimers\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":937,"doi":"10.3389/fphar.2026.1882227","pmid":"42851802","nct_ids":"[]","title":"SGLT2 inhibitors, semaglutide, and finerenone in diabetic kidney disease: a Bayesian network meta-analysis","authors":"[\"He Z\", \"Wang X\", \"Zhang L\", \"Chen X\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Despite optimal renin-angiotensin system (RAS) blockade, patients with diabetic kidney disease (DKD) face substantial residual cardiorenal risk. The 2024 FLOW trial established semaglutide as the first GLP-1 receptor agonist with a dedicated primary renal outcome benefit. We conducted a Bayesian network meta-analysis comparing SGLT2 inhibitors, semaglutide, and finerenone-the three therapies with contemporary phase 3 cardiorenal evidence-to define their comparative efficacy and safety hierarchy in type 2 diabetes with chronic kidney disease. [METHODS] We systematically searched PubMed, Embase, and the Cochrane Library through 31 July 2025 for phase 3 randomized trials reporting kidney, cardiovascular, or safety outcomes. We treated FIDELIO-DKD and FIGARO-DKD as separate evidence nodes to preserve between-trial heterogeneity. For DAPA-CKD and EMPA-KIDNEY, only the pre-specified type 2 diabetes subgroup data were used. Efficacy was synthesized using hazard ratios (HRs) with 95% credible intervals (CrIs); safety was modeled using a binomial likelihood for treatment discontinuation. Treatment hierarchy was quantified by the surface under the cumulative ranking curve (SUCRA). Four pre-specified sensitivity analyses evaluated robustness (±SCORED trial; fixed-vs. random-effects models). [RESULTS] Six trial-level datasets (CREDENCE, DAPA-CKD T2D subgroup, EMPA-KIDNEY T2D subgroup, FIDELIO-DKD, FIGARO-DKD, FLOW; N = 20,521) were included in the main analysis. All trials were at low risk of bias. Kidney outcomes: SGLT2 inhibitors demonstrated the greatest risk reduction (HR 0.70, 95% CrI 0.64-0.76; SUCRA 94.5%), followed by semaglutide (HR 0.76, 95% CrI 0.66-0.88; SUCRA 68.0%) and finerenone (HR 0.84, 95% CrI 0.77-0.92; SUCRA 37.5%). The indirect comparison between SGLT2 inhibitors and finerenone reached statistical significance (HR 0.83, 95% CrI 0.73-0.95; posterior probability of SGLT2i superiority >99.9% [fixed effects]; 96% [random effects]). In contrast to prior NMAs that pooled finerenone trials via the FIDELITY estimate (HR 0.77), our approach of separating FIDELIO-DKD and FIGARO-DKD yielded a pooled finerenone HR of 0.84, allowing this indirect detection. This finding is sensitive to the analytic decision to separate the two finerenone trials and should be interpreted as hypothesis-generating. Semaglutide was numerically but not statistically superior to finerenone (HR 0.90, 95% CrI 0.76-1.07; posterior probability = 88%). [CARDIOVASCULAR OUTCOMES] All three active agents significantly reduced cardiovascular risk versus placebo, with no statistically significant differences between active agents. Robustness: All key findings were stable across four sensitivity analyses; the posterior probability of SGLT2 inhibitor superiority to finerenone for kidney protection remained ≥96% in all specifications. [CONCLUSION] SGLT2 inhibitors provide the greatest kidney protection in this network; when the two finerenone trials are analyzed separately, an indirect statistically significant SGLT2i advantage emerges (HR 0.83, 95% CrI 0.73-0.95 [fixed effects]). This finding is analytic-choice-dependent and hypothesis-generating. Semaglutide provides substantial renal protection that is numerically superior to finerenone. These findings support a four-pillar framework-RAS blockade and SGLT2 inhibition as the foundational combination, with semaglutide and finerenone as complementary phenotype-matched additions-and provide a probabilistic evidence base for individualized prescribing.","url":"https://pubmed.ncbi.nlm.nih.gov/42851802/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-11T11:52:10+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":954,"doi":"10.1093/biomethods/bpag048","pmid":"42857675","nct_ids":"[]","title":"Comparison of cardiometabolic benefits and tolerability in patients on sustained low doses of semaglutide or tirzepatide","authors":"[\"Murugadoss K\", \"Venkatakrishnan AJ\", \"Soundararajan V\"]","journal":"Biology methods & protocols","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide and tirzepatide are typically evaluated through dose escalation, yet many patients in routine care do not reach a recommended maintenance dose due to tolerability, access, cost, supply, or individualized goals. Here, we used repeated 0.25 mg only semaglutide and 2.5 mg only tirzepatide prescription records as real-world proxies for sustained treatment at the lowest approved dose, a prescribing pattern that may overlap with, but does not establish, intentional microdosing. We analyzed de-identified electronic health records (EHRs) from a federated system of 29 million patients. Among 490 072 semaglutide-treated patients, 814 met the stringent sustained low-dose criterion of at least three distinct 0.25-mg prescriptions spanning at least 6 months from the first to the last qualifying prescription and among 322 442 tirzepatide-treated patients, 1016 met the analogous criterion of at least three distinct 2.5-mg prescriptions spanning at least 6 months. In a matched head-to-head comparison aided by AI-enabled curation of clinical notes, sustained low-dose tirzepatide showed higher 24-month adverse event rates (P < .05) than sustained low-dose semaglutide for constipation (32.6% vs. 22.4%), acute kidney injury (2.7% vs. 0.4%), muscle cramps (8.3% vs. 4%), lumbar disc disease (3.3% vs. 0.3%), dyspnea on exertion (9.6% vs. 6.8%), lentigo (4.7% vs. 0.8%), and actinic keratosis (3.3% vs. 0.6%), whereas sustained low-dose semaglutide (vs. tirzepatide) had higher rates of including otitis (5.6% vs. 2.1%), diaphoresis (5.5% vs. 3.2%), and ankle swelling (6.9% vs. 3.7%). Sustained low-dose tirzepatide was associated with greater weight loss than semaglutide (mean 12-month percent weight change -5.5% vs. -2.2%; P < .05 at all timepoints). Analyses of prescription patterns supported the findings from clinical notes. For example, renal-supportive and hyperkalemia therapies increased after low-dose tirzepatide (5.6% to 9.5% at 12 months, P = .016) but not after low-dose semaglutide (8.2% to 6.6%, P = .382). Taken together, these observational associations motivate prospective studies to better characterize the outcomes and pharmacology of sustained initiation-dose semaglutide or tirzepatide, and related microdosing studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42857675/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors are employees of nference, Inc., which conducts research collaborations with various biopharmaceutical companies whose therapeutic products are included in this study. None of these companies, nor any other nference collaborator, funded, supported, or had any role in the independent study design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit this work for publication. All analyses were conducted by the authors using de-identified electronic health record data. The authors declare no additional competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"kidney\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":967,"doi":"10.3389/fendo.2026.1912138","pmid":"42840192","nct_ids":"[]","title":"Liraglutide use in congenital generalized lipodystrophy: glycemic and metabolic outcomes","authors":"[\"Araújo JS\", \"Boris NP\", \"Lopes FKM\", \"Flor AC\", \"Leite LMBF\", \"Linard LLP\", \"Bezerra IC\", \"Cavalcante JEA\", \"Tanaka E\", \"Sandrini F\", \"Fernandes VO\", \"Montenegro Junior RM\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Evidence on glucagon-like peptide 1 receptor agonists (GLP-1RAs) in lipodystrophies is limited. We evaluated the effects of liraglutide on metabolic control and satiety in patients with congenital generalized lipodystrophy (CGL). [METHODS] In this case series, patients with CGL received liraglutide 1.8 mg/day for 12 weeks. Metabolic parameters, satiety, and body composition were assessed at baseline, week 12, and after a 12-week post-treatment follow-up (week 24). Liver imaging was performed at baseline and week 12. [RESULTS] Eight patients were enrolled (aged 24-45 years; 75% female), and three discontinued treatment due to gastrointestinal adverse events during the dose-escalation phase. Among the five participants who completed the 12-week intervention, liraglutide significantly reduced HbA1c (median change, -2.5%; p=0.012) and total daily insulin dose (-20%; p=0.042), whereas the reduction in triglyceride levels was not statistically significant. Twelve weeks after liraglutide discontinuation, median HbA1c and body weight increased by 2.2% (p=0.026) and 3.7% (p=0.001), respectively. Triglyceride levels increased in 80% of participants, with a median increase of 421.5 mg/dL (p=0.334). Insulin requirements also increased overall: one participant resumed insulin therapy, while the remaining participants increased their insulin dose by a median of 22% (p=0.024). [CONCLUSIONS] This first study of liraglutide in CGL provides an exploratory signal of improved glycemic control and reduced insulin requirements, but treatment tolerability remains a limitation. Larger, controlled, and longer-term studies are needed to confirm these effects and assess potential benefits on satiety, body composition, and liver disease.","url":"https://pubmed.ncbi.nlm.nih.gov/42840192/","source_name":"pubmed","source_tier":1,"coi_statement":"Authors JA, NB, FL, AF, LBL, LPL, IB and RM were employed by Brazilian Hospital Services Company. The remaining author(s) declared that this work was conducted in the absence of anycommercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"case_series","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"body_composition\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1014,"doi":"10.5114/aoms/225241","pmid":"42877202","nct_ids":"[]","title":"GLP-1 receptor agonists and tendon healing: a systematic review and meta-analysis","authors":"[\"Khayyat MY\", \"Khayyat YM\"]","journal":"Archives of medical science : AMS","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are prescribed for cardiometabolic indications and may exert anti-inflammatory and tissue-regenerative effects. However, their effect on tendon healing and tendon-related surgical outcomes remains unclear. In this systematic review and meta-analysis, we evaluated the available preclinical and clinical evidence on the effects of GLP-1RAs on tendon healing and related musculoskeletal outcomes. [METHODS] A systematic search of the PubMed, Embase, Medline, Scopus, Clinical Key, Google Scholar, and Cochrane databases was conducted from database inception to December 31, 2025. Eligible studies included animal studies, human experimental studies, and retrospective clinical cohorts that evaluated GLP-1RA exposure in relation to tendon biology, tendon healing, or tendon-related orthopedic outcomes. Risk of bias was assessed using design-appropriate tools, including SYRCLE, ROBINS-I, the Newcastle-Ottawa Scale, SANRA, AMSTAR 2, and the NIH assessment tool. [RESULTS] A total of 41 studies were included: eight animal studies, three human experimental studies, six retrospective cohort studies, one prospective study, 18 review or commentary articles, and five systematic reviews. Preclinical evidence generally supported the tendon-promoting effects of GLP-1RAs through the modulation of inflammation, fibroblast activity, angiogenesis, and extracellular matrix remodeling. Quantitative synthesis of two retrospective cohorts evaluating revision risk after total shoulder arthroplasty suggested a lower risk among GLP-1RA users than non-users. However, only two studies were eligible for pooling, and significant clinical heterogeneity remained across the available cohorts. [CONCLUSIONS] GLP-1RAs demonstrate biologically plausible tendon healing benefits in preclinical models, with a potentially favorable association with selected postoperative outcomes; however, causal inference remains limited by retrospective design, heterogeneity, and potential confounding factors.","url":"https://pubmed.ncbi.nlm.nih.gov/42877202/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:22:00+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1015,"doi":"10.3389/fendo.2026.1945735","pmid":"42876703","nct_ids":"[]","title":"Research trends and knowledge structure of pancreatic cancer and type 2 diabetes mellitus research: a two-decade CiteSpace analysis","authors":"[\"Dong Z\", \"Zhou T\", \"Ma S\", \"Chen X\", \"Lai Y\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Pancreatic cancer and type 2 diabetes mellitus (T2DM) are closely linked through complex epidemiological and biological interactions. However, the development, knowledge structure, and research trends of this field have not been systematically characterized. This study aimed to investigate the research landscape and knowledge structure of pancreatic cancer and T2DM research from 2006 to 2025. [METHODS] We conducted the primary bibliometric analysis using WOSCC records, and separately analyzed PubMed-indexed clinical trials as a supplementary dataset. A total of 1,989 WOSCC publications were included in the bibliometric analysis, while 54 PubMed-indexed Clinical Trial records were included in the supplementary clinical trial assessment. CiteSpace was used to perform collaboration, co-citation, keyword, timeline, and burst analyses of the WOSCC dataset. [RESULTS] The number of publications increased steadily over the study period, particularly after 2015. The United States and China were the leading contributors, while the University of California System and Harvard University were among the most productive institutions. Major research themes included cancer risk, insulin resistance, metabolic inflammation, incretin-based therapies, and new-onset diabetes. Keyword evolution and burst analyses indicated increasing attention to mechanistic investigation, biomarker discovery, risk stratification, and precision medicine approaches. [CONCLUSION] This study characterizes the development and knowledge structure of research on the relationship between pancreatic cancer and T2DM and highlights major research themes, emerging hotspots, and future directions for mechanistic investigation and clinical translation.","url":"https://pubmed.ncbi.nlm.nih.gov/42876703/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:22:00+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1020,"doi":"10.46889/joar.2026.7306","pmid":"42872071","nct_ids":"[]","title":"Impact of Glucagon-Like Peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP) Receptor Agonists on Intraocular Pressure in Glaucoma: A Case Series","authors":"[\"Steel C\", \"Johnson C\", \"Paulson C\", \"Terrell J\", \"Cui QN\", \"Blieden L\", \"Wirostko B\"]","journal":"Journal of ophthalmology and advance research","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Glucagon-Like Peptide 1 Receptor Agonists (GLP-1RAs) are antidiabetic and weight management medications that bind to GLP-1 receptors throughout the body. Growing interest in this class has led to several retrospective cohort studies reporting a decreased occurrence of glaucoma in diabetic and non-diabetic patients with the use of GLP-1RAs, suggestive of anti-inflammatory and neuroprotective effects. Here we report five real world cases evaluating the impact of GLP-1RA and dual GLP-1/Gastric Inhibitory Polypeptide (GIP) receptor agonist use on Intraocular Pressure (IOP) measurements and subsequent disease management in glaucoma patients. [OBSERVATIONS] Case 1 (severe pigment dispersion glaucoma OU) was started on semaglutide on two separate occasions and exhibited clinically significant declines in home IOP tonometry readings after each initiation (OD max: 20 to 18, 16 to 14; OS: 22 to 15, then 20 to 17). Case 2 (severe primary open angle glaucoma OU) was a candidate for filtration device surgery when he began taking tirzepatide, after which a decrease in home IOP tonometry readings was observed (OD: 11 to 8; OS: 21 to 14), resulting in surgery postponement. Case 3 (secondary glaucoma OD following trauma) began taking tirzepatide shortly following glaucoma drainage device implantation and experienced unexplained hypotony (IOP: 25 to 4). Case 4 (severe POAG OU) was taking semaglutide with stable IOPs until pancreatitis prompted cessation of semaglutide, whereupon an increase in IOP was subsequently observed (OD: 23 to 30; OS: 16 to 18). Case 5 (undiagnosed) is a patient naïve to IOP-lowering therapy and initiation of tirzepatide correlated with an abrupt reduction in IOP observed in clinic (OU: 24 to 10). [CONCLUSION AND IMPORTANCE] These cases demonstrate a potential association between GLP-1/GIP receptor agonist use and IOP lowering in patients with glaucoma and help substantiate existing literature with real world cases, thereby highlighting the need for further prospective research on this emerging topic.","url":"https://pubmed.ncbi.nlm.nih.gov/42872071/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflict of Interest The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:22:00+00:00","study_design":"case_series","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"neuroinflammation\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1033,"doi":"10.3389/fendo.2026.1903335","pmid":"42890523","nct_ids":"[]","title":"CagriSema versus Semaglutide 2.4 mg monotherapy for weight management in adults with overweight or obesity, with or without type 2 diabetes: a systematic review, meta-analysis, and trial sequential analysis","authors":"[\"Rasool ZK\", \"Shah R\", \"Batool AEZ\", \"Shah R\", \"Khachatryan M\", \"Bhardwaj S\", \"Ali A\", \"Atta M\", \"Bakthavatchalam P\", \"Khawar MMH\", \"Khawar M\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Semaglutide 2.4 mg is the reference pharmacotherapy for weight management, yet many patients do not reach ambitious weight-loss targets. CagriSema, a fixed-dose combination of cagrilintide and semaglutide, may offer additional benefit through complementary mechanisms. We quantified its incremental efficacy and safety against semaglutide 2.4 mg monotherapy in adults with overweight or obesity, with and without type 2 diabetes. [METHODS] This PRISMA 2020-compliant review (PROSPERO CRD420261380458) searched PubMed, Embase, Cochrane CENTRAL, ScienceDirect, ClinicalTrials.gov and WHO ICTRP to 30 June 2026 for randomised controlled trials comparing CagriSema with semaglutide 2.4 mg or placebo. Effects were pooled within two prespecified comparator strata using random-effects models with restricted maximum likelihood estimation of τ² and a Hartung-Knapp-Sidik-Jonkman small-sample adjustment, with prediction intervals, leave-one-out and phase-3a-restricted sensitivity analyses, trial sequential analysis. [RESULTS] Five trials (4,746 unique participants) were included. Versus semaglutide 2.4 mg, CagriSema produced greater weight loss (mean difference -6.89 percentage points, 95% CI -8.70 to -5.06; I² = 33%; prediction interval -8.91 to -4.86), a greater absolute reduction in body weight (-7.16 kg, 95% CI -9.15 to -5.17) and in body-mass index (-2.41 kg/m², 95% CI -2.83 to -1.99), and roughly twice the likelihood of reaching a 20% reduction (RR 2.10, 95% CI 1.78 to 2.47). Waist circumference fell further (-4.07 cm, 95% CI -5.10 to -3.04). No incremental glycaemic benefit was detected, with intervals for glycated haemoglobin (-0.07, 95% CI -0.14 to 0.01) and fasting plasma glucose lying entirely within prespecified minimal important differences. Injection-site reactions were more frequent (RR 3.14, 95% CI 1.42 to 6.96); gastrointestinal adverse events were not significantly increased under the primary model (RR 1.09, 95% CI 0.97 to 1.21). [CONCLUSION] CagriSema produces clinically meaningful additional weight loss and modest improvements in surrogate cardiometabolic measures compared with semaglutide 2.4 mg alone, at the cost of more frequent injection-site reactions and, at most, modestly more frequent gastrointestinal events. The evidence is insufficient to determine whether serious adverse events or neoplasms differ between treatments, and long-term durability, cardiovascular outcomes and body composition remain undetermined. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/prospero/, identifier CRD420261380458.","url":"https://pubmed.ncbi.nlm.nih.gov/42890523/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"cagrisema\"]","drug_details":null,"domains":"[\"cardiovascular\", \"body_composition\", \"cancer\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1037,"doi":"10.2337/doc26-0027","pmid":"42888997","nct_ids":"[]","title":"Trends in Diabetes Medications After Metformin in Patients at High Versus Moderate Cardiovascular Risk: The BESTMED Consortium 2014-2022","authors":"[\"Lansang MC\", \"Petito LC\", \"Hegermiller E\", \"Chelliah I\", \"Carnahan RM\", \"McDonnell ME\", \"DeVries A\", \"Priest E\", \"Willey V\", \"Nair V\", \"Goel S\", \"Kaul AF\", \"Turchin A\", \"BESTMED Research Group* \"]","journal":"Diabetes, obesity, and cardiometabolic CARE","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To compare nationwide prescription trends in medications (dipeptidyl peptidase 4 inhibitors [DPP-4i], glucagon-like peptide 1 receptor agonists [GLP-1 RAs], sodium-glucose cotransporter 2 inhibitors [SGLT2i], or sulfonylureas [SUs]) after treatment with metformin in patients with type 2 diabetes (T2D) at high versus moderate cardiovascular risk by key sociodemographic and health characteristics. [RESEARCH DESIGN AND METHODS] Electronic health records and insurance claims from 2014 to 2022 from 10 health systems and two insurance plans from different U.S. regions were evaluated. Risk-stratified multinomial log-linear models were used to model trends in prescribing patterns, adjusted for sociodemographic variables. [RESULTS] A total of 104,474 patients were included (28% at high and 72% at moderate cardiovascular risk). Among those at high cardiovascular risk, DPP-4i (2014 24.0%; 2022 11.0%) and SU (66.4%; 35.7%) prescriptions declined, whereas GLP-1 RA (4.4%; 20.5%) and SGLT2i (5.2%; 32.8%) prescriptions increased. Among those at moderate cardiovascular risk, DPP-4i (23.7%; 11.7%) and SU (63.7%; 31.5%) prescriptions declined, whereas GLP-1 RA (5.7%; 30.0%) and SGLT2i (6.9%; 26.8%) prescriptions increased. Annual increases differed by high versus moderate cardiovascular risk for GLP-1 RAs (+2.5% vs. +3.6%/year; P < 0.001) and SGLT2i (+4.0% vs. +3.0%/year; P < 0.001). Greater annual increases in GLP-1 RA prescriptions occurred in women, those aged <65 years, and those with class 2 or 3 obesity, and greater annual increases in SGLT2i prescriptions were seen in men, those aged ≥65 years, and those without class 2 or 3 obesity (all P < 0.01). Greater increases in SGLT2i prescriptions occurred among Black patients, and greater increases in GLP-1 RA prescriptions occurred among those of Hispanic ethnicity at moderate cardiovascular risk. [CONCLUSIONS] Prescribing patterns for second-line T2D therapies in those at moderate cardiovascular risk are approaching guideline recommendations for those at high risk. Some trends are potentially clinically explainable, whereas certain racial/ethnic differences may warrant exploration. [UNLABELLED] Video 1.Video abstract3e51f820-63ec-4c76-86f4-002f78d7c5f0doc260027video1.","url":"https://pubmed.ncbi.nlm.nih.gov/42888997/","source_name":"pubmed","source_tier":1,"coi_statement":"A.T. reported receiving grants from Eli Lilly and personal fees from Novo Nordisk and Proteomics International. M.C.L. serves as site principal investigator for Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1051,"doi":"10.3389/fcvm.2026.1884895","pmid":"42870927","nct_ids":"[]","title":"Cardiovascular outcomes of oral incretin-based drugs in type 2 diabetes: a GRADE-assessed meta-analysis of 67,679 patients","authors":"[\"Ali MF\", \"Mohammed OF\", \"Suhail A\", \"Naseer F\", \"Shafi N\", \"Arshad MU\", \"Shazly O\", \"Mohmand MS\", \"Ahmad H\", \"Binashikhbubkr NK\", \"Maaz M\", \"Khan M\", \"Neppala S\", \"Al-Jarshawi M\", \"Hemida MF\"]","journal":"Frontiers in cardiovascular medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] While injectable GLP-1 receptor agonists like semaglutide have demonstrated clear cardiovascular benefits in type 2 diabetes mellitus (T2DM), the role of oral incretin-based therapies, including oral semaglutide and DPP-4 inhibitors-remains less well defined. Comprehensive evaluation of their cardiovascular efficacy is warranted. [RESEARCH QUESTION] What are the cardiovascular outcomes associated with oral incretin-based therapies, specifically oral semaglutide and DPP-4 inhibitors, in patients with T2DM compared to placebo or standard care. [METHODS] We searched electronic databases for randomized controlled trials (RCTs). Meta-analysis was conducted in R version 4.4.3 using the \"meta\" and \"metasens\" packages. Statistical analysis was performed using R software and RStudio (version 4.4.2). We calculated pooled estimates using risk ratios (RR) with 95% confidence intervals (CIs). [RESULTS] A total of 9 studies comprising 67,679 patients were included, of which two evaluated oral semaglutide and the remaining seven assessed DPP-4 inhibitors. There was no significant reduction in all-cause mortality (RR 0.97, 95% CI 0.90-1.04, p = 0.35) or cardiovascular death (RR 0.98, 95% CI 0.91-1.05, p = 0.48). Major adverse cardiovascular events (MACE) showed a non-significant reduction overall (RR 0.95, 95% CI 0.91-1.00, p = 0.06), with oral semaglutide demonstrating a significant benefit (RR 0.86, 95% CI 0.78-0.95, p = 0.003). Non-fatal myocardial infarction (MI) (RR 0.98, 95% CI 0.88-1.09) and non-fatal stroke (RR 0.93, 95% CI 0.83-1.03) were not significantly affected. Hospitalizations due to heart failure (RR 0.98, 95% CI 0.84-1.13) and unstable angina (RR 1.00, 95% CI 0.87-1.15) remained unchanged. Coronary revascularization was slightly reduced with oral semaglutide (RR 0.76, 95% CI 0.64-0.91). Adverse events leading to discontinuation were higher with oral semaglutide (RR 1.51, 95% CI 1.15-1.98), while serious adverse events were significantly reduced (RR 0.96, 95% CI 0.94-0.99, p = 0.003). Sensitivity analyses were conducted due to significant heterogeneity in key outcomes. While omitting certain studies reduced heterogeneity, the overall results remained consistent. [CONCLUSION] Oral incretin-based therapies were not associated with significant reductions in all-cause mortality, cardiovascular death, or MACE overall, though oral semaglutide showed a significant MACE benefit and reduced coronary revascularization on subgroup analysis. Non-fatal MI, fatal or non-fatal MI, non-fatal stroke, fatal or non-fatal stroke and hospitalization due to heart failure or unstable angina were unaffected, and oral semaglutide carried a higher risk of treatment discontinuation. These findings suggest no clear class-wide cardiovascular benefit of oral incretins, with signals specific to oral semaglutide warranting confirmation in dedicated trials. [SYSTEMATIC REVIEW REGISTRATION] PROSPERO CRD420251113835.","url":"https://pubmed.ncbi.nlm.nih.gov/42870927/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:29:46+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1055,"doi":"10.1136/bmjmed-2026-002780","pmid":"42866418","nct_ids":"[]","title":"Values, preferences, and treatment burden for initiation of GLP-1 receptor agonists, SGLT-2 inhibitors, tirzepatide, and finerenone in adults with type 2 diabetes: systematic review","authors":"[\"González-Cruz DC\", \"Garcia-Campa M\", \"Moreno-Peña PJ\", \"Avalos-Bishop A\", \"Manzanares-Gallegos DM\", \"Garcia-Garcia FM\", \"Montiel Labastida JA\", \"González-González JG\", \"Agarwal A\", \"Manja V\", \"Olav Vandvik P\", \"Agoritsas T\", \"Mustafa RA\", \"Rodríguez-Gutiérrez R\"]","journal":"BMJ medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] To summarise existing evidence regarding the values, preferences, and perceived treatment burden of adults with type 2 diabetes when considering initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), finerenone, or tirzepatide. [DESIGN] Systematic review. [DATA SOURCES] Medline, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched from database inception to 7 January 2025 (updating a previous systematic review that captured literature up to 23 May 2020). [ELIGIBILITY CRITERIA] Quantitative or qualitative studies were included if they reported patient reported values, preferences, or treatment burden among adults with type 2 diabetes and compared initiation of GLP-1 RA, SGLT-2i, tirzepatide, or finerenone with each other or with other glucose-lowering treatments. [DATA EXTRACTION AND SYNTHESIS] Paired reviewers independently screened studies, extracted data, and assessed risk of bias. Certainty of evidence was evaluated using GRADE. Findings were synthesised narratively. [RESULTS] Thirty four studies (15 656 patients) were included, 17 of which were new since the previous 2021 review (8360 patients). Of the newly included studies, 10 evaluated GLP-1 RA, seven evaluated SGLT-2i, and one evaluated tirzepatide; no studies evaluated finerenone (because several studies compared multiple drug classes, these categories are not mutually exclusive). Across comparisons, patients consistently reported glycaemic efficacy, cardiovascular risk reduction, and simplicity of administration as their priorities. Oral once-daily regimens and once-weekly injectable treatments with easy-to-use devices were generally preferred. Weight loss was valued but was typically secondary to glycaemic and cardiovascular benefits. SGLT-2i and GLP-1 RA were often preferred over dipeptidyl peptidase 4-inhibitors (DPP-4i), thiazolidinediones, and insulins, but no consistent preference emerged for SGLT-2i over GLP-1 RA. Tirzepatide was favoured over semaglutide in a single study, largely due to greater haemoglobin A1c reduction and lower hypoglycaemia risk. Certainty of evidence for all comparisons was low or very low certainty. [CONCLUSION] Adults with type 2 diabetes prioritise treatment effectiveness and convenience among glucose-lowering treatments. Current evidence does not support a clear preference between SGLT-2i and GLP-1 RA, and data for finerenone are absent. These findings underscore the importance of shared decision making informed by individual patient priorities. [PROSPERO REGISTRATION] CRD42023429170.","url":"https://pubmed.ncbi.nlm.nih.gov/42866418/","source_name":"pubmed","source_tier":1,"coi_statement":"All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1066,"doi":"10.22454/primer.2026.826203","pmid":"42871656","nct_ids":"[]","title":"Glycemic Outcomes Associated With GLP-1 Receptor Agonist Shortages in Type 2 Diabetes","authors":"[\"Fu Z\", \"Adelman M\", \"Garlock J\"]","journal":"PRiMER (Leawood, Kan.)","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are integral in managing type 2 diabetes mellitus (T2DM) due to glycemic control, weight loss, and cardio-renal benefits. National shortages beginning in 2022 limited access to these medications. This study assessed the effect of GLP-1 RA shortages on hemoglobin A1c (HbA1c) and other outcomes. [METHODS] We conducted a retrospective pre-post cohort study of patients with T2DM prescribed dulaglutide or semaglutide before March 2022 at Cleveland Clinic Akron General. The primary outcome was HbA1c change from preshortage to shortage periods. Secondary outcomes included prevalence of patients affected, weight change, and provider responses. [RESULTS] Of 177 patients, 55 (31.1%) were affected. Median HbA1c increased by+0.4% (P<0.001), while weight decreased by -4.33 kg (95% CI -6.50 to -2.16, P<0.001). [CONCLUSION] The GLP-1 RA shortage adversely affected glycemic control, underscoring the need for improved management strategies during supply disruptions.","url":"https://pubmed.ncbi.nlm.nih.gov/42871656/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflict Disclosure: The authors have no conflicts of interest to disclose.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1074,"doi":"10.1002/trc2.70334","pmid":"42890838","nct_ids":"[]","title":"GLP-1 receptor agonists in Alzheimer's disease and MCI: a meta-analysis","authors":"[\"Siqueira RGP\", \"Ranalli C\", \"Yılmaz D\", \"da Silva M\", \"Maltez BRP\", \"Berton GG\", \"Cummings JL\"]","journal":"Alzheimer's & dementia (New York, N. Y.)","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Alzheimer's disease (AD) is the leading cause of dementia in older individuals and remains a major clinical and socioeconomic burden. Despite the success of anti-amyloid therapies in reducing biomarker burden, more effective and safer treatments are still needed. Given the emerging evidence of a role for metabolic dysfunction and brain insulin resistance in AD pathophysiology, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been proposed as potential disease-modifying therapies. [METHODS] We conducted a systematic review and meta-analysis of PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to April 22, 2026 to evaluate the efficacy and safety of GLP-1 RAs in AD and mild cognitive impairment. Randomized controlled trials comparing GLP-1 RAs with placebo, standard care, or non-intervention across the Alzheimer's continuum were eligible; abstracts and studies with unavailable results were excluded. Random-effects models were used. Risk ratios (RRs) were calculated for binary outcomes, and mean or standardized mean differences for continuous outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. [RESULTS] Seven studies comprising 4132 participants met the inclusion criteria. The mean age of the pooled studies was 72.1 years, while the mean baseline Clinical Dementia Rating-Sum of Boxes (CDR-SB) varied from 2.71 to 3.8. GLP-1 RAs were not associated with significant improvement in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale: standard mean difference -0.05; 95% confidence interval [CI]: -0.12 to 0.02; p = 0.1928) or disease progression (CDR-SB: mean difference: 0.09; 95% CI: -0.10 to 0.28; p = 0.362). They were associated with a higher frequency of adverse events (RR 1.07; 95% CI: 1.04 to 1.10; p < 0.0001) and weight loss (RR 5.01; 95% CI: 3.99 to 6.27; p < 0.0001). Biomarker and neuroimaging findings were inconsistent and failed to translate to clinical benefit. [DISCUSSION] GLP-1 RAs did not improve cognitive or functional outcomes in AD and were associated with adverse events. Their role may be better explored in biomarker-enriched, metabolically selected populations or assessment of GLP-1 RAs with greater brain penetrance.","url":"https://pubmed.ncbi.nlm.nih.gov/42890838/","source_name":"pubmed","source_tier":1,"coi_statement":"JLC has provided consultation to AbbVie, Acadia, ALZpath, Annovis Bio, Artery, Axsome, Biogen, Bristol Myers Squibb, Eisai, Fosun, GAP Foundation, IGC, Janssen, Julius Clinical, Kinoxis, Eli Lilly, Lundbeck, LSP/EQT, Merck (Merck, Sharp, and Dohme), MoCA Cognition, Neurocrine, Novo Nordisk, NSC Therapeutics, Otsuka, ReMYND, Roche, Sanofi, Scottish Brain Sciences, Signant Health, Simcere, Sinaptica, Takeda, and UCB therapeutics, assessment, and investment companies. The remaining authors declare that they have no competing interests. Author disclosures are available in the Supporting Information.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cognition\", \"dementia\", \"alzheimers\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1091,"doi":"10.3389/fmed.2026.1800909","pmid":"42865473","nct_ids":"[]","title":"GLP-1 receptor agonists in metabolic dysfunction-associated steatohepatitis: protocol for a systematic review and meta-analysis of randomized controlled trials","authors":"[\"Sun SP\", \"Fang Y\", \"Liu L\", \"Li Y\", \"Min H\"]","journal":"Frontiers in medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic dysfunction-associated steatohepatitis (MASH) is a major global chronic liver disease without approved pharmacotherapy. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show therapeutic promise due to their multi-faceted metabolic benefits, but their efficacy on histological endpoints in MASH requires definitive synthesis. [METHODS AND ANALYSIS] We will conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1 RAs versus placebo/standard care in adults with MASH. Literature searches will be performed in PubMed, Embase, Cochrane Library, and Web of Science. Two reviewers will independently screen studies, extract data, and assess risk of bias using Cochrane's ROB 2 tool. The primary outcome is histological improvement (MASH resolution/fibrosis reduction). Secondary outcomes include changes in liver enzymes, metabolic parameters, and adverse events. Data will be pooled using random-effects models. Trial Sequential Analysis (TSA) will be performed to control random errors and evaluate evidence robustness. Subgroup and sensitivity analyses are planned. [ETHICS AND DISSEMINATION] Ethical approval is not required because this study is a secondary analysis of existing data. We will disseminate the findings through peer- reviewed publications. [SYSTEMATIC REVIEW REGISTRATION] PROSPERO CRD420261287573.","url":"https://pubmed.ncbi.nlm.nih.gov/42865473/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:29:55+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"liver\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1105,"doi":"10.2147/opth.s629343","pmid":"42890826","nct_ids":"[]","title":"Semaglutide Use and Risk of Diabetic Retinopathy and Non-Arteritic Anterior Ischemic Optic Neuropathy in Type 2 Diabetes: A Single-Center Retrospective Cohort Study","authors":"[\"Kemchoknatee P\", \"Pakaymaskul P\", \"Piyawannarat N\"]","journal":"Clinical ophthalmology (Auckland, N.Z.)","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, are increasingly adopted for type 2 diabetes mellitus (T2DM) due to improvements in glycemic control and weight loss. Although concerns have been raised about a potential association with non-arteritic anterior ischemic optic neuropathy (NAION), this relationship remains uncertain. [OBJECTIVE AND METHOD] In this single-center retrospective cohort study, we reviewed patients with T2DM treated with semaglutide at Rajavithi Hospital. A Kaplan-Meier time-to-event analysis was conducted to estimate the incidence of NAION and proliferative diabetic retinopathy (PDR) progression. [RESULTS] Among 100 patients with T2DM treated with semaglutide, no cases of NAION were observed over 299 person-years of follow-up (crude incidence rate: 0 per 1,000 person-years; 95% CI: 0-6.17). PDR and diabetic macular edema (DME) were the main findings, accounting for 10.00% and 3.00%, respectively. Ophthalmic complications group (13 patients) demonstrated higher body mass index (23.72 ± 1.38 vs 21.18 ± 2.51 kg/m2; p < 0.001), higher fasting plasma glucose (197.77 ± 48.28 vs 148.70 ± 27.84 mg/dL; p < 0.001), and worse baseline best-corrected visual acuity ([BCVA]; 1.71 ± 0.74 vs 0.45 ± 0.39 logarithm of the Minimum Angle of Resolution [logMAR]; p < 0.001). Final BCVA remained significantly worse in the complication group (p < 0.001). Ophthalmic complication remained stable over the 60-month follow-up; longer diabetes duration (>60 months) was modestly associated with better survival (log-rank p = 0.049). By contrast, other demographic, optic disc characteristics, and concomitant systemic vascular diseases were not significantly linked to ophthalmic complication. [CONCLUSIONS] No NAION events were observed over 299 person-years; however, the limited sample size precludes definitive conclusions about NAION risk. A modest trend toward higher proliferative diabetic retinopathy rates suggests that ophthalmic monitoring may be warranted in at-risk patients. Larger prospective studies are needed to confirm these preliminary findings.","url":"https://pubmed.ncbi.nlm.nih.gov/42890826/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors report no conflicts of interest in this work.","assessment_version":4,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T20:45:21+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"none (single group of semaglutide users; the only comparisons are between users with and without ophthalmic complications)\", \"dose\": \"subcutaneous 0.25–1.0 mg weekly or oral 7–14 mg daily\", \"route\": \"various\", \"treatment_duration\": \"median exposure 30 months (Table 1: mean 29.96 ± 14.38 months); at least 12 months of GLP-1RA therapy required for entry\"}","domains":"[\"mortality\", \"metabolic\", \"ophthalmologic\"]","outcome_type":"hard","primary_outcome":"New-onset NAION (secondary: new proliferative diabetic retinopathy or diabetic macular edema)","endpoints":null,"effect_estimate":"No NAION cases over 299 person-years (crude incidence 0 per 1,000 person-years); proliferative diabetic retinopathy in 10.00% and diabetic macular edema in 3.00%; no comparison group","confidence_interval":"95% CI: 0-6.17 (crude NAION incidence per 1,000 person-years)","p_value":null,"sample_size":100,"follow_up":"299 person-years in total; mean follow-up 35.86 ± 14.82 months (Table 1); Kaplan-Meier analysis to 60 months","direction":"unclear","population":"{\"mean_age\": \"59.74 ± 21.13 years (Table 1, total)\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": \"64% women (64 of 100)\", \"bmi_mean\": 21.51, \"bmi_min\": null, \"obesity_status\": \"mixed (obesity not required; 17 of 100 had obesity; mean BMI 21.51)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes treated with semaglutide (GLP-1RA therapy for at least 12 months), without diabetic retinopathy or macular edema at baseline\", \"sample_size\": 100, \"inclusion_exclusion\": \"Adults 18 or older with T2DM on a GLP-1RA for at least 12 months; excluded prior NAION or other optic neuropathy, baseline diabetic retinopathy or macular edema, follow-up under 12 months, and laser or anti-VEGF treatment in the prior 12 months\", \"healthy_volunteers\": false, \"normal_weight_included\": true, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: every participant had type 2 diabetes. Otherwise the group was close to the target profile (mean BMI 21.51, 17 of 100 with obesity, mean age 59.74), but diabetes is a metabolic disease the target group does not have, and no results are reported for anyone without it.","mediation":"possibly","mediation_notes":"No weight or HbA1c change on treatment and no mediation analysis are reported; HbA1c was recorded at baseline only. The authors suggest the retinal findings may reflect rapid glucose lowering rather than the drug itself, which they could not test without serial HbA1c.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 100, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"none (single group of semaglutide users; the only comparisons are between users with and without ophthalmic complications)\", \"follow_up_duration\": \"299 person-years in total; mean follow-up 35.86 ± 14.82 months (Table 1); Kaplan-Meier analysis to 60 months\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: 0-6.17 (crude NAION incidence per 1,000 person-years)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"VERY_LOW: a single-centre retrospective cohort of 100 semaglutide users with no comparison group, no NAION events and 13 composite eye complications; uncontrolled and too small for a rare outcome, the single-centre, few-event case the model rates VERY_LOW.","funding_source":"No funding was received","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare no conflicts","sponsor_role":"not reported","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No NAION events; new proliferative diabetic retinopathy in 10.00% and diabetic macular edema in 3.00% of semaglutide users, with no comparison group","limitations":"Small single-centre retrospective cohort of 100 patients with no comparison group and few events; the authors say the sample size precludes definitive conclusions about NAION risk and note intermediate follow-up, possible surveillance bias from uneven examination intervals, no serial HbA1c, a composite endpoint and an exploratory Cox model.","plain_summary":"This study reviewed the records of 100 people with type 2 diabetes treated with semaglutide at one hospital in Thailand; their average BMI was 21.51 and 17 of 100 had obesity, and there was no comparison group. No cases of NAION, a sudden loss of blood supply to the optic nerve, were seen over 299 person-years, but the authors say the group was too small to draw conclusions about NAION risk. Advanced (proliferative) diabetic retinopathy developed in 10.00% and diabetic macular swelling in 3.00%; without a comparison group, these figures cannot show whether semaglutide raised or lowered either risk.","methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1113,"doi":"10.3389/fphar.2026.1936967","pmid":"42871459","nct_ids":"[]","title":"Indication-specific adverse event profiles of semaglutide and liraglutide: a FAERS disproportionality analysis","authors":"[\"Fisch SA\", \"Neugut EJ\", \"Cornet N\", \"Quigee D\", \"Neugut AI\", \"Freedberg DE\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] By 2021, regulatory agencies had approved two glucagon-like peptide-1 receptor agonists (GLP-1RAs), semaglutide and liraglutide, for the treatment of type 2 diabetes and obesity. Since then, concerns have emerged about whether adverse events (AEs) differ by GLP-1RA or indication. [RESEARCH DESIGN AND METHODS] We analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) reports (2021-2025) to compare adverse events associated with semaglutide and liraglutide indications. Comparisons with metformin and orlistat helped distinguish drug-related signals from disease-related signals. We defined safety signals by a positive reporting odds ratio and at least one other positive disproportionality metric. [RESULTS] Among 8,213,105 FAERS reports, 33,259 met the inclusion criteria. Semaglutide generated more reports for type 2 diabetes than for obesity (13,168 vs. 5,444), and liraglutide showed a similar pattern (1,201 vs. 837). GLP-1RAs exhibited gastrointestinal AEs. Semaglutide showed signals for slowed gastrointestinal motility across both indications, particularly impaired gastric emptying, in both type 2 diabetes and obesity reports (ROR = 8.35, 95% CI = 1.16-59.97 and ROR = 4.01, 95% CI = 2.12-7.58, respectively). Liraglutide demonstrated signals for more severe gastrointestinal AEs, including abdominal distention in type 2 diabetes (ROR = 1.46, 95% CI = 1.12-1.91) and pancreatitis in obesity (ROR = 2.90, 95% CI = 1.91-4.39) reports. Additional notable safety signals included optic ischemic neuropathy with semaglutide (ROR = 4.42, 95% CI = 1.41-13.87) and psychiatric AEs, including suicidal ideation (ROR = 5.98, 95% CI = 1.24-24.19). [CONCLUSION] We identified robust signals for GLP-1RAs, including impaired gastric emptying, ileus, and ischemic optic neuropathy. Additionally, we identified signals for suicidal ideation. Future studies are needed to evaluate for causal relationships.","url":"https://pubmed.ncbi.nlm.nih.gov/42871459/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:39+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\", \"psychiatric\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1118,"doi":"10.3389/fendo.2026.1907270","pmid":"42865447","nct_ids":"[]","title":"Long-term GLP-1 receptor agonist therapy in obesity: expert panel recommendations for good clinical practice","authors":"[\"Brancato D\", \"Borretta G\", \"Chianelli M\", \"Disoteo O\", \"Grasso M\", \"Grimaldi F\", \"Guastamacchia E\", \"Muratori F\", \"Oleandri S\", \"Orio M\", \"Pantanetti P\", \"Papini E\", \"Persichetti A\", \"Vettor R\", \"Vinciguerra F\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as highly effective therapies for obesity, facilitating weight loss and improving cardiometabolic risk factors. However, several challenges persist regarding optimal long-term management in real-world clinical practice. A board of clinicians with expertise in obesity and metabolic diseases discussed practical recommendations for the sustainable long-term management of GLP-1RA therapy. Key themes included the maintenance of clinical benefits, prevention of weight regain, treatment sustainability, and long-term safety and tolerability. The panel highlighted the necessity of approaching obesity as a chronic, relapsing disease requiring long-term therapeutic strategies. Comprehensive baseline phenotyping and a treat-to-benefit approach were identified as essential for defining clinically meaningful treatment targets beyond weight loss alone. Maintenance therapy after achievement of initial outcomes, flexible dose management, and early recognition of relapse signals were considered essential for preserving benefits and preventing weight regain. Pharmacotherapy should be integrated within a multimodal care model that includes nutritional counseling, physical activity, and behavioral support, while addressing real-world barriers such as economic sustainability. Proactive management of adverse events and patient education were recognized as critical for ensuring long-term adherence. Sustainable use of GLP-1RA therapy requires integrated, patient-centered management strategies that combine pharmacological treatment with lifestyle interventions and pragmatic dose adjustment. Future collaborative real-world data initiatives may further refine these practical recommendations and help optimize long-term obesity care.","url":"https://pubmed.ncbi.nlm.nih.gov/42865447/","source_name":"pubmed","source_tier":1,"coi_statement":"DB has received speaker honoraria from Novo Nordisk and Eli Lilly. MC has received honoraria from Novo Nordisk and Eli Lilly. FG has received invitation and speaker honoraria for conference attendance from Novo Nordisk and Eli Lilly. EG has received speaker honoraria from Lilly and Astra Zeneca. RV has served on scientific boards and has received consulting honoraria from Novo Nordisk and Lilly.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cognition\", \"adverse_effects\", \"nutrition\", \"discontinuation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1119,"doi":"10.3389/fendo.2026.1941948","pmid":"42865361","nct_ids":"[]","title":"Pancreatic and biliary safety signals of GLP-1 receptor agonists and tirzepatide: a disproportionality analysis of FAERS reports","authors":"[\"Wu Y\", \"Li K\", \"Wang Y\", \"Chen Z\", \"Shi M\", \"Zhao J\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide is increasing rapidly worldwide, and the pancreatic and biliary safety of these drugs has been a concern. This study was based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate the pancreatic and biliary adverse event reporting signals of liraglutide, semaglutide, tirzepatide and dulaglutide. [OBJECTIVES] To describe the reporting patterns of pancreatic and biliary adverse events for liraglutide, semaglutide, dulaglutide, and tirzepatide, and to identify signals in both organ systems within a single framework. [DESIGN] Retrospective disproportionality analysis of individual case safety reports. [METHODS] FAERS data from Q3-2009 through Q3-2025 were extracted, and deduplicated ICSRs were used as the unit of analysis. Reporting odds ratios (RORs) and information components (ICs) were computed at composite and Preferred Term levels; signals required the lower 95% confidence bound for the ROR to exceed 1 and IC025 to exceed 0. Metformin and sodium-glucose cotransporter-2 inhibitors were included as contextual benchmarks. Analyses were stratified by brand (diabetes/obesity indication), sex, age, and reporter type, and time to onset was examined. [RESULTS] A disproportionality signal for pancreatic adverse events was observed for all four study drugs, but the control drugs metformin and SGLT2i also showed positive signals. For biliary events, all four study drugs showed signals, whereas the two control drugs showed no signals. After stratification by brand, the pancreatic signal remained for brands with diabetes indications, while the signal was weaker for brands with obesity indications. After excluding the cases of biliary tract co-reporting, the pancreatic signal still existed. Median time to onset ranged from 85.5 to 136 days for pancreatic events and from 146.5 to 320 days for biliary events. [CONCLUSION] Both GLP-1RAs and tirzepatide are associated with disproportionate reporting of pancreatic and biliary adverse events in FAERS. Signals are influenced by indication, reporting behavior, and time effects and cannot be used to estimate incidence or prove causality. These signals suggest the need for further validation in real-world cohort studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42865361/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-10-18T11:30:03+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1130,"doi":"10.3389/fendo.2026.1980239","pmid":"42922894","nct_ids":"[]","title":"GLP-1 receptor agonists and lymphedema: from weight loss to potential direct modulation of lymphatic function","authors":"[\"Merzel Šabović EK\", \"Janić M\", \"Planinšek Ručigaj T\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Obesity and lymphedema are linked through increased interstitial fluid load, impaired collecting-vessel pumping, inflammation, and progressive fibro-adipose remodeling. This bidirectional relationship makes glucagon-like peptide-1 receptor agonists (GLP-1RAs) relevant through two potentially distinct pathways. First, substantial weight loss may unload a compromised lymphatic system, improve mobility, and reduce adipose-driven inflammation. Second, GLP-1 signaling may directly influence lymphatic vessel function. Case reports and a retrospective cohort have described reduced limb volume, improved symptoms or imaging findings, and a lower incidence of breast cancer-related lymphedema among GLP-1RA users. Experimental work has identified GLP-1 receptors in lymphatic endothelial cells and shown that pharmacological activation with semaglutide increases the pumping capacity of isolated collecting lymphatic vessels. These findings support a potential direct lymphatic effect but do not establish clinical efficacy in human lymphedema. Improvement during treatment may instead reflect reduced fat mass, greater mobility, or changes in conventional care. Future studies should distinguish weight-loss-dependent unloading from weight-loss-independent effects by combining standardized clinical outcomes, functional imaging, body-composition measurements, and, where feasible, weight-matched comparison groups. The available evidence therefore supports prospective investigation rather than clinical adoption. Trials should assess early vascular responses before major weight loss, longer-term changes in tissue composition and inflammation, and durability after treatment withdrawal, while maintaining standardized compression, exercise, skin care, and other components of established lymphedema management throughout. Until such evidence is available, GLP-1RAs should be prescribed for established metabolic indications rather than lymphedema itself, and any lymphatic benefit should be regarded as a promising clinical signal rather than a treatment claim.","url":"https://pubmed.ncbi.nlm.nih.gov/42922894/","source_name":"pubmed","source_tier":1,"coi_statement":"EK Merzel Šabović has received honoraria from Abbvie, Eli Lilly, Johnson & Johnson, L'Oreal, Medis, Novartis, Rilastil and Valens. M Janić has received honoraria and speaker fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Krka, Merch Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Sanofi, Swixx Biopharma, and Viatris. The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"cancer\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1132,"doi":"10.3389/fphar.2026.1917340","pmid":"42920623","nct_ids":"[]","title":"Tirzepatide versus other glucose-lowering therapies and risk of COPD exacerbations in patients with comorbid type 2 diabetes: a retrospective cohort study","authors":"[\"Hsu WH\", \"Chan YE\", \"Wu JY\", \"Chuang YM\", \"Kuo CY\", \"Shiau BW\", \"Huang PY\", \"Lai CC\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D) frequently coexist, sharing inflammatory and metabolic pathways. Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has demonstrated metabolic and anti-inflammatory effects. However, its impact on pulmonary outcomes in patients with COPD and T2D remains uncertain. [METHODS] Using the TriNetX global research network, we conducted a retrospective cohort study of adults with coexisting COPD and T2D prescribed TZP, sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), or glucagon-like peptide-1 receptor agonists (GLP-1RA). Propensity score matching (1:1) was performed separately for each comparison. Primary outcome was COPD exacerbation; secondary outcomes included all-cause mortality, acute respiratory failure, and lower respiratory tract infection. Outcomes were assessed during a prespecified observation period from day one through day 365 after the index date. [RESULTS] Matched populations included 6,080 patients per group (TZP-SGLT2i), 4,684 (TZP-DPP-4i), and 6,727 (TZP-GLP-1RA). In the independently matched comparisons, median follow-up was 232 versus 365 days for TZP versus SGLT2i, 235 versus 365 days for TZP versus DPP-4i, and 233 versus 365 days for TZP versus other GLP-1RAs; incidence rates were expressed per 1,000 person-years. Compared with SGLT2i and DPP-4i, TZP significantly reduced COPD exacerbation risk (hazard ratio [HR] 0.73 [95% CI 0.64-0.82] and 0.72 [95% CI 0.63-0.82], respectively) and all-cause mortality (HR 0.30 [95% CI 0.23-0.38] and 0.24 [95% CI 0.18-0.31], respectively). TZP also reduced acute respiratory failure and lower respiratory tract infection risks. Outcomes were similar between TZP and GLP-1RA, except TZP showed lower mortality (HR 0.55 [95% CI 0.42-0.72]). [CONCLUSION] Among patients with COPD and T2D, TZP use was associated with lower risks of COPD exacerbations, respiratory complications, and mortality compared with SGLT2i and DPP-4i, findings that warrant confirmation through randomized clinical trials.","url":"https://pubmed.ncbi.nlm.nih.gov/42920623/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:05+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"mortality\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1133,"doi":"10.3389/fmed.2026.1921737","pmid":"42920458","nct_ids":"[]","title":"Effects of liraglutide on blood pressure and renal function in patients with type 2 diabetic nephropathy: a meta-analysis of randomized controlled trials","authors":"[\"Gao S\", \"Shan Y\", \"Ma D\", \"Zhou X\", \"Gao W\"]","journal":"Frontiers in medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] The effects of liraglutide on blood pressure in patients with T2DN remain unclear. This meta-analysis aimed to systematically evaluate the effects of liraglutide on blood pressure and renal function in patients with T2DN. [METHODS] We conducted comprehensive searches of Web of Science, PubMed, the Cochrane Library, Elsevier ScienceDirect, CNKI, Wanfang Data, and VIP databases. Eligible studies were RCTs of ≥12 weeks' duration evaluating liraglutide for T2DN. Two independent reviewers screened citations, extracted data, and assessed methodological quality using the Cochrane Risk-of-Bias Tool. Statistical analyses were performed in Stata 17.0 and RevMan 5.4, with effect sizes presented as RR or MD and 95% CI. The Cochrane Q test and I2 statistic were used to quantify statistical heterogeneity. [RESULTS] This meta-analysis included 23 RCTs involving 1,723 participants. Compared with the control group, liraglutide significantly reduced SBP [MD = -5.00, 95% CI (-7.17, -2.84)], while no significant effect was observed on DBP. In addition, liraglutide was associated with favorable changes in some renal biomarkers, as evidenced by reductions in Scr, UACR, Cys-C, BUN, and β2-MG, as well as elevations in eGFR. Improvements were also observed in glycemic control, lipid profiles, BMI, and inflammatory markers. Subgroup analyses indicated dose-dependent differences in UACR and LDL-C. In addition, both UACR and Scr were affected by intervention-regimen type, while HbA1c was affected by baseline albuminuria category. Sensitivity analyses confirmed the robustness of the findings, and adjustment for publication bias did not alter the statistical significance of the key outcomes. [CONCLUSION] Liraglutide may be associated with favorable changes in selected BP, renal, metabolic, and inflammatory outcomes in patients with T2DN. However, further high-quality studies are needed to confirm these findings. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420251232844, PROSPERO CRD420251232844.","url":"https://pubmed.ncbi.nlm.nih.gov/42920458/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:05+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1175,"doi":"10.7150/ijms.141099","pmid":"42910111","nct_ids":"[]","title":"Association of GLP-1 Receptor Agonist Use with Thyroid Outcomes in Adults with Type 2 Diabetes","authors":"[\"Hsiao CC\", \"Tsai MH\", \"Jhu JY\", \"Liu YF\", \"Yen CL\", \"Chen JJ\", \"Chen PC\"]","journal":"International journal of medical sciences","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used to treat type 2 diabetes mellitus, but their associations with thyroid disorders remain uncertain. We evaluated whether initiating a GLP-1 RA, compared with initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i), was associated with newly recorded autoimmune thyroiditis and other thyroid outcomes. [METHODS] This new-user, active-comparator cohort study emulated a target trial using the TriNetX Collaborative Network. Adults with type 2 diabetes who initiated a GLP-1 RA or DPP-4i between January 1, 2018, and December 31, 2022, and had no prior use of either drug class were eligible. Patients with pre-existing thyroid disease, any neoplasm, immunosuppressant or immunostimulant use, transplantation, or end-stage kidney disease or dialysis were excluded. Propensity score matching yielded 107,912 patients per group. The primary outcome was newly recorded autoimmune thyroiditis; secondary outcomes were nontoxic uninodular goiter, nontoxic multinodular goiter, and thyroid malignancy. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with false discovery rate adjustment. Follow-up extended from 1 day after treatment initiation to 4 years. [RESULTS] Autoimmune thyroiditis occurred in 524 GLP-1 RA users (0.49%) and 417 DPP-4i users (0.39%). GLP-1 RA initiation was associated with a higher risk of autoimmune thyroiditis (HR, 1.26; 95% CI, 1.11-1.43; FDR-adjusted P = 0.002). Modestly higher risks were also observed for nontoxic uninodular goiter (HR, 1.07; 95% CI, 1.01-1.13) and nontoxic multinodular goiter (HR, 1.11; 95% CI, 1.03-1.19). The risk of thyroid malignancy did not differ significantly (HR, 0.93; 95% CI, 0.77-1.12). Findings were generally consistent across sensitivity and subgroup analyses, although heterogeneity was observed across body mass index strata. [CONCLUSION] Among adults with type 2 diabetes, GLP-1 RA initiation was associated with small increases in newly recorded autoimmune thyroiditis and benign nodular thyroid disease, but not with thyroid malignancy. Given the small absolute differences and the potential for residual confounding and surveillance bias, these findings require validation in future studies.","url":"https://pubmed.ncbi.nlm.nih.gov/42910111/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing Interests: The authors have declared that no competing interest exists.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"rheumatologic\", \"immune\", \"cancer\", \"metabolic\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1217,"doi":"10.3389/fendo.2026.1914378","pmid":"42908606","nct_ids":"[]","title":"Liraglutide reduces lipid accumulation in human orbital fibroblasts in Graves' orbitopathy","authors":"[\"Shih CW\", \"Shih SR\", \"Wei YH\", \"Lin CH\", \"Liao SL\", \"Chou TA\", \"Chu I\", \"Chen HJ\", \"Liao NL\", \"Tsai FC\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Graves' orbitopathy (GO) is characterized by proliferation and differentiation of orbital fibroblasts. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders and have been reported to modulate cell proliferation and differentiation. The present study aimed to examine the effects of GLP-1RAs on key fibroblast-mediated pathogenic processes relevant to GO using human orbital fibroblasts. Orbital fibroblasts were isolated from patients with GO and non-GO controls. Cells were treated with the GLP-1RAs liraglutide (100 nM) or semaglutide (200 nM). Fibroblast proliferation was assessed by nuclear counting, lipid accumulation was evaluated by Oil Red O staining of oil droplets, and myofibroblastic differentiation was assessed by α-smooth muscle actin (α-SMA) immunostaining. Hyaluronan production was measured by ELISA. GLP1R mRNA expression was examined using reverse transcription quantitative PCR. Among the outcomes assessed, liraglutide significantly reduced lipid accumulation in GO-derived orbital fibroblasts, whereas semaglutide showed a nonsignificant trend in the same direction. Neither liraglutide nor semaglutide significantly altered lipid accumulation in non-GO fibroblasts. Importantly, neither GLP-1RA increased fibroblast proliferation, TGF-β-induced myofibroblastic differentiation, or IL-1β-induced hyaluronan production in GO or non-GO fibroblasts under the tested conditions. GLP1R mRNA was not reliably detected, and the underlying mechanism remains uncertain. Taken together, this in vitro study showed a significant reduction in lipid accumulation following liraglutide treatment in GO-derived orbital fibroblasts, while semaglutide showed a trend in the same direction that did not reach statistical significance. Neither agent enhanced fibroblast proliferation, myofibroblastic differentiation, or hyaluronan production under the tested conditions. These findings suggest a potentially favorable biological profile of liraglutide in GO and warrant further studies to clarify the underlying mechanisms and assess its clinical relevance, particularly in patients with metabolic comorbidities.","url":"https://pubmed.ncbi.nlm.nih.gov/42908606/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"cellular_in_vitro","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"immune\", \"metabolic\", \"ophthalmologic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1222,"doi":"10.3389/fendo.2026.1948361","pmid":"42898168","nct_ids":"[]","title":"Effects of intensive insulin therapy combined with non-insulin antihyperglycemic agents on glycemic control, variability, and metabolic outcomes in patients with type 2 diabetes mellitus: a systematic review and meta-analysis","authors":"[\"Shen Z\", \"Li J\", \"Zhao Z\", \"Chen Z\", \"Ma X\", \"Zhou J\", \"Jiao L\", \"Wang J\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Intensive insulin therapy (IIT) induces clinical remission in newly diagnosed or poorly controlled type 2 diabetes mellitus (T2DM), but is limited by hypoglycemia risk and weight gain. Combining IIT with non-insulin antihyperglycemic agents may mitigate these drawbacks while improving glycemic variability. [METHODS] This review was registered with PROSPERO (CRD42024582974). We searched PubMed, Embase, Cochrane, Web of Science, ClinicalTrials.gov, and Chinese databases (CNKI, VIP, Wanfang, and Chinese Medical Association journals) for randomized controlled trials (RCTs) comparing intensive insulin therapy (IIT) alone with IIT plus metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), or glucagon-like peptide-1 receptor agonists (GLP-1RA) in adults with type 2 diabetes mellitus (T2DM). The primary outcomes were glycemic variability indices, including mean amplitude of glycemic excursions (MAGE), standard deviation of blood glucose (SDBG), and largest amplitude of glycemic excursions (LAGE). Secondary outcomes included fasting plasma glucose (FPG), 2-h postprandial glucose (PPG-2h), mean blood glucose (MBG), glycated hemoglobin (HbA1c), homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), and insulin requirements, including total daily insulin dose (TDD), basal insulin dose, and bolus insulin dose. Time in range (TIR), body weight, hypoglycemia, and gastrointestinal adverse events (GI-AEs) were analyzed as post hoc exploratory outcomes. [RESULTS] Thirty-nine RCTs were included. For the primary glycemic-variability outcomes, GRADE assessments indicated that IIT plus DPP-4i likely reduced MAGE (MD -1.39 mmol/L, 95% CI -1.77 to -1.01) and LAGE (MD -1.20 mmol/L, 95% CI -1.66 to -0.75), while IIT plus SGLT2i likely reduced SDBG (MD -0.28 mmol/L, 95% CI -0.44 to -0.11). Evidence was very uncertain for the effects of IIT plus GLP-1RA on MAGE and IIT plus DPP-4i on SDBG. Among secondary outcomes, IIT plus DPP-4i likely reduced FPG (MD -0.44 mmol/L, 95% CI -0.67 to -0.21), while IIT plus GLP-1RA likely reduced HbA1c (MD -0.73%, 95% CI -1.01 to -0.45). IIT plus GLP-1RA, metformin, or SGLT2i may reduce FPG; IIT plus DPP-4i, GLP-1RA, or metformin may reduce PPG-2h; and IIT plus SGLT2i may reduce HbA1c. IIT plus DPP-4i and IIT plus GLP-1RA may also modestly reduce total daily insulin dose. Evidence for the effect of IIT plus SGLT2i on PPG-2h was very uncertain. Among post hoc exploratory outcomes, IIT plus SGLT2i likely increased TIR (MD 8.23 percentage points, 95% CI 4.13 to 12.32), while IIT plus DPP-4i may reduce hypoglycemia risk (RR 0.53, 95% CI 0.31 to 0.91) and IIT plus GLP-1RA may increase GI-AEs (RR 5.28, 95% CI 1.81 to 15.40). Longer-duration IIT plus GLP-1RA may be associated with greater weight loss (MD -3.63 kg, 95% CI -4.94 to -2.32) in a post hoc exploratory subgroup analysis, whereas evidence for the effect of IIT plus SGLT2i on hypoglycemia was very uncertain. [CONCLUSIONS] Adjunctive non-insulin antihyperglycemic agents may improve glycemic variability and overall glycemic control in adults with T2DM receiving intensive insulin therapy. The most consistent evidence supported reductions in MAGE and LAGE with DPP-4i and in SDBG with SGLT2i. Reductions in FPG and PPG-2h were observed across several drug classes, while HbA1c was reduced with GLP-1RA and SGLT2i. Post hoc analyses suggested improved TIR with SGLT2i, reduced body weight with longer-duration GLP-1RA therapy, a lower risk of hypoglycemia with DPP-4i, and a higher risk of gastrointestinal adverse events with GLP-1RA; however, these exploratory findings should be interpreted cautiously. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024582974.","url":"https://pubmed.ncbi.nlm.nih.gov/42898168/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1225,"doi":"10.2147/dmso.s614243","pmid":"42893177","nct_ids":"[]","title":"Adherence and Persistence to Injectable versus Oral GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus: A Comparative Systematic Review and Analysis","authors":"[\"Ashour AM\"]","journal":"Diabetes, metabolic syndrome and obesity : targets and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Type 2 diabetes mellitus (T2DM) requires sustained glycemic control to prevent long-term complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective therapies, traditionally administered via injection. The introduction of oral formulations, such as oral semaglutide, may improve patient adherence and persistence. [METHODS] A systematic review with descriptive pooled synthesis was conducted using studies identified from PubMed, ClinicalTrials.gov, and relevant real-world observational data sources. Adherence and persistence outcomes were summarized and compared descriptively between injectable and oral GLP-1 RAs. [RESULTS] Across the included total of 13 studies and medical records, data from 1348 patients were summarized. Oral GLP-1 RAs were associated with higher reported adherence (70.8% vs 62.4%) and persistence (62.1% vs 47.8%) compared with injectable formulations. A chi-square test of independence showed that the difference in adherence between oral and injectable GLP-1 was significant; (χ 2 = 10.8, p < 0.01). Similarly, chi-square test showed that the observed variation in persistence between Oral-GLP vs injectable GLP-1 was also significant (χ 2 = 37.9, p < 0.001). Injectable therapies were associated with higher rates of adverse events, particularly injection-site reactions. [CONCLUSION] Oral GLP-1 RAs may be associated with improved adherence and persistence in patients with T2DM. These findings suggest that formulation choice may influence long-term diabetes treatment continuation, although further study-level meta-analytic research is needed.","url":"https://pubmed.ncbi.nlm.nih.gov/42893177/","source_name":"pubmed","source_tier":1,"coi_statement":"The author declares that there are no conflicts of interest in this study.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-25T11:15:25+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1226,"doi":"10.2337/doc25-0026","pmid":"42920957","nct_ids":"[]","title":"Patterns of Prescription Discontinuation, Reinitiation, and Switching of Subcutaneous Semaglutide and Tirzepatide in Adults With Obesity","authors":"[\"Ali D\", \"Kudaya D\", \"Ngige A\", \"Chao AM\"]","journal":"Diabetes, obesity, and cardiometabolic CARE","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs), such as semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide RAs, such as tirzepatide, are increasingly used for obesity management. However, real-world patterns of discontinuation, reinitiation, and switching among individuals without diabetes remain poorly described. This study describes the real-world patterns of discontinuation and reinitiation of subcutaneous semaglutide and tirzepatide in adults with obesity but without diabetes in an academic medical center. Secondary objectives included evaluating transitions between semaglutide and tirzepatide and switches from these agents to first-generation antiobesity medications (AOMs). [RESEARCH DESIGN AND METHODS] A retrospective cohort study of adults with obesity but without diabetes who were prescribed semaglutide or tirzepatide was conducted using electronic health record data. Patterns of discontinuation, reinitiation, and switching (change from one agent to another or to a first-generation AOM) were assessed over 12 months. [RESULTS] Among 9,189 adults initiating subcutaneous semaglutide or tirzepatide, 36.7% of the sample had a prescription that lasted <32 days (mean, 3.6 days), with 82.7% receiving no further prescriptions for AOMs that year. Prescription coverage was 32-179 days and 180-335 days in 27.0% and 17.7% of participants, respectively, with most (72.3% and 89.5%) not having any prescriptions for AOMs thereafter. Persistent prescriptions (coverage for ≥336 days) were observed in 18.6% of participants. Prescriptions to reinitiate or switch to another GLP-1 RA or first-generation AOM were rare. [CONCLUSIONS] In a real-world academic setting, a substantial proportion of individuals with obesity, but without diabetes, discontinued GLP-1-based treatments.","url":"https://pubmed.ncbi.nlm.nih.gov/42920957/","source_name":"pubmed","source_tier":1,"coi_statement":"A.M.C. has served on advisory boards to Boehringer Ingelheim, Eli Lilly and Company, and Novo Nordisk and received grant support, on behalf of Johns Hopkins University, from Eli Lilly and Company. No other potential conflicts of interest relevant to this article were reported.