[{"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":4,"assessed_by":"ai:two-pass","assessed_at":"2026-09-13T23:31:00+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","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\", \"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: 95% CI -0\", \"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. 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."},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","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\": \"type 2 diabetes present (all or most)\", \"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] Participants had type 2 diabetes (age/BMI not reported in abstract).","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"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.\"","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"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\": \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, AstraZeneca","author_conflicts":"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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:56+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"15 mg\", \"comparator\": \"placebo\"}","domains":"[\"muscle\", \"lean_mass\", \"body_composition\", \"aging\", \"adverse_effects\", \"nutrition\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"65 years","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\": \"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\": \"placebo\", \"follow_up_duration\": \"65 years\", \"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\": \"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":"Novo Nordisk, Eli Lilly, Lilly","author_conflicts":"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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"adverse_effects\", \"discontinuation\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":261,"follow_up":"6 years","direction":"harm","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\": 261, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).","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\": \"Retrospective cohort\", \"sample_size\": 261, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"6 years\", \"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] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, Boehringer Ingelheim","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"Semaglutide\"}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":381,"follow_up":"24 weeks of 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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 381, \"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\": 381, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"24 weeks of follow-up\", \"outcome_type\": \"intermediate\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI -5\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"3 mg\", \"route\": \"oral\"}","domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"sleep\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":116,"follow_up":"18 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": 116, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight without diabetes (BMI ≥30 required); effects may be mediated by weight loss.","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\": \"Randomized controlled trial\", \"sample_size\": 116, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 years\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"case_control","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{}","domains":"[\"adverse_effects\", \"psychiatric\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":15,"follow_up":"21 years","direction":"null","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\": 15, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"VERY_LOW","evidence_components":"{\"study_design\": \"Case-control\", \"sample_size\": 15, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"21 years\", \"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] Hypothesis-generating design (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:56+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"osteoarthritis\", \"muscle\", \"lean_mass\", \"bone\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1250717,"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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"knee osteoarthritis\", \"sample_size\": 1250717, \"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\": 1250717, \"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\": \"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: 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 p","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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 th","methodological_notes":null},{"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":"{\"route\": \"subcutaneous\"}","domains":"[\"inflammation\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"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":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"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":"[Auto] Preclinical evidence; not clinical evidence for any human population.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"mendelian_randomization","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":"biomarker","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\": \"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":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Mendelian randomization\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Declaration of competing interest The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":"{}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"kidney\", \"immune\", \"mortality\", \"adverse_effects\", \"perioperative\", \"other_emerging\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":830,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 830, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 830, \"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\": \"CI reported: 95% confidence intervals (CIs\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:56+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"controls\"}","domains":"[\"bone\", \"mortality\", \"perioperative\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1262,"follow_up":"5 years","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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1262, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","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\": \"Retrospective cohort\", \"sample_size\": 1262, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"5 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI, 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"mendelian_randomization","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\"]","drug_details":"{}","domains":"[\"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":"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\": \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","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\": \"Mendelian randomization\", \"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\": \"CI reported: 95% confidence interval [CI], 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":"{\"treatment_duration\": \"18 months\", \"comparator\": \"GLP-1RAs\"}","domains":"[\"inflammation\", \"rheumatologic\", \"adverse_effects\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3042,"follow_up":"18 years","direction":"benefit","population":"{\"mean_age\": 54.6, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": \"71.3% female\", \"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\": 3042, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (mean age 54.6). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 3042, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI], 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"diet and exercise alone\"}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"unknown","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\": 30.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (BMI ≥30 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":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk","author_conflicts":"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: conc","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Semaglutide offers both clinical and environmental benefits in obesity management, supporting the UK's net-zero emissions goals.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"umbrella_review","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","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\": \"type 1 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":"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\": \"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 (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence intervals (CIs\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"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":"Ministry of Health and Welfare; Ministry of Science and ICT, South Korea; Soonchunhyang University Research Fund","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"DPP-4i\"}","domains":"[\"immune\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","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\": \"diabetes mentioned\", \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI: 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":6515,"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\": \"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\": 6515, \"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\": 6515, \"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\": \"not extracted\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"comparator\": \"dipeptidyl peptidase-4 inhibitors\"}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"2 years","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\": \"not reported\", \"baseline_condition\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"2 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":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":"{\"comparator\": \"GLP-1 RAs\"}","domains":"[\"cardiovascular\", \"kidney\", \"liver\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":391,"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\": 391, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 391, \"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\": \"CI reported: 95% CI 1\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"cardiovascular\", \"kidney\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"6 months","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 present (all or most)\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"6 months\", \"outcome_type\": \"intermediate\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:56+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"bone\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":73138,"follow_up":"59 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"47% female\", \"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\": 73138, \"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\": \"Retrospective cohort\", \"sample_size\": 73138, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"59 years\", \"outcome_type\": \"hard\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"gastrointestinal\", \"perioperative\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":67,"follow_up":null,"direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 10.