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1247,"doi":"10.3389/fphar.2026.1942307","pmid":"42953016","nct_ids":"[]","title":"Associations of glucose- and lipid-lowering medications with incident or first-recorded psoriasis: a systematic review of real-world observational studies","authors":"[\"Li Z\", \"Yang J\", \"Chen D\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucose-lowering and lipid-lowering medications may influence psoriasis development through metabolic, inflammatory, and immune pathways, but real-world evidence remains inconsistent. [OBJECTIVE] To systematically evaluate associations between these medications and the risk of incident or first-recorded psoriasis, with particular attention to comparator choice, outcome definition, study design, and data-source overlap. [METHODS] PubMed, Embase, Web of Science Core Collection, and the Cochrane Library were searched from inception to 1 July 2026, with an updated search conducted on 11 September 2026 during manuscript revision. Longitudinal observational studies evaluating glucose-lowering or lipid-lowering medication use and incident or first-recorded psoriasis were included. Evidence was grouped by medication class, comparator, and outcome type and synthesized narratively. Psoriasis-specific outcomes and broader or composite psoriatic-disease outcomes were treated as distinct evidence categories. Risk of bias was assessed using ROBINS-I. Meta-analysis was not performed because sufficiently comparable and mutually independent estimates were unavailable within most medication-comparator-outcome strata. [RESULTS] Eighteen reports were included. Dipeptidyl peptidase-4 inhibitor estimates were generally below 1; in an active-comparator study using a broader psoriasis-related outcome including psoriatic arthritis codes, the hazard ratio versus sulfonylureas was 0.422 (95% confidence interval, 0.273-0.716). Glucagon-like peptide-1 receptor agonist estimates were notably comparator dependent: estimates were above 1 in comparisons with dipeptidyl peptidase-4 inhibitors, approximately null in comparison with sodium-glucose cotransporter-2 inhibitors, and inconsistent across comparisons with GLP-1RA nonuse. Most sodium-glucose cotransporter-2 inhibitor estimates were near or above the null. Metformin and thiazolidinediones yielded lower estimates in some studies, whereas statins showed no consistent association or exposure-response gradient. Of the 18 report-level ROBINS-I assessment anchors, 13 (72.2%) had a serious overall risk of bias and five (27.8%) had a moderate risk; none had a low risk of bias. Several reports may also have included overlapping populations and were therefore not interpreted as independent replications. [CONCLUSION] The available observational evidence does not establish causal effects of glucose-lowering or lipid-lowering medications on incident or first-recorded psoriasis. This review does not support choosing or avoiding these medications solely to prevent psoriasis or modifying standard diabetes or cardiovascular treatment on the basis of the reported associations. The findings remain hypothesis-generating because of confounding by indication, other risks of bias, and limited independent evidence. [SYSTEMATIC REVIEW REGISTRATION] https://doi.org/10.37766/inplasy2026.7.0070, identifier INPLASY202670070.","url":"https://pubmed.ncbi.nlm.nih.gov/42953016/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:19+00:00","study_design":"systematic_review","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"rheumatologic\", \"immune\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1288,"doi":"10.3389/fendo.2026.1955431","pmid":"42952754","nct_ids":"[]","title":"Network and pairwise meta-analysis of the effects of novel hypoglycemic agents on cardiorenal outcomes in patients with type 2 diabetes and heart failure","authors":"[\"Ye X\", \"Wu Q\", \"Li L\", \"Huang M\", \"Wang S\"]","journal":"Frontiers in endocrinology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This study aims to evaluate the cardiovascular and renal benefits of novel hypoglycemic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT-2is), and glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 dual receptor agonists (GIP/GLP-1RAs) in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). [METHODS] Systematic literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 30 April 2026. Randomized controlled trials (RCTs) for cardiovascular outcomes (CVOTs) or post hoc analyses of CVOTs comparing SGLT-2is, DPP-4is, GLP-1RAs, or GIP/GLP-1RAs in patients with T2DM and HF were selected. Network meta-analysis was used for indirect comparisons, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). [RESULTS] A total of 10 RCTs and two post hoc analyses of CVOTs involving 13,886 patients were included. Compared with placebo, SGLT-2is (HR [95% CI]: 0.75 [0.68, 0.82]) and GLP-1RAs (HR [95% CI]: 0.77 [0.61, 0.97]) both significantly reduced the risk of HF-related composite endpoints in patients with T2DM and HF. No statistically significant difference was observed between SGLT-2is and GLP-1RAs (HR [95% CI]: 0.98 [0.76, 1.25]). SGLT-2is also reduced the risk of HF worsening (HR [95% CI]: 0.72 [0.53, 0.96]), HF hospitalization (HR [95% CI]: 0.74 [0.66, 0.83]), and cardiovascular (CV) death (HR [95% CI]: 0.87 [0.77, 0.98]). For all-cause death, SGLT-2is showed a trend toward reduced risk compared to placebo, but this difference did not reach statistical significance (HR [95% CI]: 0.83 [0.67, 1.02]). For the renal composite outcome, SGLT-2is did not demonstrate a statistically significant benefit (HR [95% CI]: 0.76 [0.51, 1.14]). [CONCLUSION] Optimal clinical management of T2DM requires a comprehensive assessment of cardiovascular and renal comorbidities. This network meta-analysis indicates that SGLT-2is significantly reduce the risk of HF-related composite endpoints and CV death in T2DM patients with HF, although their renoprotective effect does not reach statistical significance. GLP-1RAs also demonstrate beneficial effects on HF-related composite endpoints. These findings suggest that both SGLT-2is and GLP-1RAs are preferred glycemic control strategies for improving cardiovascular outcomes in T2DM patients with HF, while further evidence is needed to confirm their definitive renal benefits. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD42026142123, identifier: CRD420261421235.","url":"https://pubmed.ncbi.nlm.nih.gov/42952754/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:21+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1311,"doi":"10.3389/fphar.2026.1994366","pmid":"42964193","nct_ids":"[]","title":"Pregnancy and perinatal outcomes following exposure to GLP-1 and dual GLP-1/GIP receptor agonists: a time-window-stratified systematic review and meta-analysis","authors":"[\"Mavigök E\", \"Mavigök AN\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] To evaluate maternal, fetal, and neonatal outcomes after preconception or gestational exposure to glucagon-like peptide-1 receptor agonists and dual glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonists, and to assess the reproducibility of reported safety signals. [METHODS] Six databases plus a drug-level safety search were searched through 16 July 2026. Exposure was classified into four clinically defined time windows. Independent studies or data sources were the analytic unit; one primary comparator was selected per study, and odds ratios and risk ratios were synthesized separately. Random-effects meta-analysis, timing-stratified and dominant-study sensitivity analyses, Newcastle-Ottawa Scale assessment, and GRADE certainty assessment were used. [RESULTS] Fourteen comparative data sources were included; 13 were quantitatively eligible and eight contributed to at least one pooled estimate. In the timing-specific analysis of major congenital malformations, four studies with verified periconceptional/first-trimester exposure yielded an odds ratio of 0.99 (95% confidence interval 0.77-1.27). A secondary pregnancy-period analysis that added one unadjusted, trimester-unspecified cohort yielded 1.00 (0.94-1.06); that cohort contributed 93.5% of the weight. Pooled preterm birth, small-for-gestational-age birth, and stillbirth analyses showed no statistically significant differences. Preeclampsia and other sparse outcomes were not pooled. Certainty was very low for all key outcomes. [CONCLUSION] Current evidence does not demonstrate a clear or consistent increase in major congenital malformation risk, but very low certainty, imprecision, residual confounding, heterogeneous comparators, sparse agent-specific data, and uncertain exposure timing preclude conclusions of safety. Reported preeclampsia and renal or urinary signals have not been independently replicated.","url":"https://pubmed.ncbi.nlm.nih.gov/42964193/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:24+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"kidney\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1321,"doi":"10.1002/trc2.70336","pmid":"42959452","nct_ids":"[]","title":"Combined administration of buntanetap and dulaglutide counteracts synaptic dysfunction and memory loss in an Alzheimer's disease mouse model","authors":"[\"Acquarone E\", \"Gutierrez SBG\", \"Zhang H\", \"Morin A\", \"Maccecchini M\", \"Arancio O\"]","journal":"Alzheimer's & dementia (New York, N. Y.)","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Alzheimer's disease (AD) results from disruptions in proteostasis, metabolism, and neurotrophic signaling that impair synaptic plasticity and memory. Dulaglutide, a blood-brain barrier (BBB)-permeant glucagon-like peptide-1 (GLP-1) receptor agonist, enhances phosphoinositide 3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling, while buntanetap reduces translation of aggregation-prone proteins such as amyloid precursor protein (APP), tau, α-synuclein, and transactive response DNA-binding protein of 43 kDa. Although both compounds show cognitive benefits individually, their potential synergistic effects remain unexplored. [METHODS] APP/presenilin 1 (PS1) mice and wild-type (WT) littermates were treated with dulaglutide or buntanetap at high or subthreshold doses, alone or in combination, beginning at plaque deposition. Spatial memory was assessed through the 2-day radial arm water maze (RAWM), associative memory using contextual fear conditioning, and hippocampal Schaffer collateral-CA1 long-term potentiation (LTP) was evaluated as a measure of synaptic plasticity. Motor, sensory, motivational, and shock-sensitivity controls were included to rule out confounding non-cognitive effects. Meso Scale Discovery and Western blotting analyses were performed on frozen hippocampal tissue to assess amyloid beta (Aβ) and the postsynaptic density protein 95 (PSD95) marker levels. [RESULTS] High doses of either dulaglutide or buntanetap alone rescued deficits in spatial and contextual memory as well as LTP in APP/PS1 mice, whereas lower doses produced minimal or partial benefit. Concurrent administration of low, individually ineffective doses of buntanetap (1 mg/kg) and dulaglutide (0.1 mg/kg) fully rescued RAWM performance, restored contextual fear memory and CA1 LTP, reduced Aβ levels, and restored PSD95. The combination treatment did not alter behavior in WT mice across control behavioral tasks, confirming treatment specificity for AD-related deficits. [DISCUSSION] Our findings demonstrate a strong synergistic interaction between BBB-permeant dulaglutide and buntanetap at subthreshold doses, showing that combined enhancement of neurotrophic signaling and reduction of proteotoxic stress can rescue hippocampal dysfunction in early AD. This convergence between GLP-1 receptor-mediated pathways and inhibition of neurotoxic protein synthesis supports the clinical evaluation of GLP-1-based combination therapies with proteostatic modulators such as buntanetap.","url":"https://pubmed.ncbi.nlm.nih.gov/42959452/","source_name":"pubmed","source_tier":1,"coi_statement":"This research was funded by Annovis Bio. Maria Maccecchini (M.M.) serves as Chief Executive Officer of Annovis Bio. Erica Acquarone (E.A.), Maria Maccecchini (M.M.), and Ottavio Arancio (O.A.) are co‐inventors on patent application US2025/0025444A1. Alexander Morin (A.M.) is an employee of Annovis Bio. Steve B. Garcia Gutierrez (S.B.G.G.) and Hong Zhang (H.H.) declare no conflicts of interest. Author disclosures are available in the Supporting Information.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"preclinical_animal","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"cognition\", \"alzheimers\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1322,"doi":"10.3389/fphar.2026.1822158","pmid":"42959192","nct_ids":"[]","title":"Exploring the impact of GLP-1 analogues and DPP-4 inhibitors on cognitive decline in elderly patients with type 2 diabetes: a competing risks analysis from a real-world cohort","authors":"[\"Battini V\", \"Biganzoli G\", \"Di Pierro F\", \"Terlizzi AP\", \"Rizzi FV\", \"Ancona D\", \"Boracchi P\", \"Carnovale C\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Older adults with type 2 diabetes (T2DM) face an increased risk of cognitive decline. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective effects, comparative evidence versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in real-world older populations is limited. [METHODS] We conducted a retrospective cohort study using health administrative data, including individuals aged ≥65 initiating GLP-1RAs or DPP-4i therapy between 2010 and 2018. Patients with prior cognitive disorders were excluded. The primary outcome was a composite of incident cognitive disorders or death. Analyses were adjusted for clinical and demographic characteristics. Marginal structural models and competing risks methods were used to estimate treatment effects. Both an 'As treated' (AT) and an 'Intention to Treat' (ITT) designs were employed. [RESULTS] A total of 2,579 individuals were included (GLP-1RAs: 393; DPP-4i: 2,186), with a median follow-up of 44 months in the AT analysis. GLP-1RAs users had a lower risk of the composite outcome, especially in the early follow-up (HR at 2 years: 0.5 [95% CI: 0.26-0.93]). Competing-risk analysis showed a lower early risk of death without prior cognitive disorders among GLP-1RA initiators. The point estimate of sub-distribution HR was 0.4 also for cognitive disorders, yet not statistically significant because of the small number of events. [CONCLUSION] GLP-1RAs use was associated with a lower early risk of the composite outcome of cognitive disorders or death compared with DPP-4i in older adults with T2DM. The observed association with cognitive disorders alone was directionally consistent with a potentially lower risk, but the very small number of events precludes firm conclusions regarding a protective effect on cognitive outcomes. Longer follow-up and cognitive-specific evaluations are needed to confirm these associations.","url":"https://pubmed.ncbi.nlm.nih.gov/42959192/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:15:26+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cognition\", \"neuroinflammation\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1365,"doi":"10.2147/dmso.s637243","pmid":"42948670","nct_ids":"[]","title":"Pancreatic and Gallbladder Adverse Events Associated with Tirzepatide in Obesity Management: A Scoping Review","authors":"[\"Kutsyba T\", \"Raj S\", \"van der Berg M\"]","journal":"Diabetes, metabolic syndrome and obesity : targets and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is a chronic and relapsing condition that affects all demographics and results in comorbidities, rising healthcare costs, and social challenges. Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a promising therapy offering significant weight reduction. However, uncertainty remains regarding its pancreatic and gallbladder safety profile across different populations and evidence sources. [AIM] To systematically map existing evidence on the safety of tirzepatide in obesity management, with an emphasis on pancreatic- and gallbladder-related adverse events (AEs) across randomized controlled trials (RCTs), observational studies, case reports, and pharmacovigilance evidence. [METHODS] Following the methodological framework of Arksey and O'Malley (2005), expanded with Joanna Briggs Institute guidance, this scoping review included RCTs, observational studies, and post-marketing safety reports identified between December 2019 and September 2025. The searches were conducted across PubMed, EMBASE, the Cochrane Library, and the FDA Adverse Event Reporting System (FAERS), with additional evidence identified through gray literature, targeted journal searches, and published pharmacovigilance studies based on the EudraVigilance database. ClinicalTrials.gov was subsequently searched as an additional source to identify relevant clinical trials. Studies were eligible if they examined pancreatic or gallbladder AEs in the context of tirzepatide exposure among individuals with obesity. The review included 11 RCTs, 5 observational studies, 4 case reports, 1 EudraVigilance pharmacovigilance analysis, and 575 FAERS reports. Pancreatic and gallbladder AEs were systematically extracted and coded using MedDRA version 28.1, following the predetermined hierarchy. Findings were mapped descriptively across data sources without formal comparative statistical testing. [RESULTS] Pancreatic and gallbladder AEs were reported infrequently in RCTs. Pancreatitis was reported in 11 participants across five RCTs, with study-specific frequencies ranging from 0.2% (3 of 1,896) to 3.7% (1 of 27), while cholelithiasis was reported in 73 participants across 11 RCTs, with frequencies ranging from 0.3% (1 of 335 and 1 of 364) to 3.7% (1 of 27). Among observational studies, pancreatitis was reported in three studies, with proportions of 0.6% (63/10,002), 0.9% (1/110), and 2.1% (5,882/280,094). One retrospective cohort study reported an incidence rate of 3.84 events per 1,000 person-years among 9,193 participants, while cholelithiasis was reported at 11.89 events per 1,000 person-years in the same cohort. In the EudraVigilance pharmacovigilance analysis, pancreatitis represented 363 reported AEs (6.3% of all AEs and 19.4% of gastrointestinal AEs). In the FAERS database, pancreatitis accounted for 155/288 pancreatic-related reports [53.8%] and cholelithiasis for 143/249 gallbladder-related reports [57.4%]. Four case reports described six distinct AEs: edematous pancreatitis, acute pancreatitis, pancreatitis necrotizing, acalculous cholecystitis, gallstones, and gallbladder wall thickening, each reported once. Female participants, White participants, adults aged 18-64 years, and participants from the United States (US) predominated among reported demographic characteristics; however, demographic characteristics and comorbidity profiles were inconsistently reported and varied across studies. [CONCLUSION] Pancreatic and gallbladder AEs were reported across clinical trials, observational studies, case reports, and pharmacovigilance databases. RCTs generally reported low frequencies of pancreatobiliary AEs, whereas pharmacovigilance databases captured a broader spectrum of reported events. Variability in study populations, comorbidity profiles, reporting methods, and the absence of exposure denominators limited direct comparison across evidence sources. Vigilant monitoring and standardized AE reporting are needed to further characterize the pancreatobiliary safety profile of tirzepatide.","url":"https://pubmed.ncbi.nlm.nih.gov/42948670/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no competing interests. Tetiana Kutsyba is employed by Macleods Pharmaceuticals Ltd. The company had no role in the design, conduct, analysis, interpretation, writing, or publication of this study. The author reports no other conflicts of interest in relation to this work.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-11-01T12:35:50+00:00","study_design":"pharmacovigilance","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1435,"doi":"10.1177/20420188261490985","pmid":"42985179","nct_ids":"[]","title":"Associations of mortality and sepsis after GLP-1 receptor agonist initiation versus SGLT2 inhibitor or metformin initiation in people with HIV, overweight or obesity, and type 2 diabetes: A target trial emulation","authors":"[\"Huang YN\", \"Li PY\", \"Liu KW\", \"Li PH\", \"Chen SC\", \"Chen JC\", \"Meyerowitz-Katz G\", \"Huang JY\", \"Su PH\"]","journal":"Therapeutic advances in endocrinology and metabolism","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] People living with HIV (PLWH) with overweight or obesity and type 2 diabetes (T2D) carry elevated cardiometabolic and infectious morbidity. Comparative effectiveness data for glucagon-like peptide-1 receptor agonists (GLP-1 RAs)against active comparators are scarce in this population. [OBJECTIVES] To estimate associations between GLP-1 RA initiation andclinical outcomes compared withsodium-glucose cotransporter-2 inhibitors (SGLT2i) or metformin. [DESIGN] Target trial emulation of new-user, active-comparator cohorts in the TriNetX US Collaborative Network (2017 to 2025), with pre-specified replication in the Global Collaborative Network. [METHODS] Adults with HIV, overweight or obesity (ICD-10-CM E66 or body mass index 27 kg/m2 or higher), and T2D newly starting a GLP-1 RA, SGLT2i, or metformin after a 6-month washout were eligible. The primary endpoint was all-cause mortality within 3 years of the index date; secondary endpoints were A41.9-coded sepsis, candidiasis, major adverse cardiovascular events, major adverse kidney events, other or unspecified encephalopathy, and three nested exploratory code-based neurocognitive definitions (definitions 1, 1 to 2, and 1 to 3). We built 1:1 propensity score matched cohorts and fitted Cox models with Benjamini-Hochberg correction within each comparator stratum. [RESULTS] Analyses included 2,720 matched pairs vs SGLT2i and 4,604 vs metformin. GLP-1 RA initiation was associated with a lower estimated hazard of all-cause mortality during up to 3 years of follow-up vs SGLT2i (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49-0.81) and vs metformin (HR 0.65, 0.53-0.81). Kaplan-Meier estimated 3-year mortality risk was 6.7% versus 9.4% against SGLT2i and 5.4% versus 7.4% against metformin. A41.9-coded sepsis showed a lower hazard vs SGLT2i (HR 0.71, 0.53-0.94) and metformin (HR 0.75, 0.60-0.94). Cardiovascular and kidney composites differed less clearly, with renal outcomes directionally favoring SGLT2i. Code-based neurocognitive endpoints were lower vs metformin, but were exploratory and limited by administrative coding; reported significance reflects adjusted P values. [CONCLUSION] GLP-1 RA initiation was associated with a lower observed hazard of all-cause mortality and of A41.9-coded sepsis than SGLT2i or metformin in PLWH with overweight or obesity and T2D. These associations remainvulnerable to residual confounding and require prospective confirmation. Emulation is not equivalent to randomization.","url":"https://pubmed.ncbi.nlm.nih.gov/42985179/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Yu-Nan Huang, Pei-Yun Li, Kai-Wen Liu, Pin-Hung Li, Shao-Chia Chen, Jo-Ching Chen, Gideon Meyerowitz-Katz, Jing-Yang Huang, and Pen-Hua Su declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:09+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cognition\", \"mortality\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1472,"doi":"10.2147/dmso.s628886","pmid":"42997476","nct_ids":"[]","title":"SGLT-2 Inhibitors versus GLP-1 Receptor Agonists for Dementia and Depression in Type 2 Diabetes Mellitus: A Meta-Analysis","authors":"[\"Pan R\", \"Wang B\", \"Li Y\", \"Li H\", \"Liang X\", \"Zhang Y\", \"Liu X\", \"Huang X\", \"Wang R\", \"Ji H\", \"Zhao Y\"]","journal":"Diabetes, metabolic syndrome and obesity : targets and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia and depression risk in patients with type 2 diabetes mellitus (T2DM) remain unclear. We conducted a meta-analysis to directly compare the incidence of dementia and depression-related outcomes between users of these two drug classes. [METHODS] A systematic literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from inception to June 1, 2026. Observational studies reporting quantifiable data on dementia or depression-related events in adults with T2DM were included. Detailed information on study design, age, demographic characteristics, eligibility criteria, outcome definitions, and outcome incidence was extracted. Data were pooled using a random-effects model to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analyses involved sequential exclusion of individual studies. Prespecified subgroup analyses examined effect modifiers including geographic region, study design, age, and follow-up duration. Study quality was assessed using the Newcastle-Ottawa Scale, and the overall certainty of evidence and methodological rigor of this meta-analysis were evaluated using the AMSTAR 2 checklist. [RESULTS] Thirteen observational studies comprising 1,055,315 participants were included. Compared with GLP-1RA users, SGLT-2i users had lower rates of all-cause dementia (OR 0.85, 95% CI 0.77-0.94; P = 0.001), vascular dementia (OR 0.75, 95% CI 0.71-0.80; P < 0.001), Alzheimer's disease (OR 0.76, 95% CI 0.72-0.79; P < 0.001), and composite depression-related outcomes (OR 0.76, 95% CI 0.67-0.88; P = 0.001), including suicide/self-harm (OR 0.69, 95% CI 0.60-0.80; P < 0.001) and depression/anxiety (OR 0.78, 95% CI 0.65-0.93; P = 0.006). Subgroup analyses revealed more pronounced differences in Asian populations (dementia: OR 0.86, 95% CI 0.75-0.99; I2 = 0%), European cohorts (depression: OR 0.67, 95% CI 0.54-0.84; I2 = 83%), and in studies that enrolled younger adults (minimum age 18 years, without an upper age restriction) (dementia: OR 0.79, 95% CI 0.76-0.81; I2 = 0%; depression: OR 0.67, 95% CI 0.54-0.84; I2 = 83%). [CONCLUSIONS] In this meta-analysis of observational studies, SGLT-2i use was associated with lower rates of dementia and depression-related outcomes compared with GLP-1RA use in patients with T2DM. Age and geographic region may influence the observed associations. Future randomized controlled trials and studies reporting outcomes stratified by sex, socioeconomic status, and educational level are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/42997476/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that there are no conflicts of interest in this study.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:13+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"dementia\", \"alzheimers\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1476,"doi":"10.2147/dmso.s629991","pmid":"42974480","nct_ids":"[]","title":"Management of Obesity in Special Populations and Limited-Resource Settings: An Egyptian Medical Position Statement","authors":"[\"Hegazy MA\", \"Mattar A\", \"Shawky MM\", \"Soliman D\", \"Mowafy M\", \"NourEldin YM\", \"Noweir AM\", \"Aboulghate MK\", \"Elshazli M\", \"Hassaballa MA\", \"Abdelghaffar S\", \"Bahgat HM\", \"Sabry N\", \"Salah Eldin Taha H\", \"Shaltout I\", \"Yousry M\"]","journal":"Diabetes, metabolic syndrome and obesity : targets and therapy","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity/adiposity-based chronic disease is a chronic progressive relapsing disease linked to several comorbidities, with rising prevalence in Egypt. Limited local guidelines and healthcare challenges necessitate evidence-based, culturally adapted strategies. [METHODS] The Egyptian Medical Association for the Study of Obesity convened a clinical multidisciplinary panel to develop consensus recommendations. Evidence was synthesized from literature, prioritizing resource-limited settings and special situations. [RESULT] Assessment: Move beyond Body Mass Index to include waist circumference, waist/height ratio, body composition, and screening for obesity-related complications and diseases. Lifestyle Interventions: a-Nutrition: Mediterranean/dietary approach to stop hypertension diets, slow eating, and supervised fasting (eg Ramadan and Christian). b-Activity: Culturally tailored approaches (eg prayer-time movement and Arabic apps). c-Behavior: Cognitive-behavioral therapy and family-inclusive support. Pharmacotherapy: Use of approved agents (orlistat, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide) according to obesity-related complications and diseases and age group. Avoid GLP-1, GLP-1/GIP analogues in patients with medullary thyroid cancer, and all agents during pregnancy. Bariatric Surgery: Indicated for body mass index ≥40 kg/m2 (or ≥35 with obesity-related complications and diseases), with lifelong micronutrient supplementation. Special Populations: a-Adolescents: Focus on growth, not only weight-loss; consider pharmacotherapy in different age groups. b-Elderly: Prioritize muscle preservation; avoid weight loss unless obesity-related complications and diseases exist. c-Pregnancy: No weight loss; delay postpartum interventions until lactation is established. Policy Actions: Mandate food labeling, tax sugar-sweetened beverages, and integrate obesity services into primary healthcare. [CONCLUSION] These recommendations provide a pragmatic framework for obesity/adiposity-based chronic disease management in Egypt, emphasizing affordable, patient-centered care, and clinical multidisciplinary collaboration and policy support.","url":"https://pubmed.ncbi.nlm.nih.gov/42974480/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:13+00:00","study_design":"guideline","drugs":"[\"semaglutide\", \"liraglutide\", \"tirzepatide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cognition\", \"body_composition\", \"cancer\", \"nutrition\", \"endocrine\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1492,"doi":"10.3389/fphar.2026.1957757","pmid":"42997292","nct_ids":"[]","title":"The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments","authors":"[\"Huang S\", \"Feng Y\", \"Liu Y\", \"Mo X\", \"Hu H\", \"Chen H\", \"Han M\", \"Huang W\", \"Zheng W\", \"Hou X\", \"Wen R\", \"Liu C\", \"Wang J\", \"Wang Y\"]","journal":"Frontiers in pharmacology","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Emerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored. [METHODS] Data from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model. [RESULTS] Glucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10-17) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10-11) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = -0.12, P = 2.32 × 10-3). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity. [CONCLUSION] GLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.","url":"https://pubmed.ncbi.nlm.nih.gov/42997292/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:21+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1502,"doi":"10.2147/copd.s602087","pmid":"42979119","nct_ids":"[]","title":"Comparative Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors on Sepsis in Patients with Chronic Obstructive Pulmonary Disease: A Population-Based Cohort Study","authors":"[\"Wu TJ\", \"Chen CH\", \"Wu HC\", \"Wang YH\", \"Wang CY\", \"Lai CC\"]","journal":"International journal of chronic obstructive pulmonary disease","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Sepsis is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Antihyperglycemic agents may influence infection risk through distinct immunometabolic pathways. We compared glucagon-like peptide-1 receptor agonists (GLP-1RAs) with dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with COPD and type 2 diabetes mellitus (T2DM). [METHODS] This population-based, active-comparator, new-user cohort study used the TriNetX Global Network. Adults aged 40-100 years with COPD and T2DM who initiated a GLP-1RA or DPP-4i between 2007 and 2019 were included. Propensity score matching (1:1) adjusted for demographics, BMI, HbA1c, COPD severity proxies, comorbidities, and medications. The primary outcome was sepsis; secondary outcomes were pneumonia, severe sepsis, and all-cause mortality, assessed at 1, 3, 6, 12, and 24 months. [RESULTS] Before matching, 21,622 patients started a GLP-1RA and 67,259 a DPP-4i; after matching, 20,074 remained in each group with balanced characteristics (all standardized mean differences <0.10). Compared with DPP-4i users, GLP-1RA users had a significantly lower risk of sepsis at 1 year (hazard ratio [HR] 0.852; 95% confidence interval [CI] 0.770-0.942). The risks of secondary outcomes at 1 year were numerically lower in the GLP-1RA group, with statistically significant reductions in pneumonia (HR 0.729; 95% CI 0.671-0.792) and all-cause mortality (HR 0.656; 95% CI 0.587-0.732), while the association with severe sepsis did not reach statistical significance (HR 0.891; 95% CI 0.770-1.033). [CONCLUSION] In patients with COPD and T2DM, initiation of GLP-1RAs was associated with lower risks of sepsis, pneumonia, and all-cause mortality compared with DPP-4is. However, given the observational design, causality cannot be established and residual confounding remains a potential limitation. While these findings suggest potential benefits of GLP-1RAs beyond glycemic control, further confirmation through randomized controlled trials is warranted to guide clinical decision-making.","url":"https://pubmed.ncbi.nlm.nih.gov/42979119/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors report there are no competing interests to declare.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:15:26+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"immune\", \"mortality\", \"metabolic\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1523,"doi":"10.1136/bmjmed-2025-002150","pmid":"41877758","nct_ids":"[]","title":"Glucagon-like peptide 1 receptor agonist discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: target trial emulation","authors":"[\"Xie Y\", \"Choi T\", \"Al-Aly Z\"]","journal":"BMJ medicine","publication_date":"2026","year":2026,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVES] To characterise patterns of use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and assess the associations between various GLP-1RA treatment scenarios and the risk of major adverse cardiovascular events. [DESIGN] Target trial emulation. [SETTING] Electronic healthcare databases of US Department of Veterans Affairs, 1 January 2017 to 31 December 2023. Data obtained from domains in the Veterans Affairs Corporate Data Warehouse. [PARTICIPANTS] Veterans Affairs users with type 2 diabetes who started treatment with GLP-1RAs (n=132 551) or sulfonylureas (n=201 136), followed up for three years. Veterans Affairs users were defined as having at least two visits to Veterans Affairs and having used the Veterans Affairs outpatient pharmacy within a year before receiving treatment with GLP-1RAs or sulfonylureas. [INTERVENTIONS] GLP-1RAs or sulfonylureas. In the GLP-1RA arm, treatment status was reassigned every six months, generating 16 prespecified treatment strategies that varied in length of continued use, discontinuation, or interruption. [MAIN OUTCOME MEASURES] Three year cumulative incidence of major adverse cardiovascular events (myocardial infarction, stroke, or all cause death). [RESULTS] The cohort included 132 551 incident users of GLP-1RAs and 201 136 incident users of sulfonylureas (defined as no prescription for GLP-1RAs or sulfonylureas within a year of the first prescription). A duration dependent association was found between the use of GLP-1RAs and the cumulative three year risk of major adverse cardiovascular events. Compared with the sulfonylurea reference group, participants who used GLP-1RAs for 0.5, 1, or 1.5 years, before discontinuing for the remainder of the three years, showed incidence risk ratios close to 1.0, with no significant reduction in the risk of major adverse cardiovascular events at three years. Compared with the sulfonylurea group, the reduction in the risk of major adverse cardiovascular events was significant in people who continued to use GLP-1RAs for 2 and 2.5 years, before discontinuing for the remainder of the three years (incidence risk ratio 0.93, 95% confidence interval (CI) 0.88 to 0.98 and 0.85, 0.81 to 0.90, respectively). Participants who continued to use GLP-1RAs for the whole three year follow-up period had the most pronounced risk reduction (incidence risk ratio 0.82, 95% CI 0.78 to 0.85) compared with the sulfonylurea group. Compared with continued use of GLP-1RA, discontinuing treatment for 0.5 years was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio 1.04, 95% CI 1.01 to 1.08); the risk increased progressively with a longer duration of discontinuation, with an incidence risk ratio of 1.14 (1.09 to 1.18) and 1.22 (1.16 to 1.27) for one and two years of discontinuation, respectively. Compared with continued use of GLP-1RA, 0.5 years of interruption was associated with an increased risk of major adverse cardiovascular events; longer durations of interruption were progressively associated with a higher risk of major adverse cardiovascular events, with an incidence risk ratio of 1.12 (95% CI 1.06 to 1.19) and 1.16 (1.11 to 1.22) for one and two years of interrupted use, respectively. [CONCLUSIONS] The cardiovascular benefit of GLP-1RAs accumulated with continuous use, but even brief periods of discontinuations or interruptions might progressively erode and could ultimately reverse this protection, increasing the risk of cardiovascular events.","url":"https://pubmed.ncbi.nlm.nih.gov/41877758/","source_name":"pubmed","source_tier":1,"coi_statement":"All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the US Department of Veterans Affairs for the submitted work; ZA-A and YX report consulting (uncompensated) for Pfizer; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-11-11T20:25:44+00:00","study_design":"retrospective_cohort","drugs":"[\"glp-1 receptor agonists\"]","drug_details":"{\"treatment_duration\": \"varied by strategy: continued use for three years, use for 0.5, 1, 1.5, 2 or 2.5 years followed by permanent discontinuation, or use with interruptions; 16 prespecified strategies\", \"comparator\": \"sulfonylureas (primary estimand); for the continue-versus-stop comparison, people who discontinued or interrupted the GLP-1RA, against continued use (secondary estimand)\", \"dose\": \"various\", \"route\": \"various\"}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"three year cumulative incidence of major adverse cardiovascular events (myocardial infarction, stroke or all cause death)","endpoints":null,"effect_estimate":"Against sulfonylureas: continued GLP-1RA use for three years IRR 0.82; use for 2 or 2.5 years then stopping IRR 0.93 and 0.85; use for 0.5, 1 or 1.5 years then stopping close to 1.0, not significant; all who discontinued IRR 0.96 (0.92 to 1.01), not significant; interrupted then resumed IRR 0.88; any incident GLP-1RA use IRR 0.87. Against continued use: discontinuing for 0.5, one and two years IRR 1.04, 1.14 and 1.22; interruption for one and two years IRR 1.12 and 1.16.","confidence_interval":"95% CI 0.78 to 0.85 (three years of continued use vs sulfonylureas); 95% CI 1.01 to 1.08, 1.09 to 1.18 and 1.16 to 1.27 (0.5, one and two years of discontinuation vs continued use); 0.92 to 1.01 (all who discontinued vs sulfonylureas)","p_value":null,"sample_size":333687,"follow_up":"up to three years (overall median 3.00 years; 914 898 person years)","direction":"benefit","population":"{\"mean_age\": \"65.87 (SD 10.58) in the GLP-1RA group and 65.97 (SD 10.91) in the sulfonylurea group, after weighting\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"91.65% men (GLP-1RA group); 90.32% men (sulfonylurea group)\", \"bmi_mean\": \"35.43 (GLP-1RA group) and 35.31 (sulfonylurea group), after weighting\", \"bmi_min\": null, \"obesity_status\": \"mixed (not required; mean BMI 35.43; subgroups BMI ≤30, >30 and >35 analysed)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"mixed (not an entry criterion; for example heart failure 11.95% and stroke 3.48% in the GLP-1RA group)\", \"ckd_status\": \"eGFR <30, dialysis or kidney transplant excluded; mean eGFR 73.44 in the GLP-1RA group\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes, newly starting a GLP-1RA or a sulfonylurea\", \"sample_size\": 333687, \"inclusion_exclusion\": \"VA users (at least two VA visits and VA pharmacy use within a year) with type 2 diabetes who newly started a GLP-1RA or sulfonylurea in 2017 to 2023 without either drug in the prior year; excluded medullary thyroid carcinoma, MEN2, gastroparesis, eGFR <30, dialysis or transplant, severe hypoglycaemia, pancreatitis and pancreatic cancer\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and mean BMI was 35.43 in the GLP-1RA group; mean age 65.87 falls in the target range, but 91.65% were men and the BMI ≤30 subgroup does not separate normal weight.","mediation":"possibly","mediation_notes":"The study reports no on-treatment weight or HbA1c change and no mediation analysis. Baseline BMI and HbA1c were balanced by inverse probability weighting, which addresses confounding, not mediation. The authors suggest weight regain and loss of glycaemic and other cardiometabolic benefits after stopping as possible explanations but say this needs to be confirmed; similar results across BMI subgroups do not separate weight effects.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 333687, \"randomization\": \"no\", \"blinding\": \"n/a\", \"comparator\": \"sulfonylureas (primary estimand); for the continue-versus-stop comparison, people who discontinued or interrupted the GLP-1RA, against continued use (secondary estimand)\", \"follow_up_duration\": \"up to three years (overall median 3.00 years; 914 898 person years)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0.78 to 0.85 (three years of continued use vs sulfonylureas); 95% CI 1.01 to 1.08, 1.09 to 1.18 and 1.16 to 1.27 (0.5, one and two years of discontinuation vs continued use); 0.92 to 1.01 (all who discontinued vs sulfonylureas)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: one well-designed observational cohort (a target trial emulation in 132 551 GLP-1RA and 201 136 sulfonylurea starters with time-varying weighting, hard outcomes and many sensitivity analyses), capped at LOW for a single observational study under rule 2; residual confounding and the reasons people stopped cannot be ruled out, and the protocol was not pre-registered.","funding_source":"United States Department of Veterans Affairs","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"Authors declare support from the US Department of Veterans Affairs for the work; two authors (ZA-A and YX) report uncompensated consulting for Pfizer; no other relevant financial relationships.","sponsor_role":"The funder had no role in study design, data collection, analysis, interpretation, writing of the report or the decision to submit.","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported","limitations":"Observational emulation open to residual confounding and to misclassification from health-record and pharmacy-fill data, which are a proxy for drug taking; older, mostly male US veterans; drug class only, with no comparison of individual drugs, routes or indications; protocol not pre-registered. People who stop a drug may already differ in risk.","plain_summary":"This study used US Veterans Affairs health records for 132 551 adults with type 2 diabetes who started a GLP-1 receptor agonist and 201 136 who started a sulfonylurea, following them for up to three years. Against sulfonylureas, people who kept taking the GLP-1 drug for all three years had a lower risk of heart attack, stroke or death (risk ratio 0.82), while those who used it for 1.5 years or less and then stopped showed no significant reduction; compared with continuing, stopping for one or two years was linked to higher risk (1.14 and 1.22). That comparison is with people who stopped the drug, not with people who never took it, and because the study is observational these are associations: stopping may mark people already at higher risk. Participants were mostly older men with diabetes and a mean BMI of 35.43.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":59,"doi":"10.1056/nejmoa2505928","pmid":"41406444","nct_ids":"[\"NCT04255433\"]","title":"Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes","authors":"[\"Nicholls SJ\", \"Pavo I\", \"Bhatt DL\", \"Buse JB\", \"Del Prato S\", \"Kahn SE\", \"Lincoff AM\", \"McGuire DK\", \"Miller D\", \"Nauck MA\", \"Nishiyama H\", \"Nissen SE\", \"Sattar N\", \"Weerakkody G\", \"Wiese RJ\", \"Zinman B\", \"Zoungas S\", \"Basile J\", \"Davies MJ\", \"Giorgino F\", \"Kellerer M\", \"Ji L\", \"Varkonyi T\", \"Menon V\", \"Broder JC\", \"Herschtal A\", \"D'Alessio D\", \"SURPASS-CVOT Investigators\"]","journal":"The New England journal of medicine","publication_date":"2025-12-18","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. [METHODS] We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. [RESULTS] A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. [CONCLUSIONS] Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).","url":"https://pubmed.ncbi.nlm.nih.gov/41406444/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"tirzepatide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"tirzepatide up to 15 mg vs dulaglutide 1.5 mg weekly\", \"route\": \"subcutaneous\", \"comparator\": \"dulaglutide (active comparator)\", \"treatment_duration\": \"median exposure 47.6 months (tirzepatide) and 47.7 months (dulaglutide) (full text)\"}","domains":"[\"cardiovascular\", \"mortality\", \"body_composition\"]","outcome_type":"hard","primary_outcome":"CV death, MI or stroke (noninferiority margin 1.05)","endpoints":null,"effect_estimate":"HR 0.92 (12.2% vs 13.1%); noninferior; superiority not met","confidence_interval":"0.83 to 1.01 (95.3%)","p_value":"0.003 noninferiority; 0.09 superiority","sample_size":13165,"follow_up":"median 4.0 years (full text)","direction":"mixed","population":"{\"mean_age\": 64.1, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"29.0% female\", \"bmi_mean\": 32.6, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required (mean duration 14.7 years)\", \"cvd_status\": \"established ASCVD\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 13165, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Long-standing type 2 diabetes with atherosclerotic disease; mean age 64.","mediation":"unlikely","mediation_notes":"No mediation analysis: the abstract reports no weight change, and the main result was null on superiority (tirzepatide was noninferior to dulaglutide but not superior), so there is no effect for weight loss to explain.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 13165, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"dulaglutide (active comparator)\", \"follow_up_duration\": \"median 4.0 years (full text)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"1663 events\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large double-blind active-comparator outcome trial.","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"More GI adverse events with tirzepatide.","limitations":null,"plain_summary":"In 13,165 people with type 2 diabetes and atherosclerotic heart and blood-vessel disease, tirzepatide was shown to be no worse than dulaglutide at preventing heart attack, stroke or cardiovascular death (HR 0.92, 95.3% CI 0.83-1.01); it was not shown to be better (P=0.09). Gastrointestinal side effects were more common with tirzepatide. Weight change is not reported in the abstract.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":295,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-11-13","authors":"[\"Lupin Pharmaceuticals, Inc.\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2025-11-13","year":2025,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS WARNING: RISK OF THYROID C-CELL TUMORS Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide injection causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [ see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 ) ]. Liraglutide injection is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection [ see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) ]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide injection causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ) . • Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide injection. Discontinue if pancreatitis is suspected. ( 5.2 ) Never Share a liraglutide injection Pen Between Patients, even if the needle is changed. ( 5.3 ) Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide injection regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.4 ) A cute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) S evere Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide injection is not recommended in patients with severe gastroparesis. ( 5.6 ) Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide injection and promptly seek medical advice. ( 5.7 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide injection will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide injection have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide injection use in humans. Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions (6)] . After initiation of liraglutide injection, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue \n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. ( 6.1 ) Immunogenicity-related events, including urticaria, were more common among liraglutide injection-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide injection and a mean duration of exposure to liraglutide injection of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide injection than on placebo and occurred in at least 5% of patients treated with liraglutide injection. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1: Adverse reactions reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 Diabetes Mellitus Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions: In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide injection-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide injection (1.2 mg 4.4 %, 1.8 mg 4.2 %) th\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications: Liraglutide injection delays gastric emptying and may impact absorption of concomitantly administered oral medications. ( 7 ) 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Liraglutide injection is contraindicated in patients with a: personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection [see Warnings and Precautions ( 5.7 )]. Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. ( 4 ) Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0450d8a2-a88e-4849-9788-ed4f5246f223","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":41,"doi":"10.1016/s0140-6736(25)01375-3","pmid":"41138739","nct_ids":"[\"NCT03574597\"]","title":"Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial","authors":"[\"Deanfield J\", \"Lincoff AM\", \"Kahn SE\", \"Emerson SS\", \"Lingvay I\", \"Scirica BM\", \"Plutzky J\", \"Kushner RF\", \"Colhoun HM\", \"Hovingh GK\", \"Stensen S\", \"Weeke PE\", \"Jeppesen OK\", \"Bravo R\", \"Wu CC\", \"Komuro I\", \"Santini F\", \"Hjelmesæth J\", \"Urina-Triana M\", \"Buscemi S\", \"Ryan DH\"]","journal":"Lancet (London, England)","publication_date":"2025-11-08","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk. [METHODS] Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597. [FINDINGS] Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE-an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94-0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93-0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94-0·99]; p=0·007), but not bodyweight (0·99 [0·97-1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77-0·97] after adjustment for time-varying changes in waist circumference). [INTERPRETATION] The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction. [FUNDING] Novo Nordisk.","url":"https://pubmed.ncbi.nlm.nih.gov/41138739/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests JD declares having received consulting honoraria from Aegerion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda; and research grants from Aegerion, Alzheimer's Research UK, British Heart Foundation, Colgate, Medical Research Council (UK), MSD, National Institute for Health and Care Research, Pfizer, Public Health England, and Roche. AML declares having received consulting honoraria from Akebia, Alnylam, Amgen, Ardelyx, Becton Dickson, Brainstorm Cell, Eli Lilly, Endologix, Fibrogen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Novo Nordisk, Provention Bio, and ReCor; and research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, and Novartis. SEK declares having received consulting honoraria from Anji Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Oramed; and holds stock options from Altpep. SSE declares having received consulting honoraria from 89 Bio, Amylyx, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, BridgeBio, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, NSABP, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, SOLVD, Sutro Biopharma, and TG Therapeutics; and participation on a data monitoring or advisory board for 89 Bio, AstraZeneca, Bayer, BioAtla, Bristol Myers Squibb, Daiichi Sankyo, Denovo, Fore Therapeutics, and Immunome. IL declares having received research funding to their institution from Boehringer Ingelheim, Mylan, Novo Nordisk, and Sanofi; and advisory or consulting fees or other support from Altimmune, AstraZeneca, Bayer, Biomea, Boehringer Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen and J&J, MannKind, Mediflix, Merck, Metsera, Novo Nordisk, Pfizer, PharmaVentures, Regeneron, Sanofi, Shionogi, Structure Therapeutics, Target RWE, Terns Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. BMS declares having received institutional research grants to Brigham and Women's Hospital from Amgen, Better Therapeutics, Merck, Milestone Therapeutics, Novo Nordisk, and Pfizer; consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Better Therapeutics, Elsevier PracticeUpdate Cardiology, Esperion, Hanmi, Lexicon, and Novo Nordisk; and equity in health at Scale, Arboretum LifeSciences, and AIwithCare. JP declares having received consulting honoraria from Altimmune, Amgen, Boehringer Ingelheim, Corcept, Esperion Therapeutics, Merck, New Amsterdam, and Novo Nordisk; speakers' honoraria from Amgen, Boehringer Ingelheim, Corcept, Esperion Therapeutics, Merck, New Amsterdam, and Novo Nordisk; meeting and travel support from Amgen, Boehringer Ingelheim, Corcept, Esperion Therapeutics, Merck, New Amsterdam, and Novo Nordisk; grants from Boehringer Ingelheim and Novartis; and leadership or fiduciary roles in World Congress Insulin Resistance and Diabetes, Sarnoff Foundation, and cardiometabolic Alliance. RFK declares having received consulting honoraria from Altimmune, Antag, AstraZeneca, Boehringer Ingelheim, Currax, Eli Lilly, Novo Nordisk, Regeneron, Structure, and Weight Watchers. HMC declares serving on advisory panels for Bayer and Novo Nordisk; receiving research grants from Chief Scientist Office, Diabetes UK, European Commission, IQVIA, Juvenile Diabetes Research Foundation, and Medical Research Council; and holding stock options in Roche Pharmaceuticals. GKH, SS, PEW, OKJ, and RB are employees and stockholders of Novo Nordisk. C-CW declares institutional research grants from Amgen, Daiichi Sankyo, Gi Tai, MAC, MSD, Novo Nordisk, and Sanofi; speakers' honoraria from AstraZeneca, Chen-Hua, Daiichi Sankyo, Gi Tai, MAC, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, and Tanabe; and consulting honoraria from Daiichi Sankyo, MAC, Power-Biotech, Sanofi, and Tanabe. IK declares research grants from Daiichi Sankyo, Kowa Pharmaceutical, and Tanabe Mitsubishi Pharma Corporation; speakers' honoraria from AstraZeneca, Bayer, Kowa Pharmaceutical, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, and Tanabe Mitsubishi Pharma Corporation; and affiliation with endowed Chairs from BioStream, Idorsia Pharmaceuticals Japan, Nippon Boehringer Ingelheim, Novo Nordisk, Takara Bio, and Toa Eiyo. FS has worked as a consultant, participated in studies, or received travel funds from the following companies that are involved with obesity, lipodystrophy, and diabetes: Aegerion (Amryt), BioItalia, Boehringer Ingelheim, Bruno Pharma, Lilly, Novo Nordisk, and Pfizer. JH declares having received consulting honoraria from AstraZeneca, Eli Lilly, Novo Nordisk, and Vivus. MU-T declares having received consulting and research honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Frosst Laboratories, Johnson & Johnson, Menarini, Novartis, Novo Nordisk, Pfizer, Procaps, Sanofi-Aventis, Servier, and Tecnofarma. SB declares having received advisory or consulting honoraria from Boehringer Ingelheim, Dompè, Eli Lilly, Novo Nordisk, and Pfizer. DHR declares having received consulting honoraria from AbbVie, Altimmune, Amgen, AstraZeneca, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics (Roche), CinRx, Eli Lilly, eMedd, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Regeneron, Rhythm, Scientific Intake, Source Bio, Structure Therapeutics, Tenvie, Wondr Health, and Zealand Pharma; and stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"body_composition\", \"mortality\"]","outcome_type":"hard","primary_outcome":"Prespecified: MACE by baseline adiposity and by early adiposity change","endpoints":null,"effect_estimate":"Benefit consistent across baseline weight and waist categories; no linear trend between week-20 weight loss and later MACE; ~33% of benefit mediated via waist reduction (HR 0.86 after time-varying waist adjustment)","confidence_interval":null,"p_value":null,"sample_size":17604,"follow_up":"total follow-up not stated in the abstract; the analyses use adiposity change over the first 20 weeks (MACE after week 20) and over 104 weeks (all in-trial MACE)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 45.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"BMI >= 27 required\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"established CVD\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 17604, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"All BMI >= 27; consistency across BMI categories cannot be extrapolated below 27.","mediation":"specifically_tested","mediation_notes":"Cardioprotective effect independent of baseline adiposity and of weight loss; only a small association with waist reduction (about a third of benefit). Suggests mechanisms beyond adiposity reduction within an obese population.","adjusted_for":"[\"time-varying waist circumference\"]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 17604, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"total follow-up not stated in the abstract; the analyses use adiposity change over the first 20 weeks (MACE after week 20) and over 104 weeks (all in-trial MACE)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"Mediation: HR 0.86 (95% CI 0.77-0.97) after adjustment for time-varying waist circumference. Baseline-weight trend in the semaglutide group: HR 0.96 (95% CI 0.94-0.99) per 5 kg lower bodyweight.\", \"risk_of_bias\": \"prespecified but observational mediation analysis within RCT\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Prespecified analysis of a large RCT with a mediation model; supports but does not prove weight-independence.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk and other relationships; sponsor co-authors.","sponsor_role":"Sponsor analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"A prespecified SELECT analysis found the cardiovascular benefit of semaglutide was similar whatever the starting weight or waist size, and weight lost in the first 20 weeks did not track later risk; only about a third of the benefit was explained by waist reduction. On semaglutide, people with lower starting weight and waist had fewer events, and a shrinking waist was linked to lower risk. These are observational comparisons within the trial. Evidence that the benefit is not simply weight loss, within people who all had BMI 27 or higher.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":368,"doi":"10.1002/ejhf.70049","pmid":"41290376","nct_ids":"[]","title":"Effects of semaglutide in obesity-related heart failure with preserved ejection fraction across the age spectrum: Findings from the STEP-HFpEF programme","authors":"[\"Pandey A\", \"Moroney M\", \"Verma S\", \"Borlaug BA\", \"Butler J\", \"Davies MJ\", \"Kitzman DW\", \"Shah SJ\", \"Petrie MC\", \"Rönnbäck C\", \"Domdey A\", \"Rasmussen S\", \"Chinnakondepalli KM\", \"Patel S\", \"Kosiborod MN\"]","journal":"European journal of heart failure","publication_date":"2025-11","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age, and older adults with HFpEF have worse physical function, quality of life, and clinical outcomes. Semaglutide demonstrated efficacy in the treatment of obesity-related HFpEF in the STEP-HFpEF trials. Some have speculated that older patients may have less to gain from incretin therapies (and perhaps more to lose) than younger patients. [AIMS] In this pre-specified pooled subanalysis of the STEP-HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. [METHODS] The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF and randomized them to semaglutide 2.4 mg once weekly (n = 573) or placebo (n = 572) for 52 weeks. Dual primary outcomes (change in Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS] and change in body weight) and secondary outcome measures (6-minute walk distance [6MWD], C-reactive protein, hierarchical composite endpoint containing all-cause death, heart failure events, changes in KCCQ-CSS and 6MWD) were compared across specific age groups; <55 years, 55-64 years, 65-74 years and ≥75 years. [RESULTS] Among 1145 randomized participants, 8.8% (N = 101) were <55, 23.3% (N = 267) were aged between 55-64, 42.4% (N = 485) were between 65-74, and 25.5% (N = 292) were 75 years or over. The efficacy of semaglutide on the dual primary endpoints was consistent across the age spectrum, KCCQ-CSS (p-interaction = 0.80), and body weight (p-interaction = 0.41). Similar benefits were observed for the key secondary endpoints, with no treatment effect heterogeneity across age groups. Moreover, the safety of semaglutide was consistent across age groups. [CONCLUSION] In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.","url":"https://pubmed.ncbi.nlm.nih.gov/41290376/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":376,"doi":"10.1016/j.jchf.2025.102660","pmid":"41045908","nct_ids":"[\"NCT04916470\", \"NCT04788511\"]","title":"Semaglutide and Exercise Function in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program","authors":"[\"Borlaug BA\", \"Kitzman DW\", \"Patel S\", \"Chinnakondepalli KM\", \"Butler J\", \"Davies MJ\", \"Petrie MC\", \"Shah SJ\", \"Verma S\", \"Núñez J\", \"Einfeldt MN\", \"Liisberg K\", \"Salsali A\", \"Kosiborod MN\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"JACC. Heart failure","publication_date":"2025-11","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Exercise function quantified by 6-minute walk distance (6MWD) is severely impaired in patients with heart failure with preserved ejection fraction (HFpEF). [OBJECTIVES] This prespecified secondary analysis of pooled data from the STEP-HFpEF Program (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) examined factors associated with impaired exercise function at baseline, detailed effects of semaglutide on 6MWD, and on other key trial endpoints according to baseline 6MWD in patients with HFpEF. [METHODS] Associates of 6MWD were assessed at baseline, and effects of semaglutide on 6MWD were evaluated at early (20 weeks) and final (52 weeks) time points, across subgroups, and according to the magnitude of weight loss achieved. Effects of semaglutide on the dual primary (changes in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score [KCCQ-CSS] and body weight) and secondary/exploratory endpoints were contrasted by tertiles of baseline 6MWD. [RESULTS] The authors randomized 1,145 patients to semaglutide or placebo. Compared with patients who had obesity-related HFpEF and higher 6MWD, those with lower 6MWD were older and had lower KCCQ-CSS, higher body mass index and waist circumference, greater systemic inflammation (higher C-reactive protein), and more severe congestion (higher N-terminal pro-B-type natriuretic peptide, more diuretic use). Treatment with semaglutide increased 6MWD compared with placebo, an effect apparent at 20 weeks (treatment difference 14.6 m [95% CI: 8.6-20.7 m]; P < 0.0001) that was maintained at 52 weeks (treatment difference 17.1 m [95% CI: 9.2-25.0 m]; P < 0.0001). Increases in 6MWD with semaglutide (vs placebo) were similar across all relevant subgroups, with no significant interactions. Treatment with semaglutide increased KCCQ-CSS and reduced body weight, reduced C-reactive protein, improved the hierarchical composite (death, heart failure events, change in KCCQ-CSS and 6MWD), and reduced N-terminal pro-B-type natriuretic peptide across the spectrum of baseline 6MWD (all Pinteraction = NS). Each 1-unit decrease in body mass index on treatment with semaglutide was associated with a 4.1 m (95% CI: 2.4-5.7 m) increase in 6MWD (P < 0.0001). [CONCLUSIONS] In patients with obesity-related HFpEF, impaired 6MWD is most strongly associated with excess adiposity, congestion, and inflammation. Semaglutide-mediated improvements in HF-related symptoms, physical limitations, and exercise function were consistent across the spectrum of baseline 6MWD, observed as early as 20 weeks after the initiation of treatment, preceding maximal weight loss. The effects were consistent across subgroups. There was strong correlation between greater magnitude of weight loss and greater improvements in 6MWD. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF], NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM], NCT04916470).","url":"https://pubmed.ncbi.nlm.nih.gov/41045908/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures This trial was funded by Novo Nordisk A/S, Søborg, Denmark. Administrative support for manuscript development was funded by Novo Nordisk A/S. Dr Borlaug is supported in part by the National Institutes of Health (NIH) grants R01HL128526, R01HL162828, and U01HL160226, and by the U.S. Department of Defense grant W81XWH2210245; has received research support from the NIH and the United States Department of Defense; has received research grant funding from AstraZeneca, Axon Therapies, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (U.S. patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat HF. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Davies is supported by the Leicester National Institute for Health Research (NIHR) Biomedical Research Centre, Leicester General Hospital, Leicester, United Kingdom. Dr Petrie is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+). Dr Shah was supported by NIH grants U54HL160273, R01HL107577, R01HL127028, R01HL140731, and R01HL149423; has received research grants from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada, and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery; has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday, Foundry, G3P, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Davies has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; an advisory board member for AstraZeneca, Carmot/Roche, Medtronic, Pfizer, and Zealand Pharma; a speaker for Amgen and AstraZeneca; and has received grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr Patel was supported by the British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Drs Einfeldt, Liisberg, and Salsali are employees and shareholders of Novo Nordisk A/S. Dr Kitzman has received speaking honoraria and/or consulting fees from Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr. Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He has also received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":296,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-10-16","authors":"[\"Biocon Pharma Inc.\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2025-10-16","year":2025,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide injection causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )] . Liraglutide injection is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection [see Contraindications ( 4 ) , Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide injection causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined (5.1). • Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors (4, 5.1, 13.1).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide injection. Discontinue if pancreatitis is suspected. ( 5.2 ) Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.3 ) Hypoglycemia: Can occur in adults when liraglutide injection is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin. The risk may be lowered by a reduction in the dose of concomitantly administered insulin secretagogues or insulin. In the pediatric clinical trial, patients did not have type 2 diabetes. Hypoglycemia occurred in liraglutide injection-treated pediatric patients. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.4 ) Heart Rate Increase: Monitor heart rate at regular intervals. ( 5.5 ) Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.6 ) Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide injection is not recommended in patients with severe gastroparesis. ( 5.7 ) Hypersensitivity Reactions: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide injection and other suspect medications and promptly seek medical advice. ( 5.8 ) Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue liraglutide injection if symptoms develop. ( 5.9 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology (13.1) ] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide injection will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions (6) ] . After initiation of liraglutide, observe patients carefu\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-Cell Tumors [see Warnings and Precautions (5.1) ] Acute Pancreatitis [see Warnings and Precautions (5.2) ] Acute Gallbladder Disease [see Warnings and Precautions (5.3) ] Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions (5.4) ] Heart Rate Increase [see Warnings and Precautions (5.5) ] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.6) ] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.9) ] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] Most common adverse reactions, reported in greater than or equal to 5% are: nausea, diarrhea, constipation, vomiting, injection site reactions, headache, hypoglycemia, dyspepsia, fatigue, dizziness, abdominal pain, increased lipase, upper abdominal pain, pyrexia, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc. at 1-866-924-626 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Liraglutide was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or obese adult patients treated with liraglutide for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial) and one trial of 56 weeks in 125 pediatric patients with obesity aged 12 years and older [see Clinical Studies ( 14.1 , 14.2 )]. All patients received study drug in addition to a reduced-calorie diet and increased physical activity counseling. In the adult trials, patients received liraglutide for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% female, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m 2 , and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) [see Clinical Studies ( 14.1 )] were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received liraglutide for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In adult clinical trials, 9.8% of patients treated with liraglutide and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for liraglutide and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of liraglutide-treated adult patients and more frequently than in placebo-treated patients are shown in Table 2 . Adverse reactions reported in greater than or equal to 3% of liraglutide-treated pediatric patients and more frequently than in placebo-treated patients are shown in Table 3 . Table 2. Adverse Reactions Occurring in > 2% of Liraglutide-treated Adult Patients and More Frequently than Placebo Placebo N=1941 % Liraglutide N=3384 % Nausea 13.8 39.3 Diarrhea 9.9 20.9 Constipation 8.5 19.4 Vomiting 3.9 15.7 Injection Site Reaction 1 10.5 13.9 Headache 12.6 13.6 Hypoglycemia in T2DM 2 6.6 12.6 Dyspepsia 2.7 9.6 Fatigue 4.6 7.5 Dizzin\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Liraglutide injection delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution. ( 7 ) 7.1 Oral Medications Liraglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly administered with liraglutide.\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Liraglutide injection is contraindicated in: Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1) ]. Patients with a serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection [see Warnings and Precautions (5.7) ] . Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. ( 4 ) Hypersensitivity to liraglutide or any excipients in liraglutide injection. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0b898330-eca1-f60a-71d2-b91716e336ed","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"psychiatric\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":803,"doi":"10.1111/dom.16661","pmid":"40726454","nct_ids":"[]","title":"Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids","authors":"[\"Wen Y\", \"Lemen D\", \"Lin Y\", \"Chen YQ\", \"Regmi A\", \"Roell WC\", \"Thomas MK\", \"Hartman ML\", \"Coskun T\", \"Milicevic Z\", \"Haupt A\", \"Ruotolo G\", \"Konrad RJ\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2025-10","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8). [MATERIALS AND METHODS] In post-hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and metabolic parameters at baseline were analysed. Correlations of the changes in ANGPTL protein and complex levels versus the changes in lipid and metabolic parameters at study endpoints were also analysed. Direct effects of retatrutide itself, GIP, GLP-1, GCG and a GCG receptor (GCGR) antagonist antibody on ANGPTL3/8 secretion were studied in vitro using primary human hepatocytes. [RESULTS] ANGPTL3/8 reductions were observed with 8 and 12 mg retatrutide doses in participants with type 2 diabetes, and with 1, 4, 8 and 12 mg retatrutide doses in participants with obesity or overweight but without diabetes. In both cases, ANGPTL3/8 decreases paralleled retatrutide-induced reductions in TG and LDL-C. In primary human hepatocytes, both glucagon and retatrutide decreased ANGPTL3/8 secretion, and these reductions were blocked with the GCGR antagonist antibody. [CONCLUSIONS] Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels.","url":"https://pubmed.ncbi.nlm.nih.gov/40726454/","source_name":"pubmed","source_tier":1,"coi_statement":"All authors are employees and shareholders of Eli Lilly and Company.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:51:16+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"1, 4, 8 and 12 mg\"}","domains":"[\"metabolic\", \"gastrointestinal\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"mixed (one trial in type 2 diabetes, one without diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"Post-hoc biomarker analysis of two phase 2 human trials (people with type 2 diabetes, and people with obesity or overweight without diabetes) plus in-vitro human hepatocyte experiments; the outcomes are blood protein and lipid changes, not clinical outcomes.","mediation":"possibly","mediation_notes":"Human trial data: ANGPTL3/8 decreases paralleled reductions in triglycerides and LDL-C, and the abstract does not separate them from weight loss.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"VERY_INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Post-hoc biomarker analysis of two phase 2 human RCTs plus in-vitro hepatocyte work; exploratory, with no clinical outcomes, so low.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Eli Lilly, Lilly","author_conflicts":"All authors are employees and shareholders of Eli Lilly and Company.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":null,"plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels.","methodological_notes":"Post-hoc biomarker analysis of two randomized phase 2 retatrutide trials, plus in-vitro human hepatocyte experiments; not a randomized test of these outcomes.","reviewed_by":null,"reviewed_at":null},{"id":305,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Byetta (EXENATIDE) - label effective 2025-09-02","authors":"[\"AstraZeneca Pharmaceuticals LP\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2025-09-02","year":2025,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including BYETTA. Discontinue if pancreatitis is suspected. ( 5.1 ) • Never share a BYETTA pen between patients, even if the needle is changed. ( 5.2 ) • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.3 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion ( 5.4 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. BYETTA is not recommended in patients with severe gastroparesis. ( 5.5 ) • Immunogenicity: Patients may develop antibodies to exenatide. If there is worsening glycemic control or failure to achieve target glycemic control, consider alternative antidiabetic therapy. ( 5.6 ) • Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue BYETTA and promptly seek medical advice. ( 5.7 ) • Drug-induced Immune-mediated Thrombocytopenia: Serious bleeding which may be fatal has been reported. Discontinue BYETTA promptly and avoid re-exposure to exenatide. ( 5.8 ) • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.9 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 ) 5.1 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, including BYETTA [see Adverse Reactions (6.2) ] . After initiation of BYETTA, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue BYETTA and initiate appropriate management. 5.2 Never Share a BYETTA Pen Between Patients BYETTA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving BYETTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia including severe hypoglycemia [see Adverse Reactions (6) and Drug Interactions (7) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.4 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, BYETTA [see Adverse Reactions (6.2) ] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6) ] . Monitor renal function in patients reporting adverse reactions to BYETTA that could lead to volume depletion, especially during dosage initiation and escalation of BYETTA. BYETTA is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease and should be used with caution in patients with re\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Acute Pancreatitis [see Warnings and Precautions (5.1) ] • Never Share a BYETTA Pen Between Patients [see Warnings and Precautions (5.2) ] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3) ] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.4) ] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.5) ] • Immunogenicity [see Warnings and Precautions (5.6) ] • Hypersensitivity [see Warnings and Precautions (5.7) ] • Drug-Induced Thrombocytopenia [see Warnings and Precautions (5.8) ] • Acute Gallbladder Disease [see Warnings and Precautions (5.9) ] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10) ] • Most common (≥5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia, constipation, asthenia. Nausea usually decreases over time. ( 5.3 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypoglycemia Table 1 summarizes the incidence and rate of hypoglycemia with BYETTA in six placebo-controlled clinical trials. Table 1: Incidence (%) and Rate of Hypoglycemia when BYETTA was used as Monotherapy or with Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a documented blood glucose value <54 mg/dL or prompt recovery after treatment for hypoglycemia. Placebo BID BYETTA 5 mcg BID BYETTA 10 mcg BID Monotherapy (24 Weeks) N 77 77 78 % Overall 1.3% 5.2% 3.8% Rate (episodes/patient-year) 0.03 0.21 0.52 % Severe 0.0% 0.0% 0.0% With Metformin (30 Weeks) N 113 110 113 % Overall 5.3% 4.5% 5.3% Rate (episodes/patient-year) 0.12 0.13 0.12 % Severe 0.0% 0.0% 0.0% With a Sulfonylurea (30 Weeks) N 123 125 129 % Overall 3.3% 14.4% 35.7% Rate (episodes/patient-year) 0.07 0.64 1.61 % Severe 0.0% 0.0% 0.0% With Metformin and a Sulfonylurea (30 Weeks) N 247 245 241 % Overall 12.6% 19.2% 27.8% Rate (episodes/patient-year) 0.58 0.78 1.71 % Severe 0.0% 0.4% 0.0% With a Thiazolidinedione (16 Weeks) N 112 not evaluated 121 % Overall 7.1% not evaluated 10.7% Rate (episodes/patient-years) 0.56 not evaluated 0.98 % Severe 0.0% not evaluated 0.0% With Insulin Glargine with or without Metformin and/or Thiazolidinedione (30 Weeks) When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was decreased by 20% in patients with an HbA 1c ≤8.0% to minimize the risk of hypoglycemia. See Table 9 for insulin dose titration algorithm. N 122 not evaluated 137 % Overall 29.5% not evaluated 24.8% Rate (episodes/patient-years) 1.58 not evaluated 1.61 % Severe 0.8% not evaluated 0.0% N = number of Intent-to-Treat subjects in each treatment group. Immunogenicity Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, antibodies were assessed at 2- to 6-week intervals. The mean antibody titer peaked at Week 6 and was reduced by 55% by Week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks. Th\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS • May impact absorption of orally administered medications. ( 7 ) • Warfarin: Postmarketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy. ( 7 ) Generic Section Table 6: Clinically Relevant Interactions with BYETTA Concomitant Use of Insulin Secretagogues or Insulin Clinical Impact Exenatide promotes insulin release from pancreatic beta-cells in the presence of elevated glucose concentrations. The risk of hypoglycemia is increased when exenatide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin [see Warnings and Precautions (5.3) and Adverse Reactions (6) ] . Intervention When initiating BYETTA, consider reducing the dose of concomitantly administered insulin secretagogue or insulin to reduce the risk of hypoglycemia. Warfarin Clinical Impact In a drug interaction study, BYETTA did not have a significant effect on INR [see Clinical Pharmacology (12.3) ] . There have been postmarketing reports for BYETTA of increased INR with concomitant use of warfarin, sometimes associated with bleeding [see Adverse Reactions (6.2) ] . Intervention In patients taking warfarin, the prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, the prothrombin time can be monitored at the intervals recommended for patients taking warfarin. Orally Administered Drugs (e.g., acetaminophen) Clinical Impact Exenatide slows gastric emptying. Therefore, BYETTA has the potential to reduce the rate of absorption of orally administered drugs [see Clinical Pharmacology (12.3) ]. Intervention Use caution when administering oral medications with BYETTA where a slower rate of oral absorption may be clinically meaningful. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before BYETTA injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when BYETTA is not administered [see Clinical Pharmacology (12.3) ] .\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS BYETTA is contraindicated in patients with: • A prior severe hypersensitivity reaction to exenatide or to any of the excipients in BYETTA. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with BYETTA [see Warnings and Precautions (5.7) ]. • A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8) ] . • History of severe hypersensitivity to exenatide or any of the excipients in BYETTA. (4) • History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=53d03c03-ebf7-418d-88a8-533eabd2ee4f","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"regulatory","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"metabolic\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":387,"doi":"10.1111/acer.70110","pmid":"40630018","nct_ids":"[]","title":"Effect of the GLP-1 receptor agonist exenatide on pro-inflammatory and metabolic biomarkers in individuals with alcohol use disorder: Post hoc results from a randomized, double-blinded, placebo-controlled clinical trial","authors":"[\"Hviid MEB\", \"Christoffersen LAN\", \"Klausen MK\", \"Brodersen T\", \"Pedersen OB\", \"Ostrowski SR\", \"Larsen MH\", \"Kongstad M\", \"Jensen ME\", \"Vilsbøll T\", \"Fink-Jensen A\"]","journal":"Alcohol, clinical & experimental research","publication_date":"2025-08","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Alcohol use disorder (AUD) has been associated with inflammation, metabolic syndrome, and increased risk of all-cause mortality. This study aimed to compare the pro-inflammatory and metabolic biomarker profiles in individuals with AUD with individuals without AUD, and to evaluate the effect of exenatide on these biomarkers in individuals with AUD. [METHODS] Serum concentrations of 25 biomarkers (interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α], interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemoattractant protein-1 [MCP-1], C-peptide, gastric inhibitory polypeptide [GIP], glucagon-like peptide [GLP-1], glucagon, insulin, leptin, pancreatic polypeptide [PP], adiponectin, high sensitivity C-reactive protein [hsCRP], fibroblast growth factor 21 [FGF-21], total cholesterol [CHOL], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides [TG]) from individuals with AUD were measured at baseline and after 26 weeks of treatment with the GLP-1 receptor agonist (GLP-1RA) exenatide once-weekly or placebo, using multiplexed immunoassays, enzyme-linked immunosorbent assay (ELISA), and line immunoassays. Serum samples from 23 individuals with no record of AUD or treatment with a GLP-1RA were measured once for comparison with individuals with AUD. [RESULTS] IL-6 (1.56 vs. 0.62 pg/mL), hsCRP (3.30 vs. 1.34 mg/L), and FGF-21 (1794.97 vs. 306.11 pg/mL) were significantly higher, whereas GIP (63.06 vs. 111.07 pg/mL) was significantly lower in individuals with AUD (n = 124) than in those without AUD (n = 23). No significant changes in biomarker levels were observed after treatment with exenatide (n = 40) compared with treatment with placebo (n = 37). [CONCLUSION] Our findings support the well-established link between AUD and inflammation. However, treatment with the GLP-1 receptor agonist exenatide did not impact pro-inflammatory and metabolic biomarkers.","url":"https://pubmed.ncbi.nlm.nih.gov/40630018/","source_name":"pubmed","source_tier":1,"coi_statement":"TV has been part of speaker's bureaus, served on scientific advisory panels, served as a consultant to and/or received research support from Amgen, Boehringer Ingelheim, Eli Lilly, Gilead, AstraZeneca, Mundipharma, MSD/Merck, Novo Nordisk, and Sun Pharmaceuticals. AF‐J has received an unrestricted research grant from Novo Nordisk to investigate the effects of GLP‐1 receptor stimulation on metabolic disturbances in antipsychotic‐treated patients with a diagnosis of schizophrenia and serves on an advisory panel for Novo Nordisk (no honorarium).","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"addiction\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":796,"doi":"10.1016/s2213-8587(25)00092-0","pmid":"40609566","nct_ids":"[\"NCT04867785\"]","title":"Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial","authors":"[\"Coskun T\", \"Wu Q\", \"Schloot NC\", \"Haupt A\", \"Milicevic Z\", \"Khouli C\", \"Harris C\"]","journal":"The lancet. Diabetes & endocrinology","publication_date":"2025-08","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, has demonstrated robust glucose and bodyweight reductions in participants with type 2 diabetes. This substudy assessed percent change from baseline to week 36 in total body fat mass versus placebo and dulaglutide. [METHODS] This phase 2, double-blind, parallel-group, placebo-controlled, randomised controlled trial was done in 42 medical centres in the USA. Eligible participants were adults aged 18-75 years with type 2 diabetes, HbA1c of 7·0-10·5%, stable bodyweight, and BMI of 25-50 kg/m2. Eligible participants were randomly assigned in a 2:2:2:1:1:1:1:2 ratio to once-weekly subcutaneous placebo, dulaglutide 1·5 mg, or retatrutide 0·5 mg, 4 mg (2 mg initial dose), 4 mg (4 mg initial dose), 8 mg (2 mg initial dose), 8 mg (4 mg initial dose), or 12 mg. The prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass, as measured by dual-energy X-ray absorptiometry (DXA). Regression methods with on-treatment data before study drug discontinuation from all randomly assigned participants with non-missing DXA scans were included in efficacy analysis. All participants who received at least one dose of study drug were included in the safety analysis population. The completed trial is registered with ClinicalTrials.gov, NCT04867785. [FINDINGS] Between May 13, 2021 and June 13, 2022, 534 participants were screened for inclusion into the main study. 253 were excluded and 281 participants were enrolled and randomly assigned to the main study. Of the main study participants, 189 participants were enrolled to the body composition substudy (29 in the placebo group, 32 in the retatrutide 0·5 mg group, 31 in the retatrutide 4 mg groups [pooled], 33 in the retatrutide 8 mg group [pooled], 30 in the retatrutide 12 mg group, and 34 in the dulaglutide 1·5 mg group). Of these, 155 had a baseline DXA scan and 103 completed treatment and both baseline and week 36 DXA scans. 105 (56%) of 189 participants were female and 84 (44%) were male. 160 (85%) of 189 participants were White, 24 (13%) were Black, and five (3%) were Asian. Percent reduction from baseline in total fat mass was 4·9% (SE 1·4%) with retatrutide 0·5 mg, 15·2% (3·2%) with retatrutide 4 mg (pooled), 26·1% (2·5%) with retatrutide 8 mg (pooled), 23·2% (3·0%) with retatrutide 12 mg, 2·6% (1·6%) with dulaglutide, and 4·5% (1·2%) with placebo. Least squares mean change from baseline in total fat mass compared to placebo was -0·4 (95% CI -4·0 to 3·2, p=0·83 with retatrutide 0·5 mg, -10·7 (-17·2 to -4·2, p=0·0013) with retatrutide 4 mg (pooled), -21·6 (-27·1 to -16·1, p<0·0001) with retatrutide 8 mg (pooled), and -18·7 (-25·1 to -12·3, p<0·0001) with retatrutide 12 mg. Adverse events were similar between groups. Serious adverse events occurred in two (7%) of 29 participants in the placebo group, two (6%) of 32 participants in the retatrutide 0·5 mg group, zero of 31 participants in the retatrutide 4 mg group, three (9%) of 33 participants in the retatrutide 8 mg group, one (3%) of 30 participants in the retatrutide 12 mg group, and zero of 34 participants in the dulaglutide group. Gastrointestinal events were the most frequently reported adverse events, and no deaths were reported. [INTERPRETATION] In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared with placebo and dulaglutide. The proportion of lean mass loss to weight loss was similar to other obesity treatments. These findings could provide reassurance that a greater proportion of lean mass is not lost with retatrutide despite the overall increased weight loss. [FUNDING] The study was funded by Eli Lilly and Company.","url":"https://pubmed.ncbi.nlm.nih.gov/40609566/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests TC, QW, NCS, AH, ZM, CK, and CH are employees and shareholders of Eli Lilly and Company.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"dulaglutide\", \"retatrutide\"]","drug_details":"{\"dose\": \"0.5, 4, 8 or 12 mg once weekly (dulaglutide 1.5 mg arm)\", \"route\": \"subcutaneous\", \"comparator\": \"placebo; dulaglutide 1.5 mg\"}","domains":"[\"lean_mass\", \"body_composition\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":189,"follow_up":"36 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": \"18-75\", \"age_min\": 18.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 25.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 189, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes and obesity/overweight (age range 18-75; BMI ≥25 required).","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 189, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo; dulaglutide 1.5 mg\", \"follow_up_duration\": \"36 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -4·0 to 3·2, p=0·83 with retatrutide 0·5 mg, -10·7 (-17·2 t\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"The study was funded by Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly, Lilly","author_conflicts":"Declaration of interests TC, QW, NCS, AH, ZM, CK, and CH are employees and shareholders of Eli Lilly and Company.","sponsor_role":"manufacturer funded the study (sponsor role in design/analysis not stated in abstract)","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly, Eli Lilly","adverse_events":"Adverse events similar between groups; gastrointestinal events most frequent; no deaths.","limitations":null,"plain_summary":"In adults with type 2 diabetes, retatrutide 4, 8 and 12 mg reduced total body fat about 11 to 22 percentage points more than placebo over 36 weeks; the 0.5 mg dose did not differ from placebo. The abstract gives no lean-mass figures, so the authors' reassurance about lean mass cannot be checked here. Only 103 of the 189 substudy participants completed treatment with both body scans. Adverse events were similar between groups.","methodological_notes":"Sample size 189 is the number enrolled in the body-composition substudy; 155 had a baseline DXA scan and 103 completed treatment with both baseline and week-36 DXA scans.","reviewed_by":null,"reviewed_at":null},{"id":386,"doi":"10.1016/j.jacc.2025.04.059","pmid":"40701669","nct_ids":"[\"NCT04847557\"]","title":"Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial","authors":"[\"Borlaug BA\", \"Zile MR\", \"Kramer CM\", \"Ye W\", \"Ou Y\", \"Hurt K\", \"Murakami M\", \"Packer M\", \"SUMMIT Trial Study Group\"]","journal":"Journal of the American College of Cardiology","publication_date":"2025-07-29","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide 1 receptor agonist tirzepatide decreased the risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Effects may differ by baseline obesity severity, distribution, or magnitude of weight loss. [OBJECTIVES] In this analysis, the authors compared baseline characteristics and effects of tirzepatide on primary and other endpoints according to baseline obesity severity and distribution, and we explored relationships between degree of weight loss achieved and outcomes. [METHODS] In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein (CRP), and body weight (BW) at 52 weeks. In this secondary analysis, primary and secondary endpoints were analyzed based on obesity severity (BMI) and distribution (waist-height ratio [WHR]). Time-to-event endpoints were analyzed with the use of a Cox regression model, and continuous endpoints were assessed with the use of a mixed-effects model for repeated measures. Relationships between changes in BW and waist circumference (WC) on treatment with tirzepatide and changes in key endpoints also were evaluated. [RESULTS] Patients with obesity-related HFpEF and higher BMI were younger and more likely to be female, with more severe HF symptoms and physical limitations, greater volume expansion despite higher diuretic use and lower natriuretic peptide levels, and more severe systemic inflammation compared with patients with lower BMI. These findings were largely similar when contrasting patients by baseline WHR, but those with higher WHR also had poorer exercise capacity and more severe kidney disease. There was no evidence of heterogeneity in the effect of tirzepatide on the risk of worsening HF or cardiovascular death by BMI or WHR tertile. However, with increasing tertiles of baseline BMI, there were greater improvements in 6MWD (estimated treatment difference [ETD]: 9.9 vs 26.3 vs 37.5 m; P = 0.025), and greater decreases in BW (ETD: -10.7% vs -11.8% vs -14.4%; P = 0.006) and systolic blood pressure (ETD: -1.00 vs -6.65 vs -6.62 mm Hg; P = 0.035) with tirzepatide compared with placebo, with a trend for greater improvement in KCCQ-CSS (P = 0.097). Among those randomized to tirzepatide, greater weight loss at 52 weeks was associated with larger improvements in 6MWD, KCCQ-CSS, CRP, and blood pressure, and a greater decrease in WC was associated with larger increases in 6MWD and KCCQ-CSS. Patients with elevated WHR but lower BMI had higher NYHA functional class and N-terminal pro-B-type natriuretic peptide, poorer kidney function, and lower 6MWD compared with those with lower WHR but higher BMI. [CONCLUSIONS] Among patients with obesity-related HFpEF, greater BMI is associated with younger age, female sex, more volume overload and inflammation, and more severe HF, and those with greater WHR also showed greater impairment in kidney function and exercise capacity. Tirzepatide consistently reduced the risk of HF or cardiovascular death regardless of baseline BMI, but there was evidence suggesting greater improvement in 6MWD in those with higher BMI at baseline. Greater weight loss on treatment with tirzepatide was associated with greater improvements in 6MWD and KCCQ. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HfpEF] and Obesity [SUMMIT]; NCT04847557).","url":"https://pubmed.ncbi.nlm.nih.gov/40701669/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures The SUMMIT trial was funded by Eli Lilly and Company. Dr Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the National Heart, Lung, and Blood Institute and W81XWH2210245 from the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Zile has received research support from the Department of Veterans Affairs; and has served as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation Clinical Trials Center, CVRx, Diastol Therapeutics, EBR, Edwards, Lilly, GenKardia, Innoventric, KestraMedical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnova, Salubris Biotherapeutics, Sonata, Srnalytics, V-Wave, and Vectorious. Dr Kramer has served as a consultant for Eli Lilly. Drs Ye, Ou, Hurt, and Murakami are employees of Eli Lilly and Company. Dr Packer has served as a consultant for 89bio, Abbvie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, Armgo, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche, and Salamandra.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"kidney\", \"body_composition\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":385,"doi":"10.1186/s12958-025-01447-3","pmid":"40713699","nct_ids":"[]","title":"Effects of combined metformin and semaglutide therapy on body weight, metabolic parameters, and reproductive outcomes in overweight/obese women with polycystic ovary syndrome: a prospective, randomized, controlled, open-label clinical trial","authors":"[\"Chen H\", \"Lei X\", \"Yang Z\", \"Xu Y\", \"Liu D\", \"Wang C\", \"Du H\"]","journal":"Reproductive biology and endocrinology : RB&E","publication_date":"2025-07-26","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] This study aimed to assess the effects of metformin (MET) monotherapy versus a combination of semaglutide and MET on weight, metabolism, reproductive function, and inflammatory markers in women with polycystic ovary syndrome (PCOS). [METHODS] A total of 100 overweight or obese women with PCOS diagnosed according to the Rotterdam criteria were randomly assigned to two groups: MET (1000 mg twice daily [BID] for 16 weeks) and combination therapy (COM) (1000  mg MET BID plus 1- mg semaglutide once weekly [QW] for 16 weeks). Primary outcomes, assessed at Week 0 and Week 16, included changes in anthropometric measures related to obesity, while the secondary outcomes included alterations in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein (CRP) levels, Between Weeks 16 and 40, all participants received metformin monotherapy (1000 mg BID) to evaluate pregnancy outcomes. [RESULT] A total of 80 participants (80%) completed the study. After 16 weeks of intervention, the COM group exhibited significantly greater reductions in body weight, BMI, and waist-to-hip ratio (WHR) compared to the MET group (all P < 0.01). The COM group experienced an average weight loss of 6.09 ± 3.34 kg, while the MET group lost only 2.25 ± 4.27 kg. The COM group also demonstrated greater improvements in testosterone (TEST), Chinese visceral adiposity index (CVAI), and CRP levels compared to the MET group. Additionally, the COM group showed higher rates of menstrual cycle recovery than the MET group. From weeks 16 to 40, the COM group demonstrated a significantly higher natural pregnancy rate than the MET group (35% vs. 15%, P < 0.05). [CONCLUSION] Compared to MET monotherapy, combination therapy with semaglutide and MET significantly reduced body weight, improved insulin resistance, decreased inflammatory markers, alleviated and menstrual irregularities and increased natural pregnancy rates in overweight/obese women with PCOS. [CLINICAL TRIAL REGISTRATION] chictr.org.cn ID: ChiCTR2400090908 (Registration time: 2024-10-15).","url":"https://pubmed.ncbi.nlm.nih.gov/40713699/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: The study was approved by the hospital’s ethics committee of the Second Affiliated Hospital of Chongqing Medical University (Approval No. 2024204) and registered on Chinese Clinical Trial Registry (ChiCTR2400090908) in October 15, 2024. All participants received written and oral information and signed informed consent before any examination. Consent for publication: Not applicable. Disclaimers: Any opinions or recommendations discussed are solely those of the author(s). Source(s)of support: Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (2025MSXM106), the First batch of key Disciplines on Public Health in Chongqing, the National Natural Science Foundation of China (Grants 81501199 to C.W.), the Natural Science Foundation Project of Chongqing CSTC (cstc2017jcyjAX0016 to C.W. and CSTB2022NSCQ-MSX1008 to C.W.). Competing interests: The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":393,"doi":"10.1111/dom.16419","pmid":"40276845","nct_ids":"[]","title":"Liraglutide improves peripheral perfusion and markers of angiogenesis and inflammation in people with type 2 diabetes and peripheral artery disease: An 18-month follow-up of a randomized clinical trial","authors":"[\"Caruso P\", \"Maiorino MI\", \"Longo M\", \"Maio A\", \"Scappaticcio L\", \"Di Martino N\", \"Carbone C\", \"Barrasso M\", \"Caputo M\", \"Gicchino M\", \"Bellastella G\", \"Giugliano D\", \"Esposito K\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2025-07","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] In a six-month randomized clinical trial, improved peripheral perfusion has been shown with liraglutide, associated with favourable vascular effects in people with type 2 diabetes and peripheral artery disease (PAD). We aimed to evaluate the durability of these benefits and to elucidate some mechanisms underlying liraglutide's effect over an 18-month follow-up. [METHODS] STARDUST was a randomized clinical trial which compared liraglutide up to 1.8 mg/day with tailored therapeutic prescriptions to manage cardiovascular risk factors in 55 participants with type 2 diabetes and PAD. We report data of people who have reached the 18-month follow-up for the primary outcome (transcutaneous oxygen pressure, TcPO2) and also for additional secondary outcomes (markers of inflammation, angiogenesis and kidney function), as well as glycemic and metabolic parameters. TcPO2 was assessed with transcutaneous oximetry. Circulating levels of angiogenic progenitor cells and serum inflammation markers were evaluated by flow cytometry and enzyme-linked immunosorbent assay, respectively. [RESULTS] Compared with the control group, significant differences favouring the liraglutide group were observed at 18 months for TcPO2 [estimated treated difference (95% CI), 10.9 mmHg (7.6 to 14.1 mmHg), p < 0.001]. At 18 months of follow-up, participants in the liraglutide group, as compared with those in the control group, had a significant reduction in urine albumin to creatinine ratio (estimated difference, -103.9 mg/g Cr, 95%CI, -170.8 to -37.1, p = 0.003), C-reactive protein (-0.5 mg/dL, 95%CI, -0.8 to -0.2, p = 0.002), as well as interleukin-6 (-32.6 pg/mL, 95%CI, -54.6 to -10.5, p = 0.004). Compared with the control group, participants in the liraglutide group showed significantly higher concentrations of circulating progenitor cells and endothelial progenitor cells at both 6 and 18 months, for CD34+, CD133+, KDR+, CD34+/KDR+ and CD34+/CD133+/KDR+. Liraglutide was also associated with a higher increase in vascular endothelial growth factor A at 18 months (70.1 pg/mL, 95%CI, 44.7 to 95.4, p < 0.001). [CONCLUSIONS] In people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion, with amelioration of markers of angiogenesis and inflammation over an 18-month follow-up.","url":"https://pubmed.ncbi.nlm.nih.gov/40276845/","source_name":"pubmed","source_tier":1,"coi_statement":"DG received a consultancy fee from Eli Lilly and has given lectures from Eli Lilly, Sanofi, Novartis, Astrazeneca and Novo Nordisk. MIM has given lectures for Novo Nordisk, Eli Lilly, and Sanofi. KE received a consultancy fee from Eli Lilly and has given lectures from Eli Lilly, Sanofi, Novo Nordisk, Roche, Bayer and Lifescan. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":395,"doi":"10.1111/dom.16366","pmid":"40230207","nct_ids":"[]","title":"The effect of GLP-1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta-analysis","authors":"[\"Ren Y\", \"Chen Y\", \"Zheng W\", \"Kong W\", \"Liao Y\", \"Zhang J\", \"Wang M\", \"Zeng T\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2025-07","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To investigate whether the antidiabetic agent glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can exert anti-inflammatory effects while lowering blood glucose, we performed a meta-analysis and systematic review. [METHODS] We searched 4 online databases (Medline, Embase, Cochrane Library and the Web of Science) for randomised controlled trials (RCTs) that examined changes after GLP-1RAs intervention in commonly accepted biomarkers of inflammation: C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1(MCP-1) and advanced glycation end products (AGEs). [RESULTS] This meta-analysis included 52 eligible RCTs (n = 4734) with a median follow-up of 24 weeks, a mean age of 54.13 years, 44.46% females, body mass index (BMI) 29.80 kg/m2, glycated haemoglobin (HbA1c) 8.28% and diabetes duration 7.27 years. GLP-1 RAs treatment, compared to placebo or conventional diabetes therapies (including oral medicine and insulin), resulted in significant reductions in CRP, TNF-α, IL-6, IL-1β and leptin (standard mean difference [SMD] -0.63 [-1.03, -0.23]; SMD -0.92 [-1.57, -0.27]; SMD -0.76 [-1.32, -0.20], SMD -3.89 [-6.56, -1.22], SMD -0.67 [-1.09, -0.26], respectively), as well as significant increases in adiponectin (SMD 0.69 [0.19, 1.19]). [CONCLUSIONS] Our meta-analysis demonstrates that GLP-1 RAs exert significant anti-inflammatory effects in patients with T2DM. Our findings provide important insights that may guide the therapeutic application of GLP-1 RAs and inform the development of related therapies.","url":"https://pubmed.ncbi.nlm.nih.gov/40230207/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":389,"doi":"10.1186/s12933-025-02706-8","pmid":"40514652","nct_ids":"[]","title":"Interleukin-1β in circulating mononuclear cells predicts steatotic liver disease improvement after weight loss in subjects with obesity and prediabetes or type 2 diabetes","authors":"[\"Simeone PG\", \"Costantino S\", \"Liani R\", \"Tripaldi R\", \"Di Castelnuovo A\", \"Tartaro A\", \"Mengozzi A\", \"Cosentino F\", \"Cipollone F\", \"Consoli A\", \"Paneni F\", \"Santilli F\"]","journal":"Cardiovascular diabetology","publication_date":"2025-06-13","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cardiovascular risk (CV) factor. Interleukin-1β (IL-1β), a cytokine involved in the pathogenesis of obesity-associated inflammation and type 2 diabetes (T2D), promotes hepatic steatosis. The Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOS) trial showed that the inhibition of the IL-1β pathway was associated with a reduction of CV events in high-risk patients. The present study was designed to determine: (i) whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on MASLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; (ii) whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. [METHODS] Thirty-two obese subjects with prediabetes (n = 16) or newly diagnosed T2D (n = 16), were randomized to the glucagon-like peptide receptor agonist (GLP1-RA) liraglutide or lifestyle counselling until achieving a comparable weight loss. Visceral adipose tissue (VAT) and gene expression of IL-1β in peripheral blood mononuclear cells were assessed by magnetic resonance and real time PCR, respectively. [RESULTS] At baseline, IL-1β was positively correlated to body mass index (BMI), fasting plasma glucose, HbA1c, VAT, MASLD extent, platelet count, chemerin and interleukin-1 receptor antagonist (IL1-RA). After achievement of the weight loss target in the two groups, a significant but comparable reduction of IL-1β (p for difference = 0.56) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C reactive protein (CRP), BMI and MASLD. Furthermore, basal IL-1β levels independently predicted the extent of MASLD decrease (p = 0.030); subjects in the highest tertile showed a median decrease of - 8.0 (95% CI - 12.3 to - 4.8) compared with - 23.0 (95% CI - 39.5 to - 16.3) in the lowest tertile. [CONCLUSION] In patients with obesity with initial impairment of glucose metabolism successful weight loss is associated with a reduction of both IL-1β levels and MASLD degree. Of interest, basal levels of IL-1β predict the extent of MASLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a level as a drug-response biomarker.","url":"https://pubmed.ncbi.nlm.nih.gov/40514652/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethics approval and consent to participate: The trial was approved by the Italian Ethics Committee of the University of Chieti (Approval n. 10 (protocol 20131) 23.05.2013). Each patient provided written informed consent before participation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":390,"doi":"10.1186/s12933-025-02781-x","pmid":"40481478","nct_ids":"[\"NCT05051579\", \"NCT05048719\"]","title":"Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes","authors":"[\"Wharton S\", \"Rosenstock J\", \"Konige M\", \"Lin Y\", \"Duffin K\", \"Wilson J\", \"Banerjee H\", \"Pirro V\", \"Kazda C\", \"Mather K\"]","journal":"Cardiovascular diabetology","publication_date":"2025-06-06","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Orforglipron, a novel oral, non-peptide glucagon like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in improving body weight reduction and glycemic control. However, its potential benefits in improving cardiovascular (CV) risk factors have yet to be determined. We assessed the effect of orforglipron in participants with type 2 diabetes (T2D) and/or overweight or obesity on blood pressure, lipid, and inflammatory biomarkers associated with risk for major adverse cardiovascular events. [METHODS] Using data from participants with available samples from Phase 2 trials of orforglipron in participants with T2D (N = 361) or with overweight or obesity without diabetes mellitus (N = 234), we performed an exploratory analysis of changes in CV risk markers. For the T2D study, participants mean age 59 years, 40% were assigned female at birth with a mean HbA1c of 8.1% and mean BMI of 35.3 kg/m2; they received once daily orforglipron doses (3, 12, 24, 36, or 45 mg) or once weekly subcutaneous dulaglutide 1.5 mg, or placebo. In the obesity study, participants had a mean age 54 years, 60% were assigned female at birth, and mean BMI was 37.9 kg/m2; they received once daily orforglipron (12, 24, 36, or 45 mg) or placebo. The change from baseline at 26 weeks (T2D study) or 36 weeks (obesity study) in blood pressure, lipids (cholesterol, triglycerides, Apolipoprotein B (ApoB), Apolipoprotein C3 (ApoC3), N-terminal pro-b-type natriuretic peptide (NT-pro-BNP), and inflammatory biomarkers (high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6)) were assessed. [RESULTS] Significant placebo-adjusted decreases from baseline in blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, ApoB, ApoC3, and hsCRP were observed following orforglipron treatment in participants with T2D and/or overweight or obesity. In both studies, improvements in blood pressure, lipid parameters, and most of the evaluated biomarkers were of similar magnitude after treatment with 12 mg orforglipron as with 24, 36, and 45 mg. [CONCLUSION] Orforglipron treatment was associated with beneficial changes in CV risk markers in participants with T2D and in participants with overweight/obesity without T2D. (Clinicaltrials.gov: NCT05048719, NCT05051579).","url":"https://pubmed.ncbi.nlm.nih.gov/40481478/","source_name":"pubmed","source_tier":1,"coi_statement":"Declarations. Ethical approval and informed consent: The trials adhered to the principles of the Declaration of Helsinki and received approval from an independent ethics committee or institutional review board at each participating site. Participants provided informed consent for study participation. Conflict of interest: SW reports receiving grants from Novo Nordisk, speaking engagement fees from Bausch and Lomb, Eli Lilly and Company, Novo Nordisk, advisory board fees from Biohaven Pharmaceuticals, Inc., Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk; JR reports receiving grants from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceutical Co. Ltd, Intarcia, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi US Services Inc, travel support from applied therapeutics, Boehringer Ingelheim, Intarcia, Novo Nordisk, Oramed, Sanofi US Services Inc, serves on scientific advisory boards for applied therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Intarcia, Novo Nordisk, Oramed, Sanofi US Services Inc, Zealand, speaker fees honoraria from Boehringer Ingelheim, Novo Nordisk, Sanofi US Services Inc, and consulting fees for Hanmi Pharmaceutical Co. MK was an employee at Eli Lilly, during which she contributed to this article. MK is currently employed at Pfizer Inc. which provided no review of, or other support for, this article. KM, YL, KD, JW, HB, VP, and CK are employees and shareholders of Eli Lilly and Company.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"dulaglutide\", \"orforglipron\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":6,"doi":"10.1056/nejmoa2413258","pmid":"40305708","nct_ids":"[\"NCT04822181\"]","title":"Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis","authors":"[\"Sanyal AJ\", \"Newsome PN\", \"Kliers I\", \"Østergaard LH\", \"Long MT\", \"Kjær MS\", \"Cali AMG\", \"Bugianesi E\", \"Rinella ME\", \"Roden M\", \"Ratziu V\", \"ESSENCE Study Group\"]","journal":"The New England journal of medicine","publication_date":"2025-06-05","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). [METHODS] In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. [RESULTS] Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. [CONCLUSIONS] In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).","url":"https://pubmed.ncbi.nlm.nih.gov/40305708/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"72 weeks (interim of a 240-week trial)\", \"comparator\": \"placebo\"}","domains":"[\"liver\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"Resolution of steatohepatitis without worsening fibrosis; reduction in fibrosis without worsening steatohepatitis (histology at 72 weeks)","endpoints":null,"effect_estimate":"62.9% vs 34.3% (difference 28.7 pp); fibrosis 36.8% vs 22.4% (difference 14.4 pp); weight -10.5% vs -2.0%","confidence_interval":"21.1 to 36.2; 7.5 to 21.3","p_value":"<0.001","sample_size":800,"follow_up":"72 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not required; majority had obesity (full text)\", \"diabetes_status\": \"mixed (about half with T2D, full text)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"biopsy-proven MASH with fibrosis stage 2-3\", \"sample_size\": 800, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Participants had biopsy-proven MASH with significant fibrosis; most had obesity and many had diabetes. Histologic endpoints, not clinical outcomes.","mediation":"possibly","mediation_notes":"Weight loss (-10.5%) is itself an effective MASH treatment; the abstract does not separate drug and weight effects.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 800, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"72 weeks\", \"outcome_type\": \"histologic surrogate accepted by regulators\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 21.1 to 36.2; 7.5 to 21.3\", \"risk_of_bias\": \"interim analysis of ongoing trial\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large phase 3 RCT meeting both histologic primary endpoints; clinical-outcome part still ongoing.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"no","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"GI adverse events more common with semaglutide.","limitations":null,"plain_summary":"In a planned interim analysis of the first 800 of 1,197 people with MASH and moderate-to-advanced liver fibrosis, 72 weeks of semaglutide resolved steatohepatitis in 63% vs 34% on placebo and improved fibrosis in 37% vs 22%, judged by liver biopsy. Bodily pain scores did not differ between the groups, and gastrointestinal side effects were more common with semaglutide. Strong evidence of improved liver biopsy results in this liver disease (an interim result of an ongoing trial); effects on clinical outcomes are not yet reported. Unknown whether it applies to lean MASH or to people without liver disease.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":388,"doi":"10.7759/cureus.85250","pmid":"40605908","nct_ids":"[]","title":"Effect of Semaglutide Versus Placebo on Heart Failure With Preserved Ejection Fraction in Obese Patients: A Systematic Review","authors":"[\"Umaña Mejia CA\", \"Sañudo Soto CV\", \"Robalino J\", \"Hernández M\", \"Santos Bretón MB\", \"Garcia-Vasquez EA\", \"Rocha P\", \"Palacios Brambila LM\", \"Morales S\", \"Romo M\", \"Castillo JL\", \"Montelongo Quevedo M\", \"Flores Valdés JR\"]","journal":"Cureus","publication_date":"2025-06","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Heart failure (HF) is a major global health concern and can be classified into different phenotypes based on left ventricular ejection fraction (LVEF), including heart failure with preserved ejection fraction (HFpEF), reduced ejection fraction, and mildly reduced ejection fraction. This systematic review aims to determine the effect of semaglutide compared to placebo in obese patients with HFpEF. Following PRISMA 2020 guidelines, relevant studies published from January 2021 to August 2024 were identified through searches in PubMed and Science Direct. Randomized clinical trials (RCTs), cohort studies, and case-control studies were considered; however, only two randomized controlled trials (RCTs) and one retrospective cohort ultimately met the inclusion criteria, encompassing a total of 1463 participants with HFpEF and obesity. The risk of bias was evaluated utilizing the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale (NOS) for the retrospective cohort. In each study, participants were divided into two groups receiving either semaglutide or placebo. The findings after a 52-week follow-up showed that treatment with semaglutide 2.4 mg once weekly resulted in a significant reduction in biomarkers associated with HF. Specifically, baseline C-reactive protein (CRP) values decreased by 43% and 42% in the RCTs and 37% in the retrospective cohort. NT-proBNP levels declined by 20.90% and 23.20% in the RCTs and 15.80% in the cohort, compared to the placebo group. The reductions in CRP and NT-proBNP are clinically relevant, as elevated levels of these biomarkers are associated with worse outcomes in HFpEF. In addition, participants in the semaglutide group experienced a reduction in body weight ranging from 9% to 13% across the three studies, while those in the placebo group showed weight loss between 2% and 7% across the studies. Functional improvement was also observed, with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) increasing by 13 to 16 points in the semaglutide group compared to the placebo. These results suggest that semaglutide may be a promising treatment for HFpEF in obese patients, offering not only significant weight loss but also improvements in biomarkers and quality of life. Therefore, semaglutide appears to provide potential cardiovascular and metabolic benefits in addition to its established weight-reducing effects, although findings should be interpreted with caution given the limited number of included studies.","url":"https://pubmed.ncbi.nlm.nih.gov/40605908/","source_name":"pubmed","source_tier":1,"coi_statement":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1463,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": \"about 69-70 years across the included studies\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"mixed (one included RCT enrolled people with HFpEF and type 2 diabetes)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure with preserved ejection fraction\", \"sample_size\": 1463, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": 1463, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 4, 7; non-critical weaknesses on items 3, 6, 10, 14\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"No\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Partial Yes\", \"10\": \"No\", \"11\": \"Not applicable\", \"12\": \"Not applicable\", \"13\": \"Yes\", \"14\": \"No\", \"15\": \"Not applicable\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 7, \"Not applicable\": 3, \"Partial Yes\": 2, \"Yes\": 4}, \"settled_by_ruling\": [\"item 4: No (IN-058; the passes read Partial Yes and No)\", \"item 9: Partial Yes (IN-058; the passes read No information and Partial Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/40605908/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/40605908/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-02-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"Systematic review (no pooled meta-analysis) of two RCTs and one retrospective cohort; the authors caution that few studies were included.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Systematic review of three studies (two RCTs, one retrospective cohort; 1,463 people with obesity and HFpEF): over 52 weeks semaglutide lowered CRP and NT-proBNP (blood markers), body weight and symptoms compared with placebo. No cardiovascular event outcomes were reported, and the authors caution that few studies were included.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":35,"doi":"10.1056/nejmoa2501006","pmid":"40162642","nct_ids":"[\"NCT03914326\"]","title":"Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes","authors":"[\"McGuire DK\", \"Marx N\", \"Mulvagh SL\", \"Deanfield JE\", \"Inzucchi SE\", \"Pop-Busui R\", \"Mann JFE\", \"Emerson SS\", \"Poulter NR\", \"Engelmann MDM\", \"Ripa MS\", \"Hovingh GK\", \"Brown-Frandsen K\", \"Bain SC\", \"Cavender MA\", \"Gislum M\", \"David JP\", \"Buse JB\", \"SOUL Study Group\"]","journal":"The New England journal of medicine","publication_date":"2025-05-29","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk. An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed. [METHODS] In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care. The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome). [RESULTS] Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months. A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P = 0.006). The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively. [CONCLUSIONS] Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events. (Funded by Novo Nordisk; SOUL ClinicalTrials.gov number, NCT03914326.).","url":"https://pubmed.ncbi.nlm.nih.gov/40162642/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"oral, up to 14 mg daily\", \"route\": \"oral\", \"treatment_duration\": \"mean 47.5 months\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":"hard","primary_outcome":"MACE (CV death, nonfatal MI, nonfatal stroke)","endpoints":null,"effect_estimate":"HR 0.86 (12.0% vs 13.8%); kidney composite not significantly different","confidence_interval":"0.77 to 0.96","p_value":"0.006","sample_size":9650,"follow_up":"mean 47.5 months","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 50, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"ASCVD and/or CKD required\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"atherosclerotic cardiovascular disease, chronic kidney disease, or both\", \"sample_size\": 9650, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes with established vascular or kidney disease.","mediation":"possibly","mediation_notes":"All participants had type 2 diabetes with atherosclerotic cardiovascular disease and/or chronic kidney disease (obesity was not an entry criterion); the abstract does not separate direct drug effects from weight loss or glucose lowering.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 9650, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"mean 47.5 months\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.77 to 0.96\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet assessed).","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"Not reported in the abstract; full text not checked.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Serious adverse events 47.9% vs 50.3%; GI disorders 5.0% vs 4.4%.","limitations":null,"plain_summary":"Oral semaglutide reduced major cardiovascular events by 14% over four years in 9,650 people with type 2 diabetes and vascular or kidney disease; kidney outcomes were not significantly improved. Same diabetes-population caveat as other outcome trials.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":21,"doi":"10.1001/jamaneurol.2025.0353","pmid":"40193118","nct_ids":"[]","title":"GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias","authors":"[\"Tang H\", \"Donahoo WT\", \"DeKosky ST\", \"Lee YA\", \"Kotecha P\", \"Svensson M\", \"Bian J\", \"Guo J\"]","journal":"JAMA neurology","publication_date":"2025-05-01","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) and risk of Alzheimer disease and related dementias (ADRD) remains to be confirmed. [OBJECTIVE] To assess the risk of ADRD associated with GLP-1RAs and SGLT2is in people with type 2 diabetes (T2D). [DESIGN, SETTING, AND PARTICIPANTS] This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium from January 2014 to June 2023. Patients were 50 years or older with T2D and no prior diagnosis of ADRD or antidementia treatment. Among the 396 963 eligible patients with T2D, 33 858 were included in the GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 in the SGLT2i vs other GLD cohort, and 24 117 in the GLP-1RA vs SGLT2i cohort. [EXPOSURES] Initiation of treatment with a GLP-1RA, SGLT2i, or other second-line GLD. [MAIN OUTCOMES AND MEASURES] ADRD was identified using clinical diagnosis codes. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression models with inverse probability of treatment weighting (IPTW) to adjust for potential confounders. [RESULTS] This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], -2.26 per 1000 person-years [95% CI, -2.88 to -1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, -3.05 per 1000 person-years [95% CI, -3.68 to -2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of -0.09 per 1000 person-years (95% CI, -0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32). [CONCLUSION AND RELEVANCE] In people with T2D, both GLP-1RAs and SGLT2is were statistically significantly associated with decreased risk of ADRD compared with other GLDs, and no difference was observed between both drugs.","url":"https://pubmed.ncbi.nlm.nih.gov/40193118/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"other glucose-lowering drugs; SGLT2 inhibitors\"}","domains":"[\"dementia\", \"alzheimers\", \"cognition\"]","outcome_type":"hard","primary_outcome":"Alzheimer's disease and related dementias (diagnosis codes), target-trial emulation","endpoints":null,"effect_estimate":"GLP-1RA vs other GLD HR 0.67 (RD -2.26/1000 py); vs SGLT2i HR 0.97","confidence_interval":"0.47 to 0.96","p_value":null,"sample_size":33858,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": 65, \"age_range\": null, \"age_min\": 50, \"sex_distribution\": \"53.1% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes without prior Alzheimer's disease or related dementia\", \"sample_size\": 33858, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes aged 50+; mean age 65 matches the target age band but the metabolic condition does not.","mediation":"possibly","mediation_notes":"Not tested in the study. Our reading: because SGLT2 inhibitors were also linked to lower dementia rates (HR 0.57 vs other drugs, compared with 0.67 for GLP-1 drugs) and the two classes did not differ head-to-head (HR 0.97), the link may not be specific to GLP-1 drugs; shared glycaemic or vascular improvements are one possible explanation.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 33858, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"other glucose-lowering drugs; SGLT2 inhibitors\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"consistent with other EHR cohorts\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.47 to 0.96\", \"risk_of_bias\": \"confounding by indication; diagnostic-code outcome\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Well-designed emulation but observational with coded outcomes.","funding_source":"NIH (NIDDK)","industry_funded":"no","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"yes (other EHR cohorts)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Among Florida patients with type 2 diabetes aged 50+, starting a GLP-1 drug was associated with a third lower rate of dementia diagnoses than other diabetes drugs (HR 0.67), but no lower than SGLT2 inhibitors (HR 0.97). Our reading: because SGLT2 inhibitors were also linked to lower dementia rates (HR 0.57 vs other drugs), the link may not be specific to GLP-1 drugs. Observational.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":22,"doi":"10.1001/jamaneurol.2025.0360","pmid":"40193122","nct_ids":"[]","title":"Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis","authors":"[\"Seminer A\", \"Mulihano A\", \"O'Brien C\", \"Krewer F\", \"Costello M\", \"Judge C\", \"O'Donnell M\", \"Reddin C\"]","journal":"JAMA neurology","publication_date":"2025-05-01","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Although diabetes is a risk factor for dementia, the effect of glucose-lowering therapy for prevention of incident dementia is uncertain. [OBJECTIVE] To determine whether cardioprotective glucose-lowering therapy (sodium-glucose cotransporter-2 inhibitors [SGLT2is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], metformin, and pioglitazone), compared with controls, was associated with a reduction in risk of dementia or cognitive impairment, and among primary dementia subtypes. [DATA SOURCES] The PubMed and Embase databases were searched for studies published from inception of the database to July 11, 2024. [STUDY SELECTION] Randomized clinical trials comparing cardioprotective glucose-lowering therapy with controls that reported dementia or change in cognitive scores. Cardioprotective glucose-lowering therapies were defined as drug classes recommended by guidelines for reduction of cardiovascular events, based on evidence from phase III randomized clinical trials. Inclusion criteria were assessed independently and inconsistencies were resolved by consensus. [DATA EXTRACTION AND SYNTHESIS] Data were screened and extracted independently by 2 authors adhering to the PRISMA guidelines in August 2024. Random-effects meta-analysis models were used to estimate a pooled treatment effect. [MAIN OUTCOMES AND MEASURES] The primary outcome measure was dementia or cognitive impairment. The secondary outcomes were primary dementia subtypes, including vascular and Alzheimer dementia, and change in cognitive scores. [RESULTS] Twenty-six randomized clinical trials were eligible for inclusion (N = 164 531 participants), of which 23 trials (n = 160 191 participants) reported the incidence of dementia or cognitive impairment, including 12 trials evaluating SGLT2is, 10 trials evaluating GLP-1RAs, and 1 trial evaluating pioglitazone (no trials of metformin were identified). The mean (SD) age of trial participants was 64.4 (3.5) years and 57 470 (34.9%) were women. Overall, cardioprotective glucose-lowering therapy was not significantly associated with a reduction in cognitive impairment or dementia (odds ratio [OR], 0.83 [95% CI, 0.60-1.14]). Among drug classes, GLP-1RAs were associated with a statistically significant reduction in dementia (OR, 0.55 [95% CI, 0.35-0.86]), but not SGLT2is (OR, 1.20 [95% CI, 0.67-2.17]; P value for heterogeneity = .04). [CONCLUSIONS AND RELEVANCE] While cardioprotective glucose-lowering therapies were not associated with an overall reduction in all-cause dementia, this meta-analysis of randomized clinical trials found that glucose lowering with GLP-1RAs was associated with a statistically significant reduction in all-cause dementia.","url":"https://pubmed.ncbi.nlm.nih.gov/40193122/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"controls\"}","domains":"[\"dementia\", \"cognition\", \"cardiovascular\"]","outcome_type":"hard","primary_outcome":"Dementia or cognitive impairment reported in RCTs of cardioprotective glucose-lowering drugs","endpoints":null,"effect_estimate":"All classes OR 0.83 (NS); GLP-1RAs OR 0.55; SGLT2i OR 1.20","confidence_interval":"0.35 to 0.86 (GLP-1RA)","p_value":null,"sample_size":164531,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": 64.4, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"34.9% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes (most trials)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"participants in cardioprotective glucose-lowering trials (dementia was an outcome)\", \"sample_size\": 164531, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"RCTs in diabetes and cardiovascular populations; dementia was an adverse-event or secondary outcome, not a designed endpoint.","mediation":"possibly","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 164531, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"controls\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"10 GLP-1RA trials pooled\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.35 to 0.86 (GLP-1RA)\", \"risk_of_bias\": \"dementia not prespecified; ascertainment via adverse-event reporting; few events\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Meta-analysis of randomized trials; the overall result for all drug classes was null (OR 0.83, 0.60-1.14), and the reduction was seen only in the GLP-1 subgroup.","funding_source":"Not stated in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"not reported in abstract","independent_replication_exists":"no RCT designed for this outcome","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Pooling 26 randomized trials, diabetes drugs with heart benefits did not, as a group, significantly reduce dementia or cognitive impairment (OR 0.83, 95% CI 0.60-1.14), but the GLP-1 subgroup had lower odds of dementia (OR 0.55, 0.35-0.86); the SGLT2 inhibitor subgroup did not (OR 1.20, 0.67-2.17).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":394,"doi":"10.1097/crd.0000000000000915","pmid":"40243299","nct_ids":"[]","title":"Efficacy of Semaglutide and Other GLP-1 Agonists in Patients with Heart Failure With Preserved Ejection Fraction and Obesity: A Systemic Review and Meta-Analysis","authors":"[\"Beshr MS\", \"Shembesh RH\", \"Kara AO\", \"Salama AH\", \"Arhaym E\", \"Abuajamieh M\", \"Elhadi M\"]","journal":"Cardiology in review","publication_date":"2025-04-17","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Semaglutide, a novel drug, has shown potential benefits for heart failure with preserved ejection fraction (HFpEF) and obesity in early trials. This study aims to evaluate the efficacy and safety of semaglutide and other glucagon-like peptide-1 (GLP-1) agonists in HFpEF patients with obesity. A comprehensive electronic search was conducted on October 18, 2024, using PubMed, Scopus, Web of Science, Embase, and Cochrane. Eligible studies included those comparing semaglutide or other GLP-1 agonists to placebo in this patient population. Primary outcomes included changes in 6-minute walking distance, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), body weight, and secondary endpoints. Of 1116 studies, 4 met the inclusion criteria, comprising 2194 patients. GLP-1 agonists demonstrated a mean difference (MD) in 6-minute walking distance of 17.14 m [95% confidence interval (CI): 11.92-22.35, P < 0.001] and an MD in KCCQ-CSS of 7.3 (95% CI: 5.09-9.51, P < 0.001), indicating significant improvements in physical function and quality of life. Weight loss was substantial, with an MD of -7.19 kg (95% CI: -11.28 to -3.09, P = 0.001), alongside reduced inflammatory markers (C-reactive protein MD: -30.18, 95% CI: -38.16 to -22.2, P < 0.001). Hospitalizations or urgent care visits for heart failure were reduced (OR: 0.32, 95% CI: 0.15-0.66, P < 0.001). However, gastrointestinal adverse events leading to discontinuation were higher in the other GLP-1 agonists group (OR: 2.996, 95% CI: 1.683-5.331, P < 0.001). In HFpEF patients with obesity, GLP-1 agonists significantly improved symptoms, quality of life, physical function, and weight loss while reducing heart failure-related hospitalizations, though with increased gastrointestinal side effects.","url":"https://pubmed.ncbi.nlm.nih.gov/40243299/","source_name":"pubmed","source_tier":1,"coi_statement":"Disclosures: The authors have no conflicts of interest to report.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":23,"doi":"10.1001/jamapsychiatry.2024.4789","pmid":"39937469","nct_ids":"[\"NCT05520775\"]","title":"Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial","authors":"[\"Hendershot CS\", \"Bremmer MP\", \"Paladino MB\", \"Kostantinis G\", \"Gilmore TA\", \"Sullivan NR\", \"Tow AC\", \"Dermody SS\", \"Prince MA\", \"Jordan R\", \"McKee SA\", \"Fletcher PJ\", \"Claus ED\", \"Klein KR\"]","journal":"JAMA psychiatry","publication_date":"2025-04-01","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings. [OBJECTIVE] To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD). [DESIGN, SETTING, AND PARTICIPANTS] This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non-treatment-seeking participants with AUD were randomized. [INTERVENTION] Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits. [MAIN OUTCOMES AND MEASURES] The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits. [RESULTS] Forty-eight participants (34 [71%] female; mean [SD] age, 39.9 [10.6] years) were randomized. Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (β, -0.48; 95% CI, -0.85 to -0.11; P = .01) and peak breath alcohol concentration (β, -0.46; 95% CI, -0.87 to -0.06; P = .03). Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (β, -0.41; 95% CI, -0.73 to -0.09; P = .04) and weekly alcohol craving (β, -0.39; 95% CI, -0.73 to -0.06; P = .01), also predicting greater reductions in heavy drinking over time relative to placebo (β, 0.84; 95% CI, 0.71 to 0.99; P = .04). A significant treatment-by-time interaction indicated that semaglutide treatment predicted greater relative reductions in cigarettes per day in a subsample of individuals with current cigarette use (β, -0.10; 95% CI, -0.16 to -0.03; P = .005). [CONCLUSIONS AND RELEVANCE] These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate GLP-1RAs for alcohol use disorder. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT05520775.","url":"https://pubmed.ncbi.nlm.nih.gov/39937469/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":7,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"0.25 mg escalating to 1.0 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"9 weeks\", \"comparator\": \"placebo\"}","domains":"[\"addiction\", \"psychiatric\"]","outcome_type":"intermediate","primary_outcome":"Laboratory alcohol self-administration","endpoints":null,"effect_estimate":"Grams consumed beta -0.48; drinks per drinking day beta -0.41; craving beta -0.39; no effect on average drinks per calendar day or number of drinking days","confidence_interval":"-0.85 to -0.11","p_value":"0.01","sample_size":48,"follow_up":"9 weeks","direction":"benefit","population":"{\"mean_age\": 39.9, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"71% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract; full text not checked\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"alcohol use disorder, non-treatment-seeking\", \"sample_size\": 48, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Participants selected for alcohol use disorder, not weight; but young (mean 40), and the outcome is drinking behaviour.","mediation":"unlikely","mediation_notes":"Nine weeks at low doses; appetite/reward effects rather than weight loss are the proposed mechanism, though reduced intake generally could contribute.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 48, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"9 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"none yet\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"n=48; wide CIs\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small, short phase 2 trial with a laboratory primary outcome.","funding_source":"National Institute on Alcohol Abuse and Alcoholism; National Center for Advancing Translational Sciences (both NIH) (full text)","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"The funders had no role in the design, conduct, analysis or reporting of the study (full text)","independent_replication_exists":"no","conflict_notes":null,"adverse_events":"Not detailed in abstract.","limitations":null,"plain_summary":"In a 9-week trial of 48 adults with alcohol use disorder, low-dose semaglutide reduced how much they drank in a lab session, drinks per drinking day and craving, but did not change average drinks per calendar day or the number of drinking days. Promising but small and short; larger trials are needed.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":398,"doi":"10.1111/1753-0407.70082","pmid":"40207414","nct_ids":"[]","title":"Efficacy of GLP-1 Receptor Agonist-Based Therapies on Cardiovascular Events and Cardiometabolic Parameters in Obese Individuals Without Diabetes: A Meta-Analysis of Randomized Controlled Trials","authors":"[\"Yin Y\", \"Zhang M\", \"Cao Q\", \"Lin L\", \"Lu J\", \"Bi Y\", \"Chen Y\"]","journal":"Journal of diabetes","publication_date":"2025-04","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The cardioprotective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA)-based therapies in nondiabetic individuals with overweight or obesity remain underexplored. This meta-analysis evaluates their impact on cardiovascular events and metabolic parameters in this population. [METHODS] A meta-analysis was conducted using PubMed, Embase, Cochrane, and Web of Science databases from inception to June 18, 2024. Eligible studies were randomized controlled trials (RCTs) enrolling nondiabetic adults with overweight or obesity. These studies compared GLP-1RA-based therapies with placebo and reported cardiovascular events and metabolic parameters. [RESULTS] A total of 29 RCTs involving 9 GLP-1RA-based drugs and 37 348 eligible participants were included. Compared to placebo, GLP-1RA-based therapies significantly reduced the risk of total cardiovascular events (relative risk: 0.81, 95% confidence interval [CI]: [0.76, 0.87]), major adverse cardiovascular events (0.80, [0.72, 0.89]), myocardial infarction (0.72, [0.61, 0.85]), and all-cause mortality (0.81, [0.71, 0.93]). No significant differences were observed in cardiovascular death or stroke. Additionally, GLP-1RA-based therapies were associated with significant reductions in some cardiometabolic parameters. Among GLP-1RA-based therapies, orfroglipron demonstrated strong benefits in reducing systolic blood pressure (mean difference: -7.10 mmHg, 95% CI: [-11.00, -2.70]). Tirzepatide induced the greatest reduction in body mass index (-6.50 kg/m2, [-7.90, -5.10]) and hemoglobin A1c concentrations (-0.39%, [-0.52, -0.26]). Retatrutide and semaglutide were most effective in improving lipid profiles and reducing C-reactive protein levels (-1.20 mg/dL, [-1.80, -0.63]), respectively. [CONCLUSIONS] In nondiabetic individuals with overweight or obesity, GLP-1RA-based therapies significantly reduce cardiovascular events and improve cardiometabolic parameters. These findings underscore the potential for individualized GLP-1RA-based therapies targeting cardiovascular risk factors.","url":"https://pubmed.ncbi.nlm.nih.gov/40207414/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":37348,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"not an entry criterion (mixed; includes SELECT, which required established CVD)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 37348, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"Participants had overweight or obesity without diabetes; the abstract does not separate direct drug effects from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 37348, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI]: [0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 4, 7, 11, 13, 15; non-critical weaknesses on items 3, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"Yes\", \"15\": \"No\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 9, \"Partial Yes\": 1, \"Yes\": 6}, \"settled_by_ruling\": [\"item 3: No (IN-058; the passes read Yes and No)\", \"item 9: Yes (IN-058; the passes read Partial Yes and Yes)\", \"item 11: No (IN-058; the passes read No and Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/40207414/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/40207414/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-02-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"National Natural Science Foundation of China; Innovative Research Team of High Level Local Universities in Shanghai; Science and Technology Commission of Shanghai Municipality; Shanghai Municipal Health Commission; National Key Research and Development Program of China; Natural Science Foundation of Shanghai","industry_funded":"no","manufacturer":null,"author_conflicts":"The authors declare no conflicts of interest.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 29 trials of adults with overweight or obesity and no diabetes, GLP-1-based drugs lowered major cardiovascular events (RR 0.80), heart attacks (0.72) and all-cause death (0.81), but not cardiovascular death or stroke. They also improved some cardiometabolic measures such as blood pressure, BMI, lipids and C-reactive protein. Review rated critically low confidence (AMSTAR 2).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":400,"doi":"10.1093/ofid/ofaf152","pmid":"40160348","nct_ids":"[\"NCT04019197\"]","title":"The Effects of Semaglutide on Inflammation and Immune Activation in HIV-associated Lipohypertrophy","authors":"[\"Funderburg NT\", \"Ross Eckard A\", \"Wu Q\", \"Sattar A\", \"Ailstock K\", \"Cummings M\", \"Labbato D\", \"McComsey GA\"]","journal":"Open forum infectious diseases","publication_date":"2025-04","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Cardiovascular and metabolic comorbidities are common in people with HIV (PWH) and are linked to chronic inflammation and immune activation. We assessed the effects of semaglutide on plasma markers of immune activation/inflammation that are known to be increased in PWH and are associated with morbidity and mortality in this population. [METHODS] We conducted a single-site, randomized, double-blinded, placebo-controlled trial of virologically suppressed, nondiabetic PWH ≥18 years of age on stable antiretroviral therapy with body mass index ≥ 25 kg/m2, increased waist circumference/waist-to-hip ratio, and subjective increased abdominal girth after antiretroviral therapy initiation (clinicaltrials.gov: NCT04019197). Participants were randomized 1:1 to 32 weeks of semaglutide (8-week titration + 24 weeks of 1.0 mg weekly subcutaneous injection) or matching placebo. Signed-rank tests were used to determine changes over 32 weeks in soluble markers and cellular phenotypes of inflammation/immune activation within groups; semaglutide effects were assessed using linear or quantile regression analyses. [RESULTS] A total of 108 participants were enrolled and evenly randomized to semaglutide versus placebo. Eight (15%) in each group withdrew prematurely. Thirty-two weeks of semaglutide treatment reduced baseline levels of C-reactive protein, interleukin-6, and soluble CD163 (all P < .02) and trended to reduce levels of sCD14 (P = .08). Circulating monocyte proportions and T-cell phenotypes were not altered by semaglutide. [CONCLUSIONS] In this randomized controlled trial of semaglutide in PWH, we report significant decreases in markers of inflammation that are associated with morbidity and mortality in this population. These results add to the growing literature demonstrating the anti-inflammatory effects of semaglutide. Further studies in PWH are warranted.","url":"https://pubmed.ncbi.nlm.nih.gov/40160348/","source_name":"pubmed","source_tier":1,"coi_statement":"Potential conflicts of interests. N.F. has received research funding from Gilead unrelated to this project. G.A.M. served as a consultant for Merck, Gilead, and ViiV/GSK. A.R.E. served as an advisor for Gilead Sciences and Theratechnologies. All other authors report no potential conflicts.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"immune\", \"mortality\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":20,"doi":"10.1038/s41591-024-03412-w","pmid":"39833406","nct_ids":"[]","title":"Mapping the effectiveness and risks of GLP-1 receptor agonists","authors":"[\"Xie Y\", \"Choi T\", \"Al-Aly Z\"]","journal":"Nature medicine","publication_date":"2025-03","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.","url":"https://pubmed.ncbi.nlm.nih.gov/39833406/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: Y.X. and Z.A.A. are uncompensated consultants for Pfizer. No other potential competing interests relevant to this article are reported.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T13:04:18+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"sulfonylureas, DPP-4i, SGLT2i, and usual care\"}","domains":"[\"adverse_effects\", \"addiction\", \"psychiatric\", \"dementia\", \"cardiovascular\", \"gastrointestinal\", \"kidney\", \"rheumatologic\", \"immune\"]","outcome_type":"hard","primary_outcome":"Discovery atlas of 175 outcomes (VA cohort of people with diabetes)","endpoints":null,"effect_estimate":"Reduced: substance use, psychotic disorders, seizures, neurocognitive disorders, cardiometabolic, infections, respiratory. Increased: GI disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, drug-induced pancreatitis (vs usual care)","confidence_interval":null,"p_value":null,"sample_size":215970,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"predominantly male (VA)\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"diabetes (all; US veterans)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"diabetes\", \"sample_size\": 215970, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Veterans with diabetes, mostly older men; useful hypothesis atlas for both benefits and harms, not causal evidence.","mediation":"unknown","mediation_notes":"Discovery-approach cohort; no mediation analysis.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 215970, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"sulfonylureas, DPP-4i, SGLT2i, and usual care\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"single cohort\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"confounding by indication and healthy-adherer bias; multiple comparisons\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large systematic observational screen; hypothesis-generating across all outcomes.","funding_source":"US Department of Veterans Affairs (full text, not checked)","industry_funded":"no","manufacturer":"Pfizer","author_conflicts":"Authors are uncompensated consultants for Pfizer.","sponsor_role":"not reported in abstract","independent_replication_exists":"partial for individual outcomes","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A systematic scan of 175 outcomes in 215,970 US veterans with diabetes starting GLP-1 drugs found lower rates of many conditions (including substance use and dementia) and higher rates of gastrointestinal problems, low blood pressure, fainting, joint disorders, kidney stones and pancreatitis. Observational; useful for generating hypotheses in both directions.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":8,"doi":"10.1016/s0140-6736(24)02808-3","pmid":"39919773","nct_ids":"[\"NCT04232969\"]","title":"Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial","authors":"[\"Vijiaratnam N\", \"Girges C\", \"Auld G\", \"McComish R\", \"King A\", \"Skene SS\", \"Hibbert S\", \"Wong A\", \"Melander S\", \"Gibson R\", \"Matthews H\", \"Dickson J\", \"Carroll C\", \"Patrick A\", \"Inches J\", \"Silverdale M\", \"Blackledge B\", \"Whiston J\", \"Hu M\", \"Welch J\", \"Duncan G\", \"Power K\", \"Gallen S\", \"Kerr J\", \"Chaudhuri KR\", \"Batzu L\", \"Rota S\", \"Jabbari E\", \"Morris H\", \"Limousin P\", \"Greig N\", \"Li Y\", \"Libri V\", \"Gandhi S\", \"Athauda D\", \"Chowdhury K\", \"Foltynie T\"]","journal":"Lancet (London, England)","publication_date":"2025-02-22","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] GLP-1 receptor agonists have neurotrophic properties in in-vitro and in-vivo models of Parkinson's disease and results of epidemiological studies and small randomised trials have suggested possible benefits for risk and progression of Parkinson's disease. We aimed to establish whether the GLP-1 receptor agonist, exenatide, could slow the rate of progression of Parkinson's disease. [METHODS] We did a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial at six research hospitals in the UK. Participants were aged 25-80 years with a diagnosis of Parkinson's disease, were at Hoehn and Yahr stage 2·5 or less when on dopaminergic treatment, and were on dopaminergic treatment for at least 4 weeks before enrolment. Participants were randomly assigned (1:1) using a web-based system with minimisation according to Hoehn and Yahr stage and study site to receive extended-release exenatide 2 mg by subcutaneous pen injection once per week over 96 weeks, or visually identical placebo. All participants and all research team members at study sites were masked to randomisation allocation. The primary outcome was the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, off dopaminergic medication at 96 weeks, analysed in the intention-to-treat population using a linear mixed modelling approach. This study is registered with ISRCTN (14552789), EudraCT (2018-003028-35), and ClinicalTrials.gov (NCT04232969). [FINDINGS] Between Jan 23, 2020, and April 23, 2022, 215 participants were screened for eligibility, of whom 194 were randomly assigned to exenatide (n=97) or placebo (n=97). 56 (29%) participants were female and 138 (71%) were male. 92 participants in the exenatide group and 96 in the placebo group had at least one follow-up visit and were included in analyses. At 96 weeks, MDS-UPDRS III OFF-medication scores had increased (worsened) by a mean of 5·7 points (SD 11·2) in the exenatide group, and by 4·5 points (SD 11·4) points in the placebo group (adjusted coefficient for the effect of exenatide 0·92 [95% CI -1·56 to 3·39]; p=0·47). Nine (9%) participants in the exenatide group had at least one serious adverse event compared with 11 (11%) in the placebo group. [INTERPRETATION] Our findings suggest that exenatide is safe and well tolerated. We found no evidence to support exenatide as a disease-modifying treatment for people with Parkinson's disease. Studies with agents that show better target engagement or in specific subgroups of patients are needed to establish whether there is any support for the use of GLP-1 receptor agonists for Parkinson's disease. [FUNDING] National Institute for Health and Care Research and Cure Parkinson's.","url":"https://pubmed.ncbi.nlm.nih.gov/39919773/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests TF has received grants from the National Institute of Health Research, Edmond J Safra Foundation, Michael J Fox Foundation, John Black Charitable Foundation, Cure Parkinson's, Innovate UK, Janet Owens Research Fellowship, Rosetrees Trust, Van Andel Research Institute, and Defeat MSA; has served on advisory boards for Peptron, Voyager Therapeutics, Handl Therapeutics, Gain Therapeutics, Living Cell Technologies, AbbVie, Bluerock, Bayer, and Bial; and has received honoraria for talks sponsored by Bayer, Bial, Profile Pharma, Boston Scientific, and Novo Nordisk. CC has received advisory, consulting, or lecture fees from AbbVie, Bial, Britannia, Scient, Global Kinetics, Kyowa Kirin, Medscape, Mission Therapeutics, MODAG, and Roche, and research funding from Parkinson's UK, Edmond J Safra Foundation, National Institute of Health and Care Research, and Cure Parkinson's. MS has received grants from Parkinson's UK, Michael J Fox Foundation, and Medical Research Council; and has received honoraria for lecturing and consulting from Bial and Medtronic. DA has received grant funding from Cure Parkinson's, the National Institute for Health Research, and Medical Research Council Clinical Academic Research Partnership. EJ has received grant funding from Progressive Supranuclear Palsy Association, Cure Progressive Supranuclear Palsy, and Medical Research Council. GD has received honoraria for talks sponsored by GE Healthcare and AbbVie and support from Bial. JD has received consulting fees from Clario. HMo has received funding from Michael J Fox Foundation, Cure Parkinson's, Progressive Supranuclear Palsy Association, Corticobasal Degeneration Solutions, Drake Foundation, Parkinson's UK, and the Medical Research Council; has received consulting fees from Roche, Amylyx, and Aprinoia; and has received honoraria for speaking at meetings supported by Kyowa Kirin, The British Medical Journal, and Movement Disorders Society. All other authors declare no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"2 mg extended-release once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"96 weeks\", \"comparator\": \"placebo\"}","domains":"[\"parkinsons\", \"neuroinflammation\", \"cognition\"]","outcome_type":"intermediate","primary_outcome":"MDS-UPDRS part III off-medication at 96 weeks","endpoints":null,"effect_estimate":"Adjusted difference 0.92 points (worse with exenatide; not significant)","confidence_interval":"-1.56 to 3.39","p_value":"0.47","sample_size":194,"follow_up":"96 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": \"25-80\", \"age_min\": 25.0, \"sex_distribution\": \"29% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not an entry criterion (not selected for weight)\", \"diabetes_status\": \"not an entry criterion\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Parkinson's disease, Hoehn and Yahr <= 2.5 on treatment\", \"sample_size\": 194, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Participants were selected for Parkinson's disease, not for obesity or diabetes, and were mostly older adults; so the population is closer to the target than metabolic trials, but the outcome (motor progression in PD) does not transfer to healthy people.","mediation":"unlikely","mediation_notes":"Null result; weight loss not a plausible confounder of a null finding.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 194, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"96 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"does not replicate the earlier phase 2 exenatide signal\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"CI reported: -1.56 to 3.39\", \"risk_of_bias\": \"low\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Adequately powered phase 3 trial with the longest follow-up in this indication; robust null.","funding_source":"National Institute for Health and Care Research and Cure Parkinson's","industry_funded":"no","manufacturer":null,"author_conflicts":"Lead author reports honoraria including from Novo Nordisk; trial publicly funded.","sponsor_role":"Academic sponsor; no manufacturer role stated.","independent_replication_exists":"yes (independent of manufacturer)","conflict_notes":null,"adverse_events":"Serious adverse events 9% vs 11%; well tolerated.","limitations":null,"plain_summary":"A publicly funded phase 3 trial in 194 people with Parkinson's disease found no slowing of motor progression with weekly exenatide over two years. The authors say other GLP-1 drugs with better target engagement, or specific patient subgroups, still need study.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":56,"doi":"10.1111/add.16679","pmid":"39415416","nct_ids":"[]","title":"The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis","authors":"[\"Qeadan F\", \"McCunn A\", \"Tingey B\"]","journal":"Addiction (Abingdon, England)","publication_date":"2025-02","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] This study aimed to estimate the strength of association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP-1 RA and substance use-outcome association among patients with comorbid type 2 diabetes and obesity. [DESIGN] A retrospective cohort study analyzing de-identified electronic health record data from the Oracle Cerner Real-World Data. [SETTING] About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022. [PARTICIPANTS] The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older. [MEASUREMENTS] The exposure indicated the presence (one or more) or absence of GIP/GLP-1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors. [FINDINGS] Patients with GIP/GLP-1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43-0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40-0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP-1 RA among patients with OUD and AUD. [CONCLUSIONS] Prescriptions of glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.","url":"https://pubmed.ncbi.nlm.nih.gov/39415416/","source_name":"pubmed","source_tier":1,"coi_statement":"None.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"addiction\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":"Opioid overdose in OUD; alcohol intoxication in AUD (EHR, 136 US health systems)","endpoints":null,"effect_estimate":"aIRR 0.60 (opioid overdose); aIRR 0.50 (alcohol intoxication); consistent across diabetes/obesity subgroups","confidence_interval":"0.43 to 0.83; 0.40 to 0.63","p_value":null,"sample_size":1321056,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed; subgroups with and without obesity\", \"diabetes_status\": \"mixed\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"opioid or alcohol use disorder\", \"sample_size\": 1321056, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Not restricted to diabetes or obesity and effects consistent in subgroups without them; but a substance-use-disorder population and observational.","mediation":"unlikely","mediation_notes":"Effect consistent regardless of comorbid obesity or diabetes, arguing against weight mediation; confounding by prescribing patterns remains.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 1321056, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"CI reported: 0.43 to 0.83; 0.40 to 0.63\", \"risk_of_bias\": \"confounding by indication; exposure defined as any prescription\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large observational cohort with plausible confounding.","funding_source":"Not reported in the abstract; full text not checked.","industry_funded":"no","manufacturer":null,"author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In US health-system records, people with opioid or alcohol use disorder who were prescribed GLP-1/GIP drugs had 40-50% lower rates of overdose and alcohol intoxication, and the association was similar in subgroups with type 2 diabetes or obesity. Observational, and based on any prescription of these drugs.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":405,"doi":"10.1038/s41591-024-03374-z","pmid":"39551891","nct_ids":"[\"NCT04847557\"]","title":"Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial","authors":"[\"Borlaug BA\", \"Zile MR\", \"Kramer CM\", \"Baum SJ\", \"Hurt K\", \"Litwin SE\", \"Murakami M\", \"Ou Y\", \"Upadhyay N\", \"Packer M\"]","journal":"Nature medicine","publication_date":"2025-02","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) -5 mmHg, 95% confidence interval (CI) -7 to -3; P < 0.001), decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001) and reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min-1 1.73 m-2 yr-1, 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001; 52 weeks, -15%, 95% CI -28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks -10.5%, 95% CI -20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 .","url":"https://pubmed.ncbi.nlm.nih.gov/39551891/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: B.A.B. receives research support from the National Institutes of Health (NIH) and the US Department of Defense, as well as research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk and Tenax Therapeutics. B.A.B. has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT and VADovations and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat HF. M.R.Z. receives research support from the Department of Veterans Affairs and serves as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Inc., Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, DIASTOL Therapeutics, LLC, EBR, Edwards, Lilly, GenKardia, Innoventric, Kestra Medical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnovo, Salubris Biotherapeutics, Sonata, sRNAlytics Inc., V-WAVE and Vectorious. C.M.K. has served as a consultant for Eli Lilly. S.J.B. has served as consultant for Altimmune, Amgen, Beren Therapeutics, Boehringer Ingelheim, Lilly, Esperion, Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novartis and Regeneron. S.E.L. reported being on the patient selection committee for Corvia and Axon and being a consultant for Novo Nordisk and Lilly. K.H., M.M., Y.O. and N.U. are employed by Eli Lilly and Company. M.P. has served as a consultant for 89bio, AbbVie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Imara, Medtronic, Moderna, Novartis, Pharmacocosmos, Reata, Regeneron, Roche and Salamandra.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"kidney\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":4,"doi":"10.1056/nejmoa2410027","pmid":"39555826","nct_ids":"[\"NCT04847557\"]","title":"Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity","authors":"[\"Packer M\", \"Zile MR\", \"Kramer CM\", \"Baum SJ\", \"Litwin SE\", \"Menon V\", \"Ge J\", \"Weerakkody GJ\", \"Ou Y\", \"Bunck MC\", \"Hurt KC\", \"Murakami M\", \"Borlaug BA\", \"SUMMIT Trial Study Group\"]","journal":"The New England journal of medicine","publication_date":"2025-01-30","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes. [METHODS] In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life). [RESULTS] A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group. [CONCLUSIONS] Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.).","url":"https://pubmed.ncbi.nlm.nih.gov/39555826/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"up to 15 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"median follow-up 104 weeks\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"mixed","primary_outcome":"CV death or worsening heart-failure event; change in KCCQ-CSS at 52 weeks","endpoints":null,"effect_estimate":"HR 0.62 (9.9% vs 15.3%); worsening HF HR 0.54; CV death HR 1.58 (8 vs 5 events); KCCQ +6.9","confidence_interval":"0.41 to 0.95 (composite)","p_value":"0.026","sample_size":731,"follow_up":"median 104 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"obesity required (BMI >= 30)\", \"diabetes_status\": \"mixed (not excluded)\", \"cvd_status\": \"HFpEF required\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"heart failure with preserved ejection fraction\", \"sample_size\": 731, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obese HFpEF population; composite benefit driven by heart-failure events, with numerically more CV deaths on tirzepatide (few events).","mediation":"likely","mediation_notes":"Tirzepatide produces very large weight loss; mediation not analysed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 731, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"median 104 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"92 composite events; CV-death estimate very imprecise\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Moderate-sized RCT with a composite driven by HF events; CV death component uninformative.","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"no","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"Discontinuation for adverse events (mainly GI) 6.3% vs 1.4%.","limitations":"Obese HFpEF only; modest event count.","plain_summary":"In 731 people with HFpEF and obesity, tirzepatide lowered the combined risk of cardiovascular death or worsening heart failure (about 10% vs 15%) over roughly two years, mainly by reducing heart-failure events. Cardiovascular deaths were slightly more frequent on tirzepatide, though numbers were tiny. Not applicable outside obesity.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":297,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-01-30","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2025-01-30","year":2025,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), Nonclinical Toxicology ( 13.1 )] . • Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ) . • Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Pancreatitis : Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed (5.2) . • Never share a liraglutide pen between patients, even if the needle is changed (5.3) . • Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary (5.4) . • Acute Kidney Injury : Postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration which may sometimes require hemodialysis. Use caution when initiating or escalating doses of liraglutide in patients with renal impairment (5.5) . • Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide and promptly seek medical advice (5.6) . • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.7) . 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology (13.1) ] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, liraglutide should not be restarted. In glycemic control trials of liraglutide, there have been 13 cases of pancreatitis among liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1000 patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were reported as chronic pancreatitis. In on\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1) ] • Pancreatitis [see Warnings and Precautions (5.2) ] • Hypoglycemia [see Warnings and Precautions (5.4) ] • Acute Kidney Injury [see Warnings and Precautions (5.5) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] • Acute Gallbladder Disease [see Warnings and Precautions (5.7) ] • Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation (6.1) . • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials (12.6) . To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies (14.1) ] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide and a mean duration of exposure to liraglutide of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide than on placebo and occurred in at least 5% of patients treated with liraglutide. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with Liraglutide for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N=645 Liraglutide 1.8 mg N=1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide-treated patients and 0.5% of placebo-treated patients. Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of liraglutide-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glyc\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS • Effects of delayed gastric emptying on oral medications: Liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications (7). 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology (12.3) ] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) , Adverse Reactions (6.1) ].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS Liraglutide is contraindicated in patients with a: • personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1) ] . • serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide [see Warnings and Precautions (5.6) ]. • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4) . • Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide (4) .","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0ba917f7-b974-4364-a745-7494ecae3e73","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":404,"doi":"10.3390/biom15010046","pmid":"39858442","nct_ids":"[]","title":"Effects of Semaglutide Treatment on Psoriatic Lesions in Obese Patients with Type 2 Diabetes Mellitus: An Open-Label, Randomized Clinical Trial","authors":"[\"Petković-Dabić J\", \"Binić I\", \"Carić B\", \"Božić L\", \"Umičević-Šipka S\", \"Bednarčuk N\", \"Dabić S\", \"Šitum M\", \"Popović-Pejičić S\", \"Stojiljković MP\", \"Škrbić R\"]","journal":"Biomolecules","publication_date":"2025-01-01","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Psoriasis is a chronic inflammatory skin disease with relapsing nature. Estimates are that approximately 2-3% of the world's population suffers from this disease. More severe forms of psoriasis are conditions of high inflammation, which is confirmed by the clinical picture and numerous inflammatory parameters such as C-reactive protein (CRP), cytokines and homocysteine, which vary with disease activity. The objective of this clinical study was to investigate the effect of GLP-1 receptor agonist semaglutide therapy on pro-inflammatory factors in the serum and the severity of the clinical picture of psoriasis in obese patients with type 2 diabetes mellitus (T2DM) on chronic metformin therapy. This randomized clinical study was conducted on 31 psoriatic patients with T2DM that were randomized into two groups: one that received semaglutide during the 12-week trial (n = 15), while the second was control (n = 16). The results demonstrated that the severity of the clinical picture of psoriasis, determined by the Psoriasis Area and Severity Index (PASI) score, was significantly better after the administration of semaglutide (the median baseline PASI score in patients treated with semaglutide was 21 (IQR = 19.8), while after 12 weeks of therapy the score was 10 (IQR = 6; p = 0.002). Also, the quality of life in the group of patients who received the drug, measured by the Dermatology Life Quality Index (DLQI), improved significantly after 3 months (a median baseline DLQI score in the semaglutide group was 14 (IQR = 5) at the beginning of the study, and after 12 weeks of treatment the median DLQI score was 4 (IQR = 4; p = 0.002)). The use of semaglutide led to a significant decrease in pro-inflammatory cytokines in the serum (IL6), as well as a significant decrease in CRP values (p < 0.05). A significant decrease in the body mass index (BMI) value in the semaglutide-treated group was also identified, as well as a significant decrease in the level of low-density cholesterol (LDL) (p < 0.05). In conclusion, semaglutide, based on its systemic anti-inflammatory characteristics, could contribute to the treatment of psoriatic obese patients with T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/39858442/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no conflicts of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"prospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"continued metformin without semaglutide\", \"dose\": \"1.0 mg per week\", \"treatment_duration\": \"12 weeks\"}","domains":"[\"inflammation\", \"rheumatologic\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":31,"follow_up":"12 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 31, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes and obesity/overweight (age/BMI not reported in abstract).","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Prospective cohort\", \"sample_size\": 31, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"continued metformin without semaglutide\", \"follow_up_duration\": \"12 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"No external funding (per full text).","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In an open-label study of 31 people with psoriasis, obesity and type 2 diabetes on metformin, psoriasis severity fell over 12 weeks with semaglutide (median PASI 21 to 10) and also, less, in controls who stayed on metformin alone (mean PASI 20.6 to 15.9). BMI fell in both groups; IL-6 fell only with semaglutide. Small, unblinded and short.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":34,"doi":"10.1016/s2213-8587(24)00271-7","pmid":"39608381","nct_ids":"[\"NCT03574597\"]","title":"Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials","authors":"[\"Badve SV\", \"Bilal A\", \"Lee MMY\", \"Sattar N\", \"Gerstein HC\", \"Ruff CT\", \"McMurray JJV\", \"Rossing P\", \"Bakris G\", \"Mahaffey KW\", \"Mann JFE\", \"Colhoun HM\", \"Tuttle KR\", \"Pratley RE\", \"Perkovic V\"]","journal":"The lancet. Diabetes & endocrinology","publication_date":"2025-01","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACE) and can also have kidney benefits. However, whether GLP-1 receptor agonists improve clinically important kidney outcomes remains uncertain. We aimed to comprehensively assess the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes by performing a meta-analysis of randomised controlled trials. [METHODS] For this meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials that included at least 500 participants with type 2 diabetes, compared a GLP-1 receptor agonist with placebo with at least 12 months of follow-up, and reported a primary clinical kidney or cardiovascular outcome, from database inception to March 26, 2024. Post hoc, we included the SELECT trial (NCT03574597), which enrolled participants with cardiovascular disease and a BMI of 27 kg/m2 or more without diabetes. Study-level summary data were extracted independently by two authors for inclusion in this random-effects analysis. The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent estimated glomerular filtration rate [eGFR] <15 mL/min per 1·73 m2), a sustained reduction in eGFR by at least 50% or the nearest equivalent, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. This study is registered with PROSPERO, CRD42024528864. [FINDINGS] Of the 5140 records identified through the literature search, 11 trials, involving 85 373 participants (29 386 female, 55 987 male), were included in the meta-analysis. In participants with type 2 diabetes (67 769), GLP-1 receptor agonists reduced the composite kidney outcome by 18% compared with placebo (hazard ratio [HR] 0·82, 95% CI 0·73-0·93; I2 =26·41%), kidney failure by 16% (HR 0·84, 0·72-0·99; I2 =0%), MACE by 13% (HR 0·87, 0·81-0·93; I2 =49·75%), and all-cause death by 12% (HR 0·88, 0·83-0·93; I2 =0%). The effect on the composite kidney outcome (HR 0·81, 95% CI 0·72-0·92; I2 =23·11%), kidney failure (HR 0·84, 0·72-0·98; I2 =0%), MACE (HR 0·86, 0·80-0·92; I2 =48·9%), and all-cause death (HR 0·87, 0·82-0·91; I2 =0%) was similar when the SELECT trial was included, with no evidence of heterogeneity between this trial and those including participants with type 2 diabetes (pheterogeneity >0·05). There was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycaemia, between the GLP-1 receptor agonist and placebo groups (risk ratio [RR] 0·95, 95% CI 0·90-1·01; I2 =88·5%). However, treatment discontinuation due to adverse events occurred more frequently in the GLP-1 receptor agonist groups (RR 1·51, 95% CI 1·18-1·94; I2 =96·3%). [INTERPRETATION] We found evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events. [FUNDING] None.","url":"https://pubmed.ncbi.nlm.nih.gov/39608381/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests SVB reports consulting fees from Bayer, AstraZeneca, GSK, and Vifor Pharma; speaking fees from Bayer, AstraZeneca, Pfizer, and Vifor Pharma (all honoraria paid to his institution); and non-financial research support from Bayer. MMYL reports receiving grants through his employer, the University of Glasgow, from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics; MMYL is a member of a trial steering committee for Cytokinetics and a clinical endpoints committee for Bayer. NS reports consulting and speaking fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and ZP Therapeutics; and grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, paid to the University of Glasgow. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing education grants from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Sanofi, Carbon Brand, and Jiangsu Hanson; and consulting fees from Abbott, Bayer, Eli Lilly, Novo Nordisk, Pfizer, Sanofi, Kowa, and Hanmi. CTR reports research grants through Brigham and Women's Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis; and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. JJVM reports payments to his employer, the University of Glasgow, for work on clinical trials, consulting, lecturing, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees from Abbott, Hikma, Sun Pharmaceuticals, Servier, and Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. PR has received grants to his institution from Novo Nordisk, AstraZeneca, and Bayer; and has received honoraria for scientific advisory boards and steering groups from AstraZeneca, Abbott, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Sanofi, Eli Lilly, and Novartis. GB has received honoraria from Bayer, KBP Biosciences, Alnylam, AstraZeneca, Novo Nordisk, and InREGEN. KWM has received grants from AHA, Apple, Bayer, California Institute Regenerative Medicine (CIRM), CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and consulting fees from Applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson & Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance; and has equity in Human, Medeloop, Precordior, and Regencor. JFEM reports grants from Novo Nordisk, the EU, and McMaster University (Hamilton, Canada); consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, and has had a leadership role in the Kidney Disease Improving Global Outcomes group. HMC reports serving on advisory panels for Novo Nordisk and Bayer; receiving research funding from Sanofi, Roche, and IQVIA; receiving grants from the Chief Scientist Office, Diabetes UK, the European Commission, JDRF (Breakthrough T1D), and the Medical Research Council; serving on a speaker's bureau for Novo Nordisk; and holding stock in Roche and Bayer. KRT is supported by National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, OT2OD032581 and Centers for Disease Control and Prevention project numbers 75D301–21-P-12254 and 75D301–23-C-18264. She has also received investigator-initiated grant support from Travere Therapeutics, Bayer, and the Doris Duke Charitable Foundation, outside of the submitted work. She reports consultancy fees from AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly, Novo Nordisk, Travere Therapeutics, and Pfizer; and speaker fees from Novo Nordisk. REP reports speaker fees from Eli Lilly and Novo Nordisk; consulting fees from Bayer, Bayer HealthCare Pharmaceuticals, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Intas Pharmaceuticals, Eli Lilly, Novo Nordisk, Pfizer, and Sun Pharmaceutical Industries; and grants from Biomea Fusion, Carmot Therapeutics, Dompé, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi. VP has received honoraria for roles on steering committees, data monitoring committees, or advisory boards or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UpToDate; and is Board Director for George Clinical, St Vincents Health Australia and several independent medical research institutes. AB declares no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\", \"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"efpeglenatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"kidney\", \"cardiovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Composite kidney outcome (kidney failure, sustained >=50% eGFR loss, kidney death) and MACE across 11 RCTs","endpoints":null,"effect_estimate":"Kidney composite HR 0.82; kidney failure HR 0.84; MACE HR 0.87; all-cause death HR 0.88 (T2D); similar including SELECT","confidence_interval":"0.73 to 0.93 (kidney composite)","p_value":null,"sample_size":85373,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes in 10 trials; SELECT (no diabetes, obesity) added post hoc\", \"cvd_status\": \"mixed; cardiovascular disease was an entry requirement only in SELECT\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 85373, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Diabetes trials plus SELECT; no heterogeneity between SELECT and the diabetes trials, which modestly extends the finding to obesity without diabetes.","mediation":"possibly","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 85373, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"11 trials; low heterogeneity for kidney failure\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.73 to 0.93 (kidney composite)\", \"risk_of_bias\": \"trial-level; SELECT added post hoc\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Meta-analysis of large randomized trials with hard kidney outcomes.","funding_source":"None (the abstract states no funding)","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, Hanmi","author_conflicts":"Authors report consulting/speaking fees from Bayer, AstraZeneca, Novo Nordisk and others.","sponsor_role":"not reported in abstract","independent_replication_exists":"yes (consistent with PMID 34425083)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across 11 randomized trials (85,373 people, mostly with type 2 diabetes), GLP-1 receptor agonists reduced kidney failure by 16% and a composite kidney outcome by 18%, with consistent results when SELECT was added. No increase in serious adverse events, including acute pancreatitis, but stopping treatment because of side effects was about 50% more common (RR 1.51, 95% CI 1.18-1.94).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":358,"doi":"10.3389/fendo.2025.1734549","pmid":"41625236","nct_ids":"[]","title":"Inflammatory biomarker response to GLP-1 receptor agonists versus other glucose-lowering medications in patients with type 2 diabetes: a systematic review and meta-analysis","authors":"[\"Alrasheed T\", \"Mostafa MEA\", \"Madkhali MA\", \"Khairy HA\"]","journal":"Frontiers in endocrinology","publication_date":"2025","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Type 2 diabetes (T2D) is strongly linked to chronic inflammation and oxidative stress, which drive cardiovascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate cardioprotective benefits that may extend beyond glycemic control, but their effects on key inflammatory and oxidative stress biomarkers compared to other glucose-lowering medications remain inconsistently reported across individual studies. [METHODS] A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. Databases were searched for RCTs comparing GLP-1 RAs against other antidiabetic drugs or placebo in adults with T2D, reporting changes in inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α]) or the oxidative stress marker malondialdehyde (MDA). Data were pooled using a random-effects model, and outcomes were stratified by comparator type (placebo, insulin, other oral antidiabetic drugs [OADs]). [RESULTS] Forty RCTs (n=6029 participants) were included. GLP-1 RA therapy significantly reduced CRP levels compared to placebo (SMD = -0.59; 95% CI: -0.84 to -0.34) and other OADs (SMD = -1.06; 95% CI: -1.64 to -0.47). A significant reduction in TNF-α was observed versus placebo (SMD = -0.61; 95% CI: -0.89 to -0.32) and oral antidiabetic drugs add on (SMD = -1.62; 95% CI: -2.86 to -0.38). Data for MDA were limited and showed a non-significant trend toward reduction. GLP-1 RAs also significantly reduced IL-6 versus insulin (SMD = -0.24; 95% CI: -0.46 to -0.02). While significant heterogeneity was noted across the analyses, sensitivity analyses confirmed a consistent direction of effect, reinforcing the class-wide anti-inflammatory properties of GLP-1 RAs. [CONCLUSION] GLP-1 RAs significantly improve key biomarkers of systemic inflammation (CRP, TNF-α) in patients with T2D compared to various active comparators and placebo. These pleiotropic effects provide a mechanistic rationale for their cardiovascular benefits and support their use as a multifaceted therapeutic strategy in T2D management. [SYSTEMATIC REVIEW REGISTRATION] https://www.crd.york.ac.uk/PROSPERO/view/CRD420251157476, identifier CRD420251157476.","url":"https://pubmed.ncbi.nlm.nih.gov/41625236/","source_name":"pubmed","source_tier":1,"coi_statement":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo, insulin or other oral antidiabetic drugs\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":6029,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 6029, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 6029, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo, insulin or other oral antidiabetic drugs\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 4, 7, 11, 13; non-critical weaknesses on items 3, 5, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"Partial Yes\", \"3\": \"No\", \"4\": \"No\", \"5\": \"No\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 8, \"Partial Yes\": 2, \"Yes\": 6}, \"settled_by_ruling\": [\"item 11: No (IN-057; the passes read No and Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/41625236/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/41625236/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-01-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"No financial support received (full text)","industry_funded":"no","manufacturer":null,"author_conflicts":"The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 40 randomized trials (6,029 people) with type 2 diabetes, GLP-1 drugs lowered CRP and TNF-α (blood markers of inflammation) compared with placebo and some other diabetes drugs, and lowered IL-6 compared with insulin, with substantial variation between studies; data for the oxidative-stress marker MDA were limited and showed no significant change. These are blood-marker changes, not health outcomes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":371,"doi":"10.3389/fcvm.2025.1633114","pmid":"41112222","nct_ids":"[]","title":"Efficacy and safety of GLP-1 receptor agonists in the treatment of obese patients with chronic heart failure: a meta-analysis","authors":"[\"Jia A\", \"Yang M\", \"Wang T\", \"Hua Y\", \"Lu H\"]","journal":"Frontiers in cardiovascular medicine","publication_date":"2025","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To investigate the efficacy and safety of Glucagon-Like Peptide-1 Receptor Agonists(GLP-1RAs) (Liraglutide, Semaglutide, Exenatide, Dulaglutide, Lixisenatide, and Tirzepatide) in obese patients with chronic heart failure (CHF). [METHOD] A systematic search was performed in 3 databases (Pubmed, Embase, and Cochrane Library) for articles evaluating the effectiveness and safety of GLP-1RAs (Liraglutide, Semaglutide, Exenatide, Dulaglutide, Lixisenatide, and Tirzepatide) for the treatment of obese patients with CHF from the time the database was created until 5 January 2025. Meta-analyses were performed to evaluate: primary outcomes, including all-cause mortality, cardiovascular mortality, and worsening heart failure events; secondary outcomes, encompassing changes in body weight, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), 6-minute walk distance, B-type Natriuretic Peptide (BNP) level, high-sensitivity C-Reactive Protein (hs-CRP) level, and left ventricular ejection fraction (LVEF) level; and safety outcomes, specifically gastrointestinal adverse events and serious adverse events. [RESULTS] A total of 6 papers were included for Meta-analysis. The primary clinical outcomes: all-cause mortality [OR=0.89, 95% confidence interval (CI): 0.40-2.00, p = 0.78], cardiovascular mortality (OR = 0.93, 95% CI: 0.22-4.00, p = 0.92) and worsening heart failure events (OR=0.43, 95% CI: 0.30-0.59, p < 0.00001); For secondary outcomes, change in body weight (MD = -7.90, 95% CI: -15.44 to -0.35, p = 0.04), change in the KCCQ-CSS (MD = 6.81, 95% CI: 6.62-6.99, p < 0.00001),change in the 6-minute walk distance (MD = 15.91, 95% CI: 15.36-16.47, p < 0.00001), change in the BNP level (MD = -0.13, 95% CI: -0.21 to -0.05, p = 0.001), changes in the hs-CRP level (MD = -16.61, 95% CI: -48.53 to 15.31, p = 0.31) and change in the LVEF level (MD = -0.91, 95% CI: -2.12 to 0.29, p = 0.14). For safety outcomes, gastrointestinal adverse events (OR=0.87, 95% CI: 0.11-7.05, p = 0.90) and serious adverse events (OR=0.63, 95% CI: 0.37-1.08, p = 0.09). [CONCLUSION] The study results show that GLP-1RAs significantly reduce the risk of worsening heart failure events and improve cardiac function, suggesting that GLP-1RAs are promising treatment options for obese patients with CHF.","url":"https://pubmed.ncbi.nlm.nih.gov/41112222/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"mortality\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval (CI\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 7, 11, 13, 15; non-critical weaknesses on items 1, 3, 10, 12, 14\", \"items\": {\"1\": \"No\", \"2\": \"No\", \"3\": \"No\", \"4\": \"Partial Yes\", \"5\": \"Yes\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"No\", \"15\": \"No\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 10, \"Partial Yes\": 2, \"Yes\": 4}, \"settled_by_ruling\": [], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/41112222/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/41112222/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-03-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.2\", \"label\": \"AI: two passes agreed\"}}","evidence_rationale":"Systematic review and meta-analysis of randomized controlled trials only (seven trials in six papers).","funding_source":"No financial support received (per full text).","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across 6 papers (7 randomized trials) in people with obesity and chronic heart failure, GLP-1 drugs lowered worsening heart-failure events (OR 0.43) and improved symptom scores, walking distance, BNP and weight, but did not significantly change deaths from any cause, cardiovascular deaths, heart pumping function (LVEF), hs-CRP, or gastrointestinal or serious adverse events.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":401,"doi":"10.1080/20018525.2025.2484048","pmid":"40144943","nct_ids":"[]","title":"Safety and efficacy of glucagon-like peptide-1 receptor agonists in patients with obstructive sleep apnea: a systematic review and meta-analysis of randomized controlled trials","authors":"[\"Altobaishat O\", \"Farid Gadelmawla A\", \"Balbaa E\", \"Turkmani M\", \"Abouzid M\"]","journal":"European clinical respiratory journal","publication_date":"2025","year":2025,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obstructive sleep apnea (OSA) is a common condition affecting around one billion people worldwide. Emerging evidence from recent studies suggests that Glucagon-like peptide 1 receptor (GLP-1) agonists may reduce OSA severity. Hence, this meta-analysis aims to evaluate the efficacy and safety of GLP-1 agonists in patients with OSA. [METHODS] Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science) to identify eligible studies reported up to 24 June 2024. Using Review Manager software, we reported outcomes as risk ratios (RRs) or mean difference (MD) and confidence intervals (CIs). The protocol for this review has been registered and published in PROSPERO with the ID (CRD42024562853). [RESULTS] The meta-analysis included three randomized controlled trials with 828 patients. Pooled analysis of patients administered GLP-1 agonists or tirzepatide showed improvement in Apnea/Hypopnea Index (MD -16.57 events per hour, 95% CI [-27.41, -5.73], p = 0.003), weight reduction (MD -12.71%, 95% CI [-21.38, -4.03], p = 0.004), and systolic blood pressure (MD -4.93 mmHg,95% CI [-7.67, -2.19], p = 0.0004). Tirzepatide showed a reduction in high-sensitivity C-reactive protein (MD -0.89 mg/dl, 95% CI [-1.25, -0.54], p < 0.0001) and sleep apnea-specific hypoxic burden (MD -66.21%/min, 95% CI [-81.75, -50.67], p < 0.0001). Despite the heterogeneity observed in the AHI and weight, it was resolved, and the results were consistent. GLP-1 agonists/tirzepatide showed comparable outcomes concerning diastolic blood pressure (MD -1.34 mmHg, 95% CI [-2.80, 0.12], p = 0.07). No significant serious adverse events were observed for GLP-1 agonists/tirzepatide, but it was associated with a higher incidence of gastrointestinal adverse events. [CONCLUSION] GLP-1 agonists, including tirzepatide, improved Apnea/Hypopnea Index, weight, and systolic blood pressure in adults with moderate-to-severe OSA. However, the evidence remains limited to two published studies comprising three randomized controlled trials using different pharmacological agents. Consequently, further research is needed before firm conclusions can be drawn.","url":"https://pubmed.ncbi.nlm.nih.gov/40144943/","source_name":"pubmed","source_tier":1,"coi_statement":"No potential conflict of interest was reported by the author(s).","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\", \"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"sleep\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":828,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity in all included trials (full text)\", \"diabetes_status\": \"excluded (eligibility required non-diabetic patients; full text)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obstructive sleep apnea\", \"sample_size\": 828, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Synthesis; population mix not determinable from abstract. Review the included-study populations.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 828, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI [-27\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 4, 7; non-critical weaknesses on items 3, 10\", \"items\": {\"1\": \"Yes\", \"2\": \"Partial Yes\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"Yes\", \"12\": \"Yes\", \"13\": \"Yes\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 4, \"Partial Yes\": 1, \"Yes\": 11}, \"settled_by_ruling\": [], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/40144943/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/40144943/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-02-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"No funding (full text)","industry_funded":"no","manufacturer":null,"author_conflicts":"No potential conflict of interest was reported by the author(s).","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"No significant serious adverse events observed; gastrointestinal adverse events more frequent with GLP-1 agonists/tirzepatide.","limitations":null,"plain_summary":"Pooling three randomized trials in 828 adults with moderate-to-severe sleep apnea (two of tirzepatide, one of liraglutide), the drugs improved the Apnea/Hypopnea Index, weight and systolic blood pressure; diastolic blood pressure did not differ significantly. No significant serious adverse events were seen, but gastrointestinal side effects were more common. The evidence is limited to two published studies of three trials using different drugs, so firm conclusions cannot yet be drawn.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":43,"doi":"10.1002/alz.14313","pmid":"39445596","nct_ids":"[]","title":"Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US","authors":"[\"Wang W\", \"Wang Q\", \"Qi X\", \"Gurney M\", \"Perry G\", \"Volkow ND\", \"Davis PB\", \"Kaelber DC\", \"Xu R\"]","journal":"Alzheimer's & dementia : the journal of the Alzheimer's Association","publication_date":"2024-12","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. [METHODS] We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. [RESULTS] Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. [DISCUSSION] These findings support further studies to assess semaglutide's potential in preventing AD. [HIGHLIGHTS] Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.","url":"https://pubmed.ncbi.nlm.nih.gov/39445596/","source_name":"pubmed","source_tier":1,"coi_statement":"All authors declare no competing interests. Author disclosures are available in the Supporting Information.","assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"seven other antidiabetic drug classes\"}","domains":"[\"alzheimers\", \"dementia\"]","outcome_type":"hard","primary_outcome":"First-time Alzheimer's disease diagnosis within 3 years","endpoints":null,"effect_estimate":"HR 0.33 vs insulin; HR 0.59 vs other GLP-1RAs","confidence_interval":"0.21 to 0.51; 0.37 to 0.95","p_value":null,"sample_size":1094761,"follow_up":"3 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes without prior Alzheimer's disease\", \"sample_size\": 1094761, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes; EHR diagnoses; 3-year window is short for AD onset, suggesting detection or reverse-causation effects.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 1094761, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"seven other antidiabetic drug classes\", \"follow_up_duration\": \"3 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"large\", \"risk_of_bias\": \"reverse causation (prodromal AD reduces prescribing), coded outcomes, short window\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Hypothesis-generating EHR emulation; effect sizes implausibly large for a 3-year window; contradicted by evoke RCTs in established AD.","funding_source":"NIA NIH HHS; NCATS NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"consistent with other EHR cohorts; not with RCTs","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In US electronic records of people with type 2 diabetes, semaglutide use was associated with a 40-70% lower chance of a first Alzheimer's diagnosis within 3 years than use of other diabetes drugs, including other GLP-1 drugs. The size and speed of the effect suggest bias (people with early cognitive decline may not be prescribed new injectables).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":57,"doi":"10.1016/j.soard.2024.08.033","pmid":"39482213","nct_ids":"[]","title":"Multisociety clinical practice guidance for the safe use of glucagon-like peptide-1 receptor agonists in the perioperative period","authors":"[\"Kindel TL\", \"Wang AY\", \"Wadhwa A\", \"Schulman AR\", \"Sharaiha RZ\", \"Kroh M\", \"Ghanem OM\", \"Levy S\", \"Joshi GP\", \"LaMasters TL\", \"American Gastroenterological Association\", \"American Society for Metabolic and Bariatric Surgery\", \"American Society of Anesthesiologists\", \"International Society of Perioperative Care of Patients with Obesity\", \"Society of American Gastrointestinal and Endoscopic Surgeons\"]","journal":"Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery","publication_date":"2024-12","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":null,"url":"https://pubmed.ncbi.nlm.nih.gov/39482213/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"guideline","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"perioperative\", \"gastrointestinal\", \"adverse_effects\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"Practice guidance; applies to any user undergoing anaesthesia.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Guideline / practice guidance\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Multisociety consensus guidance on perioperative management (delayed gastric emptying and aspiration risk); no abstract in PubMed.","funding_source":"Professional societies","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Guidance from several surgical, anaesthesia and gastroenterology societies on managing GLP-1 users around procedures because of delayed stomach emptying and aspiration risk. Consult the full document for specifics.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":17,"doi":"10.1001/jamainternmed.2024.4369","pmid":"39226030","nct_ids":"[]","title":"GLP-1 Receptor Agonist Use and Risk of Suicide Death","authors":"[\"Ueda P\", \"Söderling J\", \"Wintzell V\", \"Svanström H\", \"Pazzagli L\", \"Eliasson B\", \"Melbye M\", \"Hviid A\", \"Pasternak B\"]","journal":"JAMA internal medicine","publication_date":"2024-11-01","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Concerns have been raised regarding a link between use of glucagon-like peptide-1 (GLP-1) receptor agonists and increased risk of suicidality and self-harm. [OBJECTIVE] To assess the association between use of GLP-1 receptor agonists and the risk of suicide death in routine clinical practice. [DESIGN, SETTING, AND PARTICIPANTS] This active-comparator new-user cohort study used nationwide register data from Sweden and Denmark from 2013 to 2021. Adults 18 to 84 years old who initiated treatment with GLP-1 receptor agonists or the comparator sodium-glucose cotransporter-2 (SGLT2) inhibitors were included. Data were analyzed from March to June 2024. [EXPOSURE] Initiation of treatment with a GLP-1 receptor agonist or SGLT2 inhibitor. [MAIN OUTCOMES AND MEASURES] The primary outcome was suicide death recorded in the cause of death registers. Secondary outcomes were the composite of suicide death and nonfatal self-harm and the composite of incident depression and anxiety-related disorders. Using propensity score weighting, hazard ratios (HRs) with 95% CIs were calculated separately in the 2 countries and pooled in a meta-analysis. [RESULTS] In total, 124 517 adults initiated a GLP-1 receptor agonist and 174 036 initiated an SGLT2 inhibitor; among GLP-1 receptor agonist users, the mean (SD) age was 60 (13) years, and 45% were women. During a mean (SD) follow-up of 2.5 (1.7) years, 77 suicide deaths occurred among users of GLP-1 receptor agonists and 71 suicide deaths occurred among users of SGLT2 inhibitors: weighted incidences were 0.23 vs 0.18 events per 1000 person-years (HR, 1.25; 95% CI, 0.83-1.88), with an absolute difference of 0.05 (95% CI, -0.03 to 0.16) events per 1000 person-years. The HR was 0.83 (95% CI, 0.70-0.97) for suicide death and nonfatal self-harm, and the HR was 1.01 (95% CI, 0.97-1.06) for incident depression and anxiety-related disorders. [CONCLUSIONS AND RELEVANCE] This cohort study, including mostly patients with type 2 diabetes, does not show an association between use of GLP-1 receptor agonists and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders. Suicide death among GLP-1 receptor agonist users was rare, and the upper limit of the confidence interval was compatible with an absolute risk increase of no more than 0.16 events per 1000 person-years.","url":"https://pubmed.ncbi.nlm.nih.gov/39226030/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"SGLT2 inhibitors (active comparator, new-user design)\"}","domains":"[\"psychiatric\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Suicide death (national cause-of-death registers, Sweden and Denmark)","endpoints":null,"effect_estimate":"HR 1.25; absolute difference 0.05 per 1000 person-years; self-harm composite HR 0.83; depression/anxiety HR 1.01","confidence_interval":"0.83 to 1.88","p_value":null,"sample_size":298553,"follow_up":"mean 2.5 years","direction":"null","population":"{\"mean_age\": 60, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"45% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"mostly type 2 diabetes\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 298553, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Mostly type 2 diabetes; mean age 60 overlaps target. Register-based, high-quality outcome ascertainment.","mediation":"unknown","mediation_notes":"Participants were mostly people with type 2 diabetes; obesity status not reported. The abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 298553, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"SGLT2 inhibitors (active comparator, new-user design)\", \"follow_up_duration\": \"mean 2.5 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"148 suicide deaths; CI upper bound 1.88\", \"risk_of_bias\": \"active-comparator new-user design minimises bias; observational\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Well-designed register study; rare outcome limits precision but excludes large absolute increases.","funding_source":"Non-US government / foundation (per PubMed)","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"not reported in abstract","independent_replication_exists":"yes (US EHR cohort)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across Sweden and Denmark, 124,517 new GLP-1 users and 174,036 SGLT2-inhibitor users, mostly people with type 2 diabetes, had similar, very low suicide death rates over 2.5 years (HR 1.25, 95% CI 0.83-1.88; not a significant difference). The results are compatible with at most 0.16 extra suicide deaths per 1,000 person-years. Suicide or self-harm combined was lower among GLP-1 users (HR 0.83), and new depression or anxiety was unchanged (HR 1.01). Observational: these are associations, not proof of cause.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":31,"doi":"10.1016/s2213-8587(24)00272-9","pmid":"39265590","nct_ids":"[]","title":"Muscle matters: the effects of medically induced weight loss on skeletal muscle","authors":"[\"Prado CM\", \"Phillips SM\", \"Gonzalez MC\", \"Heymsfield SB\"]","journal":"The lancet. Diabetes & endocrinology","publication_date":"2024-11","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":null,"url":"https://pubmed.ncbi.nlm.nih.gov/39265590/","source_name":"pubmed","source_tier":1,"coi_statement":"CMP has previously received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestlé Health Science, Pfizer, AMRA Medical, and Novo Nordisk; served as a steering committee member (from 2013 to 2015) and received research funding in 2013 from GTx, the developer of Enobosarm. SMP reports grants or research contracts from the US National Dairy Council, the Canadian Institutes for Health Research, Dairy Farmers of Canada, Roquette Freres, Ontario Centre of Innovation, Nestle Health Sciences, Myos, National Science and Engineering Research Council, and the US National Institutes of Health; reports personal fees from Nestle Health Sciences; reports non-financial support from Enhanced Recovery outside the submitted work; has patents licensed to Exerkine, but reports no financial gains. MCG has previously received honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, and Nestlé Health Science Brazil. SBH serves on the Medical Advisory Boards of Tanita Corporation, Novo Nordisk, Abbott, and Medifast.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"narrative_review","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"lean_mass\", \"muscle\", \"nutrition\", \"aging\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"Review; discusses older adults as a higher-risk group.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Expert review without new data; calls for functional and muscle-quality outcomes.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":"Novo Nordisk, Pfizer","author_conflicts":"Lead author reports honoraria/consultancy including Novo Nordisk, Abbott, Nestle.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A Lancet Diabetes & Endocrinology review of muscle loss with weight-loss drugs. Emphasises that lean-mass loss is real, that its functional consequences are unstudied, and that older adults are at particular risk. Authors have nutrition-industry and Novo Nordisk relationships.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":7,"doi":"10.1056/nejmoa2403664","pmid":"39476339","nct_ids":"[\"NCT05064735\"]","title":"Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis","authors":"[\"Bliddal H\", \"Bays H\", \"Czernichow S\", \"Uddén Hemmingsson J\", \"Hjelmesæth J\", \"Hoffmann Morville T\", \"Koroleva A\", \"Skov Neergaard J\", \"Vélez Sánchez P\", \"Wharton S\", \"Wizert A\", \"Kristensen LE\", \"STEP 9 Study Group\"]","journal":"The New England journal of medicine","publication_date":"2024-10-31","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. [METHODS] We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being). [RESULTS] A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation. [CONCLUSIONS] Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).","url":"https://pubmed.ncbi.nlm.nih.gov/39476339/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"68 weeks\", \"comparator\": \"placebo (both with diet/activity counselling)\"}","domains":"[\"osteoarthritis\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"Percent change in body weight and change in WOMAC pain score at week 68","endpoints":null,"effect_estimate":"Weight -13.7% vs -3.2%; WOMAC pain -41.7 vs -27.5 points; SF-36 physical function +12.0 vs +6.5","confidence_interval":null,"p_value":"<0.001","sample_size":407,"follow_up":"68 weeks","direction":"benefit","population":"{\"mean_age\": 56, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"81.6% female\", \"bmi_mean\": 40.3, \"bmi_min\": 30, \"obesity_status\": \"obesity required; mean BMI 40.3\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"moderate knee osteoarthritis with at least moderate pain\", \"sample_size\": 407, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Mean BMI 40; weight loss is an established OA pain treatment. No normal-weight OA patients.","mediation":"likely","mediation_notes":"Pain relief is expected from 13.7% weight loss; the trial did not test weight-independent effects. Placebo group also improved substantially (-27.5).","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 407, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (both with diet/activity counselling)\", \"follow_up_duration\": \"68 weeks\", \"outcome_type\": \"patient-reported pain and function\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Adequately sized RCT with patient-reported endpoints; effect confounded with weight loss.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"Not reported in the abstract; full text not checked.","independent_replication_exists":"no","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Discontinuation due to adverse events 6.7% vs 3.0%, mostly GI; serious adverse events similar.","limitations":null,"plain_summary":"In 407 people with obesity (average BMI 40) and painful knee osteoarthritis, semaglutide produced 13.7% weight loss and greater pain reduction than placebo over 68 weeks. Because weight loss itself relieves knee pain, this does not show an anti-inflammatory or joint-specific drug effect, and it does not apply to people of normal weight.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":412,"doi":"10.1016/j.jacc.2024.08.023","pmid":"39217565","nct_ids":"[\"NCT04916470\", \"NCT04788511\"]","title":"Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program","authors":"[\"Verma S\", \"Butler J\", \"Borlaug BA\", \"Davies MJ\", \"Kitzman DW\", \"Petrie MC\", \"Shah SJ\", \"Jensen TJ\", \"Rasmussen S\", \"Rönnbäck C\", \"Merkely B\", \"O'Keefe E\", \"Kosiborod MN\", \"STEP-HFpEF and STEP-HFpEF DM Investigators\"]","journal":"Journal of the American College of Cardiology","publication_date":"2024-10-22","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. [OBJECTIVES] The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. [METHODS] This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. [RESULTS] Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. [CONCLUSIONS] In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470]).","url":"https://pubmed.ncbi.nlm.nih.gov/39217565/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures This trial was funded by Novo Nordisk A/S. Administrative support for manuscript development was funded by Novo Nordisk A/S. Dr Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada, and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Petrie is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+). Dr Borlaug is supported in part by National Institutes of Health (NIH) grants R01HL128526, R01HL162828, and U01HL160226, and by the U.S. Department of Defense grant W81XWH2210245. Dr Davies is supported by the Leicester National Institute for Health Research Biomedical Research Centre, Leicester General Hospital. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272. Dr Shah was supported by NIH grants U54HL160273, R01HL107577, R01HL127028, R01HL140731, and R01HL149423. Dr Verma has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday, Foundry, G3P, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Borlaug receives research support from the NIH and the United States Department of Defense, as well as research grant funding from AstraZeneca, Axon Therapies, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (U.S. patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; is an advisory board member for AstraZeneca, Carmot/Roche, Medtronic, Pfizer, and Zealand Pharma; is a speaker for Amgen and AstraZeneca; and has received grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Dr Shah has received research grants from AstraZeneca, Corvia, and Pfizer; and has recevied consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Drs Jensen, Rasmussen, and Rönnbäck are employees and shareholders of Novo Nordisk A/S. Dr Merkely has received speaker fees and/or research payments from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis; and has recevied institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca and Vifor. Dr O’Keefe has reported that he has no relationships relevant to the contents of this paper to disclose.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":413,"doi":"10.1016/j.jacc.2024.08.028","pmid":"39217564","nct_ids":"[\"NCT04916470\", \"NCT04788511\"]","title":"Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program","authors":"[\"Verma S\", \"Petrie MC\", \"Borlaug BA\", \"Butler J\", \"Davies MJ\", \"Kitzman DW\", \"Shah SJ\", \"Rönnbäck C\", \"Abildstrøm SZ\", \"Liisberg K\", \"Wolf D\", \"von Lewinski D\", \"Lelonek M\", \"Melenovsky V\", \"Senni M\", \"Kosiborod MN\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"Journal of the American College of Cardiology","publication_date":"2024-10-22","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. [OBJECTIVES] This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. [METHODS] This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). [RESULTS] In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). [CONCLUSIONS] Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).","url":"https://pubmed.ncbi.nlm.nih.gov/39217564/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures This trial was funded by Novo Nordisk, Søborg, Denmark. Administrative support for manuscript development was funded by Novo Nordisk. Dr Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Petrie is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+). Dr Borlaug is supported in part by National Institutes of Health (NIH) grants R01HL128526, R01HL162828, and U01HL160226 and by U.S. Department of Defense grant W81XWH2210245. Dr Davies is supported by the Leicester National Institute for Health Research Biomedical Research Centre. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272. Dr Shah was supported by NIH grants U54HL160273, R01HL107577, R01HL127028, R01HL140731, and R01HL149423. Dr Verma has received speaking honoraria and consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Borlaug receives research grant funding from AstraZeneca, Axon Therapies, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (U.S. patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler is a consultant for Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday, Foundry, G3P, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Davies has been a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi, an advisory board member for AstraZeneca, Carmot/Roche, Medtronic, Pfizer, and Zealand Pharma, and a speaker for Amgen and AstraZeneca; and has received grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Shah has received research grants from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Drs Rönnbäck, Abildstrøm, and Liisberg are employees and shareholders of Novo Nordisk. Dr Wolf has received speaking honoraria and consulting fees from Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk; and has received funding from Else Kröner-Fresenius-Stiftung Foundation, the German Research Foundation (SFB1425), and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation Program (grant agreement no. 853425). Dr von Lewinski has received research funding from Boehringer Ingelheim, Merck Sharp & Dohme, and Novartis; and served on committees or consulted for Bayer, Recardio, and Vaxxinity. Dr Lelonek received consulting fees for lectures and contracts from AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Roche, Bayer. Dr Melenovsky has received consulting fees from Bayer, MSD, and Novo Nordisk; has received research grants from Regeneron; and has received research support from the National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID project no. LX22NPO5104, funded by the European Union—Next Generation EU). Dr Senni served as a consultant, was a part of an advisory board, and received honoraria for Novartis, Bayer, Merck, MSD, Abbott, Boehringer Ingelheim, Novonordisk, Vifor, Astrazeneca, and Cardurion. Dr Kosiborod served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; and has received other research support from AstraZeneca and Vifor. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":5,"doi":"10.1056/nejmoa2404881","pmid":"38912654","nct_ids":"[\"NCT05412004\"]","title":"Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity","authors":"[\"Malhotra A\", \"Grunstein RR\", \"Fietze I\", \"Weaver TE\", \"Redline S\", \"Azarbarzin A\", \"Sands SA\", \"Schwab RJ\", \"Dunn JP\", \"Chakladar S\", \"Bunck MC\", \"Bednarik J\", \"SURMOUNT-OSA Investigators\"]","journal":"The New England journal of medicine","publication_date":"2024-10-03","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. [METHODS] We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. [RESULTS] At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. [CONCLUSIONS] Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).","url":"https://pubmed.ncbi.nlm.nih.gov/38912654/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":6,"assessed_by":"curated","assessed_at":"2026-11-09T13:53:34+00:00","study_design":"Two phase 3, double-blind, randomized, controlled trials under one master protocol; parallel-arm, placebo-controlled, 52-week treatment duration; trial 1 (GPI1, not on PAP) and trial 2 (GPI2, on PAP).","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"10 or 15 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"sleep\", \"inflammation\", \"cardiovascular\"]","outcome_type":"intermediate","primary_outcome":"Change in apnea-hypopnea index at week 52 (two trials)","endpoints":null,"effect_estimate":"AHI difference -20.0 (trial 1) and -23.8 (trial 2) events/hour; hs-CRP and systolic BP also reduced","confidence_interval":"-25.8 to -14.2; -29.6 to -17.9","p_value":"<0.001","sample_size":469,"follow_up":"52 weeks treatment; hsCRP assessed baseline to Week 52.","direction":"benefit","population":"{\"condition\": \"Moderate-to-severe obstructive sleep apnea and obesity\", \"baseline_AHI_trial1\": \"51.5 events per hour\", \"baseline_AHI_trial2\": \"49.5 events per hour\", \"mean_bmi_trial1\": 39.1, \"mean_bmi_trial2\": 38.7, \"diabetes_status\": \"Excluded — participants with type 1 or type 2 diabetes were not eligible (not simply unreported).\", \"sample_size\": 469}","applicability":"INDIRECT","applicability_rationale":"Severe obesity (mean BMI 39) with OSA; AHI improvement is expected from weight loss of this magnitude.","mediation":"likely","mediation_notes":"Body weight fell with tirzepatide (percent change not given in the abstract); AHI, hs-CRP and blood-pressure improvements are consistent with weight-loss effects and were not separated from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Two phase 3, double-blind, randomized, controlled trials under one master protocol; parallel-arm, placebo-controlled, 52-week treatment duration; trial 1 (GPI1, not on PAP) and trial 2 (GPI2, on PAP).\", \"sample_size\": 469, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks treatment; hsCRP assessed baseline to Week 52.\", \"outcome_type\": \"physiological surrogate (AHI)\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -25.8 to -14.2; -29.6 to -17.9\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\", \"rob2\": {\"O1\": {\"D1\": {\"judgment\": \"Low\", \"rationale\": \"Large industry-sponsored, multicenter phase 3 registration trial with centralized randomization/dispensing via an interactive web-response system (IWRS); per collection rule this supports allocation-concealment PY absent contradicting evidence, and nothing in the sources contradicts it. Applies identically to trial 1 and trial 2 (same master protocol/IWRS).\"}, \"D2\": {\"judgment\": \"Some concerns\", \"rationale\": \"Blinding is claimed (double-blind, participant+investigator masked) and GLP-1 GI effects can unblind participants, but per the collection rule D2 here is judged on discontinuation imbalance and ITT handling rather than unblinding per se. Discontinuation ('NOT COMPLETED') was markedly imbalanced by arm in both trials — trial 1: 34/120 (28.3%) placebo vs 13/114 (11.4%) tirzepatide; trial 2: 26/115 (\"}, \"D3\": {\"judgment\": \"High\", \"rationale\": \"The posted hsCRP denominators are well below the number randomized and are differential by arm in both trials. Trial 1: 95/114 (16.7% missing) tirzepatide vs 84/120 (30.0% missing) placebo — a 13.3-point difference; trial 2: 102/120 (15.0% missing) vs 82/115 (28.7% missing) — a 13.7-point difference (14.3% vs 28.1% against the dosed denominators). Both placebo arms exceed the guide's 20% threshold\"}, \"D4\": {\"judgment\": \"Low\", \"rationale\": \"hsCRP is an objective, central-laboratory blood assay ('Lilly-designated laboratory'), consistent with the collection rule that central-lab hsCRP measurement bias is Low absent an assay change or between-arm difference in measurement; no such change or differential measurement is reported in any source. Applies identically to both trials (same lab/assay under the master protocol).\"}, \"D5\": {\"judgment\": \"Some concerns\", \"rationale\": \"hsCRP is explicitly prespecified as a key secondary objective 'controlled for type I error' in both the protocol and SAP, tested via the closed graphical multiple-testing procedure (Bretz et al.) that strongly controls family-wise Type I error across the primary and key secondary objectives, and only one prespecified transformation/analysis (ANCOVA on log-hsCRP, reported as geometric LS means) is \"}, \"overall\": {\"judgment\": \"High\"}, \"result\": \"Change from baseline in high-sensitivity C-reactive protein (hsCRP) concentration at Week 52, tirzepatide (MTD 10/15 mg) vs placebo, key multiplicity-controlled secondary endpoint under master protocol I8F-MC-GPIF; reported separately for trial 1/GPI1 (not on PAP) and trial 2/GPI2 (on PAP) in the registry's posted results module (results_crp_measures), ANCOVA on log-hsCRP, mITT/treatment-regimen estimand population. No numeric results for this outcome appear in the abstract.\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"guide_version\": \"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)\", \"label\": \"Human-reviewed\", \"resolution\": \"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)\"}}}","evidence_rationale":"Two placebo-controlled RCTs with a physiological primary endpoint; no clinical event outcomes.","funding_source":"Eli Lilly and Company; NIH grants listed by PubMed: National Heart, Lung, and Blood Institute; National Institute on Aging","industry_funded":"yes","manufacturer":"Eli Lilly and Company (tirzepatide/LY3298176 sponsor and drug supplier)","author_conflicts":"Authors report Eli Lilly relationships.","sponsor_role":"Sponsor (Eli Lilly) is the responsible party; registry does not further break out sponsor's role in design/analysis/writing beyond this.","independent_replication_exists":"no","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"GI events most common, mostly mild to moderate.","limitations":null,"plain_summary":"In adults with obesity (average BMI about 39) and moderate-to-severe sleep apnoea, tirzepatide cut breathing interruptions from about 50 an hour by about 25-29 an hour over a year, which was 20-24 an hour more than placebo, with reductions in hs-CRP and blood pressure. These changes came alongside weight loss and do not show a weight-independent effect.","methodological_notes":"Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/38912654/); sources: abstract, registry, public protocol/SAP where available; no paper full text.","reviewed_by":null,"reviewed_at":null},{"id":410,"doi":"10.1186/s13195-024-01573-x","pmid":"39358806","nct_ids":"[\"NCT01144338\"]","title":"Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial","authors":"[\"Koychev I\", \"Reid G\", \"Nguyen M\", \"Mentz RJ\", \"Joyce D\", \"Shah SH\", \"Holman RR\"]","journal":"Alzheimer's research & therapy","publication_date":"2024-10-02","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. [METHODS] The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. [RESULTS] EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. [CONCLUSIONS] EQW treatment was associated with significant change in inflammatory proteins associated with AD. [TRIAL REGISTRATION] EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.","url":"https://pubmed.ncbi.nlm.nih.gov/39358806/","source_name":"pubmed","source_tier":1,"coi_statement":"IK received research support and honoraria from Novo Nordisk. He is a paid medical advisor for biotechnology (cfdx Ltd) and digital healthcare companies working in dementia (Five Lives SAS, Cognetivity, Mantrah Ltd). RJM received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. RRH reports personal fees from Anji Pharmaceuticals, AstraZeneca, and Novartis.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"alzheimers\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":32,"doi":"10.1111/dom.15728","pmid":"38937282","nct_ids":"[]","title":"Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies","authors":"[\"Neeland IJ\", \"Linge J\", \"Birkenfeld AL\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2024-09","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.","url":"https://pubmed.ncbi.nlm.nih.gov/38937282/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"narrative_review","drugs":"[\"class_unspecified\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"lean_mass\", \"muscle\", \"body_composition\", \"aging\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"Review; notes older age and disease severity as sarcopenia risk factors.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Narrative review\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Review; summarises lean-mass loss of 15-60% of weight lost across trials and argues muscle changes may be adaptive.","funding_source":"Not stated in abstract (check article: several authors have industry ties)","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata; verify (authors include industry-affiliated researchers).","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Review of lean-mass changes with GLP-1-based drugs: from about 15% or less up to 40-60% of weight lost is lean tissue, depending on the study; MRI data suggest muscle quality may improve; older adults may be at higher sarcopenia risk; muscle-preserving co-therapies are in development.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":420,"doi":"10.1016/j.jacc.2024.06.001","pmid":"38913003","nct_ids":"[\"NCT04916470\", \"NCT04788511\"]","title":"Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials","authors":"[\"Verma S\", \"Butler J\", \"Borlaug BA\", \"Davies M\", \"Kitzman DW\", \"Shah SJ\", \"Petrie MC\", \"Barros E\", \"Rönnbäck C\", \"Vestergaard LS\", \"Schou M\", \"Ezekowitz JA\", \"Sharma K\", \"Patel S\", \"Chinnakondepalli KM\", \"Kosiborod MN\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"Journal of the American College of Cardiology","publication_date":"2024-08-27","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] More women than men have heart failure with preserved ejection fraction (HFpEF). [OBJECTIVES] The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program. [METHODS] In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes. [RESULTS] Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo. [CONCLUSIONS] In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).","url":"https://pubmed.ncbi.nlm.nih.gov/38913003/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures This trial was funded by Novo Nordisk A/S. Administrative support for manuscript development was funded by Novo Nordisk A/S. Dr Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada; holds the Tier 1 Canada Research Chair in Cardiovascular Surgery; and has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Imbria, Impulse Dynamics, Innolife, Inventiva, Janssen, Lexicon, Lilly, LivaNova, Medtronics, Merck, Novartis, Novo Nordisk, Occlutech, Owkin, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Borlaug is supported in part by the National Institutes of Health grants R01HL128526, R01HL162828, and U01HL160226, and by the U.S. Department of Defense grant W81XWH2210245; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, Becton, Dickinson and Company, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (U.S. patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies is supported by the Leicester National Institute for Health Research Biomedical Research Centre, Leicester General Hospital; has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Shah was supported by National Institutes of Health grants U54HL160273, R01HL107577, R01HL127028, R01HL140731, and R01HL149423; has received research grants from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Petrie is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+); has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Drs Barros, Rönnbäck, and Vestergaard are employees and shareholders of Novo Nordisk A/S. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and has served as an adviser to US2.ai. Dr Sharma is an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus; and received honoraria from these companies. Dr Kosiborod has served as a consultant or as an advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":33,"doi":"10.1016/s0140-6736(24)01498-3","pmid":"39181597","nct_ids":"[\"NCT03574597\"]","title":"Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial","authors":"[\"Deanfield J\", \"Verma S\", \"Scirica BM\", \"Kahn SE\", \"Emerson SS\", \"Ryan D\", \"Lingvay I\", \"Colhoun HM\", \"Plutzky J\", \"Kosiborod MN\", \"Hovingh GK\", \"Hardt-Lindberg S\", \"Frenkel O\", \"Weeke PE\", \"Rasmussen S\", \"Goudev A\", \"Lang CC\", \"Urina-Triana M\", \"Pietilä M\", \"Lincoff AM\", \"SELECT Trial Investigators\"]","journal":"Lancet (London, England)","publication_date":"2024-08-24","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. [METHODS] The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. [FINDINGS] Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. [INTERPRETATION] In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. [FUNDING] Novo Nordisk.","url":"https://pubmed.ncbi.nlm.nih.gov/39181597/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests JD declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer, and research grants from British Heart Foundation, Medical Research Council (UK), National Institute for Health and Care Research, Public Health England, MSD, Pfizer, Aegerion, Colgate, and Roche. BMS declares having received institutional research grants to Brigham and Women's Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer, and consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier PracticeUpdate Cardiology, Esperion, Hanmi, Lexicon, Novo Nordisk, and equity in health at Scale and Doximity. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. DR declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand. DR also declares having received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. IL declares having received research funding (paid to institution) from Novo Nordisk, Sanofi, Mylan, and Boehringer Ingelheim. IL received advisory or consulting fees or other support from Altimmune, AstraZeneca, Bayer, Biomea, Boehringer Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/Johnson & Johnson, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Regeneron, Sanofi, Shionogi, Structure Therapeutics, Target RWE, Terns Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. HMC declares being a stockholder and serving on an advisory panel for Bayer; receiving research grants from Chief Scientist Office, Diabetes UK, European Commission, IQVIA, Juvenile Diabetes Research Foundation, and Medical Research Council; serving on an advisory board and speakers bureau for Novo Nordisk; and holding stock in Roche Pharmaceuticals. SEK declares having received consulting honoraria from Anii Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Oramed and stock options from Altpep. JP declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis, and Novo Nordisk; he has received a grant, paid to his institution, from Boehringer Ingelheim, and holds the position of Director, Preventive Cardiology, at Brigham and Women's Hospital. MNK declares having served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. MNK has also received other research support from AstraZeneca. SSE declares having received consulting honoraria from Amylyx, AstraZeneca, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, 89 Bio, BioAge, BioAtla, Bristol Myers Squibb, BridgeBio, Daiichi Sankyo, Denovo, Fore Therapeutics, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, National Surgical Adjuvant Breast and Bowel Project, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, Solvd, Sutro Biopharma, and TG Therapeutics. AG declares having received honoraria from Novo Nordisk, AstraZeneca, Novartis, Boehringer Ingelheim, and Bayer. CCL declares having received consulting and research honoraria from Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Moderna, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics. MU-T declares having received consulting and research honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Frosst Laboratories, Johnson and Johnson, Menarini, Novartis, Novo Nordisk, Pfizer, Procaps, Sanofi-Aventis, Servier, and Tecnofarma. MP declares having received honoraria from Novo Nordisk. AML declares having received honoraria from Novo Nordisk, Eli Lilly, Akebia, Amgen, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithkline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia for consulting activities and research funding to his institution from AbbVie, Esperion, AstraZeneca, CSL Behring, Novartis, and Eli Lilly. All other authors declare no competing interests.","assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T02:05:20+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"Prespecified SELECT analysis by heart-failure history: MACE, HF composite, CV death, all-cause death","endpoints":null,"effect_estimate":"In patients with heart failure: MACE HR 0.72; heart failure composite HR 0.79; cardiovascular death HR 0.76; benefit consistent with and without heart failure","confidence_interval":"MACE 0.60 to 0.87; HF composite 0.64 to 0.98; CV death 0.59 to 0.97","p_value":null,"sample_size":17604,"follow_up":"mean 39.8 months (SELECT primary report)","direction":"benefit","population":"{\"mean_age\": 61.6, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 33.4, \"bmi_min\": 27, \"obesity_status\": \"BMI >= 27 required\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"established CVD; 24.3% with heart failure\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"established cardiovascular disease with overweight or obesity; 24.3% had heart failure\", \"sample_size\": 17604, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"SELECT subgroup analysis; same obese secondary-prevention population.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 17604, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"mean 39.8 months (SELECT primary report)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: MACE 0.60 to 0.87; HF composite 0.64 to 0.98; CV death 0.59 to 0.97\", \"risk_of_bias\": \"prespecified subgroup analysis; not powered per subgroup\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Prespecified subgroup analysis of a large RCT.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk relationships; sponsor co-authors.","sponsor_role":"Sponsor analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Serious adverse events were less frequent with semaglutide than placebo, whatever the type of heart failure.","limitations":null,"plain_summary":"Within SELECT (adults 45 or older with established cardiovascular disease and BMI 27 or more), about a quarter of participants had heart failure at baseline. In them, semaglutide lowered heart attacks, strokes and heart deaths (MACE) in both preserved (HR 0.69) and reduced (HR 0.65) ejection fraction heart failure. The heart-failure composite outcome was not statistically significant within either type on its own (HR 0.75, 95% CI 0.52-1.07; HR 0.79, 0.58-1.08).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":15,"doi":"10.1001/jamaophthalmol.2024.2296","pmid":"38958939","nct_ids":"[]","title":"Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide","authors":"[\"Hathaway JT\", \"Shah MP\", \"Hathaway DB\", \"Zekavat SM\", \"Krasniqi D\", \"Gittinger JW\", \"Cestari D\", \"Mallery R\", \"Abbasi B\", \"Bouffard M\", \"Chwalisz BK\", \"Estrela T\", \"Rizzo JF\"]","journal":"JAMA ophthalmology","publication_date":"2024-08-01","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION). [OBJECTIVE] To investigate whether there is an association between semaglutide and risk of NAION. [DESIGN, SETTING, AND PARTICIPANTS] In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023. [EXPOSURES] Prescriptions for semaglutide vs non-GLP-1 RA medications to manage either T2D or weight. [MAIN OUTCOMES AND MEASURES] Cumulative incidence and hazard ratio of NAION. [RESULTS] Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non-GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non-GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female). In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non-GLP-1 RA antidiabetes cohort. The cumulative incidence of NAION for the semaglutide and non-GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively. A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001). In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non-GLP-1 RA cohort. The cumulative incidence of NAION for the semaglutide vs non-GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively. A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001). [CONCLUSIONS AND RELEVANCE] This study's findings suggest an association between semaglutide and NAION. As this was an observational study, future study is required to assess causality.","url":"https://pubmed.ncbi.nlm.nih.gov/38958939/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"non-GLP-1 RA medications for type 2 diabetes or weight\"}","domains":"[\"ophthalmologic\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Incident NAION (propensity-matched cohorts, single neuro-ophthalmology centre)","endpoints":null,"effect_estimate":"T2D cohort HR 4.28 (17 vs 6 events); overweight/obese cohort HR 7.64 (95% CI 2.21-26.36; 20 vs 3 events)","confidence_interval":"1.62 to 11.29 (T2D)","p_value":"<0.001","sample_size":1689,"follow_up":"36 months","direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight/obesity cohort analysed separately\", \"diabetes_status\": \"separate T2D cohort and overweight/obesity cohort (diabetes status of the latter not stated)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1689, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": [\"median age 59 (type 2 diabetes cohort) and 47 (overweight/obesity cohort)\"]}","applicability":"INDIRECT","applicability_rationale":"Referral population at one neuro-ophthalmology service; T2D or overweight/obesity cohorts; very small event counts.","mediation":"unknown","mediation_notes":"Harm signal; mechanism unknown.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 1689, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"non-GLP-1 RA medications for type 2 diabetes or weight\", \"follow_up_duration\": \"36 months\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"very wide CIs; 23 total events\", \"risk_of_bias\": \"referral bias, single centre, potential detection bias\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Hypothesis-generating single-centre cohort; later meta-analysis (PMID 42166479) supports a smaller but real association.","funding_source":"Not stated in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"not reported in abstract","independent_replication_exists":"yes (subsequent cohorts and meta-analysis)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"An early report linking semaglutide to non-arteritic anterior ischaemic optic neuropathy, from a single eye-referral centre, found roughly four- to seven-fold higher hazard with very few events. It generated a signal later examined in larger studies.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":419,"doi":"10.1016/j.jacc.2024.04.038","pmid":"38913004","nct_ids":"[\"NCT04916470\", \"NCT04788511\"]","title":"Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program","authors":"[\"Schou M\", \"Petrie MC\", \"Borlaug BA\", \"Butler J\", \"Davies MJ\", \"Kitzman DW\", \"Shah SJ\", \"Verma S\", \"Patel S\", \"Chinnakondepalli KM\", \"Harring S\", \"Abildstrøm SZ\", \"Liisberg K\", \"Kosiborod MN\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"Journal of the American College of Cardiology","publication_date":"2024-07-16","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] In the Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) program, semaglutide improved heart failure (HF)-related symptoms, physical limitations, and exercise function, and reduced bodyweight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Whether semaglutide improves functional status, as assessed by NYHA functional class, is unknown. [OBJECTIVES] The goal of this study was to examine the effects of semaglutide on change in NYHA functional class over time. We also investigated the effects of semaglutide on HF-related symptoms, physical limitations, and bodyweight and other trial endpoints across baseline NYHA functional class categories. [METHODS] This was a prespecified analysis of pooled data from 2 international, double-blind, randomized trials (STEP-HFpEF and STEP-HFpEF type 2 diabetes [STEP-HFpEF DM], comprising the STEP-HFpEF program), which collectively randomized 1,145 participants with obesity-related HFpEF to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The outcome of interest for this analysis was the change in NYHA functional class (baseline to 52 weeks). We also investigated the effects of semaglutide on the dual primary, confirmatory secondary, and selected exploratory endpoints according to baseline NYHA functional class. [RESULTS] More semaglutide-treated than placebo-treated patients had an improvement in NYHA functional class (32.6% vs 21.5%, respectively; OR: 2.20 [95% CI: 1.62-2.99; P < 0.001]) and fewer semaglutide-treated patients experienced deterioration in NYHA functional class (2.09% vs 5.24%, respectively; OR: 0.36 [95% CI: 0.19-0.70; P = 0.003]) at 52 weeks. Semaglutide (vs placebo) improved the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CCS) across NYHA functional class categories; this was especially pronounced in those in NYHA functional classes III/IV (10.5 points [95% CI: 6.6-14.4 points]) vs NYHA functional class II (6.0 points [95% CI: 3.4-8.6 points]) (P interaction = 0.06). By contrast, the degree of reduction in bodyweight was similar with semaglutide vs placebo regardless of baseline NYHA functional class category (NYHA functional class II, -8.4% [95% CI: -9.4% to -7.3%]; NYHA functional classes III/IV, -8.3% [95% CI: -9.9% to -6.8%]; P interaction = 0.96). Semaglutide consistently improved 6-minute walking distance (6MWD), the hierarchical composite endpoint (death, HF events, differences in KCCQ-CSS, and 6MWD changes), and reduced C-reactive protein and N-terminal prohormone of brain natriuretic peptide across NYHA functional class categories (all P interactions = NS). [CONCLUSIONS] In patients with obesity-related HFpEF, fewer semaglutide-treated than placebo-treated patients had a deterioration, and more had an improvement, in NYHA functional class at 52 weeks. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories. Semaglutide-mediated improvements in health status were especially large in patients with NYHA functional classes III/IV. (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure and Obesity; NCT04788511) (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes; NCT04916470).","url":"https://pubmed.ncbi.nlm.nih.gov/38913004/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures The STEP-HFpEF program was funded by Novo Nordisk. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Petri has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Dr Borlaug has received research support from the National Institutes of Health (NIH) and the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler is a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards Lifesciences, Element Science, Eli Lilly, Impulse Dynamics, Imbria, Innolife, Inventiva, Janssen, Lexicon Pharmaceuticals, LivaNova, Medtronics, Merck, Novartis, Novo Nordisk, Occlutech, Pfizer, Pharmacosmos, PharmaIN, Roche, Sequana, SQ Innovation, and Vifor. Dr Davies has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and NIH grants U01AG076928; R01AG078153; R01AG045551; R01AG18915; P30AG021332; U24AG059624; and U01HL160272; and has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Shah was supported by research grants from the U.S. National Institutes of Health (NIH; U54 HL160273; R01 HL140731; and R01 HL149423); has received research funding from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cytokinetics, Edwards Lifesciences, Eli Lilly, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Merck, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Drs Harring, Abildstrøm, and Liisberg are employees and shareholders of Novo Nordisk A/S. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":2,"doi":"10.1056/nejmoa2403347","pmid":"38785209","nct_ids":"[\"NCT03819153\"]","title":"Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes","authors":"[\"Perkovic V\", \"Tuttle KR\", \"Rossing P\", \"Mahaffey KW\", \"Mann JFE\", \"Bakris G\", \"Baeres FMM\", \"Idorn T\", \"Bosch-Traberg H\", \"Lausvig NL\", \"Pratley R\", \"FLOW Trial Committees and Investigators\"]","journal":"The New England journal of medicine","publication_date":"2024-07-11","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. [METHODS] We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. [RESULTS] Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). [CONCLUSIONS] Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).","url":"https://pubmed.ncbi.nlm.nih.gov/38785209/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1.0 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"Major kidney disease events (kidney failure, >=50% eGFR reduction, kidney or CV death)","endpoints":null,"effect_estimate":"HR 0.76 (331 vs 410 events); all-cause death HR 0.80","confidence_interval":"0.66 to 0.88","p_value":"0.0003","sample_size":3533,"follow_up":"median 3.4 years (stopped early after a prespecified interim analysis)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not an entry criterion (mean BMI ~32 in full text, not checked)\", \"diabetes_status\": \"type 2 diabetes required (all)\", \"cvd_status\": \"mixed\", \"ckd_status\": \"CKD with albuminuria required (eGFR 25-75)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease\", \"sample_size\": 3533, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Every participant had type 2 diabetes and albuminuric CKD. No inference to people with normal kidney function and no diabetes.","mediation":"possibly","mediation_notes":"Benefit could partly reflect glycaemic, blood-pressure and weight effects; the abstract does not report mediation analysis. Dose (1.0 mg) is below obesity doses.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 3533, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"median 3.4 years (stopped early after a prespecified interim analysis)\", \"outcome_type\": \"mixed\", \"replication\": \"consistent with kidney signals in SUSTAIN-6/LEADER and meta-analysis (PMID 39608381)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.66 to 0.88\", \"risk_of_bias\": \"early stopping at interim analysis may overestimate effect size\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large placebo-controlled outcome trial with hard kidney endpoints; early termination is a recognised source of effect inflation.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk relationships; sponsor employees co-authored (see disclosures).","sponsor_role":"Sponsor-designed and sponsor-analysed trial with academic steering committee.","independent_replication_exists":"no; class-level consistency","conflict_notes":"Pivotal industry trial.","adverse_events":"Serious adverse events lower with semaglutide (49.6% vs 53.8%).","limitations":"Diabetic CKD population; early stopping.","plain_summary":"In 3,533 people with type 2 diabetes and kidney disease, semaglutide 1.0 mg weekly reduced major kidney events by about a quarter and all-cause death by a fifth over a median of 3.4 years. The trial was stopped early after a planned interim analysis. It applies to people with diabetic kidney disease, not to healthy kidneys.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":30,"doi":"10.1001/jama.2024.6586","pmid":"38829659","nct_ids":"[]","title":"Is Weight Loss-Induced Muscle Mass Loss Clinically Relevant?","authors":"[\"Conte C\", \"Hall KD\", \"Klein S\"]","journal":"JAMA","publication_date":"2024-07-02","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":null,"url":"https://pubmed.ncbi.nlm.nih.gov/38829659/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"editorial","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"lean_mass\", \"muscle\", \"body_composition\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"Viewpoint; no new data.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Editorial / viewpoint\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Opinion piece arguing that proportional muscle loss during weight loss may not be clinically harmful; no primary data.","funding_source":"Not applicable","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata (JAMA viewpoint).","sponsor_role":"not reported in abstract","independent_replication_exists":"not applicable","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A JAMA viewpoint arguing that the muscle mass lost with medically induced weight loss is usually proportionate and of uncertain clinical relevance. It is an argument, not evidence, and does not address normal-weight users.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":24,"doi":"10.1001/jamanetworkopen.2024.21305","pmid":"38967919","nct_ids":"[]","title":"Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes","authors":"[\"Wang L\", \"Xu R\", \"Kaelber DC\", \"Berger NA\"]","journal":"JAMA network open","publication_date":"2024-07-01","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Thirteen human malignant neoplasms have been identified as obesity-associated cancers (OACs), ie, the presence of excess body fat is associated with increased risk of developing cancer and worse prognosis in patients with these specific tumors. The glucagon-like peptide receptor agonist (GLP-1RA) class of pharmaceuticals are effective agents for the treatment of type 2 diabetes (T2D) and for achieving weight loss, but the association of GLP-1RAs with the incident risk of 13 OACs is unclear. [OBJECTIVE] To compare the incident risk of each of the 13 OACs in patients with T2D who were prescribed GLP-1RAs vs insulins or metformin. [DESIGN, SETTING, AND PARTICIPANTS] This retrospective cohort study was based on a nationwide multicenter database of electronic health records (EHRs) of 113 million US patients. The study population included 1 651 452 patients with T2D who had no prior diagnosis of OACs and were prescribed GLP-1RAs, insulins, or metformin during March 2005 to November 2018. Data analysis was conducted on April 26, 2024. [EXPOSURES] Prescription of GLP-1RAs, insulins, or metformin. [MAIN OUTCOMES AND MEASURES] Incident (first-time) diagnosis of each of the 13 OACs occurring during a 15-year follow-up after the exposure was examined using Cox proportional hazard and Kaplan-Meier survival analyses with censoring applied. Hazard ratios (HRs), cumulative incidences, and 95% CIs were calculated. All models were adjusted for confounders at baseline by propensity-score matching baseline covariates. [RESULTS] In the study population of 1 651 452 patients with T2D (mean [SD] age, 59.8 [15.1] years; 827 873 [50.1%] male and 775 687 [47.0%] female participants; 5780 [0.4%] American Indian or Alaska Native, 65 893 [4.0%] Asian, 281 242 [17.0%] Black, 13 707 [0.8%] Native Hawaiian or Other Pacific Islander, and 1 000 780 [60.6%] White participants), GLP-1RAs compared with insulin were associated with a significant risk reduction in 10 of 13 OACs, including in gallbladder cancer (HR, 0.35; 95% CI, 0.15-0.83), meningioma (HR, 0.37; 95% CI, 0.18-0.74), pancreatic cancer (HR, 0.41; 95% CI, 0.33-0.50), hepatocellular carcinoma (HR, 0.47; 95% CI, 0.36-0.61), ovarian cancer (HR, 0.52; 95% CI, 0.03-0.74), colorectal cancer (HR, 0.54; 95% CI, 0.46-0.64), multiple myeloma (HR, 0.59; 95% CI, 0.44-0.77), esophageal cancer (HR, 0.60; 95% CI, 0.42-0.86), endometrial cancer (HR, 0.74; 95% CI, 0.60-0.91), and kidney cancer (HR, 0.76; 95% CI, 0.64-0.91). Although not statistically significant, the HR for stomach cancer was less than 1 among patients who took GLP-1RAs compared with those who took insulin (HR, 0.73; 95% CI, 0.51-1.03). GLP-1RAs were not associated with a reduced risk of postmenopausal breast cancer or thyroid cancer. Of those cancers that showed a decreased risk among patients taking GLP-1RAs compared with those taking insulin, HRs for patients taking GLP-1RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant. Compared with metformin, GLP-1RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87). [CONCLUSIONS AND RELEVANCE] In this study, GLP-1RAs were associated with lower risks of specific types of OACs compared with insulins or metformin in patients with T2D. These findings provide preliminary evidence of the potential benefit of GLP-1RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.","url":"https://pubmed.ncbi.nlm.nih.gov/38967919/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"insulin; metformin\"}","domains":"[\"cancer\"]","outcome_type":"hard","primary_outcome":"Incident diagnosis of 13 obesity-associated cancers over 15 years","endpoints":null,"effect_estimate":"vs insulin: HRs 0.35 (gallbladder) to 0.76 (kidney) for 10 of 13 cancers; no reduction for postmenopausal breast or thyroid cancer; vs metformin: no cancer reduced, kidney cancer increased (HR 1.54, 95% CI 1.27-1.87) (abstract)","confidence_interval":null,"p_value":null,"sample_size":1651452,"follow_up":"up to 15 years after the first prescription, ending at the outcome, death or loss to follow-up; mean follow-up 1967.2 to 2129.8 days by group for the colorectal and liver cancer outcomes (full text)","direction":"benefit","population":"{\"mean_age\": 59.8, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1651452, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes; insulin comparator introduces confounding by diabetes severity; metformin comparison largely null.","mediation":"likely","mediation_notes":"Obesity-associated cancers; weight and glycaemic effects are plausible mediators; not analysed.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 1651452, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"insulin; metformin\", \"follow_up_duration\": \"up to 15 years after the first prescription, ending at the outcome, death or loss to follow-up; mean follow-up 1967.2 to 2129.8 days by group for the colorectal and liver cancer outcomes (full text)\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"large cohort\", \"risk_of_bias\": \"confounding by indication (insulin users sicker); coded outcomes\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Hypothesis-generating EHR cohort with a problematic comparator.","funding_source":"NIH (NIA, NCI, NICHD)","industry_funded":"no","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"no","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 1.65 million US patients with type 2 diabetes, GLP-1 users had lower rates of 10 of 13 obesity-related cancers than insulin users; there was no reduction for postmenopausal breast or thyroid cancer. Compared with metformin, GLP-1 drugs were linked to no lower risk of any cancer and to a higher risk of kidney cancer (HR 1.54, 95% CI 1.27-1.87). Observational; the insulin comparison may be confounded by diabetes severity (editorial note), and the authors call the findings preliminary.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":44,"doi":"10.1038/s41591-024-03015-5","pmid":"38796653","nct_ids":"[\"NCT03574597\"]","title":"Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial","authors":"[\"Colhoun HM\", \"Lingvay I\", \"Brown PM\", \"Deanfield J\", \"Brown-Frandsen K\", \"Kahn SE\", \"Plutzky J\", \"Node K\", \"Parkhomenko A\", \"Rydén L\", \"Wilding JPH\", \"Mann JFE\", \"Tuttle KR\", \"Idorn T\", \"Rathor N\", \"Lincoff AM\"]","journal":"Nature medicine","publication_date":"2024-07","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide (n = 8,803) versus placebo (n = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min-1 1.73 m-2, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min-1 1.73 m-2 (95% CI 0.43, 1.06; P < 0.001) overall and 2.19 ml min-1 1.73 m-2 (95% CI 1.00, 3.38; P < 0.001) in patients with baseline eGFR <60 ml min-1 1.73 m-2. These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes.ClinicalTrials.gov identifier: NCT03574597 .","url":"https://pubmed.ncbi.nlm.nih.gov/38796653/","source_name":"pubmed","source_tier":1,"coi_statement":"P.M.B. declares being an employee of and stakeholder in Novo Nordisk. H.M.C. declares serving on advisory panels for Novo Nordisk and Bayer; receiving research funding from Sanofi, Roche and IQVIA; receiving grants from the Chief Scientist Office, Diabetes UK, the European Commission, the Juvenile Diabetes Research Foundation and the Medical Research Council (MRC); serving on a speaker’s bureau for Novo Nordisk; and holding stock in Roche and Bayer. J.D. declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk and Bayer and research grants from the British Heart Foundation, the MRC, the National Institute for Health and Care Research, Public Health England, Merck Sharp & Dohme (MSD), Pfizer, Aegerion, Colgate and Roche. K.B.-F. declares being an employee of and stockholder in Novo Nordisk. S.E.K., for the period over which SELECT was conducted, declares receiving advisory board/consulting fees from AltPep, Bayer, Boehringer Ingelheim, Casma Therapeutics, Eli Lilly, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer and Third Rock Ventures. T.I. declares being an employee of and stockholder in Novo Nordisk. I.L. declares having received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals, Novo Nordisk, Pfizer and Sanofi US Services; service as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals, Biomea Fusion, Boehringer Ingelheim, Carmot, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, MannKind Corporation, Merck, Novo Nordisk, Pfizer, Sanofi US Services, Shionogi, Structure Therapeutics, Target Pharma, Valeritas and Zealand Pharma A/S; and having received travel expenses from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson Medical Devices & Diagnostics Group– Latin America, Novo Nordisk, Sanofi US Services and Zealand Pharma A/S. A.M.L. declares having received honoraria from Akebia, Alnylam, Ardelyx, Becton Dickinson, Brainstorm Cell, Eli Lilly, Endologix, FibroGen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Novo Nordisk, Provention Bio and ReCor and consulting activities and research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion and Novartis. J.F.E.M. reports personal fees from AstraZeneca, Amgen, Braun, ACI and Fresenius; grants and personal fees from Celgene; personal fees from Gambro; grants from the European Union and McMaster University (Canada); grants and personal fees from AbbVie; personal fees from Medice; grants and personal fees from Novo Nordisk, Roche and Sandoz; and personal fees from Lanthio, Sanifit, Relypsa and ZS Pharma, all outside the submitted work. K.N. declares having received honoraria from AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Daiichi Sankyo, Eli Lilly Japan, Kowa, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Otsuka and Tsumura; research grants from Astellas, Bayer Yakuhin, Boehringer Ingelheim Japan, Fuji Yakuhin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical and Novartis Pharma; and scholarships from Abbott, Boehringer Ingelheim Japan, Daiichi Sankyo, Mitsubishi Tanabe Pharma and Teijin Pharma. A.P. declares having received research grants and personal fees during the study from Novo Nordisk. J.P. declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis and Novo Nordisk and having received a grant, paid to his institution, from Boehringer Ingelheim. J.P. also holds the position of Director, Preventive Cardiology, at Brigham and Women’s Hospital. L.R. declares research grants from Amgen, Bristol Myers Squibb, the Erling Persson Foundation, Novo Nordisk and the Swedish Heart Lung Foundation and lecture/consultant honoraria from Bayer, Eli Lilly and Novo Nordisk. N.R. declares being an employee of and stockholder in Novo Nordisk. K.R.T. declares receiving research grants from the National Institutes of Health and Travere Therapeutics and consultancy and/or speaker fees from Bayer, Boehringer Ingelheim, Eli Lilly and Novo Nordisk. J.P.H.W. is contracted via the University of Liverpool (no personal payment) to undertake consultancy for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Eli Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern, Shionogi and Ysopia and declares personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Menarini, Napp, Novo Nordisk and Rhythm.","assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-10-18T23:32:30+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"cardiovascular\"]","outcome_type":"hard","primary_outcome":"Prespecified composite kidney endpoint; eGFR change at 104 weeks","endpoints":null,"effect_estimate":"Composite 1.8% vs 2.2%, HR 0.78; eGFR benefit 0.75 mL/min/1.73m2 overall, 2.19 in baseline eGFR <60","confidence_interval":"0.63 to 0.96","p_value":"0.02","sample_size":17604,"follow_up":"mean 3.3 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27, \"obesity_status\": \"BMI >= 27 required\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"established CVD\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 17604, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity with CVD, no diabetes; low absolute event rates; kidney benefit in non-diabetic people is notable but the population still had obesity.","mediation":"possibly","mediation_notes":"Not separated; weight and blood-pressure reduction are plausible mediators.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 17604, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"mean 3.3 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"few kidney events (1.8% vs 2.2%)\", \"risk_of_bias\": \"prespecified secondary endpoint\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Prespecified secondary endpoint of a large RCT with modest event numbers.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"One author is a Novo Nordisk employee and shareholder; others report Novo Nordisk relationships.","sponsor_role":"Sponsor analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"In SELECT participants (obesity and heart disease, no diabetes), semaglutide reduced a composite kidney outcome from 2.2% to 1.8% and slowed eGFR decline slightly, more so in those with reduced kidney function. Extends kidney protection beyond diabetes, but not beyond obesity.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":421,"doi":"10.1186/s13104-024-06820-w","pmid":"38902794","nct_ids":"[\"NCT03466021\"]","title":"FDG-PET/CT-based respiration-gated lung segmentation and quantification of lung inflammation in COPD patients","authors":"[\"Dogan ADA\", \"Christensen TQ\", \"Jensen TT\", \"Juhl CB\", \"Hilberg O\", \"Bladbjerg EM\", \"Hess S\"]","journal":"BMC research notes","publication_date":"2024-06-20","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE AND RESULTS DESCRIPTION] The study objective was to investigate the potential of quantitative measures of pulmonary inflammation by [18 F]Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a surrogate marker of inflammation in COPD. Patients treated with anti-inflammatory Liraglutide were compared to placebo and correlated with inflammatory markers. 27 COPD-patients (14 receiving Liraglutide treatment and 13 receiving placebo) underwent 4D-respiratory-gated FDG-PET/CT before and after treatment. Two raters independently segmented the lungs from CT images and measured activity in whole lung, mean standard uptake values (SUVmean) corrected for lean-body-mass in the phase-matched PET images of the whole segmented lung volume, and total lesion glycolysis (TLG; SUVmean multiplied by volume). Inter-rater reliability was analyzed with Bland-Altman analysis and correlation plots. We found no differences in metabolic activity in the lungs between the two groups as a surrogate of pulmonary inflammation, and no changes in inflammation markers. The purpose of the research and brief summary of main findings. The degree of and changes in pulmonary inflammation in chronic obstructive pulmonary disease (COPD) may be difficult to ascertain. Measuring metabolic activity as a surrogate marker of inflammation by FDG-PET/CT may be useful, but data on its use in COPD including reproducibility is still limited, especially with respiration-gated technique, which should improve quantification in the lungs. We assessed several quantitative measures of metabolic activity and correlated them with inflammation markers, and we assessed reproducibility of the methods. We found no differences in metabolic activity between the two groups (before and after 40 weeks treatment with Liraglutide vs. placebo). Bland-Altman analysis showed good agreement between the two raters. [TRIAL REGISTRATION] The study was conducted between February 2018 and March 2020 at the Department of Pulmonary Diseases at Hospital South West Jutland and Lillebaelt Hospital, Denmark, and registered from March 2018 at clinicaltrials.gov with trial registration number NCT03466021.","url":"https://pubmed.ncbi.nlm.nih.gov/38902794/","source_name":"pubmed","source_tier":1,"coi_statement":"CBJ serves as a speaker for Novo Nordisk, but has no financial interest in the current study. Study medication and running costs were provided by Novo Nordisk as a part of the Investigator Sponsored Studies Program. The authors have no relevant financial or non-financial interests to disclose.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":1516,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2024-06-05","authors":"[\"Hybio Pharmaceutical Co., Ltd. (Pingshan Factory)\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2024-06-05","year":2024,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[WARNINGS_AND_CAUTIONS] 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology (13.1)]. Malignant thyroid Ccell carcinomas were detected in rats and mice. It is unknown whether liraglutide injection will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide injection have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide injection use in humans. Liraglutide injection is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide injection and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide injection. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide injection. After initiation of liraglutide injection, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide injection should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, liraglutide injection should not be restarted. In glycemic control trials of liraglutide injection, there have been 13 cases of pancreatitis among liraglutide injectiontreated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide injection were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide injection-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Liraglutide injection has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on liraglutide injection. 5.3 Never Share a Liraglutide Injection Pen Between Patients Liraglutide injection pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia Adult patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide injection regardless of insulin and/or metformin use. [see Adverse Reactions (6.1), Drug Interactions (7.2)]\n\n[ADVERSE_REACTIONS] The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Pancreatitis [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.4)] • Acute Kidney Injury [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Acute Gallbladder Disease [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebocontrolled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies (14.1)]. The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide injection and a mean duration of exposure to liraglutide injection of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide injection than on placebo and occurred in at least 5% of patients treated with liraglutide injection. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1 Adverse reactions reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide injection-treated patients and 0.5% of placebo-treated patients. Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide injection-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of liraglutide injection-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 liraglutide injection-treated patients (7.5 events per 1,000 patient-years). Of these 8 liraglutide injection-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2 Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo-controlled Trials In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of liraglutide injection-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1\n\n[DRUG_INTERACTIONS] 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology (12.3)]. Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].\n\n[CONTRAINDICATIONS] Liraglutide injection is contraindicated in patients with a: • personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. • serious hypersensitivity reaction to liraglutide or to any of the excipients in liraglutide injection. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide injection [see Warnings and Precautions (5.6)].","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1a36b801-41e2-2eed-e063-6294a90a6f27","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-08T12:27:40+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"kidney\", \"cancer\", \"addiction\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":26,"doi":"10.1001/jamanetworkopen.2024.16775","pmid":"38916894","nct_ids":"[]","title":"Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial","authors":"[\"Jensen SBK\", \"Sørensen V\", \"Sandsdal RM\", \"Lehmann EW\", \"Lundgren JR\", \"Juhl CR\", \"Janus C\", \"Ternhamar T\", \"Stallknecht BM\", \"Holst JJ\", \"Jørgensen NR\", \"Jensen JB\", \"Madsbad S\", \"Torekov SS\"]","journal":"JAMA network open","publication_date":"2024-06-03","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss. [OBJECTIVE] To investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined. [DESIGN, SETTING, AND PARTICIPANTS] This study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision. [INTERVENTIONS] After an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo. [MAIN OUTCOMES AND MEASURES] The primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population. [RESULTS] In total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, -0.006 g/cm2; 95% CI, -0.017 to 0.004 g/cm2; P = .24) and lumbar spine (-0.010 g/cm2; 95% CI, -0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, -0.013 g/cm2; 95% CI, -0.024 to -0.001 g/cm2; P = .03) and spine (mean change, -0.016 g/cm2; 95% CI, -0.032 to -0.001 g/cm2; P = .04). [CONCLUSIONS AND RELEVANCE] In this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss. [TRIAL REGISTRATION] EudraCT: 2015-005585-32.","url":"https://pubmed.ncbi.nlm.nih.gov/38916894/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"3.0 mg daily\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks after 8-week low-calorie diet\", \"comparator\": \"placebo; exercise; combination\"}","domains":"[\"bone\", \"body_composition\", \"lean_mass\"]","outcome_type":"intermediate","primary_outcome":"Change in BMD at hip, lumbar spine and distal forearm (DXA)","endpoints":null,"effect_estimate":"Liraglutide vs exercise: hip -0.013 g/cm2, spine -0.016 g/cm2; combination vs placebo: no significant BMD difference at hip (-0.006 g/cm2, P=.24) or spine (-0.010 g/cm2, P=.20)","confidence_interval":"-0.024 to -0.001 (hip)","p_value":"0.03 (hip), 0.04 (spine)","sample_size":195,"follow_up":"52 weeks","direction":"harm","population":"{\"mean_age\": 42.8, \"age_range\": \"18-65\", \"age_min\": 18.0, \"sex_distribution\": \"64% female\", \"bmi_mean\": 37.0, \"bmi_min\": null, \"obesity_status\": \"obesity required (BMI 32-43)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 195, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Younger adults (mean 43) with obesity; bone loss during weight loss is expected. Older adults have higher fracture risk and no data.","mediation":"likely","mediation_notes":"Liraglutide alone lowered bone density more than exercise alone despite similar weight loss, so weight loss alone does not explain the difference; combining exercise with liraglutide preserved bone density.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 195, \"randomization\": \"yes\", \"blinding\": \"double-blind for drug\", \"comparator\": \"placebo; exercise; combination\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"BMD surrogate; no fractures\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -0.024 to -0.001 (hip)\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Predefined secondary analysis of an RCT; surrogate outcome.","funding_source":"Novo Nordisk Foundation and others (foundation, not the company)","industry_funded":"partial","manufacturer":"Novo Nordisk Foundation","author_conflicts":"See published disclosures.","sponsor_role":"not reported in abstract","independent_replication_exists":"no","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"After diet-induced weight loss, a year of liraglutide alone was associated with lower hip and spine bone density than exercise alone; combining exercise with liraglutide preserved bone. Fracture effects unknown; participants were young adults with obesity.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":427,"doi":"10.1016/j.pcd.2024.03.005","pmid":"38555202","nct_ids":"[]","title":"Effects of GLP-1 receptor agonists on the degree of liver fibrosis and CRP in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: A systematic review and meta-analysis","authors":"[\"Fang L\", \"Li J\", \"Zeng H\", \"Liu J\"]","journal":"Primary care diabetes","publication_date":"2024-06","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Based on the rapidly growing global burden of non-alcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), in order to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of NAFLD or NASH this paper presents a systematic review and meta-analysis of randomized controlled trials(RCTs). [METHODS] In this systematic review and meta-analysis, We searched PubMed, Medline, Web of Science and The Cochrane Library databases. All randomized controlled trials involving GLP-1RAs and NAFLD or NASH were collected since the database was established. A meta-analysis of proportions was done with the generalised linear mixed model. Continuous variables were represented by Mean and Standard Deviation (SD), and binary variable were represented by Relative Risk (RR) and 95% Confidence Interval (CI) as effect indicators. The research results were presented by Revman 5.4. This study is registered with PROSPERO (CRD42023390735). [FINDING] We included 16 placebo-controlled or active drug-controlled randomized controlled trials (involving 2178 patients) that used liraglutide, exenatide, dulaglutide, or semaglutie in the treatment of NAFLD or NASH, as measured by liver biopsy or imaging techniques. This study found that the effect of GLP-1RAs on histologic resolution of NASH with no worsening of liver fibrosis (n=2 RCTs; WMD:4.08, 95%CI 2.54-6.56, p < 0.00001) has statistically significant. At the same time, GLP-1RAs affected CRP (n = 7 RCTs; WMD:-0.41, 95% CI-0.78 to -0.04, p =0.002) and other serological indicators were significantly improved. [CONCLUSION] This study evaluated the efficacy of GLP-1RAs in patients with NAFLD and NASH. These results suggest that GLP-1RAs may be a potential and viable therapeutic approach as a targeted agent to intervene in disease progression of NAFLD and NASH.","url":"https://pubmed.ncbi.nlm.nih.gov/38555202/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of Competing Interest (a) there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported; or (b) any financial or other potential conflict of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\", \"dulaglutide\", \"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":425,"doi":"10.1016/s0140-6736(24)00469-0","pmid":"38599221","nct_ids":"[\"NCT04788511\", \"NCT04916470\"]","title":"Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials","authors":"[\"Butler J\", \"Shah SJ\", \"Petrie MC\", \"Borlaug BA\", \"Abildstrøm SZ\", \"Davies MJ\", \"Hovingh GK\", \"Kitzman DW\", \"Møller DV\", \"Verma S\", \"Einfeldt MN\", \"Lindegaard ML\", \"Rasmussen S\", \"Abhayaratna W\", \"Ahmed FZ\", \"Ben-Gal T\", \"Chopra V\", \"Ezekowitz JA\", \"Fu M\", \"Ito H\", \"Lelonek M\", \"Melenovský V\", \"Merkely B\", \"Núñez J\", \"Perna E\", \"Schou M\", \"Senni M\", \"Sharma K\", \"van der Meer P\", \"Von Lewinski D\", \"Wolf D\", \"Kosiborod MN\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"Lancet (London, England)","publication_date":"2024-04-27","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. [METHODS] We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. [FINDINGS] Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. [INTERPRETATION] In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. [FUNDING] Novo Nordisk.","url":"https://pubmed.ncbi.nlm.nih.gov/38599221/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests JB is a paid consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. SJS has received research grants from AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. MCP has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations, and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. BAB has received research funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a paid consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations, and is named inventor (US patent number 10 307 179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. SZA, GKH, DVM, MNE, MLL, and SR are employees of, and shareholders in, Novo Nordisk. MJD has acted as paid consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi, a paid advisory board member and speaker for AstraZeneca, a paid advisory board member for Medtronic, Pfizer, and ShouTi Pharma, and a paid speaker for Amgen, Novartis, and Sanofi, and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. DWK reports receiving honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus, has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus, and owns stock in Gilead. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. WA reports honoraria or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. FZA reports honoraria or consulting fees from Abbott, AstraZeneca, Medtronic, Novo Nordisk, Occlutech, Pharmacosmos, and Vifor. VC reports speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy's, Lupin, Novartis, Novo Nordisk, Mankind, Pfizer, Sanofi, Sun Pharma, and Torrent. JAE reports research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk, reports honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka, and serves as an advisor to US2.ai. HI reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. ML reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. VM reports consulting fees from Bayer, Merck Sharp & Dohme, and Novo Nordisk and research grants from Regeneron. BM reports speaker fees or research payments from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis, and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor. JN reports honoraria or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Pfizer, Novartis, Novo Nordisk, Rovi, and Vifor. EP reports honoraria from Novo Nordisk. MSc reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. MSe reports honoraria or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Vifor. KS received honoraria for serving as an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus. PvdM reports institutional payments for consultancy fees or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. DVL reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. DW reports consultancy fees from Novo Nordisk. MNK served as a paid consultant or advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics, has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, holds stocks in Artera Health and Saghmos Therapeutics, has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, and has received other research support from AstraZeneca. TB-G and MF report no competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":294,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: WEGOVY (SEMAGLUTIDE) - label effective 2024-04-23","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2024-04-23","year":2024,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )] . • WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of WEGOVY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with WEGOVY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors at clinically relevant exposures. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has occurred in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). • Acute Gallbladder Disease : Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical follow-up are indicated ( 5.3 ). • Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin or insulin secretagogue may be necessary. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia ( 5.4 ). • Acute Kidney Injury: Has occurred. Monitor renal function when initiating or escalating doses of WEGOVY in patients reporting severe adverse gastrointestinal reactions or in those with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). • Hypersensitivity Reactions: Anaphylactic reactions and angioedema have been reported postmarketing. Discontinue WEGOVY if suspected and promptly seek medical advice ( 5.6 ). • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes : Has been reported in trials with semaglutide. Patients with a history of diabetic retinopathy should be monitored ( 5.7 ). • Heart Rate Increase : Monitor heart rate at regular intervals ( 5.8 ). • Suicidal Behavior and Ideation : Monitor for depression or suicidal thoughts. Discontinue WEGOVY if symptoms develop ( 5.9 ). 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether WEGOVY causes thyroid C-cell tumors, including MTC, in humans, as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of WEGOVY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with WEGOVY. Such monitoring may increase the risk of unnecessary procedures, due to the low-test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including semaglutide. Acute pancreatitis was observed in patients treated with WEGOVY in clinical trials [see Adverse Reactions ( 6 )] . After initiation of WEGOVY, observe patients carefully for signs and symptoms of acute pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, and which may or may not be accompanied by vomiting). If acute pancreatitis is suspected, WEGOVY should promptly be discontinued, and appropriate management should be initiated. If acute pancreatitis is confirmed, WEGOVY should not be restarted. There is limited exp\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-Cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.3 )] • Hypoglycemia [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes [see Warnings and Precautions ( 5.7 )] • Heart Rate Increase [see Warnings and Precautions ( 5.8 )] • Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥ 5%) in adults or pediatric patients aged 12 years and older are: nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, gastroesophageal reflux disease, and nasopharyngitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-934-6891 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials in Adults with Obesity or Overweight WEGOVY 2.4 mg Subcutaneous Weekly Dosage WEGOVY was evaluated for safety in 3 randomized, double-blind, placebo-controlled trials that included 2,116 adult patients with obesity or overweight treated with 2.4 mg WEGOVY for up to 68 weeks and a 7 week off-drug follow-up period [see Clinical Studies (14.2) ] . Baseline characteristics included a mean age of 48 years, 71% female, 72% White, 14% Asian, 9% Black or African American, and 5% reported as other or unknown; and 85% were not Hispanic or Latino ethnicity, 13% were Hispanic or Latino ethnicity, and 2% reported as unknown. The baseline characteristics were 42% with hypertension, 19% with type 2 diabetes, 43% with dyslipidemia, 28% with a BMI greater than 40 kg/m 2 , and 4% with cardiovascular disease. In these clinical trials, 6.8% of patients treated with 2.4 mg WEGOVY and 3.2% of patients treated with placebo permanently discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (1.8% versus 0.2%), vomiting (1.2% versus 0%), and diarrhea (0.7% versus 0.1%) for WEGOVY and placebo, respectively. Adverse reactions reported in clinical trials in adults and greater than or equal to 2% of WEGOVY-treated patients and more frequently than in placebo-treated patients are shown in Table 3. Table 3. Adverse Reactions (≥2% and Greater Than Placebo) in WEGOVY-treated Adults with Obesity or Overweight Placebo N = 1,261 % WEGOVY 2.4 mg N = 2,116 % Nausea 16 44 Diarrhea 16 30 Vomiting 6 24 Constipation 11 24 Abdominal Pain a 10 20 Headache 10 14 Fatigue b 5 11 Dyspepsia 3 9 Dizziness 4 8 Abdominal Distension 5 7 Eructation <1 7 Hypoglycemia in T2DM c 2 6 Flatulence 4 6 Gastroenteritis 4 6 Gastroesophageal Reflux Disease 3 5 Gastritis d 1 4 Gastroenteritis Viral 3 4 Hair Loss 1 3 Dysesthesia e 1 2 a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, abdominal tenderness, abdominal discomfort and epigastric discomfort b Includes fatigue and asthenia c Defined as blood glucose <54 mg/dL with or without symptoms of hypoglycemia or severe hypoglycemia (requiring the assistance of another person) in patients with type 2 diabetes not on concomitant insulin (Study 3, WEGOVY N=403, Placebo N=402). See text below for further information regarding hypoglycemia in patients with and without \n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS WEGOVY delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution ( 7.2 ). 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) WEGOVY lowers blood glucose and can cause hypoglycemia. The risk of hypoglycemia is increased when WEGOVY is used in combination with insulin or insulin secretagogues (e.g., sulfonylureas). The addition of WEGOVY in patients treated with insulin has not been evaluated. When initiating WEGOVY, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )] . 7.2 Oral Medications WEGOVY causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials with semaglutide 1 mg, semaglutide did not affect the absorption of orally administered medications [see Clinical Pharmacology ( 12.3 )] . Nonetheless, monitor the effects of oral medications concomitantly administered with WEGOVY.\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS WEGOVY is contraindicated in the following conditions: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions ( 5.1 )] . • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in WEGOVY. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with WEGOVY [see Warnings and Precautions ( 5.6 )]. • Personal or family history of MTC or in patients with MEN 2 ( 4 ). • Known hypersensitivity to semaglutide or any of the excipients in WEGOVY ( 4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"psychiatric\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":426,"doi":"10.1056/nejmoa2313917","pmid":"38587233","nct_ids":"[\"NCT04916470\"]","title":"Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes","authors":"[\"Kosiborod MN\", \"Petrie MC\", \"Borlaug BA\", \"Butler J\", \"Davies MJ\", \"Hovingh GK\", \"Kitzman DW\", \"Møller DV\", \"Treppendahl MB\", \"Verma S\", \"Jensen TJ\", \"Liisberg K\", \"Lindegaard ML\", \"Abhayaratna W\", \"Ahmed FZ\", \"Ben-Gal T\", \"Chopra V\", \"Ezekowitz JA\", \"Fu M\", \"Ito H\", \"Lelonek M\", \"Melenovský V\", \"Merkely B\", \"Núñez J\", \"Perna E\", \"Schou M\", \"Senni M\", \"Sharma K\", \"van der Meer P\", \"Von Lewinski D\", \"Wolf D\", \"Shah SJ\", \"STEP-HFpEF DM Trial Committees and Investigators\"]","journal":"The New England journal of medicine","publication_date":"2024-04-18","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. [METHODS] We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. [RESULTS] A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. [CONCLUSIONS] Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).","url":"https://pubmed.ncbi.nlm.nih.gov/38587233/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":18,"doi":"10.1136/bmj-2023-078225","pmid":"38683947","nct_ids":"[]","title":"Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study","authors":"[\"Pasternak B\", \"Wintzell V\", \"Hviid A\", \"Eliasson B\", \"Gudbjörnsdottir S\", \"Jonasson C\", \"Hveem K\", \"Svanström H\", \"Melbye M\", \"Ueda P\"]","journal":"BMJ (Clinical research ed.)","publication_date":"2024-04-10","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer. [DESIGN] Scandinavian cohort study. [SETTING] Denmark, Norway, and Sweden, 2007-21. [PARTICIPANTS] Patients who started GLP1 receptor agonist treatment were compared with patients who started dipeptidyl peptidase 4 (DPP4) inhibitor treatment, and in an additional analysis, patients who started sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. [MAIN OUTCOME MEASURES] Thyroid cancer identified from nationwide cancer registers. An active-comparator new user study design was used to minimise risks of confounding and time related biases from using real world studies of drug effects. Cox regression was used to estimate hazard ratios, controlling for potential confounders with propensity score weighting. [RESULTS] The mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference -0.13, 95% confidence interval -0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05). [CONCLUSIONS] In this large cohort study using nationwide data from three countries, GLP1 receptor agonist use was not associated with a substantially increased risk of thyroid cancer over a mean follow-up of 3.9 years. In the main analysis comparing GLP1 receptor agonists with DPP4 inhibitors, the upper limit of the confidence interval was consistent with no more than a 31% increase in relative risk.","url":"https://pubmed.ncbi.nlm.nih.gov/38683947/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from Swedish Cancer Society, Swedish Research Council, Karolinska Institutet, Novo Nordisk Foundation, Lundbeck Foundation, Independent Research Foundation Denmark, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, and Danish Cancer Society for the submitted work; CJ is an employee of NordicRWE; BE reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Mundipharma, Navamedic, Novo Nordisk, and Sanofi outside the submitted work; HS is a former employee of IQVIA; AH is a scientific advisory board member of VAC4EU; the other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"DPP-4 inhibitors (main) and SGLT2 inhibitors\"}","domains":"[\"cancer\", \"endocrine\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Thyroid cancer (national cancer registers)","endpoints":null,"effect_estimate":"HR 0.93; medullary HR 1.19; vs SGLT2i HR 1.16","confidence_interval":"0.66 to 1.31","p_value":null,"sample_size":437077,"follow_up":"mean 3.9 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes (glucose-lowering users)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 437077, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Diabetes populations; follow-up short for thyroid cancer latency.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 437077, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"DPP-4 inhibitors (main) and SGLT2 inhibitors\", \"follow_up_duration\": \"mean 3.9 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"upper CI 1.31 excludes large increases\", \"risk_of_bias\": \"active-comparator design; observational\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large multinational register cohort with cancer-register outcomes; short follow-up.","funding_source":"Swedish Cancer Society, Swedish Research Council, Karolinska Institutet, Novo Nordisk Foundation, other foundations","industry_funded":"partial","manufacturer":"Novo Nordisk Foundation (independent foundation; majority shareholder of the company)","author_conflicts":"One author employed by NordicRWE; another reports fees from Novo Nordisk, Eli Lilly and others.","sponsor_role":"Foundation grant; no company role stated.","independent_replication_exists":"contradicted by French case-control (PMID 36356111)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 145,410 Scandinavian GLP-1 users followed for about 4 years, GLP-1 drug use was not associated with a substantially higher risk of thyroid cancer than DPP-4 inhibitor use (HR 0.93, 95% CI 0.66-1.31); the data cannot rule out up to a 31% relative increase, and the estimate for medullary thyroid cancer was very imprecise (HR 1.19, 0.37-3.86). Follow-up is too short to rule out very long-latency effects.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":9,"doi":"10.1056/nejmoa2312323","pmid":"38598572","nct_ids":"[\"NCT03439943\"]","title":"Trial of Lixisenatide in Early Parkinson's Disease","authors":"[\"Meissner WG\", \"Remy P\", \"Giordana C\", \"Maltête D\", \"Derkinderen P\", \"Houéto JL\", \"Anheim M\", \"Benatru I\", \"Boraud T\", \"Brefel-Courbon C\", \"Carrière N\", \"Catala H\", \"Colin O\", \"Corvol JC\", \"Damier P\", \"Dellapina E\", \"Devos D\", \"Drapier S\", \"Fabbri M\", \"Ferrier V\", \"Foubert-Samier A\", \"Frismand-Kryloff S\", \"Georget A\", \"Germain C\", \"Grimaldi S\", \"Hardy C\", \"Hopes L\", \"Krystkowiak P\", \"Laurens B\", \"Lefaucheur R\", \"Mariani LL\", \"Marques A\", \"Marse C\", \"Ory-Magne F\", \"Rigalleau V\", \"Salhi H\", \"Saubion A\", \"Stott SRW\", \"Thalamas C\", \"Thiriez C\", \"Tir M\", \"Wyse RK\", \"Benard A\", \"Rascol O\", \"LIXIPARK Study Group\"]","journal":"The New England journal of medicine","publication_date":"2024-04-04","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. [METHODS] In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. [RESULTS] A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. [CONCLUSIONS] In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).","url":"https://pubmed.ncbi.nlm.nih.gov/38598572/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T13:04:18+00:00","study_design":"rct","drugs":"[\"lixisenatide\"]","drug_details":"{\"dose\": \"daily (10 then 20 micrograms, full text, not checked)\", \"route\": \"subcutaneous\", \"treatment_duration\": \"12 months plus 2-month washout\", \"comparator\": \"placebo\"}","domains":"[\"parkinsons\", \"neuroinflammation\"]","outcome_type":"intermediate","primary_outcome":"Change in MDS-UPDRS part III on-medication at 12 months","endpoints":null,"effect_estimate":"Difference 3.08 points favouring lixisenatide (-0.04 vs +3.04)","confidence_interval":"0.86 to 5.30","p_value":"0.007","sample_size":156,"follow_up":"12 months (+2 months washout)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not an entry criterion\", \"diabetes_status\": \"not an entry criterion (diabetes excluded per protocol, full text, not checked)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"early Parkinson's disease (<3 years), no motor complications\", \"sample_size\": 156, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"Not selected for obesity or diabetes; early PD patients. Outcome is disease-specific.","mediation":"unlikely","mediation_notes":"Motor progression endpoint; weight loss not a plausible mediator, but nausea (46%) may have affected blinding.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 156, \"randomization\": \"yes\", \"blinding\": \"double-blind (possible unblinding by GI effects)\", \"comparator\": \"placebo\", \"follow_up_duration\": \"12 months (+2 months washout)\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed from this record's sources; the authors say longer and larger trials are needed\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"small; CI lower bound near zero\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Small phase 2 trial with a modest, on-medication difference; secondary endpoints mostly null; larger phase 3 with a different agent was negative.","funding_source":"French Ministry of Health and others; Cure Parkinson's (full text, not checked)","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"Academic sponsor; Sanofi supplied drug (full text, not checked).","independent_replication_exists":"no","conflict_notes":null,"adverse_events":"Nausea 46%, vomiting 13%.","limitations":null,"plain_summary":"In 156 people with early Parkinson's disease, daily lixisenatide was associated with about 3 points less motor worsening than placebo over 12 months, at the cost of frequent nausea. Other measures, including other parts of the Parkinson's rating scale and medication doses, did not differ much between groups. This is a small phase 2 signal; the authors say longer and larger trials are needed.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":428,"doi":"10.1001/jamanetworkopen.2024.1545","pmid":"38470420","nct_ids":"[\"NCT04881110\"]","title":"Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease: The STARDUST Randomized Clinical Trial","authors":"[\"Caruso P\", \"Maiorino MI\", \"Longo M\", \"Porcellini C\", \"Matrone R\", \"Digitale Selvaggio L\", \"Gicchino M\", \"Carbone C\", \"Scappaticcio L\", \"Bellastella G\", \"Giugliano D\", \"Esposito K\"]","journal":"JAMA network open","publication_date":"2024-03-04","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. [OBJECTIVE] To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. [DESIGN, SETTING, AND PARTICIPANTS] This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania \"Luigi Vanvitelli,\" Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. [INTERVENTIONS] Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. [MAIN OUTCOMES AND MEASURES] Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. [RESULTS] Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). [CONCLUSIONS AND RELEVANCE] In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT04881110.","url":"https://pubmed.ncbi.nlm.nih.gov/38470420/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":429,"doi":"10.1513/annalsats.202309-821oc","pmid":"38096106","nct_ids":"[\"NCT04186494\"]","title":"Continuous Positive Airway Pressure but Not GLP1-mediated Weight Loss Improves Early Cardiovascular Disease in Obstructive Sleep Apnea: A Randomized Proof-of-Concept Study","authors":"[\"O'Donnell C\", \"Crilly S\", \"O'Mahony A\", \"O'Riordan B\", \"Traynor M\", \"Gitau R\", \"McDonald K\", \"Ledwidge M\", \"O'Shea D\", \"Murphy DJ\", \"Dodd JD\", \"Ryan S\"]","journal":"Annals of the American Thoracic Society","publication_date":"2024-03","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Rationale: Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular (CV) morbidity and mortality, but the benefit of continuous positive airway pressure (CPAP) is uncertain. However, most randomized controlled trials have focused on the role of CPAP in secondary prevention, although there is growing evidence of a potential benefit on early CV disease. Weight loss in combination with CPAP may be superior but is difficult to achieve and maintain with conventional measures alone. Objectives: The aim of this study was to gain insights into the effect of CPAP on early atherosclerotic processes and to compare it with a glucagon-like peptide (GLP)-1-mediated weight loss regimen in patients with OSA. Methods: We performed a randomized proof-of-concept study comparing CPAP, a GLP1-mediated weight-loss regimen (liraglutide [Lir]), and both in combination for 24 weeks in 30 consecutive patients with OSA (apnea-hypopnea index >15 events/h; body mass index 30-40 kg/m2; and no history of diabetes, heart failure, or unstable CV disease). In addition to extensive evaluation for CV risk factors and endothelial function at baseline and end of study, subjects underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET-CT) for the measurement of aortic wall inflammation (target-to-background ratio) and coronary computed tomography angiography for semiautomated coronary plaque analysis. Results: Baseline characteristics were similar between groups. CPAP alone and in combination resulted in greater reduction in apnea-hypopnea index than Lir alone (mean difference, -45 and -43 events/h, respectively, vs. -12 events/h; P < 0.05). Both Lir and combination treatment led to significant weight loss, but only CPAP alone resulted in significant decrease in vascular inflammation (aortic wall target-to-background ratio from 2.03 ± 0.34 to 1.84 ± 0.43; P = 0.010), associated with an improvement in endothelial function and a decrease in C-reactive protein. Low-attenuation coronary artery plaque volume as a marker of unstable plaque also decreased with CPAP (from 571 ± 490 to 334 ± 185 mm3) and with combination therapy (from 401 ± 145 to 278 ± 126 mm3) but not with Lir. Conclusions: These data suggest that CPAP therapy, but not GLP1-mediated weight loss, improves vascular inflammation and reduces unstable plaque volume in patients with OSA. Further large randomized controlled studies are warranted to assess the benefit of CPAP therapy in modifying early CV disease. Clinical trial registered with www.clinicaltrials.gov (NCT04186494).","url":"https://pubmed.ncbi.nlm.nih.gov/38096106/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"sleep\", \"mortality\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":430,"doi":"10.1111/dom.15386","pmid":"38016699","nct_ids":"[]","title":"Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial","authors":"[\"Qin W\", \"Yang J\", \"Deng C\", \"Ruan Q\", \"Duan K\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2024-03","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To explore the safety and efficacy of subcutaneous semaglutide 2.4 mg, administered once a week in non-diabetic overweight or obese individuals. [METHODS] A thorough search was performed of various databases including PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrials.gov, CNKI and Wanfang from their inception up to April 11, 2023. Our aim was to identify randomized controlled trials (RCTs) that compared the efficacy of semaglutide administered once weekly with placebo in overweight or obese adults. Through a review of the literature, data were extracted from relevant studies and assessed for quality, and a meta-analysis was conducted using RevMan 5.4.1 software. [RESULTS] Six RCTs comprising 3962 overweight or obese individuals were identified. The findings indicated that, in comparison to the placebo group, semaglutide caused a significant and sustainable reduction in the percentage of body weight (BW; mean difference [MD]: -11.80% [95% confidence interval {CI} -12.93, -10.68]; P < 0.00001) as well as a decrease in absolute BW (MD: -12.2 kg [95% CI -13.3, -11.1]; P < 0.00001), body mass index (MD: -4.5 kg/m2 [95% CI -4.9, -4.1]; P < 0.00001) and waist circumference (MD:-9.4 cm [95% CI -10.1, -8.8]; P < 0.00001). Moreover, it achieved a higher proportion of patients who experienced weight loss exceeding 5%, 10%, 15% and 20%. Furthermore, semaglutide showed significant efficacy in controlling blood pressure, blood sugar levels, C-reactive protein levels, and lipid profiles. In terms of safety, the most common adverse effects following semaglutide treatment were gastrointestinal adverse reactions (risk ratio: 1.49 [95% CI 1.38, 1.60]; P < 0.00001), which were generally mild to moderate in severity and temporary. [CONCLUSION] In overweight or obese non-diabetic individuals, semaglutide had a remarkable and sustained weight loss effect that was well tolerated and safe.","url":"https://pubmed.ncbi.nlm.nih.gov/38016699/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":432,"doi":"10.1161/circulationaha.123.067505","pmid":"37952180","nct_ids":"[\"NCT04788511\"]","title":"Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial","authors":"[\"Kosiborod MN\", \"Verma S\", \"Borlaug BA\", \"Butler J\", \"Davies MJ\", \"Jon Jensen T\", \"Rasmussen S\", \"Erlang Marstrand P\", \"Petrie MC\", \"Shah SJ\", \"Ito H\", \"Schou M\", \"Melenovský V\", \"Abhayaratna W\", \"Kitzman DW\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"Circulation","publication_date":"2024-01-16","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. [METHODS] STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. [RESULTS] Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). [CONCLUSIONS] In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. [REGISTRATION] URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.","url":"https://pubmed.ncbi.nlm.nih.gov/37952180/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":28,"doi":"10.1001/jama.2023.24945","pmid":"38078870","nct_ids":"[\"NCT04660643\"]","title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial","authors":"[\"Aronne LJ\", \"Sattar N\", \"Horn DB\", \"Bays HE\", \"Wharton S\", \"Lin WY\", \"Ahmad NN\", \"Zhang S\", \"Liao R\", \"Bunck MC\", \"Jouravskaya I\", \"Murphy MA\", \"SURMOUNT-4 Investigators\"]","journal":"JAMA","publication_date":"2024-01-02","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. [OBJECTIVE] To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. [DESIGN, SETTING, AND PARTICIPANTS] This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. [INTERVENTIONS] Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. [MAIN OUTCOMES AND MEASURES] The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. [RESULTS] Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. [CONCLUSIONS AND RELEVANCE] In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. [TRIAL REGISTRATION] ClinicalTrials.gov Identifier: NCT04660643.","url":"https://pubmed.ncbi.nlm.nih.gov/38078870/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":6,"assessed_by":"curated","assessed_at":"2026-11-09T13:53:34+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"10 or 15 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"36-week lead-in then 52-week randomized withdrawal\", \"comparator\": \"placebo\"}","domains":"[\"discontinuation\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"Percent weight change from week 36 to 88","endpoints":null,"effect_estimate":"-5.5% (continued) vs +14.0% (placebo); difference -19.4%","confidence_interval":"-21.2 to -17.7","p_value":"<0.001","sample_size":670,"follow_up":"88 weeks","direction":"benefit","population":"{\"mean_age\": 48, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"71% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity or overweight with complication\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 670, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity without diabetes; younger.","mediation":"not_applicable","mediation_notes":"Participants had obesity, or overweight with a weight-related complication; diabetes was excluded. The primary outcome is weight change itself.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 670, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"88 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -21.2 to -17.7\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"Eli Lilly; NIH grant listed by PubMed: National Center for Advancing Translational Sciences","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"consistent with STEP 1 extension","conflict_notes":null,"adverse_events":"Mostly mild-to-moderate gastrointestinal events, more common with tirzepatide than placebo.","limitations":null,"plain_summary":"People who switched from tirzepatide to placebo after 36 weeks regained about 14% of body weight within a year, while those continuing lost a further 5.5%. Stopping led to substantial regain, though after 88 weeks the placebo group was still about 10% below starting weight (versus 25% with continued tirzepatide).","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":16,"doi":"10.1038/s41591-023-02672-2","pmid":"38182782","nct_ids":"[]","title":"Association of semaglutide with risk of suicidal ideation in a real-world cohort","authors":"[\"Wang W\", \"Volkow ND\", \"Berger NA\", \"Davis PB\", \"Kaelber DC\", \"Xu R\"]","journal":"Nature medicine","publication_date":"2024-01","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.","url":"https://pubmed.ncbi.nlm.nih.gov/38182782/","source_name":"pubmed","source_tier":1,"coi_statement":"Competing interests. The authors declare no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"non-GLP-1 anti-obesity or antidiabetic medications\"}","domains":"[\"psychiatric\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Incident and recurrent suicidal ideation over 6 months","endpoints":null,"effect_estimate":"Incident HR 0.27; recurrent HR 0.44 (obesity cohort); replicated in T2D","confidence_interval":"0.32 to 0.60 (recurrent)","p_value":null,"sample_size":240618,"follow_up":"6 months","direction":"null","population":"{\"mean_age\": 50.1, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"72.6% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"overweight/obesity cohort; T2D replication cohort\", \"diabetes_status\": \"separate cohorts\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 240618, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"EHR cohorts with obesity or diabetes; younger than target.","mediation":"unknown","mediation_notes":"Safety outcome.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 240618, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"non-GLP-1 anti-obesity or antidiabetic medications\", \"follow_up_duration\": \"6 months\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"large cohort\", \"risk_of_bias\": \"EHR diagnosis codes; residual confounding; short follow-up\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large propensity-matched EHR cohort; observational; short follow-up.","funding_source":"NIH (NIA, NIAAA, NICHD, NCI)","industry_funded":"no","manufacturer":null,"author_conflicts":"Authors declare no competing interests.","sponsor_role":"Independent.","independent_replication_exists":"yes (Nordic registers, PMID 39226030)","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 240,618 US patients with overweight or obesity, semaglutide was associated with lower, not higher, rates of suicidal thoughts compared with other weight-loss drugs over six months. Publicly funded; does not support the suicidality concern.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":438,"doi":"10.1007/s12020-023-03487-4","pmid":"37653215","nct_ids":"[\"NCT03151005\"]","title":"Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial","authors":"[\"Liao M\", \"Li X\", \"Zhang H\", \"Zhou L\", \"Shi L\", \"Li W\", \"Shen R\", \"Peng G\", \"Zhao H\", \"Shao J\", \"Wang X\", \"Sun Z\", \"Zheng H\", \"Long M\"]","journal":"Endocrine","publication_date":"2024-01","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[PURPOSE] Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. [METHODS] In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-μg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. [RESULTS] Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). [CONCLUSIONS] Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. [GOV TRIAL NO] NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .","url":"https://pubmed.ncbi.nlm.nih.gov/37653215/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"immune\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":62,"doi":"10.4103/jispcd.jispcd_5_26","pmid":"42730115","nct_ids":"[]","title":"Oral Adverse Effects of Semaglutide Therapy: A Narrative Review","authors":"[\"Al-Zawawi AS\"]","journal":"Journal of International Society of Preventive & Community Dentistry","publication_date":"2024","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Semaglutide, a glucagon-like peptide-1-receptor agonist, is widely used for the management of type-2 diabetes mellitus and obesity. Despite its increasing clinical use, the drug's oral adverse effect profile remains inadequately characterized. This narrative review aimed to analyze the current evidence on semaglutide-associated oral adverse effects, with emphasis on mechanistic pathways, integration of pharmacovigilance and clinical data, and emerging implications for oral health and dental practice. [METHODS] A comprehensive literature search was conducted across PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar. Keywords related to semaglutide and oral adverse effects were used. Eligible studies included clinical trials, pharmacovigilance analyses, observational studies, case reports, and preclinical research reporting oral adverse effects or relevant mechanistic insights. Studies lacking oral health correlates were excluded. Findings were narratively reviewed in accordance with Scale for the Assessment of Narrative Review Articles guidelines. [RESULTS] Xerostomia or hyposalivation is the most consistently reported oral adverse effect, although its prevalence varies across studies. However, xerostomia often occurs secondarily to gastrointestinal symptoms including nausea, reduced oral intake, and delayed gastric emptying. Additional manifestations included dysgeusia, dry throat, oral paresthesia or hypoesthesia, halitosis, frothy saliva, and increased dental caries. Pharmacovigilance data show significant signals for dry mouth and altered taste. Case-series confirm semaglutide-associated hyposalivation. Limited evidence suggests increased susceptibility to oral candidiasis. Early experimental and observational data indicate potential modulatory effects on inflammation, tissue repair, and bone metabolism. [CONCLUSION] Semaglutide therapy is associated with oral adverse effects, mainly xerostomia and sensory disturbances, which may compromise oral health. Awareness of these outcomes highlights the need for interdisciplinary oral health monitoring.","url":"https://pubmed.ncbi.nlm.nih.gov/42730115/","source_name":"pubmed","source_tier":1,"coi_statement":"There are no conflicts of interest.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"bone\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":417,"doi":"10.3389/fcvm.2024.1379189","pmid":"39055657","nct_ids":"[]","title":"Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis","authors":"[\"Masson W\", \"Lobo M\", \"Nogueira JP\", \"Rodriguez-Granillo AM\", \"Barbagelata LE\", \"Siniawski D\"]","journal":"Frontiers in cardiovascular medicine","publication_date":"2024","year":2024,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. [METHODS] This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. [RESULTS] Thirteen randomised clinical trials were considered eligible (n = 26,131). Overall, semaglutide therapy was associated with lower CRP index values compared to the placebo group (SMD -0.56; 95% CI -0.69 to -0.43, I 2 92%) or the control group (SMD -0.45; 95% CI -0.68 to -0.23, I 2 82%).Such an association was similarly observed when different treatment regimens (subcutaneous vs. oral) or different populations (patients with or without T2DM) were analysed. The sensitivity analysis showed that the results were robust. [CONCLUSION] The present meta-analysis demonstrated that the use of semaglutide was associated with a reduction in inflammation irrespective of the population evaluated or the treatment regimen used. These findings would explain one of the mechanisms by which semaglutide reduces cardiovascular events. [SYSTEMATIC REVIEW REGISTRATION] PROSPERO [CRD42024500551].","url":"https://pubmed.ncbi.nlm.nih.gov/39055657/","source_name":"pubmed","source_tier":1,"coi_statement":"WM, ML and DS have served as a speaker from Novo Nordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"route\": \"subcutaneous and oral\", \"comparator\": \"placebo or other glucose-lowering drugs\"}","domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":26131,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed: type 2 diabetes and/or overweight or obesity (5 trials in T2D, 6 in overweight or obesity without T2D)\", \"diabetes_status\": \"mixed (with and without type 2 diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 26131, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.","mediation":"possibly","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 26131, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo or other glucose-lowering drugs\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaw on item 7; non-critical weaknesses on items 3, 5, 6, 10\", \"items\": {\"1\": \"Yes\", \"2\": \"Partial Yes\", \"3\": \"No\", \"4\": \"Partial Yes\", \"5\": \"No\", \"6\": \"No\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"Yes\", \"12\": \"Yes\", \"13\": \"Yes\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 5, \"Partial Yes\": 3, \"Yes\": 8}, \"settled_by_ruling\": [\"item 5: No (IN-057; the passes read No and Yes)\", \"item 6: No (IN-057; the passes read No and Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/39055657/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/39055657/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-01-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"Journal submission funded by Novo Nordisk Pharma Argentina S.A., which the authors say did not influence the content or take part in the study (full text)","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"WM, ML and DS have served as a speaker from Novo Nordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"Across 13 randomized trials, semaglutide lowered CRP (a blood marker of inflammation) versus placebo or other drugs, with very high heterogeneity (I2 82-92%). The drop was larger in people without type 2 diabetes than in people with it (interaction p ≤ 0.0001). The analysis did not test cardiovascular events.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":1,"doi":"10.1056/nejmoa2307563","pmid":"37952131","nct_ids":"[\"NCT03574597\"]","title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","authors":"[\"Lincoff AM\", \"Brown-Frandsen K\", \"Colhoun HM\", \"Deanfield J\", \"Emerson SS\", \"Esbjerg S\", \"Hardt-Lindberg S\", \"Hovingh GK\", \"Kahn SE\", \"Kushner RF\", \"Lingvay I\", \"Oral TK\", \"Michelsen MM\", \"Plutzky J\", \"Tornøe CW\", \"Ryan DH\", \"SELECT Trial Investigators\"]","journal":"The New England journal of medicine","publication_date":"2023-12-14","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. [METHODS] In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. [RESULTS] A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). [CONCLUSIONS] In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).","url":"https://pubmed.ncbi.nlm.nih.gov/37952131/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"mean exposure 34.2 months\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"Composite of CV death, nonfatal MI, nonfatal stroke (time to first event)","endpoints":"Primary MACE; secondary: CV death, heart-failure composite, all-cause death; safety","effect_estimate":"HR 0.80 (6.5% vs 8.0%)","confidence_interval":"0.72 to 0.90","p_value":"<0.001","sample_size":17604,"follow_up":"mean 39.8 months","direction":"benefit","population":"{\"mean_age\": 61.6, \"age_range\": null, \"age_min\": 45, \"sex_distribution\": null, \"bmi_mean\": 33.4, \"bmi_min\": 27, \"obesity_status\": \"overweight/obesity required (BMI >= 27); mean BMI 33.4\", \"diabetes_status\": \"excluded (no history of diabetes)\", \"cvd_status\": \"established cardiovascular disease required\", \"ckd_status\": \"not an entry criterion\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 17604, \"inclusion_exclusion\": \"Age >= 45, BMI >= 27, prior MI/stroke/PAD, no diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"All participants had established atherosclerotic disease and BMI >= 27 (mean 33.4); no normal-weight participants. Age range overlaps the target. Absolute benefit (1.5 percentage points over ~3.3 years) was measured in a high-risk secondary-prevention group.","mediation":"possibly","mediation_notes":"Primary paper does not separate weight-loss effects; prespecified analyses (records for PMID 41138739 and 42610271) later examined adiposity and hs-CRP mediation.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 17604, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"mean 39.8 months\", \"outcome_type\": \"hard\", \"replication\": \"consistent with T2D CVOTs (LEADER, SUSTAIN-6, REWIND); no independent replication in non-diabetic obesity\", \"consistency_with_other_evidence\": \"consistent with class effect\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"narrow CI, 1270 primary events\", \"risk_of_bias\": \"low for outcome ascertainment; 16.6% discontinuation on drug\", \"funding_conflicts\": \"manufacturer funded, sponsor employees co-authored\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large, event-driven, double-blind, placebo-controlled trial with adjudicated hard outcomes. Certainty is high for the enrolled population; the sponsor designed and analysed the trial.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Steering committee members report consulting/grant relationships with Novo Nordisk and other companies; sponsor employees are co-authors (see published disclosure forms).","sponsor_role":"Sponsor designed the trial with the steering committee, collected data and performed analyses (per trial methods; verify in the protocol/disclosures).","independent_replication_exists":"no (single trial in this population); class consistency from T2D trials","conflict_notes":"Pivotal industry trial. Design quality is high; interpretation of secondary analyses should account for sponsor involvement.","adverse_events":"Adverse events leading to permanent discontinuation 16.6% vs 8.2% (P<0.001), mainly gastrointestinal. Serious adverse events lower with semaglutide (33.4% vs 36.4%, from full text).","limitations":"Secondary-prevention population with obesity; cannot inform primary prevention or normal-weight adults. Weight loss and CV benefit not separated in the primary report.","plain_summary":"In 17,604 adults with prior heart disease or stroke and BMI of 27 or more but no diabetes, weekly semaglutide reduced the combined rate of cardiovascular death, heart attack and stroke from 8.0% to 6.5% over about 3.3 years. Twice as many people stopped the drug because of side effects, mostly gastrointestinal. This is strong evidence for people like those enrolled; it says nothing directly about people of normal weight.","methodological_notes":"Event-driven superiority design; 1270 primary events. Funded and analysed by Novo Nordisk.","reviewed_by":null,"reviewed_at":null},{"id":302,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2023-12-12","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-12-12","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Disease [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than plac\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 , 12.3 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 , 5.1 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 , 5.4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=58353438-3236-4596-9324-62fed9615cb7","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":303,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2023-12-09","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-12-09","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Disease [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than plac\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 , 12.3 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 , 5.1 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 , 5.4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6088c732-afa1-4fee-9206-22e52baf4731","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":437,"doi":"10.1016/j.molmet.2023.101801","pmid":"37690519","nct_ids":"[]","title":"Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity","authors":"[\"Friedrichsen MH\", \"Endahl L\", \"Kreiner FF\", \"Goldwater R\", \"Kankam M\", \"Toubro S\", \"Nygård SB\"]","journal":"Molecular metabolism","publication_date":"2023-12","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. [METHODS] Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 μg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 μg) or placebo, and a drug-drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-μg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. [RESULTS] For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 μg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. [CONCLUSION] Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.","url":"https://pubmed.ncbi.nlm.nih.gov/37690519/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Friedrichsen, Lars Endahl, Frederik Kreiner, Søren Toubro and Sune Nygård are employees of Novo Nordisk A/S. Martin Friedrichsen, Lars Endahl and Frederik Kreiner are shareholders in Novo Nordisk A/S. Martin Kankam has received funding from Diffusion Pharmaceutical Inc., Grifols, Urovant Sciences, ViroDefense, Merck, PhaseBio Pharmaceuticals, Inc., Idorsia Pharmaceuticals Ltd, DynPort Vaccine company/FDA/NIH, and Aerovate Therapeutics. Ronald Goldwater is an employee of Parexel International.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\", \"adverse_effects\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":431,"doi":"10.1016/j.jacc.2023.09.811","pmid":"37993201","nct_ids":"[\"NCT04788511\"]","title":"Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction","authors":"[\"Butler J\", \"Abildstrøm SZ\", \"Borlaug BA\", \"Davies MJ\", \"Kitzman DW\", \"Petrie MC\", \"Shah SJ\", \"Verma S\", \"Abhayaratna WP\", \"Chopra V\", \"Ezekowitz JA\", \"Fu M\", \"Ito H\", \"Lelonek M\", \"Núñez J\", \"Perna E\", \"Schou M\", \"Senni M\", \"van der Meer P\", \"von Lewinski D\", \"Wolf D\", \"Altschul RL\", \"Rasmussen S\", \"Kosiborod MN\"]","journal":"Journal of the American College of Cardiology","publication_date":"2023-11-28","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). [OBJECTIVES] In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. [METHODS] STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229). [RESULTS] At 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: -2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: -7.6 [95% CI: -10.7 to -4.4], EF 50%-59%: -10.6 [95% CI: -12.6 to -8.6] and EF ≥60%: -11.9 [95% CI: -13.8 to -9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories. [CONCLUSIONS] In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511).","url":"https://pubmed.ncbi.nlm.nih.gov/37993201/","source_name":"pubmed","source_tier":1,"coi_statement":"Funding Support and Author Disclosures The STEP-HFpEF trial was funded by Novo Nordisk A/S. Dr Butler is a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Borlaug has received research support from the National Institutes of Health and the U.S. Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is a named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has received consultancy and committee payments for AbbVie, Akero, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiorentis, Horizon Therapeutics, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, Takeda, Teikoku, and Vifor. Dr Shah has received consulting fees from Abbott, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Verma has received research grants or consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Napp Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, New Amsterdam, Novo Nordisk, Resverlogix, and Teikoku; and is Director of Global Clinical Trial Partners (GCTP). Dr Abhayaratna has received honoraria and/or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Chopra has received speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy’s, Lupin, Mankind, Novartis, Novo Nordisk, Pfizer, Sanofi, Sun Pharma, and Torrent. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and serves as an advisor to US2.ai. Dr Ito has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Lelonek has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. Dr Núñez has received honoraria and/or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, Novo Nordisk, Pfizer, Rovi, and Vifor. Dr Perna has received honoraria from Novo Nordisk. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Senni has received honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr van der Meer has received institutional payments for consultancy fees and/or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. Dr von Lewinski has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. Dr Wolf is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (German Research Foundation); and has received consultancy fees from Novo Nordisk and Novartis. Drs Abildstrøm, Altschul, and Rasmussen are employees of and hold shares in Novo Nordisk. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"unknown","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":292,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: Ozempic (SEMAGLUTIDE) - label effective 2023-11-22","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-11-22","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )] . • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). • Diabetic Retinopathy Complications: Has been reported in a clinical trial. Patients with a history of diabetic retinopathy should be monitored ( 5.3 ). • Never share an OZEMPIC pen between patients , even if the needle is changed ( 5.4 ). • Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary ( 5.5 ). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.6 ). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue OZEMPIC if suspected and promptly seek medical advice ( 5.7 ). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether OZEMPIC causes thyroid C-cell tumors, including MTC, in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo-treated patients (0.33 cases per 100 patient years), both on a background of standard of care. After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management initiated; if confirmed, OZEMPIC should not be restarted. 5.3 Diabetic Retinopathy Complications In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with OZEMPIC (3.0%) compared to placebo (1.8%). The a\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Pancreatitis [see Warnings and Precautions ( 5.2 )] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.5 )] • Acute Kidney Injury [see Warnings and Precautions ( 5.6 )] • Hypersensitivity [see Warnings and Precautions ( 5.7 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] The most common adverse reactions, reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] . These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5.0 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5.0 3.1 In the pool of placebo- and active-controll\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications : OZEMPIC delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution ( 7.2 ). 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6 )] . 7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6 )] .\n7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS OZEMPIC is contraindicated in patients with: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions ( 5.1 )] . • A serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with OZEMPIC [see Warnings and Precautions ( 5.7 )] . • Personal or family history of MTC or in patients with MEN 2 ( 4 ). • Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC ( 4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=979e4df4-0597-48ea-b51c-0f699fa6d166","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":293,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: OZEMPIC (SEMAGLUTIDE) - label effective 2023-11-17","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-11-17","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )] . • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications ( 4 )] . Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS • Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). • Diabetic Retinopathy Complications: Has been reported in a clinical trial. Patients with a history of diabetic retinopathy should be monitored ( 5.3 ). • Never share an OZEMPIC pen between patients , even if the needle is changed ( 5.4 ). • Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary ( 5.5 ). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.6 ). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue OZEMPIC if suspected and promptly seek medical advice ( 5.7 ). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether OZEMPIC causes thyroid C-cell tumors, including MTC, in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of OZEMPIC and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with OZEMPIC. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. In a 2-year trial, acute pancreatitis was confirmed by adjudication in 8 OZEMPIC-treated patients (0.27 cases per 100 patient years) and 10 placebo-treated patients (0.33 cases per 100 patient years), both on a background of standard of care. After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management initiated; if confirmed, OZEMPIC should not be restarted. 5.3 Diabetic Retinopathy Complications In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with OZEMPIC (3.0%) compared to placebo (1.8%). The a\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Pancreatitis [see Warnings and Precautions ( 5.2 )] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.5 )] • Acute Kidney Injury [see Warnings and Precautions ( 5.6 )] • Hypersensitivity [see Warnings and Precautions ( 5.7 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] The most common adverse reactions, reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] . These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5.0 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5.0 3.1 In the pool of placebo- and active-controll\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications : OZEMPIC delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution ( 7.2 ). 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6 )] . 7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin OZEMPIC stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving OZEMPIC in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating OZEMPIC, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6 )] .\n7.2 Oral Medications OZEMPIC causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, semaglutide did not affect the absorption of orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with OZEMPIC.\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS OZEMPIC is contraindicated in patients with: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions ( 5.1 )] . • A serious hypersensitivity reaction to semaglutide or to any of the excipients in OZEMPIC. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with OZEMPIC [see Warnings and Precautions ( 5.7 )] . • Personal or family history of MTC or in patients with MEN 2 ( 4 ). • Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC ( 4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e6da837c-0da0-41d6-973c-5559bf764367","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":14,"doi":"10.1001/jama.2023.19574","pmid":"37796527","nct_ids":"[]","title":"Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss","authors":"[\"Sodhi M\", \"Rezaeianzadeh R\", \"Kezouh A\", \"Etminan M\"]","journal":"JAMA","publication_date":"2023-11-14","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":null,"url":"https://pubmed.ncbi.nlm.nih.gov/37796527/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"comparator\": \"bupropion-naltrexone\"}","domains":"[\"gastrointestinal\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Pancreatitis, gastroparesis, bowel obstruction, biliary disease (claims data, weight-loss indication)","endpoints":null,"effect_estimate":"Not checked against the source: the letter has no abstract on file and its full text is not cached.","confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"prescribed for weight loss (non-diabetic users)\", \"diabetes_status\": \"excluded (diabetes users removed)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Non-diabetic weight-loss users in US claims data; BMI not available. Closest harm data to a non-diabetic population.","mediation":"unknown","mediation_notes":"Harm outcome; not applicable.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"bupropion-naltrexone\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not checked against the source\", \"risk_of_bias\": \"claims-based ascertainment; active comparator reduces but does not remove confounding\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Observational claims analysis with few events; relative effects are imprecise but directionally consistent with pharmacology and later cohorts.","funding_source":"Not stated in PubMed metadata (research letter)","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"Academic analysis.","independent_replication_exists":"partly (VA atlas PMID 39833406 reports pancreatitis signal)","conflict_notes":null,"adverse_events":null,"limitations":"No abstract in PubMed (JAMA research letter); figures withheld until verified against the full text.","plain_summary":"A JAMA research letter on gastrointestinal adverse events in people without diabetes using GLP-1 drugs for weight loss, compared with bupropion-naltrexone, using US insurance claims. Its figures are not shown here because they have not been checked against the source.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":3,"doi":"10.1056/nejmoa2306963","pmid":"37622681","nct_ids":"[\"NCT04788511\"]","title":"Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity","authors":"[\"Kosiborod MN\", \"Abildstrøm SZ\", \"Borlaug BA\", \"Butler J\", \"Rasmussen S\", \"Davies M\", \"Hovingh GK\", \"Kitzman DW\", \"Lindegaard ML\", \"Møller DV\", \"Shah SJ\", \"Treppendahl MB\", \"Verma S\", \"Abhayaratna W\", \"Ahmed FZ\", \"Chopra V\", \"Ezekowitz J\", \"Fu M\", \"Ito H\", \"Lelonek M\", \"Melenovsky V\", \"Merkely B\", \"Núñez J\", \"Perna E\", \"Schou M\", \"Senni M\", \"Sharma K\", \"Van der Meer P\", \"von Lewinski D\", \"Wolf D\", \"Petrie MC\", \"STEP-HFpEF Trial Committees and Investigators\"]","journal":"The New England journal of medicine","publication_date":"2023-09-21","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. [METHODS] We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. [RESULTS] The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. [CONCLUSIONS] In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).","url":"https://pubmed.ncbi.nlm.nih.gov/37622681/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"Randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase 3 trial; 52-week treatment period","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"inflammation\", \"body_composition\"]","outcome_type":"mixed","primary_outcome":"Dual: change in KCCQ-CSS and change in body weight at 52 weeks","endpoints":null,"effect_estimate":"KCCQ-CSS +7.8 points; weight -10.7 percentage points; 6MWD +20.3 m; CRP treatment ratio 0.61","confidence_interval":"KCCQ 4.8 to 10.9; weight -11.9 to -9.4; 6-minute walk 8.6 to 32.1; CRP 0.51 to 0.72 (all 95% CI)","p_value":"<0.001","sample_size":529,"follow_up":"52 weeks treatment period (plus 5-week follow-up; hierarchical composite endpoint assessed to week 57)","direction":"benefit","population":"{\"condition\": \"Heart failure with preserved ejection fraction and obesity\", \"mean_age\": \"NI\", \"sex\": \"NI\", \"bmi_criterion\": \"BMI >= 30.0 kg/m^2\", \"diabetes_status\": \"not reported (trial excluded HbA1c >=6.5%; overall diabetes prevalence/status of randomized participants not given in available sources)\", \"sample_size\": 529}","applicability":"INDIRECT","applicability_rationale":"Participants had HFpEF and BMI >= 30. Outcomes were symptoms, walking distance and CRP, not events.","mediation":"likely","mediation_notes":"Weight loss was a co-primary endpoint (-13.3%); symptom and CRP improvements were not separated from weight loss in the abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase 3 trial; 52-week treatment period\", \"sample_size\": 529, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks treatment period (plus 5-week follow-up; hierarchical composite endpoint assessed to week 57)\", \"outcome_type\": \"patient-reported and functional; CRP biomarker\", \"replication\": \"STEP-HFpEF DM and SUMMIT (tirzepatide) consistent\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: KCCQ 4.8 to 10.9; weight -11.9 to -9.4; 6-minute walk 8.6 to 32.1; CRP 0.51 to 0.72 (all 95% CI)\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\", \"rob2\": {\"O1\": {\"D1\": {\"judgment\": \"Low\", \"rationale\": \"Large industry-sponsored, multicentre phase 3 trial using a central interactive web response system (IWRS) for screening and randomisation, stratified by BMI; per the collection's domain rule this supports presumed allocation concealment (PY) absent contradicting evidence, and no baseline imbalance data were available to contradict it.\"}, \"D2\": {\"judgment\": \"Low\", \"rationale\": \"Per the guide, D2 for this lab-biomarker outcome is judged on discontinuation imbalance and ITT handling rather than on unblinding awareness. Treatment discontinuation ('NOT COMPLETED') was only modestly imbalanced (7/263, 2.7% semaglutide vs 12/266, 4.5% placebo), and the confirmatory analysis is performed on the Full Analysis Set (= all randomised participants) under a treatment-policy estimand,\"}, \"D3\": {\"judgment\": \"Low\", \"rationale\": \"CRP was analysed in 241/263 (91.6%) semaglutide and 243/266 (91.4%) placebo participants who had an observed week-52 value — missingness of 8.4% vs 8.6% (difference 0.2 points), below both the guide's >20%-missing and >5-point-differential thresholds, so the default is 'data available for nearly all' (PY) rather than PN. In addition, the prespecified primary analysis does not rely on observed case\"}, \"D4\": {\"judgment\": \"Low\", \"rationale\": \"CRP (hs-CRP) is an objective, centrally-assayed laboratory measurement per the guide's domain rule (central-lab hs-CRP is Low risk unless the assay changed or differed between arms); the protocol specifies central-laboratory testing for the trial's laboratory panel including CRP, applied identically to both arms, with no evidence of a mid-trial assay change.\"}, \"D5\": {\"judgment\": \"Low\", \"rationale\": \"CRP is explicitly prespecified as a confirmatory secondary endpoint in both the protocol (Section 3.2.2.1 / 9.4.3.1) and the SAP (Section 5.4.1), with its analysis method (log-transformed ANCOVA on ratio-to-baseline, same imputation approach as the primary endpoints) fully specified in advance, and its place in the alpha-preserving graphical multiplicity/gatekeeping procedure explicitly defined. O\"}, \"overall\": {\"judgment\": \"Low\"}, \"result\": \"CRP (high-sensitivity C-reactive protein), percentage/ratio change from baseline (week -2) to week 52, semaglutide vs placebo; confirmatory secondary endpoint; log-scale ANCOVA yielding estimated treatment (geometric-mean) ratio 0.61 (95% CI 0.51-0.72, P<0.001); numbers appear in the abstract RESULTS paragraph (no table/figure available — full text not provided) and are cross-referenced by the registry's 'Change in C-Reactive Protein (CRP): Ratio to Baseline' outcome measure.\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"guide_version\": \"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)\", \"label\": \"AI: two passes agreed\", \"resolution\": \"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)\"}}}","evidence_rationale":"Well-conducted RCT but symptom/functional outcomes over one year; not an event trial.","funding_source":"Novo Nordisk","industry_funded":"Y","manufacturer":"Novo Nordisk A/S (also lead sponsor)","author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"not reported in available sources (no explicit statement of sponsor's role in design/conduct/analysis/reporting was found in the abstract or provided protocol/SAP excerpts); registry lists sponsor as the trial's responsible party","independent_replication_exists":"no independent; consistent industry trials (SUMMIT)","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Serious adverse events 13.3% vs 26.7% (fewer with semaglutide).","limitations":"Obese HFpEF only; one year; no event outcomes.","plain_summary":"In 529 people with heart failure with preserved ejection fraction and obesity, semaglutide improved symptoms, walking distance and CRP while producing 13% weight loss over a year. Whether the heart-failure improvement is separate from weight loss was not tested.","methodological_notes":"Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/37622681/); sources: abstract, registry, public protocol/SAP where available; no paper full text.","reviewed_by":null,"reviewed_at":null},{"id":36,"doi":"10.1056/nejmoa2301972","pmid":"37366315","nct_ids":"[\"NCT04881760\"]","title":"Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial","authors":"[\"Jastreboff AM\", \"Kaplan LM\", \"Frías JP\", \"Wu Q\", \"Du Y\", \"Gurbuz S\", \"Coskun T\", \"Haupt A\", \"Milicevic Z\", \"Hartman ML\", \"Retatrutide Phase 2 Obesity Trial Investigators\"]","journal":"The New England journal of medicine","publication_date":"2023-08-10","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. [METHODS] We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. [RESULTS] We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. [CONCLUSIONS] In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).","url":"https://pubmed.ncbi.nlm.nih.gov/37366315/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"retatrutide\"]","drug_details":"{\"dose\": \"1 to 12 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"48 weeks\", \"comparator\": \"placebo\"}","domains":"[\"body_composition\", \"adverse_effects\", \"cardiovascular\"]","outcome_type":"intermediate","primary_outcome":"Percent change in body weight at 24 weeks","endpoints":null,"effect_estimate":"Primary (24 weeks): -17.5% (12 mg) vs -1.6% placebo; secondary (48 weeks): -24.2% (12 mg) vs -2.1% placebo; dose-dependent heart-rate increase peaking at 24 weeks","confidence_interval":null,"p_value":null,"sample_size":338,"follow_up":"48 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"48.2% female\", \"bmi_mean\": null, \"bmi_min\": 27.0, \"obesity_status\": \"obesity or overweight with comorbidity\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 338, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity; weight-loss dose-finding trial. Included here for the heart-rate safety signal and as the reference for triple-agonist programmes.","mediation":"not_applicable","mediation_notes":"[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 338, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"48 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"Dose-related GI events; dose-dependent heart-rate increase.","limitations":null,"plain_summary":"Phase 2 trial of the triple agonist retatrutide: up to 24% weight loss at 48 weeks in adults with obesity, with dose-related gastrointestinal effects and increases in heart rate.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":300,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: TRULICITY (DULAGLUTIDE) - label effective 2023-08-05","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-08-05","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Disease [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than plac\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 , 12.3 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 , 5.1 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 , 5.4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=0a4716d0-9c9c-4bc3-a8f1-6784599aae89","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":442,"doi":"10.3892/etm.2023.11948","pmid":"37153886","nct_ids":"[]","title":"Effect of liraglutide on atherosclerosis in patients with impaired glucose tolerance: A double‑blind, randomized controlled clinical trial","authors":"[\"Sun L\", \"Yuan Y\", \"Li Y\", \"Rao X\"]","journal":"Experimental and therapeutic medicine","publication_date":"2023-06","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 receptor agonist liraglutide may have beneficial effects on atherosclerosis development in impaired glucose tolerance (IGT). To the best of our knowledge, however, little conclusive evidence from clinical trials has been presented. The present study aimed to investigate the effect of liraglutide on atherosclerosis progression in patients with IGT. The present study was a double-blind, randomized controlled clinical trial. A total of 39 of patients aged 20-75 years who were overweight or obese (BMI, 27-40 kg/m2) and presented IGT were randomized to receive liraglutide (n=17) or lifestyle interventions (n=22) for 6 months. Serum glucose and insulin (INS) levels, lipid profile, inflammatory biomarkers and carotid intima-media thickness (CIMT) were assessed at the start and end of each treatment. Side effects were also recorded. Liraglutide treatment was found to significantly improve glycaemia, including glycosylated hemoglobin, fasting and postprandial glucose as well as INS levels (all P<0.001). Liraglutide also significantly decreased serum total cholesterol and low-density lipoprotein levels (all P<0.001). Furthermore, serum levels of inflammatory biomarkers, as well as CIMT, were decreased following liraglutide treatment compared with those in the lifestyle intervention group (all P<0.001). Kaplan-Meier analysis showed that the risk of vasculopathy in the liraglutide group was lower than that in the lifestyle intervention group (log-rank test; P=0.041). The monitoring of drug-associated side effects indicated that the dose of liraglutide (0.6 to 1.2 mg/QD via subcutaneous injection) was safe and well-tolerated. The present study suggested that liraglutide may slow atherosclerosis development and improve inflammatory status as well as intimal function in patients with IGT with few side effects. The trial was registered through the Chinese Clinical Trial Registry (ChiCTR; trial registration no. ChiCTR2200063693; retrospectively registered) on Sep 14, 2022.","url":"https://pubmed.ncbi.nlm.nih.gov/37153886/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":304,"doi":null,"pmid":null,"nct_ids":"[]","title":"FDA prescribing information: TRULICITY (DULAGLUTIDE) - label effective 2023-05-03","authors":"[\"A-S Medication Solutions\"]","journal":"U.S. FDA drug label (via openFDA)","publication_date":"2023-05-03","year":2023,"publication_type":"regulatory","peer_reviewed":"no","abstract":"[BOXED_WARNING] WARNING: RISK OF THYROID C-CELL TUMORS In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ), and Nonclinical Toxicology ( 13.1 )] . TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 , 13.1 ). TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors ( 4 , 5.1 ).\n\n[WARNINGS_AND_CAUTIONS] 5 WARNINGS AND PRECAUTIONS Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary ( 5.3 ). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice ( 5.4 ). Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). Severe Gastrointestinal Disease: Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients ( 5.6 ). Diabetic Retinopathy Complications: Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy ( 5.7 ). Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.8 ). 5.1 Risk of Thyroid C-cell Tumors In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient\n\n[ADVERSE_REACTIONS] 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Disease [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than plac\n\n[DRUG_INTERACTIONS] 7 DRUG INTERACTIONS Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 , 12.3 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].\n\n[CONTRAINDICATIONS] 4 CONTRAINDICATIONS TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 , 5.1 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 , 5.4 ).","url":"https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=80d1e766-fefc-44b4-bec9-c7b0198ec08f","source_name":"openfda","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":445,"doi":"10.2337/dc22-2397","pmid":"36897834","nct_ids":"[\"NCT01394952\"]","title":"Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis","authors":"[\"Gerstein HC\", \"Lee SF\", \"Paré G\", \"Bethel MA\", \"Colhoun HM\", \"Hoover A\", \"Lakshmanan M\", \"Lin Y\", \"Pirro V\", \"Qian HR\", \"Ruotolo G\", \"Ryden L\", \"Wilson JM\", \"Duffin KL\"]","journal":"Diabetes care","publication_date":"2023-05-01","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE). [RESEARCH DESIGN AND METHODS] In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE. [RESULTS] Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001). [CONCLUSIONS] Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.","url":"https://pubmed.ncbi.nlm.nih.gov/36897834/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":446,"doi":"10.1186/s12933-023-01765-z","pmid":"36841762","nct_ids":"[\"NCT04122716\"]","title":"Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial","authors":"[\"Sandsdal RM\", \"Juhl CR\", \"Jensen SBK\", \"Lundgren JR\", \"Janus C\", \"Blond MB\", \"Rosenkilde M\", \"Bogh AF\", \"Gliemann L\", \"Jensen JB\", \"Antoniades C\", \"Stallknecht BM\", \"Holst JJ\", \"Madsbad S\", \"Torekov SS\"]","journal":"Cardiovascular diabetology","publication_date":"2023-02-25","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. [METHODS] This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: placebo, moderate-to-vigorous exercise (minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination of both), the GLP-1 RA liraglutide 3.0 mg/day, or a combination (exercise + liraglutide). A total of 166 participants completed the trial. We assessed the prespecified secondary outcome metabolic syndrome severity z-score (MetS-Z), abdominal obesity (estimated as android fat via dual-energy X-ray absorptiometry), and inflammation marker high-sensitivity C-reactive protein (hsCRP). Statistical analysis was performed on 130 participants adherent to the study interventions (per-protocol population) using a mixed linear model. [RESULTS] The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (- 0.37, 95% CI - 0.58 to - 0.16, P < 0.001) and the combination treatment (- 0.48, 95% CI - 0.70 to - 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). [CONCLUSION] The combination of adherent exercise and liraglutide treatment reduced metabolic syndrome severity, abdominal obesity, and inflammation and may therefore reduce cardiometabolic risk more than the individual treatments. Trial registration EudraCT number: 2015-005585-32, ClinicalTrials.gov: NCT04122716.","url":"https://pubmed.ncbi.nlm.nih.gov/36841762/","source_name":"pubmed","source_tier":1,"coi_statement":"RMS: Family member holds Novo Nordisk stocks. MR: Currently employed at Novo Nordisk. JJH: Advisory boards: Novo Nordisk. SM: Advisory boards: AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi Aventis. Lecture fees: AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi Aventis. Grant Recipient: Novo Nordisk, Boehringer-Ingelheim. SST: Grant and lecture fee recipient, Novo Nordisk. JRL, CJ, CRJ, SBKJ, MBB, AFB, LG, JBJ, CA, BMS have no disclosures.","assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":19,"doi":"10.2337/dc22-1148","pmid":"36356111","nct_ids":"[]","title":"GLP-1 Receptor Agonists and the Risk of Thyroid Cancer","authors":"[\"Bezin J\", \"Gouverneur A\", \"Pénichon M\", \"Mathieu C\", \"Garrel R\", \"Hillaire-Buys D\", \"Pariente A\", \"Faillie JL\"]","journal":"Diabetes care","publication_date":"2023-02-01","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. [RESEARCH DESIGN AND METHODS] A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. [RESULTS] A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1-3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05). [CONCLUSIONS] In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1-3 years of treatment.","url":"https://pubmed.ncbi.nlm.nih.gov/36356111/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"case_control","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"cancer\", \"endocrine\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":"Thyroid cancer (nested case-control, French SNDS)","endpoints":null,"effect_estimate":"1-3 years use: all thyroid cancer aHR 1.58; medullary aHR 1.78","confidence_interval":"1.27 to 1.95; 1.04 to 3.05","p_value":null,"sample_size":47746,"follow_up":null,"direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes on second-line drugs\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 47746, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes; French claims data.","mediation":"unknown","mediation_notes":"[Auto] Harm signal; weight-loss mediation not the relevant question, but consider whether harms relate to rapid weight loss or reduced intake.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Case-control\", \"sample_size\": 47746, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"moderate\", \"risk_of_bias\": \"detection bias plausible (more thyroid imaging in GLP-1 users); claims-based diagnoses\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Nested case-control with plausible detection bias; contradicted by a larger active-comparator cohort.","funding_source":"Not reported in the abstract; full text not checked.","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"not reported in abstract","independent_replication_exists":"no; contradicted","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"A French nested case-control study in people with type 2 diabetes found that 1-3 years of GLP-1 use was associated with about 60% higher risk of thyroid cancer, and with higher risk of medullary thyroid cancer. Being observational, it cannot show cause; detection bias is a concern.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":25,"doi":"10.1111/dom.14903","pmid":"36306151","nct_ids":"[]","title":"Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial","authors":"[\"Mashayekhi M\", \"Beckman JA\", \"Nian H\", \"Garner EM\", \"Mayfield D\", \"Devin JK\", \"Koethe JR\", \"Brown JD\", \"Cahill KN\", \"Yu C\", \"Silver H\", \"Niswender K\", \"Luther JM\", \"Brown NJ\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2023-02","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. [MATERIALS AND METHODS] Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). [RESULTS] Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). [CONCLUSION] Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.","url":"https://pubmed.ncbi.nlm.nih.gov/36306151/","source_name":"pubmed","source_tier":1,"coi_statement":"None unless noted below: J.A.B.: Dr. Beckman is a consultant for JanOne, serves on a DSMB for Janssen and Novartis, and has ownership in EMX and Janacare. J.R.K: Dr. Koethe has served as a consultant to Gilead Sciences, Merck, ViiV Healthcare, Theratechnologies and Janssen. He has also received research support from Gilead Sciences and Merck. J.M.L: Dr. Luther has served on the advisory board for Mineralys. N.J.B.: Dr. Brown serves on the scientific advisory board for Alnylam Pharmaceuticals. She serves as a consultant for Pharvaris Gmbh and eBioStar Tech. Dr. Brown owns equity in Abbvie and J and J Pharmaceuticals.","assessment_version":7,"assessed_by":"curated","assessed_at":"2026-11-09T13:53:34+00:00","study_design":"Randomized, parallel-group, quadruple-blind (drug arms), placebo-controlled trial; 3 arms (liraglutide, hypocaloric diet, sitagliptin) in 2:1:1 ratio; 14 weeks; measurements at baseline, 2 weeks (pre-weight-loss), and 14 weeks.","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg daily (full text)\", \"route\": \"subcutaneous\", \"treatment_duration\": \"14 weeks\", \"comparator\": \"hypocaloric diet; sitagliptin (double-blind placebo-controlled for drugs)\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"kidney\"]","outcome_type":"biomarker","primary_outcome":"Flow-mediated vasodilation, PAI-1, urine albumin-creatinine ratio","endpoints":null,"effect_estimate":"No treatment effect on FMD or UACR; liraglutide and diet reduced weight, insulin resistance and PAI-1; MCP-1 fell within the liraglutide arm at 2 weeks (-10.7 pg/mL, 95% CI -17.6 to -3.7) and 14 weeks (-10.7 pg/mL, 95% CI -17.7 to -3.7), while diet and sitagliptin did not change it significantly; no between-arm test of MCP-1 is reported (full text)","confidence_interval":null,"p_value":null,"sample_size":88,"follow_up":"14 weeks","direction":"mixed","population":"{\"condition\": \"Obesity and prediabetes\", \"mean_age\": \"50.3 ± 10.8 years (the 88 analysed; full text Table 1)\", \"sex\": \"60 female / 28 male (the 88 analysed; full text Table 1)\", \"mean_bmi\": \"39.0 ± 6.0 kg/m² (the 88 analysed; full text Table 1)\", \"diabetes_status\": \"Prediabetes (by FPG, IGT, or HbA1c criteria per registry eligibility; not established type 1/2 diabetes)\", \"sample_size\": 88, \"randomized_and_analysed\": \"93 randomized (liraglutide 46, sitagliptin 23, diet 24); the 88 who completed at least one study day were analysed (44, 22, 22). This record's figures are for the 88.\"}","applicability":"INDIRECT","applicability_rationale":"Obesity with prediabetes; but the design (drug vs matched diet-induced weight loss, with measurements before weight loss) directly addresses weight-independence, which is the target question.","mediation":"specifically_tested","mediation_notes":"method: Both a weight-matched active comparator and a temporal (pre-weight-loss) measurement are present in this trial's design, and the task asks that both be named: (1) weight-matched comparator — the hypocaloric diet arm was explicitly designed to produce weight loss similar to that expected on liraglutide, so a liraglutide-vs-diet comparison at matched weight loss tests whether liraglutide's biomarker effect exceeds what equivalent weight loss alone produces; (2) temporal/pre-weight-loss measurement — the trial measured outcomes at baseline, 2 weeks (explicitly \"prior to significant weight loss\"), and 14 weeks, so an effect already present at 2 weeks would be attributable to a weight-independent (e.g., direct GLP-1 receptor) mechanism. The full text reports the MCP-1 fall in the liraglutide arm at 2 weeks as well as 14 weeks, so the pre-weight-loss measurement does apply to it; it reports no between-arm test of MCP-1 (see key limitation).\n; prespecified: NI; key limitation: The full text reports MCP-1 fell in the liraglutide arm at 2 weeks, before significant weight loss (-10.7 pg/mL, 95% CI -17.6 to -3.7), and at 14 weeks, while diet and sitagliptin did not change it significantly. Its Table 2 marks no significant difference between liraglutide and diet or sitagliptin, so weight-independence rests on one arm's change being significant and the others' not, not on a between-arm test. MCP-1 was not a registered outcome.","adjusted_for":"[\"weight-matched diet comparator\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized, parallel-group, quadruple-blind (drug arms), placebo-controlled trial; 3 arms (liraglutide, hypocaloric diet, sitagliptin) in 2:1:1 ratio; 14 weeks; measurements at baseline, 2 weeks (pre-weight-loss), and 14 weeks.\", \"sample_size\": 88, \"randomization\": \"yes\", \"blinding\": \"double-blind for drug vs placebo; diet open\", \"comparator\": \"hypocaloric diet; sitagliptin (double-blind placebo-controlled for drugs)\", \"follow_up_duration\": \"14 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"n=88; single biomarker positive\", \"risk_of_bias\": \"post hoc subgroup analyses\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\", \"rob2\": {\"O4\": {\"D1\": {\"judgment\": \"Some concerns\", \"rationale\": \"This is a small, single-center, investigator-initiated academic trial (Vanderbilt; N=93 randomized), not a large industry registration trial with a described central randomization/IVRS system, so per the collection's D1 rule allocation concealment requires an explicit description of method — none is given. Sequence generation is likewise undescribed in both sources. No clear baseline imbalance is \"}, \"D2\": {\"judgment\": \"Some concerns\", \"rationale\": \"Drug arms were double-blind/placebo-controlled (registry: quadruple masking of participant, care provider, investigator, outcomes assessor), but the diet arm cannot be blinded by nature of the intervention, and GI adverse events differ markedly between arms (nausea 8/46 liraglutide vs. 0/23 sitagliptin vs. 1/24 diet; diarrhea 3/46 vs. 0/23 vs. 0/24) — per the collection's D2 rule this supports \\\"aw\"}, \"D3\": {\"judgment\": \"Some concerns\", \"rationale\": \"MCP-1 is not a registered outcome measure at all (see D5), so neither source reports the number of participants with MCP-1 data available or missingness by arm — this specific signaling question is NI. As context (not direct evidence for MCP-1 itself), the registry's comparable plasma biomarker measured from the same blood draws, PAI-1, shows differential and at times substantial missingness by 14\"}, \"D4\": {\"judgment\": \"Low\", \"rationale\": \"MCP-1 is a plasma chemokine assay, the same category (objective central-lab biomarker) that the collection's D4 rule treats as Low risk of measurement bias absent evidence the assay changed or differed between arms. No such evidence is present in either source, and outcome assessors were specified as masked in the registry.\\n\"}, \"D5\": {\"judgment\": \"High\", \"rationale\": \"The abstract's own stated primary outcomes are FMD, PAI-1 and UACR; MCP-1 is not among them. Checking the registration's full outcome list (primary, secondary, and \\\"other\\\" outcomes) for MCP-1 or any inflammation-related measure finds none at all — not even as a registered secondary or exploratory outcome — despite the trial's brief summary explicitly naming \\\"inflammation\\\" as one of its three hypot\"}, \"overall\": {\"judgment\": \"High\"}, \"result\": \"Change in MCP-1 (monocyte chemoattractant protein-1), liraglutide vs. sitagliptin and vs. hypocaloric diet. The abstract does not attach a specific timepoint (2-week pre-weight-loss vs. 14-week) to the MCP-1 finding, does not report a table/figure (no numeric values, only direction), and MCP-1 is not a registered outcome measure at all (see D5 and mediation block). Location: abstract Results/Conclusion sentences only (\\\"Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1)\\\"; \\\"Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.\\\").\\n\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\"}, {\"pass\": \"B\", \"model\": \"claude-opus\"}], \"guide_version\": \"rob2-guide v1 + v1.1 calibration rulings (2026-09-13)\", \"label\": \"AI: two passes agreed\", \"resolution\": \"agreed domains accepted; disagreements decided by the owner 2026-09-13 (IN-009)\"}}}","evidence_rationale":"Small mechanistic RCT with mostly null primary endpoints; one exploratory biomarker supports weight-independence.","funding_source":"American Heart Association; NIH (National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute) (full text). The registry names Vanderbilt University Medical Center as lead sponsor.","industry_funded":"no","manufacturer":"Novo Nordisk (supplied liraglutide and matching placebo)","author_conflicts":"Multiple authors report industry ties, though none identify the study-drug manufacturers (Novo Nordisk for liraglutide, Merck for sitagliptin) as trial funders. Notably J.R. Koethe reports both consulting for and research support from Merck, which manufactures sitagliptin, one of the study's comparator arms.\n","sponsor_role":"Investigator-initiated (responsible party is the Principal Investigator, not the sponsor institution or a company)","independent_replication_exists":"no","conflict_notes":"Novo Nordisk, the maker of liraglutide, supplied the drug and matching placebo; the paper does not name it as a funder (full text).","adverse_events":null,"limitations":null,"plain_summary":"A small randomized trial compared 14 weeks of liraglutide, a low-calorie diet and sitagliptin in 88 adults with obesity and prediabetes. Neither drug nor diet changed artery dilation (FMD) or urine albumin. Liraglutide and diet both lowered weight, insulin resistance and PAI-1, a clotting-related marker that was one of the three primary outcomes; sitagliptin did not. Only liraglutide's own fall in the inflammatory chemokine MCP-1 was significant, from 2 weeks; the paper reports no significant difference from diet or sitagliptin on that marker, and MCP-1 was not a registered outcome. Mixed results, but methodologically the right kind of study.","methodological_notes":"Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/36306151/), from the abstract, registry and public protocol/SAP, without the paper's full text. On 2026-11-08 the funding, participant counts and baseline figures were checked against the published full text (author manuscript, PMC10306232); the judgments, the mediation notes and the risk-of-bias assessment were not re-reviewed against it. On 2026-11-09 the MCP-1 effect line, mediation notes and summary were rewritten to the full text (owner decision, IN-069 item 1); the O4 risk-of-bias rationale is queued for a two-pass re-check against it.","reviewed_by":null,"reviewed_at":null},{"id":450,"doi":"10.1016/j.eclinm.2022.101737","pmid":"36467859","nct_ids":"[]","title":"Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials","authors":"[\"Verma S\", \"Bhatta M\", \"Davies M\", \"Deanfield JE\", \"Garvey WT\", \"Jensen C\", \"Kandler K\", \"Kushner RF\", \"Rubino DM\", \"Kosiborod MN\"]","journal":"EClinicalMedicine","publication_date":"2023-01","year":2023,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity. [METHODS] STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2). Post hoc assessments included change in CRP by baseline characteristics (bodyweight, body mass index [BMI], glycaemic status, CRP concentration); change in CRP-defined cardiovascular risk category (<1 [low], 1-3 [intermediate], and >3 mg/L [high]); and correlation between change in CRP and change in bodyweight, waist circumference, fasting serum insulin (STEP 1 and 3), fasting plasma glucose, and homeostatic model assessment of insulin resistance (HOMA-IR). [FINDINGS] The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p < 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown). [INTERPRETATION] In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity. [FUNDING] Novo Nordisk.","url":"https://pubmed.ncbi.nlm.nih.gov/36467859/","source_name":"pubmed","source_tier":1,"coi_statement":"Dr Bhatta is an employee of Novo Nordisk A/S. Professor Davies reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Janssen, 10.13039/501100004191Novo Nordisk, and Sanofi-Aventis; has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi-Aventis; advisory board member and speaker for AstraZeneca; advisory board member for Gilead Sciences Ltd, Janssen, and Lexicon; and speaker for Napp Pharmaceuticals and Takeda Pharmaceuticals International Inc. She is co-funded by the NIHR Leicester Biomedical Research Centre. Dr. Deanfield reports personal fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer, grants from BHF, MRC(UK), NIHR, Public Health England, MSD, Pfizer, Cancer Research UK, Alzheimer’s Research UK, other from Novo Nordisk, outside the submitted work. Dr. Garvey reports grants from 10.13039/501100004191Novo Nordisk, during the conduct of the study; grants from Novo Nordisk, grants from Eli Lilly, grants from Epitomee, grants from Pfizer, personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, personal fees from Fractyl Health, personal fees from Alnylam Pharmaceuticals, personal fees from Merck, personal fees from Eli Lilly, outside the submitted work. Camilla Jensen is an employee of Novo Nordisk A/S. Dr Kandler is an employee of Novo Nordisk A/S. Dr. Kosiborod reports grants, personal fees and other from AstraZeneca, personal fees from Alnylam, personal fees from Amgen, personal fees from Applied Therapeutics, personal fees from Bayer, grants and personal fees from Boehringer Ingelheim, personal fees from Cytokinetics, personal fees from Eli Lilly, personal fees from Esperion Therapeutics, personal fees from Janssen, personal fees from Lexicon, personal fees from Merck (Diabetes and Cardiovascular), personal fees from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Sanofi, personal fees from Vifor Pharma, outside the submitted work. Dr. Kushner reports personal fees from Novo Nordisk, personal fees from Eli Lilly, outside the submitted work. Dr. Rubino reports other from Novo Nordisk, during the conduct of the study; personal fees and other from Novo Nordisk, personal fees and other from Boehringer Ingelheim, personal fees from Endocrine Society, PeerView, WebMD, outside the submitted work. Dr. Verma reports grants and personal fees from Amarin, grants and personal fees from Amgen, grants and personal fees from Bayer, grants and personal fees from Boehringer Ingelheim, personal fees from Canadian Medical and Surgical Knowledge Translation Research Group, grants and personal fees from Eli Lilly, personal fees from EOCI, grants and personal fees from HLS Therapeutics, personal fees from Janssen, personal fees from Novartis, grants and personal fees from Novo Nordisk, personal fees from Otsuka, grants and personal fees from Pfizer, grants and personal fees from PhaseBio, personal fees from Sanofi, personal fees from Sun Pharma, personal fees from TKTWG, outside the submitted work.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":452,"doi":"10.1186/s12933-022-01634-1","pmid":"36199064","nct_ids":"[]","title":"Effects of dulaglutide on endothelial progenitor cells and arterial elasticity in patients with type 2 diabetes mellitus","authors":"[\"Xie D\", \"Li Y\", \"Xu M\", \"Zhao X\", \"Chen M\"]","journal":"Cardiovascular diabetology","publication_date":"2022-10-03","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Randomised controlled trial showed that dulaglutide can reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear. This study aimed to investigate the effect of dulaglutide on the number and function of endothelial progenitor cells (EPCs) in the peripheral blood of patients with T2DM and its role in improving arterial elasticity, so as to determine potential mechanisms of preventive effect of dulaglutide on ASCVD. [METHODS] Sixty patients with T2DM were treated with 1000 mg/day of metformin and randomly divided into two groups for 12 weeks: metformin monotherapy group (MET group, n = 30), and metformin combined with dulaglutide group (MET-DUL group, n = 30). Before and after treatment, the number of CD34+CD133+KDR+ EPCs and the brachial-ankle pulse wave velocity (baPWV) of the participants were measured, and EPC proliferation, adhesion, migration, and tubule formation were assessed in vitro. [RESULTS] There were no significant differences in the number and function of EPCs and baPWV changes in MET group (P > 0.05). In MET-DUL group, nitric oxide (NO) levels and the number of EPCs increased after treatment (P < 0.05), while the levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), advanced glycation end products (AGEs), and baPWV decreased (P < 0.05). EPC proliferation, adhesion, migration, and tubule formation abilities were significantly enhanced (P < 0.05). Correlation analysis showed that in MET-DUL group, the changes in CRP, IL-6, TNF-α, and AGEs were negatively correlated with the number of EPCs and their proliferation and migration abilities (P < 0.05). Body weight, NO, CRP, and IL-6 levels were independent factors affecting the number of EPCs (P < 0.05). The changes in number of EPCs, proliferation and migration abilities of EPCs, and NO and IL-6 levels were independent influencing factors of baPWV changes (P < 0.05). [CONCLUSION] Dulaglutide can increase the number and function of EPCs in peripheral blood and improve arterial elasticity in patients with T2DM; it is accompanied by weight loss, inflammation reduction, and high NO levels. Dulaglutide regulation of EPCs may be a mechanism of cardiovascular protection.","url":"https://pubmed.ncbi.nlm.nih.gov/36199064/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no competing interests.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"cellular_in_vitro","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cancer\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":454,"doi":"10.1186/s12933-022-01585-7","pmid":"36056351","nct_ids":"[\"NCT02906930\", \"NCT02863328\", \"NCT02827708\", \"NCT01885208\"]","title":"Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials","authors":"[\"Mosenzon O\", \"Capehorn MS\", \"De Remigis A\", \"Rasmussen S\", \"Weimers P\", \"Rosenstock J\"]","journal":"Cardiovascular diabetology","publication_date":"2022-09-02","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. [METHODS] Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. [RESULTS] Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA1c and BW. [CONCLUSIONS] Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. [TRIAL REGISTRATIONS] ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).","url":"https://pubmed.ncbi.nlm.nih.gov/36056351/","source_name":"pubmed","source_tier":1,"coi_statement":"OM reports personal fees for advisory board consultancy and speaker’s bureau from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, and Sanofi; and research grant support from AstraZeneca and Novo Nordisk. MC reports being a partner at Clifton Medical Centre, a director at RIO Weight Management, Ltd, and a consultant for LighterLife and McDonald’s; he also reports research funding from Abbott, Boehringer Ingelheim/Lilly Alliance, Janssen, MSD, and Novo Nordisk; advisory board consultancy, consultancy and honoraria from Abbott, Boehringer Ingelheim/Lilly Alliance, and Novo Nordisk; and meeting support from Boehringer Ingelheim/Lilly Alliance and Novo Nordisk. ADR, SR, and PW are full-time employees of Novo Nordisk; SR also owns shares in Novo Nordisk. JR reports research funding from Applied Therapeutics Inc., Boehringer Ingelheim, Eli Lilly, Genentech, GlaxoSmithKline, Hanmi, Intarcia, Janssen, Lexicon, Merck, Metacrine, Novo Nordisk, Novartis, Oramed, Pfizer, and Sanofi; and advisory board consultancy, consultancy, and honoraria from Applied Therapeutics Inc., Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Janssen, Novo Nordisk, Oramed, Sanofi, and Zealand.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"s.c. 1.0 mg once weekly (SUSTAIN 3); oral 7 mg and 14 mg once daily (PIONEER 1); oral 14 mg once daily (PIONEER 2 and 5); only approved maintenance doses analysed\", \"route\": \"various\", \"comparator\": \"placebo; exenatide extended-release; empagliflozin\", \"treatment_duration\": \"56 weeks (SUSTAIN 3); 52 weeks (PIONEER 2); 26 weeks (PIONEER 1 and 5)\"}","domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"hsCRP ratio to baseline at end-of-treatment, semaglutide versus comparators (exploratory)","endpoints":null,"effect_estimate":"hsCRP ratio to baseline lower with semaglutide than comparators, estimated treatment ratios 0.70-0.76 (p < 0.01), except versus placebo in PIONEER 5 in people with chronic kidney disease (ETR 0.83, 95% CI 0.67-1.03, not significant)","confidence_interval":"95% CI 0.65–0.88 (SUSTAIN 3 vs exenatide ER); 0.59–0.89 and 0.62–0.93 (PIONEER 1, 7 mg and 14 mg vs placebo); 0.61–0.80 (PIONEER 2 vs empagliflozin); 0.67–1.03 (PIONEER 5 vs placebo)","p_value":"p < 0.01 versus comparators; PIONEER 5 versus placebo p = 0.08 (abstract: p > 0.05)","sample_size":2471,"follow_up":"26–56 weeks","direction":"benefit","population":"{\"mean_age\": \"56.4 ± 10.5 years (SUSTAIN 3, PIONEER 1 and 2 pooled); 70.4 ± 7.9 years (PIONEER 5)\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"1028 (47.6%) female (SUSTAIN 3, PIONEER 1 and 2 pooled); 168 (51.9%) female (PIONEER 5)\", \"bmi_mean\": \"32.9 ± 6.5 kg/m2 (pooled SUSTAIN 3, PIONEER 1 and 2); 32.4 ± 5.4 kg/m2 (PIONEER 5)\", \"bmi_min\": null, \"obesity_status\": \"not reported (no BMI entry criterion stated; mean BMI 32.9)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"mixed (all PIONEER 5 participants had CKD with eGFR 30–59; the other trials excluded eGFR below 60)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"inadequately controlled type 2 diabetes (PIONEER 5: also chronic kidney disease)\", \"sample_size\": 2471, \"inclusion_exclusion\": \"inadequately controlled type 2 diabetes; SUSTAIN 3, PIONEER 1 and 2 excluded baseline eGFR below 60; PIONEER 5 required eGFR 30–59\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes (mean BMI 32.9 in the pooled trials and 32.4 in PIONEER 5), and PIONEER 5 enrolled people with chronic kidney disease; mean ages were 56.4 and 70.4.","mediation":"specifically_tested","mediation_notes":"Mediation analyses with change in HbA1c and change in body weight as mediators, separately and combined, found that together they explained 20.6-61.8% of the hsCRP reduction, leaving a possible direct effect; the authors note the trials were not powered for mediation analyses.","adjusted_for":"[\"body-weight change\", \"HbA1c\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 2471, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo; exenatide extended-release; empagliflozin\", \"follow_up_duration\": \"26–56 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported per trial; no adjustment for multiplicity; 2471 of 2482 randomised analysed; trials not powered for mediation\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: exploratory biomarker analysis of four double-blind randomised trials without multiplicity adjustment; hsCRP is a biomarker, not a clinical outcome.","funding_source":"Novo Nordisk A/S","industry_funded":"yes","manufacturer":"Novo Nordisk A/S","author_conflicts":"Three authors are full-time Novo Nordisk employees (one also a shareholder); the others report advisory, speaker or research funding from several companies, Novo Nordisk among them.","sponsor_role":"No explicit statement of the funder's role; Novo Nordisk employees were co-authors, one of whom (S.R.) performed the statistical analyses, and Novo Nordisk funded medical writing","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"not reported","limitations":"The authors cite the exploratory design, no hard endpoints, infrequent hsCRP testing, short follow-up (26–56 weeks) and trials not powered for mediation analysis; hsCRP is a biomarker only.","plain_summary":"This exploratory analysis used patient-level data from four randomised trials of semaglutide in adults with type 2 diabetes; 2471 people had hsCRP, a blood marker of inflammation, measured. hsCRP fell more with semaglutide than with placebo, exenatide or empagliflozin in three trials (treatment ratios 0.70-0.76), but not significantly versus placebo in the trial of people with kidney disease (0.83). Changes in blood sugar and body weight explained 20.6-61.8% of the effect, and hsCRP is a marker rather than a clinical outcome.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":29,"doi":"10.1111/dom.14725","pmid":"35441470","nct_ids":"[\"NCT03548935\"]","title":"Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension","authors":"[\"Wilding JPH\", \"Batterham RL\", \"Davies M\", \"Van Gaal LF\", \"Kandler K\", \"Konakli K\", \"Lingvay I\", \"McGowan BM\", \"Oral TK\", \"Rosenstock J\", \"Wadden TA\", \"Wharton S\", \"Yokote K\", \"Kushner RF\", \"STEP 1 Study Group\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2022-08","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. [MATERIALS AND METHODS] STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. [RESULTS] Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. [CONCLUSIONS] One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.","url":"https://pubmed.ncbi.nlm.nih.gov/35441470/","source_name":"pubmed","source_tier":1,"coi_statement":"JPHW reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to the University of Liverpool, lecture fees and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees and fees for serving as an investigator, all paid to the University of Liverpool, and lecture fees from Novo Nordisk and advisory board fees from Takeda Medical Research Foundation. RLB reports research grant support from Novo Nordisk and consultancy with Boehringer Ingelheim, Eli Lilly, Gila Therapeutics Inc, GSK, Novo Nordisk, and Pfizer. MD reports receiving research funding from AstraZeneca, Boehringer Ingelheim, Janssen, Novo Nordisk and Sanofi‐Aventis, and has acted as a consultant, advisory board member and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi‐Aventis, as an advisory board member and speaker for AstraZeneca, as an advisory board member for Gilead Sciences Ltd, Janssen and Lexicon, and as a speaker for Napp Pharmaceuticals and Takeda Pharmaceuticals International Inc. She is co‐funded by the NIHR Leicester Biomedical Research Centre. LFVG reports receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk. KKa reports being employed by and owning stock in Novo Nordisk. KKo and TKO report being employed by Novo Nordisk. IL reports receiving advisory board fees and/or consulting fees from AstraZeneca, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, Novo Nordisk, Sanofi, Target Pharma, Valeritas and Zealand Pharma, and grant support, paid to UT Southwestern, from Merck, Mylan Pharmaceuticals, Novo Nordisk, Pfizer and Sanofi. BMM reports receiving educational fees from AstraZeneca, Merck and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guy's and St. Thomas' Hospital, consulting fees and educational fees from Novo Nordisk and owning stock in Reset Health Clinics. JR reports receiving grant support, advisory board fees and travel support from Applied Therapeutics, Intarcia and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees and travel support from Boehringer Ingelheim, Novo Nordisk and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer and REMD Biotherapeutics and advisory board fees from Zealand Pharma. TAW reports receiving grant support from Novo Nordisk and Epitomee Medical, paid to the University of Pennsylvania, and personal advisory board fees from Novo Nordisk and WW International. SW reports receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees and advisory board fees from Novo Nordisk. KY reports receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees and advisory board fees from Kowa Company and Novo Nordisk and lecture fees and advisory board fees from Sanofi. RFK reports receiving advisory board fees from Novo Nordisk and WW International.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"68 weeks then 52 weeks off treatment\", \"comparator\": \"placebo\"}","domains":"[\"discontinuation\", \"metabolic\", \"body_composition\"]","outcome_type":"intermediate","primary_outcome":"Exploratory: weight and cardiometabolic changes one year after withdrawal","endpoints":null,"effect_estimate":"Regained 11.6 percentage points of 17.3% loss (two-thirds); cardiometabolic variables reverted toward baseline","confidence_interval":null,"p_value":null,"sample_size":327,"follow_up":"120 weeks","direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"BMI >= 30 or >= 27 with comorbidity\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 327, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight without diabetes (age/BMI not reported in abstract); effects may be mediated by weight loss.","mediation":"not_applicable","mediation_notes":"Participants had obesity, or overweight with a weight-related condition, and no diabetes; the abstract does not separate direct drug effects from weight loss.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 327, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"120 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"exploratory off-treatment extension in a subset\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk and other industry relationships.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":null,"plain_summary":"One year after stopping semaglutide and lifestyle support, participants had regained two-thirds of the weight they lost and most metabolic improvements had faded. This exploratory follow-up covered 327 of the 1,961 original participants.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":472,"doi":"10.1017/s1092852920002217","pmid":"33308348","nct_ids":"[]","title":"Proinflammatory biomarkers are associated with prediabetes in patients with schizophrenia","authors":"[\"Møller M\", \"Fredholm S\", \"Jensen ME\", \"Wörtwein G\", \"Larsen JR\", \"Vilsbøll T\", \"Ødum N\", \"Fink-Jensen A\"]","journal":"CNS spectrums","publication_date":"2022-06","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Treatment with antipsychotics is associated with an increased risk of type 2 diabetes mellitus (T2D), and increased levels of inflammatory biomarkers are present in patients with T2D. We previously demonstrated that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. This study aims to assess the involvement of cytokines in the therapeutic effects of liraglutide. [METHODS] Serum concentrations of 10 cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α, interleukin 1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13) from fasting prediabetic and normal glucose-tolerant (NGT) patients with schizophrenia-spectrum disorders were measured using multiplexed immunoassays. Prediabetic patients were randomized to 16 weeks of treatment with liraglutide or placebo, and cytokines were measured again at the end of the treatment. [RESULTS] IFN-γ (1.98 vs 1.17 pg/ml, P = .001), IL-4 (0.02 vs 0.01 pg/ml, P < .001), and IL-6 (0.73 vs 0.46 pg/ml, P < .001) were significantly higher in prediabetic (n = 77) vs NGT patients (n = 31). No significant changes in cytokine levels following treatment with liraglutide (n = 37) vs placebo (n = 40) were found. [CONCLUSION] Prediabetic vs NGT patients with schizophrenia treated with clozapine or olanzapine had increased serum levels of several proinflammatory cytokines, further substantiating the link between inflammation and T2D. Treatment with liraglutide did not affect the investigated cytokines. Further testing of these findings in larger numbers of individuals is needed.","url":"https://pubmed.ncbi.nlm.nih.gov/33308348/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":39,"doi":"10.1001/jamainternmed.2022.0338","pmid":"35344001","nct_ids":"[]","title":"Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials","authors":"[\"He L\", \"Wang J\", \"Ping F\", \"Yang N\", \"Huang J\", \"Li Y\", \"Xu L\", \"Li W\", \"Zhang H\"]","journal":"JAMA internal medicine","publication_date":"2022-05-01","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[IMPORTANCE] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial. [OBJECTIVE] To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations. [DATA SOURCES] MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions. [STUDY SELECTION] Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non-GLP-1 RA drugs in adults. [DATA EXTRACTION AND SYNTHESIS] Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. [MAIN OUTCOMES AND MEASURES] The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021. [RESULTS] A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P  = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P  = .03 for interaction). [CONCLUSIONS AND RELEVANCE] This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss. [TRIAL REGISTRATION] PROSPERO Identifier: CRD42021271599.","url":"https://pubmed.ncbi.nlm.nih.gov/35344001/","source_name":"pubmed","source_tier":1,"coi_statement":"","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo or non-GLP-1 RA drugs\"}","domains":"[\"gastrointestinal\", \"adverse_effects\", \"cancer\"]","outcome_type":"hard","primary_outcome":"Gallbladder or biliary disease across 76 RCTs (103,371 patients)","endpoints":null,"effect_estimate":"RR 1.37; cholelithiasis RR 1.27; cholecystitis RR 1.36; weight-loss trials RR 2.29; higher dose RR 1.56 vs lower 0.99; longer duration RR 1.40","confidence_interval":"1.23 to 1.52","p_value":null,"sample_size":103371,"follow_up":null,"direction":"harm","population":"{\"mean_age\": 57.8, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"40.5% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"mixed (diabetes and weight-loss trials)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 103371, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Trial populations with diabetes or obesity; mean age 58. Dose- and duration-dependence is informative for any user.","mediation":"unknown","mediation_notes":"Harm; rapid weight loss is itself a gallstone risk factor and may contribute.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 103371, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo or non-GLP-1 RA drugs\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"76 trials\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 1.23 to 1.52\", \"risk_of_bias\": \"adverse events not always systematically ascertained\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Large meta-analysis of randomized trials with GRADE assessment; consistent dose-response.","funding_source":"Not stated in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not available in metadata.","sponsor_role":"not reported in abstract","independent_replication_exists":"yes","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across 76 randomized trials, GLP-1 receptor agonists increased gallbladder and biliary disease by 37%, more so at higher doses, with longer use and in weight-loss trials (more than doubled); no significant increase was seen at lower doses (RR 0.99) or with shorter use (RR 0.79). A consistent harm signal in randomized trials.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":473,"doi":"10.1080/09546634.2020.1826392","pmid":"32962477","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor agonist liraglutide therapy for psoriasis patients with type 2 diabetes: a randomized-controlled trial","authors":"[\"Lin L\", \"Xu X\", \"Yu Y\", \"Ye H\", \"He X\", \"Chen S\", \"Chen X\", \"Shao Z\", \"Chen P\"]","journal":"The Journal of dermatological treatment","publication_date":"2022-05","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] There were some clinical studies on GLP-1R agonist liraglutide therapy for psoriasis patients with type 2 diabetes, but there is a lack of randomized controlled trials and the mechanism of which remains unclear. [METHOD] A total of 25 psoriasis patients with type 2 diabetes were randomized 1: 1 divided into the control group (n = 13) or liraglutide group (n = 12) for 12 weeks. We determined the PASI, the DLQI, histopathology of psoriasis skin, and the expression of IL-17, IL-23, and TNF-α in the psoriasis skin. [RESULTS] After 12 weeks of treatment, the mean DLQI of the treatment group decreased from 22.00 ± 5.85 to 3.82 ± 3.60 (p < .05). Compared to week 12, the change in the baseline value of PASI and DLQI in the treatment group showed a significant difference compared with the control group (p < .05). The pathological changes of psoriasis skin and the expression of IL-17, IL-23, TNF-α in the psoriasis skin were improved in the treatment group. No serious adverse events occurred. [CONCLUSION] The skin lesions in psoriasis patients with type 2 diabetes were significantly improved after treatment with liraglutide, which may be related to the inhibition of the expression of inflammatory factors such as IL-23, IL-17, and TNF-α.","url":"https://pubmed.ncbi.nlm.nih.gov/32962477/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"rheumatologic\", \"cancer\", \"adverse_effects\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":457,"doi":"10.1186/s12902-022-01006-6","pmid":"35392872","nct_ids":"[]","title":"Efficacy of liraglutide in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials","authors":"[\"Mali N\", \"Su F\", \"Ge J\", \"Fan WX\", \"Zhang J\", \"Ma J\"]","journal":"BMC endocrine disorders","publication_date":"2022-04-07","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The efficacy of liraglutide to treat type 2 diabetic nephropathy (T2DN) remains controversial. Thus, we conducted this meta-analysis to systematically evaluate the clinical effect of liraglutide on T2DN patients. [METHODS] Eight databases (PubMed, Web of Science, the Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database, and China Biology Medicine Database (CBM)) were searched for published articles to evaluate the clinical efficacy of liraglutide in subjects with T2DN. The Revman 5.3 and Stata 13 software were used for analyses and plotting. [RESULTS] A total of 18 randomized controlled trials (RCTs) with 1580 diabetic nephropathy patients were screened. We found that the levels of UACR, Scr, Cysc were lower in the experimental group of T2DN patients treated with liraglutide than in the control group intervened without liraglutide. Liraglutide also reduced the levels of blood glucose (including FBG, PBG, and HbA1c), body mass index (BMI), and anti-inflammatory indicators (TNF-α, IL-6). However, there was no significant difference in BUN and eGFR between the experimental group and the control group. [CONCLUSIONS] Liraglutide reduced the levels of Blood Glucose, BMI, renal outcome indicators, and serum inflammatory factors of patients with T2DN, suggesting the beneficial effects of liraglutide on renal function.","url":"https://pubmed.ncbi.nlm.nih.gov/35392872/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no competing interests.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1580,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes (all)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"diabetic nephropathy (all)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1580, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Synthesis; population mix not determinable from abstract. Review the included-study populations.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1580, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 4, 7, 11, 13; non-critical weaknesses on items 3, 6, 10, 12, 14\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"No\", \"5\": \"Yes\", \"6\": \"No\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"No\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 10, \"Partial Yes\": 1, \"Yes\": 5}, \"settled_by_ruling\": [\"item 13: No (IN-059; the passes read Yes and No)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/35392872/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/35392872/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-03-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.2\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"Yunnan Health Technical Training Project of High-level Talents and Yunnan Basic Research Projects - General Program (full text)","industry_funded":"no","manufacturer":null,"author_conflicts":"The authors declare that they have no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"In 18 randomized trials (1,580 people) with type 2 diabetic kidney disease, liraglutide lowered urine albumin (UACR), serum creatinine and cystatin C (lab markers), as well as blood glucose, BMI and the inflammatory markers TNF-α and IL-6, but eGFR and BUN, standard kidney-function measures, did not differ from control. These are lab changes, not kidney outcomes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":466,"doi":"10.1111/dom.14553","pmid":"34542221","nct_ids":"[]","title":"The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis","authors":"[\"Wilson JM\", \"Lin Y\", \"Luo MJ\", \"Considine G\", \"Cox AL\", \"Bowsman LM\", \"Robins DA\", \"Haupt A\", \"Duffin KL\", \"Ruotolo G\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2022-01","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.","url":"https://pubmed.ncbi.nlm.nih.gov/34542221/","source_name":"pubmed","source_tier":1,"coi_statement":"J.M.W., Y.L., M.J.L., A.L.C., L.M.B., D.A.R., A.H., K.L.D., and G.R. are employees and shareholders of Eli Lilly and Company. G.C. is a contractor for Advanced Testing Laboratories and works with Eli Lilly and Company.","assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"1, 5, 10 or 15 mg once weekly\", \"comparator\": \"placebo; dulaglutide 1.5 mg\", \"route\": \"subcutaneous\", \"treatment_duration\": \"26 weeks\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"change in inflammation, endothelial dysfunction and cellular stress biomarkers at 26 weeks (post hoc)","endpoints":null,"effect_estimate":"Tirzepatide 15 mg at 26 weeks: hsCRP −36.2% from baseline (significant versus placebo, not versus dulaglutide), YKL-40 −30.8%, ICAM-1 −11.2%, leptin −34.1%; GlycA, IL-6, VCAM-1 and NT-proBNP not significantly changed in any group","confidence_interval":null,"p_value":"P < .001 for YKL-40 reductions with 10 and 15 mg versus baseline; other results marked P < .05 or not significant","sample_size":316,"follow_up":"26 weeks (biomarkers at baseline, 4, 12 and 26 weeks)","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": \"18‐75 years\", \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 23, \"obesity_status\": \"mixed (BMI 23‐50 kg/m2 entry range)\", \"diabetes_status\": \"type 2 diabetes required (HbA1c 7.0%-10.5%)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes inadequately controlled with diet and exercise alone or stable metformin\", \"sample_size\": 316, \"inclusion_exclusion\": \"aged 18-75; type 2 diabetes for 6 months or longer, HbA1c 7.0%-10.5%; diet and exercise alone or stable metformin; BMI 23-50\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes (HbA1c 7.0%‐10.5%), with entry BMI 23‐50 kg/m2 and age 18‐75 years; mean BMI is not reported.","mediation":"specifically_tested","mediation_notes":"Linear regression of biomarker change on body weight change found that weight change explained 0% of hsCRP and 6% of YKL-40 variability with tirzepatide, against 13% and 21% with dulaglutide, and 20% of leptin and 4% of ICAM-1 variability with tirzepatide (10 + 15 mg combined).","adjusted_for":"[\"body-weight change\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 316, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo; dulaglutide 1.5 mg\", \"follow_up_duration\": \"26 weeks (biomarkers at baseline, 4, 12 and 26 weeks)\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"LSM (SE) reported, no CI; 316 in the modified intention-to-treat population; post hoc, sample sizes set for the primary endpoints, not these biomarkers\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: post hoc, hypothesis-generating biomarker analysis of a 26-week randomised, double-blind phase 2b trial, with no clinical outcomes.","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly and Company (named as sponsor)","author_conflicts":"Nine of ten authors are employees and shareholders of Eli Lilly and Company; the tenth is a contractor who works with Lilly.","sponsor_role":"Sponsored by Eli Lilly and Company; no separate sponsor-role statement, but the author contributions credit study design, medical oversight, data analysis and the statistical analysis to authors who are Lilly employees","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly and Company","adverse_events":"not reported","limitations":"Post hoc, hypothesis-generating analysis with sample sizes set for the primary endpoints rather than these biomarkers; 26 weeks in people with type 2 diabetes; biomarker outcomes only.","plain_summary":"This post hoc analysis of a 26-week randomised, double-blind phase 2b trial in adults with type 2 diabetes compared tirzepatide with placebo and dulaglutide; 316 people were analysed. At 15 mg, tirzepatide lowered several cardiovascular risk markers, including hsCRP by 36.2% (significant versus placebo but not versus dulaglutide). GlycA, IL-6, VCAM-1 and NT-proBNP did not change significantly in any group. These are blood markers, and the authors call the analysis hypothesis-generating.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":453,"doi":"10.3389/fphar.2022.935823","pmid":"36188627","nct_ids":"[]","title":"Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials","authors":"[\"Gao X\", \"Hua X\", \"Wang X\", \"Xu W\", \"Zhang Y\", \"Shi C\", \"Gu M\"]","journal":"Frontiers in pharmacology","publication_date":"2022","year":2022,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Objectives: This study aims to explore the weight loss effect and safety of semaglutide as a conventional anti-obesity drug systematically in obese or overweight patients without diabetes. Methods: The randomized controlled trials (RCTs) of semaglutide in obese or overweight patients without diabetes were retrieved from PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov from database inception until 2 May 2022. Data extraction and quality assessment of studies meeting the inclusion criteria were performed, and statistical analysis was conducted by Review Manager 5.3 and Stata 14. Results: Eight studies involving 4,567 patients were enrolled in the meta-analysis. Compared with placebo, semaglutide induced a significant body weight loss (MD: -10.09%; 95% CI: -11.84 to -8.33; p ˂ 0.00001), elicited a larger reduction in body mass index (MD: -3.71 kg/m2; 95% CI: -4.33 to -3.09; p ˂ 0.00001) and waist circumference (MD: -8.28 cm; 95% CI: -9.51 to -7.04; p ˂ 0.00001), achieved weight loss of more than 5, 10, 15, and 20% with a higher proportion of participants. Semaglutide exhibited a positive effect on blood pressure, C-reactive protein, and lipid profiles, expressed more adverse effects than placebo, mainly gastrointestinal reactions. The results were stable and reliable with dose-dependence. Conclusion: Semaglutide indicated a significant weight loss with an acceptable safety for obese or overweight patients without diabetes.","url":"https://pubmed.ncbi.nlm.nih.gov/36188627/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:51:16+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":4567,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 4567, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with obesity/overweight.","mediation":"not_applicable","mediation_notes":"The main outcome is weight loss itself, so whether weight loss explains it is not a meaningful question; the abstract does not test whether the gastrointestinal side effects relate to weight loss or reduced intake.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 4567, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: -11\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 4, 7, 11, 13; non-critical weaknesses on items 3, 5, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"No\", \"5\": \"No\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 9, \"Partial Yes\": 1, \"Yes\": 6}, \"settled_by_ruling\": [\"item 11: No (IN-058; the passes read Yes and No)\", \"item 15: Yes (IN-058; the passes read No and Yes)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/36188627/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/36188627/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-02-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.1\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"National Key Research and Development Program of China (2017YFC0909900), per the full text","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"More adverse effects than placebo, mainly gastrointestinal.","limitations":null,"plain_summary":"In 8 trials (4,567 people without diabetes), semaglutide lowered weight about 10% more than placebo, with larger falls in BMI and waist size, and improved blood pressure, C-reactive protein and lipids, but caused more side effects, mainly gastrointestinal.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":463,"doi":"10.1097/cm9.0000000000001712","pmid":"34732660","nct_ids":"[\"NCT04029272\"]","title":"Short-term combined treatment with exenatide and metformin for overweight/obese women with polycystic ovary syndrome","authors":"[\"Ma RL\", \"Deng Y\", \"Wang YF\", \"Zhu SY\", \"Ding XS\", \"Sun AJ\"]","journal":"Chinese medical journal","publication_date":"2021-11-03","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS. [METHODS] Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein. [RESULTS] Forty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P < 0.050). Mild and moderate gastrointestinal reactions were the most common adverse events in both groups. [CONCLUSIONS] COM therapy was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects. [TRIAL REGISTRATION] ClinicalTrials.gov, NCT04029272. https://clinicaltrials.gov/ct2/show/NCT04029272.","url":"https://pubmed.ncbi.nlm.nih.gov/34732660/","source_name":"pubmed","source_tier":1,"coi_statement":"None.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"other_emerging\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":465,"doi":"10.1038/s41598-021-99527-y","pmid":"34625598","nct_ids":"[]","title":"Effects of exenatide on urinary albumin in overweight/obese patients with T2DM: a randomized clinical trial","authors":"[\"Kang C\", \"Qiao Q\", \"Tong Q\", \"Bai Q\", \"Huang C\", \"Fan R\", \"Wang H\", \"Kaliannan K\", \"Wang J\", \"Xu J\"]","journal":"Scientific reports","publication_date":"2021-10-08","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"In this study, we investigated the effect of exenatide (EXE), a glucagon-like peptide (GLP)-1 receptor agonist, on kidney function, obesity indices, and glucose control in overweight/obese patients with type 2 diabetes mellitus (T2DM). A total of 159 overweight/obese patients with T2DM were randomized to the EXE group or insulin glargine (GLAR) control group for a total treatment period of 24 weeks. EXE intervention significantly reduced the urine albumin concentration (UAC) at week 12 and 24 endpoints (P < 0.001 at week 12 and 24). The levels of the anthropometric, glucose and lipid parameters (TG and HDL-c), and inflammation biomarkers (CRP and TNF-α) in the EXE group were improved at 12 weeks or 24 weeks, respectively. Meanwhile, a comparison between two groups showed significant changes in anthropometric parameters, glucose parameters, lipid parameters (TG and HDL-c), and Inflammation biomarkers (CRP, IL-6, and TNF-α). Serum fibroblast growth factor 21 (FGF21) was increased in the EXE group (P = 0.005) at week 24, and the change was significantly improved compared with GLAR group (P = 0.003). Correlation network analysis showed that FGF21 had a more central role in improving metabolism in the EXE group, and the change of FGF 21 was significantly negatively correlated with UAC at week 12 and week 24, respectively (r = - 0.297, P = 0.010; r = - 0.294, P = 0.012). Our results showed that EXE could help patients improve UAC, glycemic levels, and inflammatory biomarkers after a follow-up period of 24 weeks intervention. These EXE effects may be partly mediated by FGF 21, indicating that EXE is an effective and safe way to control albuminuria in overweight/obese patients with T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/34625598/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare no competing interests.","assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":13,"doi":"10.1016/s2213-8587(21)00203-5","pmid":"34425083","nct_ids":"[]","title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials","authors":"[\"Sattar N\", \"Lee MMY\", \"Kristensen SL\", \"Branch KRH\", \"Del Prato S\", \"Khurmi NS\", \"Lam CSP\", \"Lopes RD\", \"McMurray JJV\", \"Pratley RE\", \"Rosenstock J\", \"Gerstein HC\"]","journal":"The lancet. Diabetes & endocrinology","publication_date":"2021-10","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes. [METHODS] We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711. [FINDINGS] Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80-0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all pinteraction≥0·14). GLP-1 receptor agonists reduced all-cause mortality by 12% (HR 0·88 [95% CI 0·82-0·94]; p=0·0001), hospital admission for heart failure by 11% (HR 0·89 [95% CI 0·82-0·98]; p=0·013), and the composite kidney outcome by 21% (HR 0·79 [95% CI 0·73-0·87]; p<0·0001), with no increase in risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR 0·82 [95% CI 0·69-0·98]; p=0·030). [INTERPRETATION] GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes. [FUNDING] None.","url":"https://pubmed.ncbi.nlm.nih.gov/34425083/","source_name":"pubmed","source_tier":1,"coi_statement":"Declaration of interests NS has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi; and received grant support from Boehringer Ingelheim, outside the submitted work. MMYL's employer, the University of Glasgow, has received grant support from Boehringer Ingelheim. SLK reports speaker fees from AstraZeneca, outside the submitted work. KRHB reports research grant funding from Bayer, Sanofi, and Eli Lilly; and consultation fees from Amgen, Bayer, Janssen, Sana, and Kestra. RDL reports research grants and personal fees from Bristol-Myers Squibb and Pfizer; personal fees from Boehringer Ingelheim and Bayer; and research grants from Amgen, GlaxoSmithKline, Medtronic, and Sanofi Aventis, outside the submitted work. CSPL has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as consultant or on the advisory board, steering committee, or executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research & Development, Medscape, MSD, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as co-founder and non-executive director of Us2.ai. SDP consulted for Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; received grant support from AstraZeneca and Boehringer Ingelheim; and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi. JJVM acknowledges payments to his employer, the University of Glasgow, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Theracos; personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. JR has participated in advisory panels for Boehringer Ingelheim, Intarcia Therapeutics, Applied Therapeutics, Eli Lilly, Hanmi, Novo Nordisk, Sanofi, Oramed, and Zealand Pharma; and has received research support from Applied Therapeutics, GlaxoSmithKline, Pfizer, Intarcia Therapeutics, Genentech, MSD, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Hanmi, and Oramed. REP reports grants from Hanmi; grants from Janssen and Poxel SA; consulting fees from MSD, Scohia, and Sun Pharmaceutical Industries; grants, speaker fees, and consulting fees from Novo Nordisk; consulting fees from Pfizer; and grants and consulting fees from Sanofi. REP's services were paid for directly to AdventHealth, a non-profit organisation. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, MSD, Novo Nordisk, and Sanofi; honoraria for speaking from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, DKSH, and Zuellig; and consulting fees from Abbott, Covance, Eli Lilly, Novo Nordisk, Sanofi, Pfizer, Kowa, and Hanmi.","assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\", \"semaglutide\", \"dulaglutide\", \"exenatide\", \"lixisenatide\", \"albiglutide\", \"efpeglenatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\", \"kidney\", \"adverse_effects\", \"cancer\"]","outcome_type":"hard","primary_outcome":"MACE across 8 placebo-controlled CVOTs (60,080 patients with T2D)","endpoints":null,"effect_estimate":"MACE HR 0.86; all-cause mortality HR 0.88; HF admission HR 0.89; composite kidney HR 0.79","confidence_interval":"0.80 to 0.93 (MACE)","p_value":"<0.0001","sample_size":60080,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes (all included trials)\", \"cvd_status\": \"mixed: the trials enrolled people with and without established cardiovascular disease (analysed as a subgroup)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 60080, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"All included trials enrolled people with type 2 diabetes.","mediation":"possibly","mediation_notes":"No heterogeneity by BMI subgroup, which argues against strong dependence on baseline adiposity; mediation by weight change not analysed.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 60080, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"8 trials, no significant heterogeneity\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.80 to 0.93 (MACE)\", \"risk_of_bias\": \"trial-level; all industry-sponsored trials\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Systematic meta-analysis of large randomized outcome trials with consistent effects.","funding_source":"None (per the abstract)","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"Independent academic meta-analysis of manufacturer-sponsored trials.","independent_replication_exists":"yes (multiple independent meta-analyses reach similar estimates)","conflict_notes":"Not reported in the abstract; full text not checked.","adverse_events":null,"limitations":null,"plain_summary":"Pooling eight cardiovascular outcome trials in 60,080 people with type 2 diabetes, GLP-1 receptor agonists reduced major cardiovascular events by 14%, death by 12%, and kidney outcomes by 21%, with no increase in pancreatitis, pancreatic cancer or retinopathy overall. Applies to diabetes populations.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":467,"doi":"10.1038/s41598-021-97967-0","pmid":"34535716","nct_ids":"[]","title":"Effect of liraglutide on expression of inflammatory genes in type 2 diabetes","authors":"[\"Zobel EH\", \"Ripa RS\", \"von Scholten BJ\", \"Rotbain Curovic V\", \"Kjaer A\", \"Hansen TW\", \"Rossing P\", \"Størling J\"]","journal":"Scientific reports","publication_date":"2021-09-17","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C-C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs' gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/34535716/","source_name":"pubmed","source_tier":1,"coi_statement":"VRC and JS declare no competing interests. RR, BS, TWH, and PR had shares in Novo Nordisk A/S. EHZ is now an employee of Novo Nordisk A/S but work related to this article was conducted while EHZ was employed by Steno Diabetes Center Copenhagen. BS is now an employee of Novo Nordisk A/S. AK has received consultancy fees from Novo Nordisk. PR has received the following: Consultancy and/or speaking fees (to Steno Diabetes Center Copenhagen) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novo Nordisk and Sanofi Aventis; Research grants to institution from AbbVie, AstraZeneca and Novo Nordisk.","assessment_version":3,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"up to 1.8 mg once daily\", \"comparator\": \"placebo (on top of standard of care)\", \"treatment_duration\": \"26 weeks\", \"route\": null}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"Change from baseline to end-of-treatment in expression of selected inflammatory genes in peripheral blood mononuclear cells (sub-study; the main trial primary endpoint was arterial FDG uptake)","endpoints":null,"effect_estimate":"Within the liraglutide group TNFA expression fell 26% (p = 0.004) and IL1B 34% (p = 0.046) and CCL5 rose (p = 0.002); none differed significantly from placebo (p ≥ 0.67 for TNFA and IL1B; p = 0.36 for CCL5); IFNG and CD163 rose in both groups; GLP1R was undetectable in blood cells","confidence_interval":"95% CI for within-group change only, e.g. TNFA liraglutide 0.43 (0.15; 0.72); none for between-group differences","p_value":"between groups p ≥ 0.67 (TNFA, IL1B); within liraglutide group TNFA p = 0.004, IL1B p = 0.046","sample_size":54,"follow_up":"26 weeks","direction":"null","population":"{\"mean_age\": \"66.8 (8.4) years\", \"age_range\": null, \"age_min\": 50, \"sex_distribution\": \"7 (13.0%) women\", \"bmi_mean\": \"30.2 (4.9) kg/m2\", \"bmi_min\": null, \"obesity_status\": \"not reported (no BMI entry criterion stated; mean BMI 30.2)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"mixed (11 (20.4%) had a history of CVD)\", \"ckd_status\": \"not reported (eGFR ≥ 30 required)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 54, \"inclusion_exclusion\": \"type 2 diabetes, above 50 years, HbA1c ≥ 48 mmol/mol (6.5%), eGFR ≥ 30; no DPP-4 inhibitor or GLP-1 RA in the prior 90 days\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes and mean BMI was 30.2; mean age 66.8 falls in the target range, and 13.0% were women.","mediation":"unlikely","mediation_notes":"No between-group effect was found, so there is no benefit for weight loss to explain; weight and HbA1c change were not analysed as mediators. Because GLP1R was not detected in the blood cells, the authors suggest any effect of liraglutide on them is most likely indirect.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 54, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo (on top of standard of care)\", \"follow_up_duration\": \"26 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs for within-group change only, none for between-group differences; 31 liraglutide and 23 placebo; sub-study not powered (power calculated for the main trial)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: exploratory, unpowered biomarker sub-study of 54 participants from a double-blind randomised placebo-controlled trial, plus in vitro cell work.","funding_source":"Novo Nordisk A/S and Skibsreder Per Henriksen, R. og hustrus fund; internal funding from Steno Diabetes Center Copenhagen and Rigshospitalet","industry_funded":"partial","manufacturer":"Novo Nordisk A/S","author_conflicts":"Four authors had Novo Nordisk shares, two are now Novo Nordisk employees, and others received consultancy fees or grants from Novo Nordisk and other companies; two declare none.","sponsor_role":"not reported","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"not reported","limitations":"The sub-study was not the trial's primary aim or powered for it, groups were numerically unbalanced (sex, smoking, SGLT-2 inhibitor use) and sample sizes skewed (31 vs 23); the THP-1 cell model has known limits.","plain_summary":"In a sub-study of a 26-week double-blind trial, 54 adults with type 2 diabetes (mean age 66.8) took liraglutide or placebo and had inflammatory gene activity measured in blood immune cells. Within the liraglutide group TNFA fell 26% and IL1B 34%, but these and the other changes did not differ significantly from placebo (p ≥ 0.67 for TNFA and IL1B). The drug's receptor was not detected in the cells, and tests on a cell line showed no direct effect of GLP-1.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":470,"doi":"10.1111/dom.14399","pmid":"33830637","nct_ids":"[]","title":"Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomised controlled trials","authors":"[\"Bray JJH\", \"Foster-Davies H\", \"Salem A\", \"Hoole AL\", \"Obaid DR\", \"Halcox JPJ\", \"Stephens JW\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2021-08","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To conduct a meta-analysis and systematic review to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on clinical biomarkers of inflammation and oxidative stress in patients with type 2 diabetes. [METHODS] Medline, Embase and the Cochrane Library were searched for randomised controlled trials (RCTs) that examined changes with GLP-1RAs in a priori selected biomarkers of inflammation: C-reactive protein (CRP), adiponectin, tumour necrosis factor-alpha (TNFα), plasminogen activator inhibitor-1, interleukin-6, leptin; and of oxidative stress: malondialdehyde (MDA); 8-iso-prostaglandin F2α; and 8-hydroxy-2'-deoxyguanosine (8-OHdG). [RESULTS] We included 40 eligible RCTs (n = 6749) with a median follow-up of 6 months, a mean participant age of 53.1 years, 56.3% females, glycated haemoglobin (HbA1c) 55.6 mmol/mol, body mass index 28.8 kg/m2 and diabetes duration 7.46 years. Analysis of GLP-1RAs versus standard diabetes therapies or placebo revealed significant reductions in CRP, TNFα and MDA, and significant increases in adiponectin for (mean difference -0.54 mg/L [-0.75, -0.34]; standard mean difference [SMD] -0.39 [-0.62, -0.15]; SMD -0.84 [-1.61, -0.06] and SMD 0.30 [0.12, 0.49], respectively [95% confidence intervals]). Systolic blood pressure decreased significantly and was significantly and strongly correlated with a reduction in CRP. Homeostatic model assessment of insulin resistance was also significantly correlated with a reduction in CRP, but HbA1c was not. [CONCLUSIONS] There is strong evidence supporting clinically relevant anti-inflammatory and antioxidant effects of GLP-1RAs. This may be used to guide future targeted clinical use of GLP-1RAs and the development of medications seeking to target the cardioprotective properties of GLP-1RAs.","url":"https://pubmed.ncbi.nlm.nih.gov/33830637/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":471,"doi":"10.1111/dom.14343","pmid":"33565691","nct_ids":"[]","title":"Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial","authors":"[\"Ahmad E\", \"Waller HL\", \"Sargeant JA\", \"Webb MA\", \"Htike ZZ\", \"McCann GP\", \"Gulsin G\", \"Khunti K\", \"Yates T\", \"Henson J\", \"Davies MJ\", \"Webb DR\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2021-06","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.","url":"https://pubmed.ncbi.nlm.nih.gov/33565691/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"unknown","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":27,"doi":"10.1056/nejmoa2028198","pmid":"33951361","nct_ids":"[\"NCT04122716\"]","title":"Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined","authors":"[\"Lundgren JR\", \"Janus C\", \"Jensen SBK\", \"Juhl CR\", \"Olsen LM\", \"Christensen RM\", \"Svane MS\", \"Bandholm T\", \"Bojsen-Møller KN\", \"Blond MB\", \"Jensen JB\", \"Stallknecht BM\", \"Holst JJ\", \"Madsbad S\", \"Torekov SS\"]","journal":"The New England journal of medicine","publication_date":"2021-05-06","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Weight regain after weight loss is a major problem in the treatment of persons with obesity. [METHODS] In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. [RESULTS] After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. [CONCLUSIONS] A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).","url":"https://pubmed.ncbi.nlm.nih.gov/33951361/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"3.0 mg daily\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo; exercise; combination\"}","domains":"[\"body_composition\", \"metabolic\", \"lean_mass\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":"Change in body weight at 1 year after 8-week low-calorie diet","endpoints":null,"effect_estimate":"vs placebo: exercise -4.1 kg; liraglutide -6.8 kg; combination -9.5 kg; combination decreased body-fat percentage by 3.9 points, about twice exercise (-1.7) or liraglutide (-1.9) alone","confidence_interval":null,"p_value":null,"sample_size":195,"follow_up":"52 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": \"not reported in abstract; full text not checked\", \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity (BMI 32-43)\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 195, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity without diabetes; young to middle-aged.","mediation":"not_applicable","mediation_notes":"Weight-maintenance trial.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 195, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo; exercise; combination\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI], -7\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Novo Nordisk Foundation and others","industry_funded":"partial","manufacturer":"Not reported in the abstract; full text not checked.","author_conflicts":"See published disclosures.","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"no","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Increased heart rate and cholelithiasis more often with liraglutide alone than combination.","limitations":null,"plain_summary":"After an 8-week low-calorie diet, all three active strategies kept off more weight over a year than placebo. Exercise plus liraglutide kept off more weight than exercise alone, but not significantly more than liraglutide alone (-2.7 kg, P=0.13). The combination lowered body-fat percentage about twice as much as either alone and was the only strategy associated with better fitness, HbA1c and insulin sensitivity. Liraglutide alone was associated with more gallstones and higher heart rate than the combination group.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":42,"doi":"10.1056/nejmoa2032183","pmid":"33567185","nct_ids":"[\"NCT03548935\"]","title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","authors":"[\"Wilding JPH\", \"Batterham RL\", \"Calanna S\", \"Davies M\", \"Van Gaal LF\", \"Lingvay I\", \"McGowan BM\", \"Rosenstock J\", \"Tran MTD\", \"Wadden TA\", \"Wharton S\", \"Yokote K\", \"Zeuthen N\", \"Kushner RF\", \"STEP 1 Study Group\"]","journal":"The New England journal of medicine","publication_date":"2021-03-18","year":2021,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. [METHODS] In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. [RESULTS] The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). [CONCLUSIONS] In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).","url":"https://pubmed.ncbi.nlm.nih.gov/33567185/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":6,"assessed_by":"ai:fact-check","assessed_at":"2026-11-09T03:30:08+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"68 weeks\", \"comparator\": \"placebo\"}","domains":"[\"body_composition\", \"metabolic\", \"gastrointestinal\", \"lean_mass\"]","outcome_type":"intermediate","primary_outcome":"Percent change in body weight; >=5% weight loss at week 68","endpoints":null,"effect_estimate":"-14.9% vs -2.4% (difference -12.4 pp)","confidence_interval":"-13.4 to -11.5","p_value":"<0.001","sample_size":1961,"follow_up":"68 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 27.0, \"obesity_status\": \"BMI >= 30 or >= 27 with comorbidity\", \"diabetes_status\": \"excluded\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1961, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Obesity without diabetes; landmark weight-loss trial; DXA substudy (full text, not checked) showed lean mass fell alongside fat mass.","mediation":"not_applicable","mediation_notes":"Participants had overweight or obesity and no diabetes; weight loss is itself the outcome here.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1961, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"68 weeks\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: -13.4 to -11.5\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"GI events most common; discontinuation for GI events 4.5% vs 0.8%.","limitations":null,"plain_summary":"Landmark trial: semaglutide 2.4 mg produced 14.9% weight loss vs 2.4% with placebo over 68 weeks in adults without diabetes who had obesity (BMI 30 or more), or overweight (BMI 27 or more) with at least one weight-related condition. Included for context.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":469,"doi":"10.24875/ric.20000308","pmid":"33861731","nct_ids":"[]","title":"Effects of Incretin-based Therapy on High-sensitivity C-reactive Protein in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis","authors":"[\"Wu Y\", \"Lu Y\", \"Yang S\", \"Zhang Q\"]","journal":"Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion","publication_date":"2020-10-21","year":2020,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. [OBJECTIVE] The objective of the study was to assess the effects of incretin-based therapies on hs- CRP in patients with T2DM by meta-analysis. [METHODS] We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. [RESULTS] Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = -0.452, p < 0.001). Subgroup analysis of different class of incretinbased drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = -0.338, p = 0.026) and glucagonlike peptide 1 receptor agonists (GLP-1 RAs, SMD = -0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = -0.465, p = 0.001), while no significant difference with < 24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. [CONCLUSIONS] This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.","url":"https://pubmed.ncbi.nlm.nih.gov/33861731/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"meta_analysis","drugs":"[\"glp-1 receptor agonists\", \"dpp-4 inhibitors\"]","drug_details":"{\"dose\": \"various\", \"route\": \"various\", \"comparator\": \"placebo or active drugs (controls)\", \"treatment_duration\": \"12 weeks to 104 weeks\"}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"Pooled standardised mean difference in serum hs-CRP, incretin-based therapy versus controls","endpoints":null,"effect_estimate":"All incretin-based therapies SMD = -0.452 (p < 0.001); GLP-1 RAs SMD = -0.544 (p = 0.003); DPP-4Is SMD = -0.338 (p = 0.026); no significant difference for durations under 24 weeks","confidence_interval":"pooled SMD −0.452, 95% CI −0.688 to −0.217; GLP-1 RAs 95% CI −0.908 to −0.181","p_value":"p < 0.001 (overall); p = 0.003 (GLP-1 RAs)","sample_size":2851,"follow_up":"median follow-up of 24 weeks","direction":"benefit","population":"{\"mean_age\": \"study means between 47.7 and 68.4 years\", \"age_range\": null, \"age_min\": 18, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"mixed (subgroups by mean baseline BMI above and below 30)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 2851, \"inclusion_exclusion\": \"randomised controlled trials in adults aged more than 18 with T2DM reporting hs-CRP change for intervention and control groups\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: every included trial enrolled adults with type 2 diabetes; study mean ages were between 47.7 and 68.4, and results were reported for subgroups with mean baseline BMI above and below 30.","mediation":"possibly","mediation_notes":"Study-level meta-regression found that better glycaemic control and greater BMI decline were associated with larger hs-CRP reductions; this is a between-trial association, not a participant-level mediation analysis, so weight and glycaemic effects are not separated.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 2851, \"randomization\": \"yes\", \"blinding\": \"n/a\", \"comparator\": \"placebo or active drugs (controls)\", \"follow_up_duration\": \"median follow-up of 24 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported; high heterogeneity (I2 = 88.1%); Egger test p = 0.103\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"MODERATE: meta-analysis of 28 randomised trials (2,851 participants), but with a biomarker outcome, high heterogeneity (I2 = 88.1%) and many small, partly open-label trials.","funding_source":"Nantong University Clinical Medicine Program (2019JQ008)","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported","sponsor_role":"not reported","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported","limitations":"The authors note small trials with low power, trials not designed to assess hs-CRP, inconsistent hs-CRP methods and some calculated data; heterogeneity was high, eight parallel and two crossover trials were open-label, and the pooled result combines GLP-1 RAs with DPP-4 inhibitors.","plain_summary":"This meta-analysis pooled 28 randomised trials (25 studies, 2,851 adults with type 2 diabetes) comparing incretin-based drugs, either GLP-1 receptor agonists or DPP-4 inhibitors, with placebo or other treatments. Both classes were linked to lower hs-CRP, an inflammation blood marker (all incretin drugs SMD = -0.452; GLP-1 receptor agonists SMD = -0.544), but trials shorter than 24 weeks showed no significant difference. Results varied widely between trials, and larger falls were associated with better blood sugar control and more BMI decline.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":474,"doi":"10.1111/dom.14078","pmid":"32543021","nct_ids":"[]","title":"Effect of short-acting exenatide administered three times daily on markers of cardiovascular disease in type 1 diabetes: A randomized double-blind placebo-controlled trial","authors":"[\"Johansen NJ\", \"Dejgaard TF\", \"Lund A\", \"Schlüntz C\", \"Larsen EL\", \"Poulsen HE\", \"Goetze JP\", \"Møller HJ\", \"Vilsbøll T\", \"Andersen HU\", \"Knop FK\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2020-09","year":2020,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To investigate the effect of adding the short-acting glucagon-like peptide 1 receptor agonist (GLP-1RA) exenatide to insulin treatment on markers of cardiovascular risk in type 1 diabetes. [MATERIALS AND METHODS] In a randomized, double-blind, parallel-group trial, 108 individuals with type 1 diabetes aged ≥18 years on multiple daily injection therapy with a body mass index >22.0 kg/m2 and glycated haemoglobin concentration of 59 to 88 mmol/mol (7.5%-10.0%) were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta®) or placebo three times daily over 26 weeks as add-on treatment to existing insulin therapy. Reported markers of cardiovascular risk were secondary endpoints and were analyzed in a baseline-adjusted linear mixed model in the intention-to-treat population. The primary results of this study, the MAG1C (Meal-time Administration of exenatide for Glycaemic control in type 1 diabetes Cases) trial, were previously reported. [RESULTS] Exenatide changed total fat mass by -2.6 kg (95% confidence interval [CI] -3.6; -1.6; P < 0.0001) and lean body mass by -1.1 kg (95% CI -1.9; -0.4; P = 0.01) compared with placebo, as assessed by dual-energy X-ray absorptiometry. Fat mass reductions were similar for central and peripheral fat mass. Exenatide did not change levels of interleukin-2 or -6; tumour necrosis factor-α; C-reactive protein; N-terminal prohormone of brain natriuretic peptide; or 8-oxo-7,8-dihydroguanosine (RNA oxidation marker) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (DNA oxidation marker). [CONCLUSIONS] Exenatide added to insulin therapy in type 1 diabetes for 26 weeks resulted in body weight loss primarily from fat mass reduction, but had no effect on biomarkers of cardiovascular disease risk.","url":"https://pubmed.ncbi.nlm.nih.gov/32543021/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"body_composition\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":486,"doi":"10.1007/s00059-018-4748-5","pmid":"30467578","nct_ids":"[]","title":"Efficacy of liraglutide intervention in myocardial infarction : A meta-analysis of randomized controlled trials","authors":"[\"Yang X\", \"Liang Z\"]","journal":"Herz","publication_date":"2020-08","year":2020,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[INTRODUCTION] The efficacy of liraglutide intervention for myocardial infarction (MI) remains controversial. We conducted a systematic review and meta-analysis to explore the influence of liraglutide intervention versus placebo on cardiac function for MI. [METHODS] We searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through April 2018 for randomized controlled trials (RCTs) assessing the effect of liraglutide intervention versus placebo on MI. This meta-analysis was performed using the random-effect model. [RESULTS] Four randomized controlled trials involving 469 patients were included in the meta-analysis. Overall, compared with control group for MI, liraglutide intervention significantly improved left ventricular ejection fraction (mean difference [MD] = 4.42; 95% confidence interval [CI] =1.71 to 7.14; P = 0.001), superoxide dismutase (MD = 6.89; 95% CI = 1.80 to 11.98; P = 0.008), and decreased high-sensitivity C‑reactive protein (MD = -0.21; 95% CI = -0.33 to -0.09; P = 0.0006), but had no remarkable influence on major adverse cardiovascular events (risk ratio = 0.56; 95% CI = 0.28-1.09; P = 0.09), recurrence of MI (risk ratio = 0.50; 95% CI = 0.19-1.30; P = 0.16), repeated revascularization (risk ratio = 0.49; 95% CI = 0.17-1.42; P = 0.19), and cardiac death (risk ratio = 0.57; 95% CI = 0.12-2.73; P = 0.48). [CONCLUSIONS] Liraglutide intervention is associated with significantly improved left ventricular ejection fraction and superoxide dismutase, reduced high-sensitivity C‑reactive protein in patients with MI, but has no remarkable impact on major adverse cardiovascular events, recurrence of MI, repeated revascularization or cardiac death.","url":"https://pubmed.ncbi.nlm.nih.gov/30467578/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"cardiovascular\", \"cerebrovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":475,"doi":"10.1186/s12933-020-01014-7","pmid":"32334592","nct_ids":"[]","title":"Comparison of the effects of twice-daily exenatide and insulin on carotid intima-media thickness in type 2 diabetes mellitus patients: a 52-week randomized, open-label, controlled trial","authors":"[\"Zhang J\", \"Xian TZ\", \"Wu MX\", \"Li C\", \"Pan Q\", \"Guo LX\"]","journal":"Cardiovascular diabetology","publication_date":"2020-04-25","year":2020,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Exenatide, a glucagon like peptide 1 analog, has been suggested to reduce the cardiovascular disease risk factors, such as body weight, blood pressure and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This was the first randomized, open-label, controlled trial to compare the effects of exenatide versus insulin on subclinical atherosclerosis, as assessed by carotid-intima media thickness (CIMT), in patients with T2DM. [METHODS] A total of 66 patients with T2DM admitted from March 10, 2015 to June 20, 2017 in the Department of Endocrinology, Beijing Hospital were randomized to receive twice-daily exenatide or aspartate 70/30 insulin for 52 weeks. The primary endpoint was change from baseline in CIMT, and secondary endpoints included changes at week 52 from baseline in body weight, glycemic markers, lipid metabolism markers, blood pressure, C-reactive protein, fibrinogen, 8-hydroxydeoxyguanosine, irisin, and brain natriuretic peptide. [RESULTS] Exenatide more significantly reduced the CIMT from baseline compared with insulin after 52 weeks, with a mean difference of - 0.14 mm (95% interval confidence: - 0.25, - 0.02; P = 0.016). Weight and body mass index were both significantly reduced in the exenatide group over 52 weeks. Exenatide reduced total lipoprotein and low-density lipoprotein cholesterol levels more significantly than insulin at weeks 16 and 40. Correlation analyses showed that CIMT was positively correlated with low-density lipoprotein cholesterol. [CONCLUSIONS] Twice-daily exenatide could prevent atherosclerosis progression in patients with T2DM over a 52-week treatment period compared with insulin therapy. Trial registration Chinese Clinical Trial Registry ChiCTR-1800015658.","url":"https://pubmed.ncbi.nlm.nih.gov/32334592/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no competing interests.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":477,"doi":"10.1111/bcp.14063","pmid":"31338868","nct_ids":"[\"NCT02138045\"]","title":"Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy","authors":"[\"Brock C\", \"Hansen CS\", \"Karmisholt J\", \"Møller HJ\", \"Juhl A\", \"Farmer AD\", \"Drewes AM\", \"Riahi S\", \"Lervang HH\", \"Jakobsen PE\", \"Brock B\"]","journal":"British journal of clinical pharmacology","publication_date":"2019-11","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function. [METHODS] The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing. [RESULTS] Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02). [CONCLUSION] Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.","url":"https://pubmed.ncbi.nlm.nih.gov/31338868/","source_name":"pubmed","source_tier":1,"coi_statement":"The study sponsor was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.","assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"neuroinflammation\", \"immune\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":478,"doi":"10.1016/j.atherosclerosis.2019.07.007","pmid":"31326727","nct_ids":"[]","title":"Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial","authors":"[\"Anholm C\", \"Kumarathurai P\", \"Pedersen LR\", \"Samkani A\", \"Walzem RL\", \"Nielsen OW\", \"Kristiansen OP\", \"Fenger M\", \"Madsbad S\", \"Sajadieh A\", \"Haugaard SB\"]","journal":"Atherosclerosis","publication_date":"2019-09","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND AND AIMS] Atherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. [METHODS] We conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. [INTERVENTION] liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Å as the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. [RESULTS] 28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. [CONCLUSIONS] In patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.","url":"https://pubmed.ncbi.nlm.nih.gov/31326727/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"crossover_trial","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":12,"doi":"10.1016/s0140-6736(19)31149-3","pmid":"31189511","nct_ids":"[\"NCT01394952\"]","title":"Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial","authors":"[\"Gerstein HC\", \"Colhoun HM\", \"Dagenais GR\", \"Diaz R\", \"Lakshmanan M\", \"Pais P\", \"Probstfield J\", \"Riesmeyer JS\", \"Riddle MC\", \"Rydén L\", \"Xavier D\", \"Atisso CM\", \"Dyal L\", \"Hall S\", \"Rao-Melacini P\", \"Wong G\", \"Avezum A\", \"Basile J\", \"Chung N\", \"Conget I\", \"Cushman WC\", \"Franek E\", \"Hancu N\", \"Hanefeld M\", \"Holt S\", \"Jansky P\", \"Keltai M\", \"Lanas F\", \"Leiter LA\", \"Lopez-Jaramillo P\", \"Cardona Munoz EG\", \"Pirags V\", \"Pogosova N\", \"Raubenheimer PJ\", \"Shaw JE\", \"Sheu WH\", \"Temelkova-Kurktschiev T\", \"REWIND Investigators\"]","journal":"Lancet (London, England)","publication_date":"2019-07-13","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. [METHODS] This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. [FINDINGS] Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). [INTERPRETATION] Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. [FUNDING] Eli Lilly and Company.","url":"https://pubmed.ncbi.nlm.nih.gov/31189511/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":6,"assessed_by":"curated","assessed_at":"2026-11-09T13:53:34+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":"{\"dose\": \"1.5 mg once weekly\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":"Nonfatal MI, nonfatal stroke or CV death","endpoints":null,"effect_estimate":"HR 0.88 (12.0% vs 13.4%); all-cause mortality HR 0.90 (NS)","confidence_interval":"0.79 to 0.99","p_value":"0.026","sample_size":9901,"follow_up":"median 5.4 years","direction":"benefit","population":"{\"mean_age\": 66.2, \"age_range\": null, \"age_min\": 50, \"sex_distribution\": \"46.3% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"31% prior CVD; remainder risk factors only (full text, not checked)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 9901, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"All had type 2 diabetes; notable for including a majority without prior cardiovascular disease and for the longest follow-up of any trial in this collection (median 5.4 years). Mean age 66 matches the target age band.","mediation":"possibly","mediation_notes":"Small weight (-1.5 kg) and HbA1c effects; benefit similar with and without prior CVD (full text, not checked).","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 9901, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"median 5.4 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.79 to 0.99\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet assessed).","funding_source":"Eli Lilly","industry_funded":"yes","manufacturer":"Eli Lilly","author_conflicts":"Authors report Eli Lilly relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed.","independent_replication_exists":"class-level","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":"GI adverse events 47.4% vs 34.1%.","limitations":null,"plain_summary":"In 9,901 people with type 2 diabetes, most without prior heart disease, dulaglutide reduced major cardiovascular events by 12% over 5.4 years; total mortality was not significantly changed. Longest follow-up of any trial in this collection; still confined to diabetes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":479,"doi":"10.3892/etm.2019.7577","pmid":"31258671","nct_ids":"[]","title":"Meta-analysis of the efficacy of liraglutide in patients with type 2 diabetes accompanied by incipient nephropathy","authors":"[\"Liu W\", \"Yu J\", \"Tian T\", \"Miao J\", \"Shang W\"]","journal":"Experimental and therapeutic medicine","publication_date":"2019-07","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The efficacy of liraglutide in patients with type 2 diabetes accompanied by early-stage nephropathy has remained to be fully elucidated. The present meta-analysis was performed to determine the clinical outcomes associated with liraglutide treatment. The PubMed, Ovid, Cochrane Library, Chinese National Knowledge Infrastructure and Wanfang databases were searched in October 2018 to identify randomized controlled trials of liraglutide for diabetes patients with early-stage nephropathy. The treatment effect was estimated by calculating the mean difference (MD). Heterogeneity was assessed using χ2 and I2 tests. In addition, risk of bias graphs and summaries were used to assess the quality of the trials included. A total of 13 randomized controlled trials were included in the present meta-analysis. In subjects with stage I-II diabetic nephropathy (DN), liraglutide had obvious advantages in lowering the urinary albumin-to-creatinine ratio [UACR; MD=-90.96, 95% confidence interval (CI)=-94.12 to -87.80, P<0.00001], urinary albumin excretion rate (UAER; MD=-64.86, 95% CI=-66.63 to -63.08, P<0.00001), serum creatinine (Scr; MD=-13.67, 95% CI=-17.88 to -9.46, P<0.00001). In subjects with stage-III DN, liraglutide had favorable effects on renal function (UACR: MD=-11.23, 95% CI=-13.14 to -9.32, P<0.00001; UAER: MD=-14.06; 95% CI=-6.93 to -11.18; P<0.00001; Scr: MD=-9.17, 95% CI=-14.61 to -3.72, P=0.0010) and exhibited anti-inflammatory effects (transforming growth factor-β1: P<0.00001; tumor necrosis factor-α: P=0.006; interleukin-6: P<0.00001). Furthermore, liraglutide also reduced the blood lipid levels, body mass index and post-prandial blood glucose. The most common adverse effects of liraglutide were gastrointestinal tract reactions and hypoglycemia, but these symptoms resolved quickly. Liraglutide appears to be effective in reducing proteinuria, improving renal function, producing an anti-inflammatory effect and ameliorating glucose and lipid metabolism in diabetic patients with early-stage nephropathy.","url":"https://pubmed.ncbi.nlm.nih.gov/31258671/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:51:16+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"kidney\", \"cancer\", \"metabolic\", \"gastrointestinal\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"early diabetic nephropathy required (stage I-III)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes with early-stage (stage I-III) diabetic nephropathy\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.","mediation":"unknown","mediation_notes":"Reported effects favour liraglutide (kidney lab markers, inflammatory markers, lipids); the abstract does not test whether they depend on weight loss, and liraglutide also lowered BMI.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval (CI\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\", \"amstar2\": {\"item\": \"Q-020b\", \"overall\": \"Critically low confidence (AMSTAR 2, full text, two passes agreed)\", \"driver\": \"critical flaws on items 2, 4, 7, 11, 13; non-critical weaknesses on items 3, 5, 10, 12\", \"items\": {\"1\": \"Yes\", \"2\": \"No\", \"3\": \"No\", \"4\": \"No\", \"5\": \"No\", \"6\": \"Yes\", \"7\": \"No\", \"8\": \"Partial Yes\", \"9\": \"Yes\", \"10\": \"No\", \"11\": \"No\", \"12\": \"No\", \"13\": \"No\", \"14\": \"Yes\", \"15\": \"Yes\", \"16\": \"Yes\"}, \"item_tally\": {\"No\": 9, \"Partial Yes\": 1, \"Yes\": 6}, \"settled_by_ruling\": [\"item 3: No (IN-059; the passes read Yes and No)\", \"item 13: No (IN-059; the passes read Yes and No)\", \"item 14: Yes (IN-059; the passes read Yes and No)\"], \"use_in_c001\": \"Used only to locate trials: a review rated Low or Critically low does not supply a pooled estimate to an outcome body (c001-outcomes; amstar2-guide)\", \"source\": \"full text and retrieved supplements, 2026-10-05\", \"passes\": [{\"pass\": \"A\", \"model\": \"claude-sonnet\", \"file\": \"data/assessments/31258671/Q-020b-amstar2-passA.yaml\"}, {\"pass\": \"B\", \"model\": \"claude-opus\", \"file\": \"data/assessments/31258671/Q-020b-amstar2-passB.yaml\"}], \"record\": \"data/assessments/Q-020b-BATCH-03-AMSTAR2-2026-10-05.md\", \"guide\": \"docs/amstar2-guide.md v1.2\", \"label\": \"AI: two passes agreed (item splits settled by owner ruling)\"}}","evidence_rationale":"[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).","funding_source":"Jiangsu Provincial Hospital of Traditional Chinese Medicine grant (per full text)","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare no competing interests (per full text).","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":"Across 13 randomized trials in type 2 diabetes with early kidney disease, liraglutide improved lab markers (urine albumin, serum creatinine, inflammatory markers, lipids); the abstract reports no kidney failure or other clinical events. The main side effects were gastrointestinal upset and low blood sugar.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":480,"doi":"10.1111/apt.15316","pmid":"31246368","nct_ids":"[]","title":"Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity","authors":"[\"Newsome P\", \"Francque S\", \"Harrison S\", \"Ratziu V\", \"Van Gaal L\", \"Calanna S\", \"Hansen M\", \"Linder M\", \"Sanyal A\"]","journal":"Alimentary pharmacology & therapeutics","publication_date":"2019-07","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. [AIM] To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. [METHODS] Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. [RESULTS] Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. [CONCLUSIONS] Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.","url":"https://pubmed.ncbi.nlm.nih.gov/31246368/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"curated","assessed_at":"2026-11-09T13:53:34+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"0.05-0.4 mg/day (weight management trial); 0.5 or 1.0 mg/week (cardiovascular outcomes trial)\", \"comparator\": \"placebo\", \"route\": \"subcutaneous\", \"treatment_duration\": \"52 weeks (weight management trial); 104 weeks (cardiovascular outcomes trial)\"}","domains":"[\"inflammation\", \"cardiovascular\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"Treatment ratios versus placebo for ALT (both trials) and hsCRP (weight management trial), by baseline ALT subgroup; post hoc","endpoints":null,"effect_estimate":"Elevated-ALT subgroup, weight management trial: ALT reductions 6%-21% (P<0.05 for doses ≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day); cardiovascular outcomes trial: no significant ALT reduction at 0.5 mg/week, 9% reduction vs placebo at 1.0 mg/week (P = 0.0024); ratios not statistically significant after adjustment for weight change","confidence_interval":null,"p_value":"P<0.05 for ALT at doses ≥0.2 mg/day and P < 0.05 for hsCRP at 0.2 and 0.4 mg/day (weight management trial); P = 0.0024 for ALT at 1.0 mg/week (cardiovascular outcomes trial)","sample_size":null,"follow_up":"52 weeks (weight management trial); 104 weeks (SUSTAIN-6)","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": \"18‐76 and 19‐86 (weight management trial); 50‐88 and 50‐89 (SUSTAIN-6), by baseline ALT subgroup\", \"age_min\": null, \"sex_distribution\": \"35% male (weight management trial); 61% male (cardiovascular outcomes trial)\", \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"mixed (weight management trial required BMI ≥30; cardiovascular outcomes trial had no BMI criterion)\", \"diabetes_status\": \"mixed (weight management trial without diabetes; cardiovascular outcomes trial type 2 diabetes)\", \"cvd_status\": \"mixed (cardiovascular outcomes trial: high risk or prior cardiovascular events; weight management trial not reported)\", \"ckd_status\": \"mixed (cardiovascular outcomes trial included people with chronic kidney disease; weight management trial not reported)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity without diabetes (weight management trial); type 2 diabetes with high cardiovascular risk (SUSTAIN-6)\", \"sample_size\": null, \"inclusion_exclusion\": \"weight trial: BMI ≥30 without diabetes; SUSTAIN-6: type 2 diabetes, age at least 50, HbA1c ≥7%, high cardiovascular risk or CKD\", \"healthy_volunteers\": false, \"normal_weight_included\": true, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: the weight management trial required obesity (BMI ≥30) without diabetes, and SUSTAIN-6 enrolled people aged at least 50 with type 2 diabetes and high cardiovascular risk; some SUSTAIN-6 participants had a normal BMI, but they are not reported separately.","mediation":"specifically_tested","mediation_notes":"A second model adjusted for change in body weight; after this adjustment no ALT or hsCRP treatment ratio was significant and the ratios clustered around 1.0, suggesting the reductions track weight loss.","adjusted_for":"[\"body-weight change\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks (weight management trial); 104 weeks (SUSTAIN-6)\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"P values and treatment ratios; CIs only in figures; 499 of 957 and 1325 of 3268 had elevated baseline ALT; post hoc subgroup analysis\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: post hoc analysis of biomarkers (ALT, hsCRP) from two randomised double-blind trials, with no liver histology or clinical liver outcomes.","funding_source":"Novo Nordisk A/S; NIH grant listed by PubMed: National Center for Advancing Translational Sciences","industry_funded":"yes","manufacturer":"Novo Nordisk (named as sponsor)","author_conflicts":"Three authors are Novo Nordisk employees and most others report grants, consultancy or fees from Novo Nordisk and many other companies.","sponsor_role":"Novo Nordisk contributed to the designs of both trials and performed site monitoring, data collection and data analysis for both","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"not reported","limitations":"Post hoc analysis; neither trial enrolled people with confirmed NASH and no liver histology was available; hsCRP was measured only in the weight management trial, where diet and exercise counselling was also given; the reductions were not significant after adjustment for weight change.","plain_summary":"This post hoc analysis used two double-blind, placebo-controlled semaglutide trials: one in 957 adults with obesity without diabetes (52 weeks) and one in people with type 2 diabetes at high cardiovascular risk (104 weeks). Among people with a raised liver enzyme (ALT), semaglutide lowered ALT by 6%-21% and the inflammation marker hsCRP by 25%-43% versus placebo in the obesity trial; in the diabetes trial ALT fell 9% at 1.0 mg/week but not significantly at 0.5 mg/week. None of these differences remained significant after allowing for weight change, and these are blood markers rather than liver outcomes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":476,"doi":"10.1155/2019/2682657","pmid":"31950036","nct_ids":"[\"NCT01648582\"]","title":"The Effects of Once-Weekly Dulaglutide and Insulin Glargine on Glucose Fluctuation in Poorly Oral-Antidiabetic Controlled Patients with Type 2 Diabetes Mellitus","authors":"[\"Wang J\", \"Li HQ\", \"Xu XH\", \"Kong XC\", \"Sun R\", \"Jing T\", \"Ye L\", \"Su XF\", \"Ma JH\"]","journal":"BioMed research international","publication_date":"2019","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Aim. To compare the effects of once-weekly Dulaglutide with once-daily glargine in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM). Method. A total of 25 patients with T2DM admitted into Department of Endocrinology from December 2012 to August 2013 were randomly assigned into two groups: Dulaglutide group (n = 16) and glargine group (n = 9). All patients received either Dulaglutide or glargine treatments for 52 weeks. Continuous glucose monitoring systems (CGMS) were applied to them for two 72 h periods at before and after the treatment each. Patient general clinical data were collected and analyzed. Result. Fast blood glucose (FBG) of the glargine group declined more significantly than the Dulaglutide group after treatment (p < 0.05). The mean blood glucose (MBG), standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE) within a day, the largest amplitude of glycemic excursion (LAGE), M-value, absolute means of daily difference (MODD) of glycemic excursion, the percentage of time (≤2.8 mmol/L, ≤3.9 mmol/L, ≥10.0 mmol/L, ≥13.9 mmol/L, 3.9-7.8 mmol/L, and 9-10.0 mmol/L), maximum glycemic value, and minimum glycemic value were similar between the two groups (p > 0.05). The incidence of hypoglycemia was also similar between the two groups (p > 0.05). Though serum levels of TNF-α, IL-6, and 8-PGF2α all decreased, significant reduction was found in TNF-α and 8-PGF2α. TNF-α was only significantly reduced in the Dulaglutide group, while 8-PGF2α was seen in both groups. Conclusion. For T2DM patients with poorly controlled oral antidiabetic drugs, once-weekly Dulaglutide not only has the same effect on glucose fluctuation as once-daily glargine but also significantly reduced TNF-α and 8-PGF2α after a 52 week treatment protocol. This trial is registered with ClinicalTrials.gov NCT01648582.","url":"https://pubmed.ncbi.nlm.nih.gov/31950036/","source_name":"pubmed","source_tier":1,"coi_statement":"The authors declare that they have no conflicts of interest.","assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":481,"doi":"10.1155/2019/6423987","pmid":"31183384","nct_ids":"[\"NCT01644500\"]","title":"A Randomized Study to Compare the Effects of Once-Weekly Dulaglutide Injection and Once-Daily Glimepiride on Glucose Fluctuation of Type 2 Diabetes Mellitus Patients: A 26-Week Follow-Up","authors":"[\"Li H\", \"Xu X\", \"Wang J\", \"Kong X\", \"Chen M\", \"Jing T\", \"Zhang Z\", \"Yin G\", \"Liu X\", \"Hu Y\", \"Ye L\", \"Su X\", \"Ma J\"]","journal":"Journal of diabetes research","publication_date":"2019","year":2019,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To evaluate the effects of once-weekly dulaglutide injection and once-daily glimepiride on glucose fluctuation in patients with type 2 diabetes mellitus (T2DM) using the Continuous Glucose Monitoring System (CGMS). [METHODS] A total of 23 patients with T2DM were randomly assigned into two groups for 26 weeks: the dulaglutide group (n = 13) and the glimepiride group (n = 10). 72-hour CGMS was applied to all patients: before and after the treatment. General clinical data were collected and measured, such as fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), tumor necrosis factor-α (TNF-α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and interleukin-6 (IL-6). [RESULTS] HbA1c of the dulaglutide group was reduced from 8.38 ± 0.93% to 6.68 ± 0.73% after the treatment (P < 0.05); similarly, it was reduced from 7.91 ± 0.98% to 6.67 ± 0.74% (P < 0.05) in the glimepiride group. The levels of serum 8-iso-PGF2α, TNF-α, and IL-6 all decreased significantly in both groups after treatment, and there was no significant difference found between the two groups (P > 0.05). The Mean Blood Glucose (MBG) of the two groups declined significantly after therapy (P < 0.05). However, the Standard Deviation of Blood Glucose (SDBG) decreased significantly only in the dulaglutide group (from 2.57 ± 0.74 mmol/L to 1.98 ± 0.74 mmol/L, P < 0.05). There were no significant changes of Mean Amplitude of Glycemic Excursion (MAGE) and Absolute Means of Daily Difference (MODD) after treatment in both groups. Furthermore, no statistically significant difference was found between the two groups in MBG, SDBG, MAGE, and MODD (P > 0.05). The percentage time (PT) (>10 mmol/L and 3.9-10 mmol/L) of the two groups was significantly changed after the treatment (P < 0.05). However, this was not seen in the PT < 3.9 mmol/L after the treatment (P > 0.05). [CONCLUSION] Once-weekly dulaglutide injection has the same effectiveness as daily glimepiride on lowering blood glucose and decreasing oxidation stress and inflammation and is more effective in controlling glucose fluctuation as compared with glimepiride. This trial is registered with ClinicalTrials.gov NCT01644500.","url":"https://pubmed.ncbi.nlm.nih.gov/31183384/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":485,"doi":"10.3390/nu10121872","pmid":"30513818","nct_ids":"[]","title":"Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss","authors":"[\"Simeone P\", \"Liani R\", \"Tripaldi R\", \"Di Castelnuovo A\", \"Guagnano MT\", \"Tartaro A\", \"Bonadonna RC\", \"Federico V\", \"Cipollone F\", \"Consoli A\", \"Santilli F\"]","journal":"Nutrients","publication_date":"2018-12-02","year":2018,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Thromboxane (TX)-dependent platelet activation and lipid peroxidation, as reflected in vivo by the urinary excretion of 11-dehydro-TXB₂ and 8-iso-prostaglandin (PG)F2α, play a key role in atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) since the earlier stages. Thirty-five metformin-treated obese subjects with prediabetes or newly-diagnosed T2DM were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/day) or lifestyle counseling until achieving a comparable weight loss (-7% of initial body weight), to assess whether changes in subcutaneous (SAT) and visceral (VAT) adipose tissue distribution (MRI), insulin sensitivity (Matsuda Index) and beta-cell performance (multiple sampling OGTT beta-index), with either intervention, might affect TX-dependent platelet activation, lipid peroxidation and inflammation. At baseline, Ln-8-iso-PGF2α (Beta = 0.31, p = 0.0088), glycosylated hemoglobin (HbA1c) (Beta = 2.64, p = 0.0011) Ln-TNF-α (Beta = 0.58, p = 0.0075) and SAT (Beta = 0.14, p = 0.044) were significant independent predictors of 11-dehydro-TXB₂. After achievement of the weight loss target, a comparable reduction in U-11-dehydro-TXB₂ (between-group p = 0.679) and 8-iso-PGF-2α (p = 0.985) was observed in both arms in parallel with a comparable improvement in glycemic control, insulin sensitivity, SAT, high-sensitivity C-reactive protein (hs-CRP). In obese patients with initial impairment of glucose metabolism, the extent of platelet activation is related to systemic inflammation, isoprostane formation and degree of glycemic control and abdominal SAT. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction in lipid peroxidation and platelet activation.","url":"https://pubmed.ncbi.nlm.nih.gov/30513818/","source_name":"pubmed","source_tier":1,"coi_statement":"Consoli received lecture fees and fees for serving on advisory boards from Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi Aventis, Merck Sharp & Dohme, and Takeda and grant support to his institution from Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.","assessment_version":2,"assessed_by":"ai:two-pass","assessed_at":"2026-10-19T01:52:18+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg/day (titrated from 0.6 mg over 3 weeks)\", \"route\": \"subcutaneous\", \"comparator\": \"lifestyle counselling, continued until the same weight loss (7% of initial body weight)\", \"treatment_duration\": \"until 7% weight loss was reached; median 4 months\"}","domains":"[\"inflammation\", \"body_composition\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"change in urinary 11-dehydro-TXB2 and 8-iso-PGF2α after 7% weight loss","endpoints":null,"effect_estimate":"U-11-dehydro-TXB2 fell −24.1% with liraglutide vs −24.3% with lifestyle (between-group p = 0.679); 8-iso-PGF2α −14.6% vs −21.2% (p = 0.985); hs-CRP improved comparably in both arms","confidence_interval":null,"p_value":"between-group p = 0.679 (U-11-dehydro-TXB2); p = 0.985 (8-iso-PGF2α)","sample_size":35,"follow_up":"until the weight-loss target (median 4 months; maximum 15 months allowed)","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"male 11 (61%) liraglutide and 8 (47%) lifestyle\", \"bmi_mean\": null, \"bmi_min\": 30, \"obesity_status\": \"obesity required (BMI ≥ 30)\", \"diabetes_status\": \"mixed (20 with prediabetes, 15 with newly diagnosed type 2 diabetes)\", \"cvd_status\": \"mixed (not an entry criterion; CVD in 1 (5.6%) liraglutide and 3 (17.6%) lifestyle participants)\", \"ckd_status\": \"excluded (glomerular filtration rate below 60 mL)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obesity with prediabetes or newly diagnosed type 2 diabetes, on metformin\", \"sample_size\": 35, \"inclusion_exclusion\": \"BMI ≥ 30; IGT/IFG or T2DM under 12 months on metformin; excluded other antidiabetic agents, uncontrolled hypertension, kidney or liver disease, antiplatelet therapy (analysis)\", \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had obesity (BMI ≥ 30; medians 36.6 and 33.5) with prediabetes or type 2 diabetes diagnosed within 12 months, all on metformin.","mediation":"specifically_tested","mediation_notes":"Weight loss was matched by design (7% target in both arms), and the mixed model adjusted for time to weight loss, baseline weight, waist and visceral fat; at equal weight loss liraglutide had no extra effect, pointing to weight loss rather than the drug.","adjusted_for":"[\"body-weight change\", \"visceral fat/waist\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 35, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"lifestyle counselling, continued until the same weight loss (7% of initial body weight)\", \"follow_up_duration\": \"until the weight-loss target (median 4 months; maximum 15 months allowed)\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported for the main comparison; 35 analysed of 62 randomised; post hoc power assessment (90% power for a 1 SD difference)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: small randomised trial (35 of 62 randomised analysed), blinding not stated, biomarker outcomes and a post hoc power assessment.","funding_source":"Italian Ministry of University and Research (PRIN No. 2010JS3PMZ)","industry_funded":"no","manufacturer":"Novo Nordisk (supplied the study liraglutide)","author_conflicts":"One author reports lecture and advisory fees from Novo Nordisk and other companies and institutional grant support from Novo Nordisk; no other conflicts were reported.","sponsor_role":"Novo Nordisk supplied the study medication; no other sponsor or funder role is stated","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"No serious adverse event took place during the treatment period","limitations":"The authors cite the small sample, short exposure (median 4 months), and that people who missed the weight-loss goal were not re-evaluated; 62 were randomised but only 35 analysed, and the trial was not stated to be blinded.","plain_summary":"This randomised trial enrolled adults with obesity and prediabetes or newly diagnosed type 2 diabetes, all taking metformin; 35 were analysed. Each person continued liraglutide or lifestyle counselling until losing 7% of body weight. A urine marker of platelet activation fell by about the same amount in both groups (−24.1% and −24.3%, between-group p = 0.679), so liraglutide added nothing beyond the weight loss. These are laboratory markers, and no serious adverse event occurred.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":493,"doi":"10.1016/j.jdiacomp.2016.05.022","pmid":"28479155","nct_ids":"[]","title":"Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials","authors":"[\"Mazidi M\", \"Karimi E\", \"Rezaie P\", \"Ferns GA\"]","journal":"Journal of diabetes and its complications","publication_date":"2017-07","year":2017,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To undertake a systematic review and meta-analysis of randomized controlled trials of the effect of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) therapy on serum C-reactive protein (CRP) concentrations. [METHOD] PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched for the period up until March 16, 2016. Prospective studies evaluating the impact of GLP-1 RAs on serum CRP were identified. A random effects model (using the DerSimonian-Laird method) and generic inverse variance methods were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I2 index. Random effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderator. International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016036868. [RESULTS] Meta-analysis of the data from 7 treatment arms revealed a significant reduction in serum CRP concentrations following treatment with GLP-1 RAs (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I2 96.1%). Removal of one study in the meta-analysis did not change the result in the sensitivity analysis (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I2 96.1%), indicating that our results could not be solely attributed to the effect of a single study. Random effects meta-regression was performed to evaluate the impact of potential moderator on the estimated effect size. Changes in serum CRP concentration were associated with the duration of treatment (slope -0.097, 95% CI -0.158, -0.042, P<0.001). [CONCLUSIONS] This meta-analysis suggests that GLP-1 RAs therapy causes a significant reduction in CRP.","url":"https://pubmed.ncbi.nlm.nih.gov/28479155/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\", \"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":495,"doi":"10.1111/dom.12884","pmid":"28105731","nct_ids":"[]","title":"Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub-analysis of a randomized, placebo-controlled, double-blind, crossover trial","authors":"[\"von Scholten BJ\", \"Persson F\", \"Rosenlund S\", \"Eugen-Olsen J\", \"Pielak T\", \"Faber J\", \"Hansen TW\", \"Rossing P\"]","journal":"Diabetes, obesity & metabolism","publication_date":"2017-06","year":2017,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"We assessed the effects of liraglutide treatment on five cardiovascular risk biomarkers, reflecting different pathophysiology: tumour necrosis factor (TNF)-α; soluble urokinase plasminogen activator receptor (suPAR); mid-regional pro-adrenomedullin (MR-proADM); mid-regional pro-atrial natriuretic peptide (MR-proANP); and copeptin, in people with type 2 diabetes with albuminuria. In a randomized, double-blind, placebo-controlled, crossover trial we enrolled people with type 2 diabetes and persistent albuminuria (urinary albumin-to-creatinine ratio [UACR] >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 . Participants received liraglutide (1.8 mg/d) and matched placebo for 12 weeks, in random order. The primary endpoint was change in albuminuria; this was a prespecified sub-study. A total of 32 participants were randomized, of whom 27 completed the study. TNF-α level was 12% (95% confidence interval [CI] 3; 20) lower after liraglutide treatment compared with placebo (P = .012); MR-proADM level was 4% (95% CI 0; 8) lower after liraglutide treatment compared with placebo (P = .038), and MR-proANP level was 13% (95% CI 4; 21) lower after liraglutide treatment compared with placebo (P = .006). In the present study, we showed anti-inflammatory effects of liraglutide treatment, reflected in reductions in levels of TNF-α and MR-proADM, while the reduction in MR-proANP levels may represent a clinically relevant benefit with regard to heart failure.","url":"https://pubmed.ncbi.nlm.nih.gov/28105731/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"crossover_trial","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":498,"doi":"10.1507/endocrj.ej16-0449","pmid":"27916783","nct_ids":"[]","title":"Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial","authors":"[\"Bouchi R\", \"Nakano Y\", \"Fukuda T\", \"Takeuchi T\", \"Murakami M\", \"Minami I\", \"Izumiyama H\", \"Hashimoto K\", \"Yoshimoto T\", \"Ogawa Y\"]","journal":"Endocrine journal","publication_date":"2017-03-31","year":2017,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Liraglutide, an analogue of human glucagon-like peptide 1, reduces cardiovascular events in patients with type 2 diabetes; however, it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events. Type 2 diabetic patients with insulin treatment were enrolled in this randomized, open-label, comparative study. Participants were randomly assigned to liraglutide plus insulin (liraglutide group) and insulin treatment (control group) at 1:1 allocation. Primary endpoint was the change in viscera fat are (VFA, cm2) at 24 weeks. Liver attenuation index (LAI) measured by abdominal computed tomography, urinary albumin-to-creatinine ratio (ACR, mg/g), and C-reactive protein (CRP) levels, skeletal muscle index (SMI), and quality of life (QOL) related to diabetes treatment were also determined. Seventeen patients (8; liraglutide group, 9; control group, mean age 59 ± 13 years; 53% female) completed this study. Liraglutide treatment significantly reduced VFA at 24 weeks; whereas, SFA was unchanged. ACR, LAI, and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups. Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI, albuminuria, and HbA1c. Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment. No severe adverse events were observed in both groups. Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation, albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes.","url":"https://pubmed.ncbi.nlm.nih.gov/27916783/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"muscle\", \"body_composition\", \"liver\", \"addiction\", \"metabolic\", \"adverse_effects\", \"psychiatric\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":496,"doi":"10.1042/cs20160803","pmid":"28049736","nct_ids":"[]","title":"GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction","authors":"[\"Pastel E\", \"McCulloch LJ\", \"Ward R\", \"Joshi S\", \"Gooding KM\", \"Shore AC\", \"Kos K\"]","journal":"Clinical science (London, England : 1979)","publication_date":"2017-03-01","year":2017,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg, P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P=0.006; COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU, P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.","url":"https://pubmed.ncbi.nlm.nih.gov/28049736/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"route\": null, \"dose\": null, \"comparator\": \"calorie restriction based on dietetic counselling\", \"treatment_duration\": \"4 months\"}","domains":"[\"inflammation\", \"body_composition\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":"Subcutaneous adipose tissue inflammatory and fibrotic responses on repeated biopsies, compared with calorie-restriction weight loss","endpoints":null,"effect_estimate":"With liraglutide, weight fell 3.12±1.72 kg (P=0.007) and visceral fat fell, but adipose tissue TNFA expression (P=0.0005), MCP-1 expression (P=0.027) and serum MCP-1 (P=0.048) rose and TGFB1 and COL1A1 expression increased; in the diet arm CD14 expression showed a lower trend (P=0.09)","confidence_interval":null,"p_value":"P=0.0005 (adipose tissue TNFA expression with liraglutide); P=0.027 and P=0.048 (MCP-1 expression and serum level)","sample_size":30,"follow_up":null,"direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported in abstract\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes\", \"sample_size\": 30, \"inclusion_exclusion\": \"type 2 diabetes; age-matched\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all participants had type 2 diabetes; the abstract gives no age, sex or BMI data.","mediation":"unlikely","mediation_notes":"The comparator was weight loss by calorie restriction, and the adipose tissue inflammatory rise seen with liraglutide did not occur with diet; the abstract does not say weight loss was matched between arms or adjusted for; no cached full text.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 30, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"calorie restriction based on dietetic counselling\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; P values only; small, unbalanced arms (22 vs 8)\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: small randomised trial (30 participants, 22 vs 8) with adipose tissue biomarker outcomes over 4 months; abstract only.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Small randomised trial with unequal arms (22 vs 8) over 4 months, adipose tissue biopsy markers only, modest weight loss and no blinding stated; only the abstract was available, and whether the changes limit fat storage capacity is unknown.","plain_summary":"This small randomised trial in 30 people with type 2 diabetes compared 4 months of liraglutide (22 people) with calorie restriction (8 people), using repeated biopsies of fat under the skin. Liraglutide led to weight loss (-3.12±1.72 kg) and lowered fasting glucose more than diet, but it raised inflammatory and scarring-related gene activity in the fat tissue (TNFA, P=0.0005), which the diet group did not show. These are tissue markers, not clinical outcomes, and only the abstract was available.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":494,"doi":"10.1016/j.orcp.2017.01.003","pmid":"28161303","nct_ids":"[]","title":"Comparison of exenatide and acarbose on intra-abdominal fat content in patients with obesity and type-2 diabetes: A randomized controlled trial","authors":"[\"Shi L\", \"Zhu J\", \"Yang P\", \"Tang X\", \"Yu W\", \"Pan C\", \"Shen M\", \"Zhu D\", \"Cheng J\", \"Ye X\"]","journal":"Obesity research & clinical practice","publication_date":"2017","year":2017,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To investigate exenatide, a GLP-1 analogue, compared with acarbose, for intra-abdominal fat reduction in patients with obesity and type-2 diabetes. [METHODS] This randomized controlled trial included 36 patients with obesity and type-2 diabetes, who were metformin-unresponsive, receiving metformin/exenatide (GLP-1 group) or metformin/acarbose (control group) for 3 months. Primary end-point: intra-abdominal fat content from baseline to 3 months; Secondary end-points: changes in fasting blood glucose, glycated haemoglobin (HbAlc), fasting insulin, blood lipids, weight, body mass index, and inflammatory cytokines from baseline to 3 months. [RESULTS] Intra-abdominal fat content decreased in the GLP-1 group from baseline to 3 months (17,947±5804; 13,717±3628mm2, P=0.001, respectively), but was not significantly reduced in the control group (P=0.197) and at 3 months post-treatment, it was significantly lower in the GLP-1 group than control group (P=0.043). Glucose control, measured by HbA1c (GLP-1: 9.72±1.38; 7.09±0.60%, P<0.001, 9.46±1.25; 7.42±0.84%, P<0.001, respectively) and insulin resistance index LN(HOMA-IR) (GLP-1: 1.58±0.40; 1.01±0.33, P<0.001, Control: 1.53±0.57; 1.10±0.33, P=0.003, respectively) significantly improved in both groups with no significant difference between them. TNF-α, IL-6, and leptin were lower and adiponectin levels higher in the GLP-1 group at 3 months compared with baseline (all P<0.05), but not significantly changed in the control group. TNF-α, IL-6 and leptin levels were similar between groups. Adiponectin level was higher in the GLP-1 group than the control group at 3 months (P=0.025). [CONCLUSION] Combined exenatide/metformin reduced intra-abdominal fat content, and enhanced insulin resistance and inflammatory status in patients with obesity and type-2 diabetes, representing a novel treatment regimen.","url":"https://pubmed.ncbi.nlm.nih.gov/28161303/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":11,"doi":"10.1056/nejmoa1607141","pmid":"27633186","nct_ids":"[\"NCT01720446\"]","title":"Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","authors":"[\"Marso SP\", \"Bain SC\", \"Consoli A\", \"Eliaschewitz FG\", \"Jódar E\", \"Leiter LA\", \"Lingvay I\", \"Rosenstock J\", \"Seufert J\", \"Warren ML\", \"Woo V\", \"Hansen O\", \"Holst AG\", \"Pettersson J\", \"Vilsbøll T\", \"SUSTAIN-6 Investigators\"]","journal":"The New England journal of medicine","publication_date":"2016-11-10","year":2016,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. [METHODS] We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. [RESULTS] At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. [CONCLUSIONS] In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).","url":"https://pubmed.ncbi.nlm.nih.gov/27633186/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T01:04:22+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"0.5 or 1.0 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"104 weeks\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"ophthalmologic\", \"kidney\"]","outcome_type":"hard","primary_outcome":"CV death, nonfatal MI or nonfatal stroke (noninferiority)","endpoints":null,"effect_estimate":"HR 0.74 (6.6% vs 8.9%); nonfatal MI HR 0.74 (0.51-1.08, not significant); cardiovascular death similar; nonfatal stroke HR 0.61; retinopathy complications HR 1.76","confidence_interval":"0.58 to 0.95","p_value":"<0.001 noninferiority","sample_size":3297,"follow_up":"104 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"83% with established CVD or CKD\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"type 2 diabetes at high cardiovascular risk (83% with CVD, CKD or both)\", \"sample_size\": 3297, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes with high CV risk.","mediation":"possibly","mediation_notes":"Not separated; retinopathy signal may relate to rapid glycaemic improvement.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 3297, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"104 weeks\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"254 events; noninferiority design\", \"risk_of_bias\": \"low; superiority not prespecified\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Moderate-sized noninferiority CVOT; superiority was a post hoc interpretation. Important source of the retinopathy safety signal.","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk","author_conflicts":"Not reported in the abstract; full text not checked.","sponsor_role":"Not reported in the abstract; full text not checked.","independent_replication_exists":"class-level","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"Retinopathy complications HR 1.76 (1.11-2.78); GI discontinuations higher.","limitations":null,"plain_summary":"In 3,297 people with type 2 diabetes at high cardiovascular risk, semaglutide lowered the combined rate of cardiovascular death, nonfatal heart attack and nonfatal stroke over two years (HR 0.74), in a trial designed to show it was no worse than placebo. Of the separate parts, only the drop in nonfatal stroke was significant; nonfatal heart attacks (HR 0.74) did not differ significantly, and rates of cardiovascular death were similar. Retinopathy complications increased (HR 1.76). Context for the retinopathy safety topic; not applicable outside diabetes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":10,"doi":"10.1056/nejmoa1603827","pmid":"27295427","nct_ids":"[\"NCT01179048\"]","title":"Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes","authors":"[\"Marso SP\", \"Daniels GH\", \"Brown-Frandsen K\", \"Kristensen P\", \"Mann JF\", \"Nauck MA\", \"Nissen SE\", \"Pocock S\", \"Poulter NR\", \"Ravn LS\", \"Steinberg WM\", \"Stockner M\", \"Zinman B\", \"Bergenstal RM\", \"Buse JB\", \"LEADER Steering Committee\", \"LEADER Trial Investigators\"]","journal":"The New England journal of medicine","publication_date":"2016-07-28","year":2016,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. [METHODS] In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. [RESULTS] A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. [CONCLUSIONS] In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).","url":"https://pubmed.ncbi.nlm.nih.gov/27295427/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":5,"assessed_by":"ai:fact-check","assessed_at":"2026-10-19T13:04:18+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg daily\", \"route\": \"subcutaneous\", \"treatment_duration\": \"median 3.8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":"CV death, nonfatal MI or nonfatal stroke","endpoints":null,"effect_estimate":"HR 0.87 (13.0% vs 14.9%); CV death HR 0.78; all-cause death HR 0.85","confidence_interval":"0.78 to 0.97","p_value":"0.01 for superiority","sample_size":9340,"follow_up":"median 3.8 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not required (mean BMI ~32.5, full text, not checked)\", \"diabetes_status\": \"type 2 diabetes required (all)\", \"cvd_status\": \"high CV risk or established CVD required\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 9340, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"Type 2 diabetes at high CV risk; landmark trial establishing class CV benefit in diabetes.","mediation":"possibly","mediation_notes":"Not addressed in the abstract: it reports no weight or HbA1c changes and no mediation analysis, so it does not separate direct drug effects from weight loss or glucose lowering.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 9340, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"median 3.8 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 0.78 to 0.97\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet assessed).","funding_source":"Novo Nordisk and NIH","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"Authors report Novo Nordisk relationships; sponsor co-authors.","sponsor_role":"Sponsor designed and analysed with steering committee.","independent_replication_exists":"class-level consistency (SUSTAIN-6, REWIND)","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":"GI events most common cause of discontinuation; pancreatitis not increased.","limitations":null,"plain_summary":"Landmark 2016 trial: in 9,340 people with type 2 diabetes at high cardiovascular risk, liraglutide reduced major cardiovascular events (HR 0.87), cardiovascular death and death from any cause over a median 3.8 years. On their own, nonfatal heart attack, nonfatal stroke and hospital admission for heart failure were not significantly reduced. Context for later trials; not applicable to people without diabetes.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":507,"doi":"10.7326/m15-1432","pmid":"26642233","nct_ids":"[]","title":"Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis","authors":"[\"Zaccardi F\", \"Htike ZZ\", \"Webb DR\", \"Khunti K\", \"Davies MJ\"]","journal":"Annals of internal medicine","publication_date":"2016-01-19","year":2016,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes. [PURPOSE] To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes. [DATA SOURCES] Electronic databases (PubMed, Web of Science, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov) and congress abstracts from inception through 26 September 2015. [STUDY SELECTION] Randomized, controlled trials (≥ 24 weeks of follow-up) studying albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide and reporting a cardiometabolic (primary outcome, hemoglobin A1c [HbA1c]) or safety outcome. [DATA EXTRACTION] Extraction was done in duplicate, and risk of bias was assessed. No language restriction was applied. [DATA SYNTHESIS] 34 trials (21,126 participants) were included. Compared with placebo, all once-weekly GLP-1RAs reduced HbA1c and fasting plasma glucose; taspoglutide, 20 mg, once-weekly exenatide, and dulaglutide, 1.5 mg, reduced body weight. Among once-weekly GLP-1RAs, the greatest differences were found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (-0.4% [95% CI, -0.7% to -0.2%]), once-weekly exenatide and albiglutide for fasting plasma glucose (-0.7 mmol/L [CI, -1.1 to -0.2 mmol/L]; -12.6 mg/dL [CI, -19.8 to -3.6 mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (-1.5 kg [CI, -2.2 to -0.8]). Clinically marginal or no differences were found for blood pressure, blood lipid levels, and C-reactive protein levels. Once-weekly exenatide increased heart rate compared with albiglutide and dulaglutide (1.4 to 3.2 beats/min). Among once-weekly GLP-1RAs, the risk for hypoglycemia was similar, whereas taspoglutide, 20 mg, had the greatest risk for nausea (odds ratios, 1.9 to 5.9). [LIMITATION] Data were unavailable for semaglutide, definitions of outcomes were heterogeneous, the last-observation-carried-forward imputation method was used in 73% of trials, and publication bias is possible. [CONCLUSION] Compared with other once-weekly GLP-1RAs, dulaglutide, 1.5 mg; once-weekly exenatide; and taspoglutide, 20 mg, showed a greater reduction of HbA1c, fasting plasma glucose, and body weight. Taspoglutide, 20 mg, had the highest risk for nausea; risk for hypoglycemia among once-weekly GLP-1RAs was similar. [PRIMARY FUNDING SOURCE] Sanofi Aventis (grant to the University of Leicester).","url":"https://pubmed.ncbi.nlm.nih.gov/26642233/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"dulaglutide\", \"exenatide\", \"albiglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":510,"doi":"10.1186/s12933-015-0279-z","pmid":"26338040","nct_ids":"[\"NCT00359762\"]","title":"Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study","authors":"[\"Simó R\", \"Guerci B\", \"Schernthaner G\", \"Gallwitz B\", \"Rosas-Guzmàn J\", \"Dotta F\", \"Festa A\", \"Zhou M\", \"Kiljański J\"]","journal":"Cardiovascular diabetology","publication_date":"2015-09-04","year":2015,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] The risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study. [RESEARCH DESIGN AND METHODS] Patients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated. [RESULTS] Over 36 months, twice-daily exenatide was associated with improved body weight (-3.9 kg), waist circumference (-3.6 cm), systolic/diastolic BP (-2.5/-2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (-0.2 mmol/L), and hsCRP (-1.7 mg/L). Heart rate did not increase (-0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4%; P = 0.026) or lipid-lowering medication (8.4 vs 12.8%; P = 0.025). [CONCLUSIONS] Add-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride. [CLINICAL TRIAL REGISTRATION] NCT00359762, http://www.ClinicalTrials.gov.","url":"https://pubmed.ncbi.nlm.nih.gov/26338040/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"mortality\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":513,"doi":"10.1016/j.diabres.2014.09.046","pmid":"25458329","nct_ids":"[]","title":"Evaluation of exenatide versus insulin glargine for the impact on endothelial functions and cardiovascular risk markers","authors":"[\"Gurkan E\", \"Tarkun I\", \"Sahin T\", \"Cetinarslan B\", \"Canturk Z\"]","journal":"Diabetes research and clinical practice","publication_date":"2014-12","year":2014,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] To demonstrate the efficacy of exenatide versus insulin glargine on endothelial functions and cardiovascular risk markers. [METHODS] Thirty-four insulin and incretin-naive patients with type 2 diabetes mellitus (body mass index 25-45 kg/m(2)) who received metformin for at least two months were randomized to exenatide or insulin glargine treatment arms and followed-up for 26 weeks. Measurements of endothelial functions were done by ultrasonography, cardiovascular risk markers by serum enzyme-linked immunosorbent assay, and total body fat mass by bioimpedance. [RESULTS] Levels of high sensitivity-C-reactive protein and endothelin-1 decreased (27.5% and 18.75%, respectively) in the exenatide arm. However, in the insulin glargine arm, fibrinogen, monocyte chemoattractant protein-1, leptin and endothelin-1 levels (13.4, 30.2, 47.5, and 80%, respectively) increased. Post-treatment flow mediated dilatation and endothelium independent vascular responses were significantly higher in both arms (p=0.0001, p=0.0001). Positive correlation was observed between the changes in body weight and endothelium-independent vasodilatation, leptin, plasminogen activator inhibitor type 1 and endothelin-1 in both arms (r=0.376, r=0.507, r=0.490, r=0.362, respectively). [CONCLUSIONS] Insulin glargine improved endothelial functions, without leading to positive changes in cardiovascular risk markers. Exenatide treatment of 26 weeks resulted in reduced body weight and improvement in certain cardiovascular risk markers and endothelial functions.","url":"https://pubmed.ncbi.nlm.nih.gov/25458329/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":516,"doi":"10.1007/s00592-014-0638-3","pmid":"25118999","nct_ids":"[]","title":"Effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in drug-naive subjects with type 2 diabetes","authors":"[\"Bi Y\", \"Zhang B\", \"Xu W\", \"Yang H\", \"Feng W\", \"Li C\", \"Tong G\", \"Li M\", \"Wang X\", \"Shen S\", \"Zhu B\", \"Weng J\", \"Zhu D\"]","journal":"Acta diabetologica","publication_date":"2014-10","year":2014,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"Ectopic accumulation of lipids in nonadipose tissues plays a primary role in the pathogenesis of type 2 diabetes mellitus (T2DM). This study was to examine the effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in T2DM. Thirty-three drug-naive T2DM patients (age 52.7 ± 1.7 years, HbA1c 8.7 ± 0.2 %, body mass index 24.5 ± 0.5 kg/m(2)) were randomized into exenatide, insulin, or pioglitazone for 6 months. Intrahepatic fat (IHF), visceral fat (VF), and subcutaneous fat (SF) were measured using proton nuclear magnetic resonance spectroscopy. Plasma tumor necrosis factor α (TNFα) and adiponectin were assayed by ELISA. HbA1c declined significantly in all three groups. Body weight, waist, and serum triglycerides decreased with exenatide. After interventions, IHF significantly reduced with three treatments (exenatide Δ = -68 %, insulin Δ = -58 %, pioglitazone Δ = -49 %). Exenatide reduced VF (Δ = -36 %) and SF (Δ = -13 %), and pioglitazone decreased VF (Δ = -30 %) with no impact on SF, whereas insulin had no impact on VF or SF. Levels of TNFα (exenatide/insulin/pioglitazone) decreased, and levels of adiponectin (exenatide/pioglitazone) increased. Analysis showed that ΔIHF correlated with ΔHbA1c and Δweight. Besides, ΔIHF correlated with Δtriglycerides and ΔTNFα, but the correlations fell short of significance after BMI adjustment. By linear regression analysis, ΔHbA1c alone explained 41.5 % of the variance of ΔIHF, and ΔHbA1c + Δweight explained 57.6 % of the variance. Liver fat content can be significantly reduced irrespective of using exenatide, insulin, and pioglitazone. Early glycaemic control plays an important role in slowing progression of fatty liver in T2DM.","url":"https://pubmed.ncbi.nlm.nih.gov/25118999/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"body_composition\", \"liver\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":517,"doi":"10.1590/s0004-27302013000900005","pmid":"24402015","nct_ids":"[]","title":"Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease","authors":"[\"Fan H\", \"Pan Q\", \"Xu Y\", \"Yang X\"]","journal":"Arquivos brasileiros de endocrinologia e metabologia","publication_date":"2013-12","year":2013,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD). [SUBJECTS AND METHODS] One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks. [RESULTS] After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group. [CONCLUSION] Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD.","url":"https://pubmed.ncbi.nlm.nih.gov/24402015/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":518,"doi":"10.2337/dc13-0354","pmid":"23835684","nct_ids":"[\"NCT01784965\"]","title":"Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes","authors":"[\"Kim SH\", \"Abbasi F\", \"Lamendola C\", \"Liu A\", \"Ariel D\", \"Schaaf P\", \"Grove K\", \"Tomasso V\", \"Ochoa H\", \"Liu YV\", \"Chen YD\", \"Reaven G\"]","journal":"Diabetes care","publication_date":"2013-10","year":2013,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD. [RESEARCH DESIGN AND METHODS] We randomized 68 older individuals (mean age, 58±8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed. [RESULTS] Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P=0.26). Subjects who continued to use liraglutide (n=24) lost twice as much weight as those using placebo (n=27; 6.8 vs. 3.3 kg; P<0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P<0.001) and significantly (P≤0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P=0.001). [CONCLUSIONS] The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.","url":"https://pubmed.ncbi.nlm.nih.gov/23835684/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":522,"doi":"10.1016/j.diabres.2013.04.005","pmid":"23706413","nct_ids":"[]","title":"Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial","authors":"[\"Liang Z\", \"Wu Q\", \"Chen B\", \"Yu P\", \"Zhao H\", \"Ouyang X\"]","journal":"Diabetes research and clinical practice","publication_date":"2013-07","year":2013,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The aim of this study was to evaluate the effect of laparoscopic Roux-en-Y gastric bypass (RYGB) surgery compared with usual care with and without Exenatide therapy in obese people with type 2 diabetes mellitus (T2DM) and hypertension. [METHODS] 108 obese T2DM with hypertension were enrolled and randomly allocated to usual care (group A), usual care plus Exenatide (group B), and RYGB surgery (group C). Demographic characteristics, metabolic parameters and cardiac structure/function along with inflammatory cytokines were measured and compared before and after 12 months. [RESULTS] At 12 months, diabetes remission had occurred in no patients in groups A and B versus 90% in group C, and there was a significant decrease in requirement of antihypertensive drugs in group C compared with groups A and B (P<0.05). Other parameters (body mass index, hemoglobin A1c, homeostasis model assessment of insulin resistance, lipids), inflammation index (high sensitivity C-reactive protein, tumor necrosis factor-α, high molecular weight adiponectin) and cardiac structure (left ventricular mass index) were significantly improved in groups B and C, but patients in group C had the greatest degree of improvement (P<0.05). [CONCLUSION] RYGB surgery improves a number of parameters including cardiovascular function in obese hypertensive people with T2DM. This is likely to be due to, at least in part, an improvement in the abnormal metabolic panel and to reduced inflammation.","url":"https://pubmed.ncbi.nlm.nih.gov/23706413/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":527,"doi":"10.1111/j.1464-5491.2012.03699.x","pmid":"22540883","nct_ids":"[]","title":"Exenatide plus metformin compared with metformin alone on β-cell function in patients with Type 2 diabetes","authors":"[\"Derosa G\", \"Franzetti IG\", \"Querci F\", \"Carbone A\", \"Ciccarelli L\", \"Piccinni MN\", \"Fogari E\", \"Maffioli P\"]","journal":"Diabetic medicine : a journal of the British Diabetic Association","publication_date":"2012-12","year":2012,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] To quantify how much exenatide added to metformin improves β-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone. [METHODS] A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 μg twice a day for the first 4 weeks and forced titration to 10 μg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and β-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor-α. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation. [RESULTS] Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment β-cell function index (HOMA-β) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-α. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin. [CONCLUSION] Exenatide is effective not only on glycaemic control, but also in protecting β-cells and in reducing inflammation.","url":"https://pubmed.ncbi.nlm.nih.gov/22540883/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":528,"doi":"10.1111/j.1464-5491.2012.03589.x","pmid":"22288732","nct_ids":"[\"NCT01208012\"]","title":"Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function","authors":"[\"Forst T\", \"Michelson G\", \"Ratter F\", \"Weber MM\", \"Anders S\", \"Mitry M\", \"Wilhelm B\", \"Pfützner A\"]","journal":"Diabetic medicine : a journal of the British Diabetic Association","publication_date":"2012-09","year":2012,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIMS] The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy. [METHODS] Forty-four patients with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA(1c) < 53 mmol/mol (7.0%), age 30-65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelial function and arterial stiffness were measured. [RESULTS] HbA(1c) levels declined from 45 ± 4 mmol/mol (6.3 ± 0.4%; mean ± SD) to 40 ± 3 mmol/mol (5.8 ± 0.3%) during liraglutide treatment. Asymmetric dimethylarginin was reduced by liraglutide treatment from 0.39 ± 0.08 to 0.35 ± 0.06 μmol/l, E-selectin from 43.6 ± 15.4 to 40.8 ± 15.1 ng/ml, plasminogen activator inhibitor 1 from 861.6 ± 584.3 to 666.1 ± 499.4 ng/ml and intact proinsulin from 9.0 ± 7.2 to 7.0 ± 4.8 pmol/l at 12 weeks of treatment. The microvascular response to flicker light increased from 7.0 ± 15.1 to 15.4 ± 11.5% after 6 weeks and to 11.1 ± 9.9% after 12 weeks. No change could be observed for high-sensitivity C-reactive protein, monocyte chemotactic protein 1, vascular cell adhesion molecule or arterial stiffness parameters. [CONCLUSIONS] In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.","url":"https://pubmed.ncbi.nlm.nih.gov/22288732/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":null,"domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":526,"doi":"10.1186/1475-2840-11-64","pmid":"22681705","nct_ids":"[\"NCT00546728\"]","title":"Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial","authors":"[\"Kelly AS\", \"Bergenstal RM\", \"Gonzalez-Campoy JM\", \"Katz H\", \"Bank AJ\"]","journal":"Cardiovascular diabetology","publication_date":"2012-06-08","year":2012,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Glucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. We compared the acute and chronic effects of the GLP-1 receptor agonist exenatide vs. metformin on endothelial function in patients with obesity and pre-diabetes. [METHODS] We performed a randomized, open-label, clinical trial in 50 non-diabetic individuals (mean age 58.5 ± 10.0; 38 females) with abdominal obesity and either impaired fasting glucose, elevated HbA1c, or impaired glucose tolerance (IGT) who were randomized to receive 3-months of exenatide or metformin. Microvascular endothelial function, assessed by digital reactive hyperemia (reactive hyperemic index: RHI), C-reactive protein (CRP), circulating oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and 3-months. Seven subjects with IGT participated in a sub-study comparing the effects of pre-administration of exenatide and metformin on postprandial endothelial function. [RESULTS] There were no differences for the change in RHI (Δ exenatide: 0.01 ± 0.68 vs. Δ metformin: -0.17 ± 0.72, P = 0.348), CRP, oxLDL, or VCAM-1 between exenatide and metformin treatment. Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032). In the sub-study, there was no difference in postprandial RHI between exenatide and metformin. [CONCLUSIONS] Three months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes. [CLINICAL TRIALS REGISTRATION] This study is registered on http://www.clinicaltrials.gov/: NCT00546728.","url":"https://pubmed.ncbi.nlm.nih.gov/22681705/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":529,"doi":"10.1210/jc.2011-1508","pmid":"22013105","nct_ids":"[]","title":"Exenatide exerts a potent antiinflammatory effect","authors":"[\"Chaudhuri A\", \"Ghanim H\", \"Vora M\", \"Sia CL\", \"Korzeniewski K\", \"Dhindsa S\", \"Makdissi A\", \"Dandona P\"]","journal":"The Journal of clinical endocrinology and metabolism","publication_date":"2012-01","year":2012,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] Our objective was to determine whether exenatide exerts an antiinflammatory effect. [RESEARCH DESIGN AND METHODS] Twenty-four patients were prospectively randomized to be injected sc with either exenatide 10 μg twice daily [n = 12; mean age = 56 ± 3 yr; mean body mass index = 39.8 ± 2 kg/m(2); mean glycosylated hemoglobin (HbA1c) = 8.6 ± 0.4%] or placebo twice daily (n = 12; mean age = 54 ± 4 yr; mean body mass index = 39.1 ± 1.6 kg/m(2); mean HbA1c = 8.5 ± 0.3%) for 12 wk. Fasting blood samples were obtained at 0, 3, 6, and 12 wk. Blood samples were also collected for up to 6 h after a single dose of exenatide (5 μg) or placebo. [RESULTS] Fasting blood glucose fell from 139 ± 17 to 110 ± 9 mg/dl, HbA1c from 8.6 ± 0.4 to 7.4 ± 0.5% (P < 0.05), and free fatty acids by 21 ± 5% from baseline (P < 0.05) with exenatide. There was no weight loss. There was a significant reduction in reactive oxygen species generation and nuclear factor-κB binding by 22 ± 9 and 26 ± 7%, respectively, and the mRNA expression of TNFα, IL-1β, JNK-1, TLR-2, TLR-4, and SOCS-3 in mononuclear cells by 31 ± 12, 22 ± 10, 20 ± 11, 22 ± 9, 16 ± 7, and 31 ± 10%, respectively (P < 0.05 for all) after 12 wk of exenatide. After a single injection of exenatide, there was a reduction by 20 ± 7% in free fatty acids, 19 ± 7% in reactive oxygen species generation, 39 ± 11% in nuclear factor-κB binding, 18 ± 9% in TNFα expression, 26 ± 7% in IL-1β expression, 18 ± 7% in JNK-1 expression, 24 ± 12% in TLR-4 expression, and 23 ± 11% in SOCS-3 expression (P < 0.05 for all). The plasma concentrations of monocyte chemoattractant protein-1, matrix metalloproteinase-9, serum amyloid A, and IL-6 were suppressed after 12 wk exenatide treatment by 15 ± 7, 20 ± 11, 16 ± 7, and 22 ± 12%, respectively (P < 0.05 for all). [CONCLUSIONS] Exenatide exerts a rapid antiinflammatory effect at the cellular and molecular level. This may contribute to a potentially beneficial antiatherogenic effect. This effect was independent of weight loss.","url":"https://pubmed.ncbi.nlm.nih.gov/22013105/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"ai:fact-check","assessed_at":"2026-11-06T15:11:33+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"10 μg twice daily for 12 wk; single 5 μg dose for acute testing\", \"comparator\": \"placebo twice daily\", \"route\": \"subcutaneous\", \"treatment_duration\": \"12 weeks\"}","domains":"[\"inflammation\", \"alzheimers\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":"inflammatory markers in mononuclear cells and plasma (ROS, NF-κB, cytokine mRNA, plasma MCP-1, MMP-9, SAA, IL-6)","endpoints":null,"effect_estimate":"After 12 wk of exenatide: ROS generation fell 22 ± 9% and NF-κB binding 26 ± 7%, TNFα mRNA 31 ± 12%, plasma IL-6 22 ± 12% (P < 0.05 for all); no weight loss; changes are within the exenatide group, comparison with placebo not reported in the abstract","confidence_interval":null,"p_value":"P < 0.05 for all reported changes","sample_size":24,"follow_up":"12 wk (samples at 0, 3, 6 and 12 wk)","direction":"unclear","population":"{\"mean_age\": \"56 ± 3 yr (exenatide); 54 ± 4 yr (placebo)\", \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": \"39.8 ± 2 kg/m2 (exenatide); 39.1 ± 1.6 kg/m2 (placebo)\", \"bmi_min\": null, \"obesity_status\": \"not reported in abstract as a criterion (mean BMI 39.8 and 39.1)\", \"diabetes_status\": \"not reported in abstract\", \"cvd_status\": \"not reported in abstract\", \"ckd_status\": \"not reported in abstract\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"not reported in abstract\", \"sample_size\": 24, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: participants had mean BMI 39.8 (exenatide) and 39.1 (placebo) and mean HbA1c 8.6% and 8.5%; the abstract does not name the condition they were enrolled for.","mediation":"possibly","mediation_notes":"There was no weight loss and acute effects were measured up to 6 h after a single dose, which separates the effect from weight loss; but fasting glucose, HbA1c and free fatty acids fell and were not separated from the inflammatory markers, so improved glycaemia could still contribute. No formal adjustment was reported.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 24, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo twice daily\", \"follow_up_duration\": \"12 wk (samples at 0, 3, 6 and 12 wk)\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"no CI reported; mean ± SE percentages with P < 0.05; 12 per arm\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: randomised placebo-controlled trial of 24 participants over 12 weeks with biomarker outcomes only; abstract only.","funding_source":"NIDDK NIH HHS","industry_funded":"no","manufacturer":"not stated in source","author_conflicts":"not reported in abstract","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":"not reported in abstract","limitations":"Very small trial (12 per arm) over 12 weeks with biomarker outcomes only; the abstract reports changes within the exenatide group rather than versus placebo, and states no blinding or diabetes diagnosis.","plain_summary":"This small randomised trial gave 24 patients (mean BMI about 39) exenatide or placebo injections for 12 weeks. With exenatide, several inflammation markers in blood cells and plasma fell, including plasma IL-6 by 22 ± 12%, HbA1c fell from 8.6 to 7.4%, and there was no weight loss. The abstract reports these changes within the exenatide group and does not give a direct comparison with placebo.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":531,"doi":"10.1016/j.ejphar.2011.05.051","pmid":"21645507","nct_ids":"[]","title":"Exenatide or glimepiride added to metformin on metabolic control and on insulin resistance in type 2 diabetic patients","authors":"[\"Derosa G\", \"Putignano P\", \"Bossi AC\", \"Bonaventura A\", \"Querci F\", \"Franzetti IG\", \"Guazzini B\", \"Testori G\", \"Fogari E\", \"Maffioli P\"]","journal":"European journal of pharmacology","publication_date":"2011-09","year":2011,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"The aim of this study was to evaluate the effect of exenatide compared to glimepiride on body weight, glycemic control and insulin resistance in type 2 diabetic patients taking metformin. One hundred and eleven patients with uncontrolled type 2 diabetes mellitus and intolerant to metformin at the highest dosages (2500-3000 mg/day) were enrolled in this study. Patients were randomized to receive exenatide 5 μg twice a day or glimepiride 1mg three times a day and titrated after 1 month to exenatide 10 μg twice a day or glimepiride 2mg three times a day for 12 months in a randomized, single-blind, controlled study. We evaluated at the baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c), glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR) index, adiponectin, tumor necrosis factor-α, and high sensitivity-C reactive protein. Both treatments gave a similar improvement of glycemic control, without any differences between the two groups. Only exenatide gave a decrease of BMI, insulin resistance parameters such as fasting plasma insulin, HOMA-IR, and adiponectin and a decrease of inflammatory parameters such as tumor necrosis factor-α, and high sensitivity-C reactive protein. Furthermore, the values obtained with exenatide were significantly better than the values recorded with glimepiride. We can conclude that exenatide was better than glimepiride in improving insulin resistance and inflammatory state. Furthermore, adiponectin increase, and tumor necrosis factor-α reduction seem to be related to weight loss obtained with exenatide.","url":"https://pubmed.ncbi.nlm.nih.gov/21645507/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":3,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T13:15:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":532,"doi":"10.1089/dia.2010.0048","pmid":"21284481","nct_ids":"[]","title":"Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus","authors":"[\"Wu JD\", \"Xu XH\", \"Zhu J\", \"Ding B\", \"Du TX\", \"Gao G\", \"Mao XM\", \"Ye L\", \"Lee KO\", \"Ma JH\"]","journal":"Diabetes technology & therapeutics","publication_date":"2011-02","year":2011,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[AIM] This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea. [SUBJECTS AND METHODS] Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 μg b.d. × 4 weeks followed by 10 μg b.d. × 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2α (PGF2α), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) were investigated. [RESULTS] Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2α was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-CRP and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2α was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all). [CONCLUSIONS] Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control.","url":"https://pubmed.ncbi.nlm.nih.gov/21284481/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.1","assessed_at":"2026-10-18T23:29:38+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"},{"id":533,"doi":"10.2337/dc09-2361","pmid":"20424219","nct_ids":"[]","title":"Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition","authors":"[\"Bunck MC\", \"Diamant M\", \"Eliasson B\", \"Cornér A\", \"Shaginian RM\", \"Heine RJ\", \"Taskinen MR\", \"Yki-Järvinen H\", \"Smith U\"]","journal":"Diabetes care","publication_date":"2010-08","year":2010,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[OBJECTIVE] To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. [RESEARCH DESIGN AND METHODS] Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. [RESULTS] Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. [CONCLUSIONS] Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.","url":"https://pubmed.ncbi.nlm.nih.gov/20424219/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":4,"assessed_by":"ruling","assessed_at":"2026-10-19T12:16:11+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"treatment_duration\": \"1 year\", \"dose\": null, \"route\": null, \"comparator\": \"insulin glargine (added to metformin)\"}","domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"body_composition\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":"Body composition (DEXA) and circulating cardiovascular risk biomarkers after 1 year","endpoints":null,"effect_estimate":"Within the exenatide arm over 1 year: body weight −6%, trunk fat −13%, total adiponectin +12%, hs-CRP −61%; weight-adjusted between-group hs-CRP −52% (P = 0.008); no significant effect on HMW adiponectin, IL-6, MCP-1 or resistin; endothelin-1 fell with insulin glargine but not with exenatide","confidence_interval":"hs-CRP between-group difference −52% (95% CI −71% to −19%)","p_value":"P = 0.008 (hs-CRP between-group, weight-adjusted)","sample_size":69,"follow_up":"1 year","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"metformin-treated type 2 diabetes\", \"sample_size\": 69, \"inclusion_exclusion\": \"metformin-treated type 2 diabetes\", \"healthy_volunteers\": false, \"normal_weight_included\": null, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"INDIRECT: all 69 participants had type 2 diabetes treated with metformin; no age or BMI data are given in the cached text.","mediation":"specifically_tested","mediation_notes":"Biomarker differences are reported as body weight change-adjusted least-squares means and stayed significant after further adjustment for total body fat mass change; the authors note a significant univariate correlation between weight change and hs-CRP and limited power. HbA1c was not adjusted for.","adjusted_for":"[\"body-weight change\", \"other\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 69, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"insulin glargine (added to metformin)\", \"follow_up_duration\": \"1 year\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed\", \"consistency_with_other_evidence\": \"not assessed\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"95% CIs reported for percentage changes; 36 exenatide and 33 insulin glargine randomised; authors note limited statistical power\", \"risk_of_bias\": \"not assessed\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"LOW: small randomised trial (69 participants) against insulin glargine with body-composition and biomarker outcomes; blinding not stated.","funding_source":"Amylin Pharmaceuticals, Inc., and Eli Lilly and Company","industry_funded":"yes","manufacturer":"Amylin Pharmaceuticals, Inc., and Eli Lilly and Company (named as sponsors)","author_conflicts":"Two authors are Eli Lilly employees (one a stockholder), several are speakers, advisers or consultants for Lilly or Amylin, and the authors' institutions received research grants from both companies.","sponsor_role":"investigators initiated and designed the study, had full data access and controlled the statistical analysis and interpretation","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly and Company, Amylin Pharmaceuticals","adverse_events":"not reported","limitations":"Small trial (69 participants) that the authors say may limit statistical power; secondary report of a trial whose design and baseline data are published elsewhere; blinding not stated.","plain_summary":"In 69 adults with type 2 diabetes on metformin, this randomised trial compared one year of exenatide with insulin glargine. Exenatide reduced body weight by 6% and trunk fat by 13%, and lowered the inflammation marker hs-CRP by 61%; the difference from glargine held after allowing for weight change. IL-6, MCP-1 and resistin did not change with either drug, and endothelin-1 fell with glargine but not with exenatide. These are blood markers in a small trial, not heart events.","methodological_notes":null,"reviewed_by":null,"reviewed_at":null},{"id":534,"doi":"10.1089/dia.2009.0141","pmid":"20151774","nct_ids":"[]","title":"Exenatide versus glibenclamide in patients with diabetes","authors":"[\"Derosa G\", \"Maffioli P\", \"Salvadeo SA\", \"Ferrari I\", \"Ragonesi PD\", \"Querci F\", \"Franzetti IG\", \"Gadaleta G\", \"Ciccarelli L\", \"Piccinni MN\", \"D'Angelo A\", \"Cicero AF\"]","journal":"Diabetes technology & therapeutics","publication_date":"2010-03","year":2010,"publication_type":"journal_article","peer_reviewed":"yes","abstract":"[BACKGROUND] Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes. [METHODS] One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months. [RESULTS] Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide. [CONCLUSIONS] Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.","url":"https://pubmed.ncbi.nlm.nih.gov/20151774/","source_name":"pubmed","source_tier":1,"coi_statement":null,"assessment_version":2,"assessed_by":"auto:auto-classifier-v1.2","assessed_at":"2026-11-06T12:50:02+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":null,"domains":"[\"inflammation\", \"metabolic\"]","outcome_type":null,"primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":null,"direction":null,"population":null,"applicability":null,"applicability_rationale":null,"mediation":null,"mediation_notes":null,"adjusted_for":null,"evidence_level":null,"evidence_components":null,"evidence_rationale":null,"funding_source":null,"industry_funded":null,"manufacturer":null,"author_conflicts":null,"sponsor_role":null,"independent_replication_exists":null,"conflict_notes":null,"adverse_events":null,"limitations":null,"plain_summary":null,"methodological_notes":null,"reviewed_by":"Carrie Schluter","reviewed_at":"2026-11-05"}]