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 67, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age ≥10).","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\": 67, \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Declaration of interest The authors declare that they have no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] We observed that 80% of adolescents on GLP1-RAs had solids on gastric ultrasound despite having fasted for over 12 h.","methodological_notes":null},{"id":282,"doi":"10.64898/2026.09.04.26362304","pmid":null,"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"dementia\", \"alzheimers\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":14364,"follow_up":"60.2 years","direction":"unclear","population":"{\"mean_age\": 60.2, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"54.2% female\", \"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\": \"Alzheimer's disease / MCI\", \"sample_size\": 14364, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (mean age 60.2).","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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 14364, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"60.2 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\"]","drug_details":"{\"treatment_duration\": \"69 months\"}","domains":"[\"cancer\", \"adverse_effects\", \"endocrine\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":101732,"follow_up":"69 months","direction":"null","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 101732, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"sample_size\": 101732, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"69 months\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"comparator\": \"standard-dose GLP-1 RA therapy\"}","domains":"[\"addiction\", \"adverse_effects\", \"perioperative\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":112065,"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\": \"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\": 112065, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Retrospective cohort\", \"sample_size\": 112065, \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:06+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"DPP-4 inhibitors\"}","domains":"[\"mortality\", \"metabolic\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":19770,"follow_up":"2 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\", \"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\": 19770, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 19770, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"2 years\", \"outcome_type\": \"hard\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] [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.","methodological_notes":null},{"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":"{}","domains":"[\"immune\", \"adverse_effects\", \"perioperative\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":5876,"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\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 5876, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 5876, \"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\": \"CI reported: 95% confidence interval (CI\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] [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.","methodological_notes":null},{"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":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":"{}","domains":"[\"cardiovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":216293,"follow_up":"5 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\", \"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\": 216293, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 216293, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"5 years\", \"outcome_type\": \"hard\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"cognition\", \"alzheimers\", \"neuroinflammation\"]","outcome_type":"unknown","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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Alzheimer's disease / MCI\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"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":"[Auto] Preclinical evidence; not clinical evidence for any human population.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Declaration of Competing Interest The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:40+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"66 years old\"}","domains":"[\"mortality\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":136,"follow_up":"66 years","direction":"harm","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 136, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).","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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 136, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"66 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [1\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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). ConclusionsTreatment with GLP-1RA is associated with shorter tracheostomy-free survival in people with ALS and comorbid DM.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:53+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":"{\"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"perioperative\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"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 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\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI], 0\", \"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 have no conflicts of interest to report.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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).","methodological_notes":null},{"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":"{\"comparator\": \"FFA\"}","domains":"[\"liver\", \"metabolic\"]","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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"VERY_INDIRECT","applicability_rationale":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Cellular / in-vitro\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"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\": \"VERY_INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Preclinical evidence; not clinical evidence for any human population.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"id":285,"doi":"10.64898/2026.09.01.748392","pmid":null,"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":null,"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":"{}","domains":"[\"inflammation\", \"bone\", \"adverse_effects\", \"discontinuation\"]","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\": \"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":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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","methodological_notes":null},{"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":"{}","domains":"[\"kidney\", \"adverse_effects\", \"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":"harm","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\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (age/BMI not reported in abstract).","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\": \"Pharmacovigilance analysis\", \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"Shanghai Municipal Science and Technology Commission Project; Pudong New District Health Technology Project","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"comparator\": \"those initiating SGLT-2i or DPP-4i\"}","domains":"[\"ophthalmologic\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":19505,"follow_up":"18 months of follow-up","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 present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 19505, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (age/BMI not reported in abstract).","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\": \"Retrospective cohort\", \"sample_size\": 19505, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 months of follow-up\", \"outcome_type\": \"hard\", \"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] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:04+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"kidney\", \"aging\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"84 years","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"60% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"diabetes mentioned\", \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"84 years\", \"outcome_type\": \"hard\", \"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\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"Novo Nordisk Foundation","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"not available in metadata","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] GLD use for T2D among Danish care home residents is high and shows limited deintensification and potential misalignment with guideline recommendations.","methodological_notes":null},{"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":"{}","domains":"[\"cognition\", \"adverse_effects\", \"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":"harm","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\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (age/BMI not reported in abstract).","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\": \"Pharmacovigilance analysis\", \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"metabolic\", \"perioperative\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":830,"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\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 830, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 830, \"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\": \"CI reported: 95% CI 1\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":"{}","domains":"[\"adverse_effects\", \"nutrition\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":480000,"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\": \"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\": 480000, \"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":"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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 480000, \"randomization\": \"n/a\", \"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\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":125,"follow_up":"6 months","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 present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 125, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (age/BMI not reported in abstract).","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"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.\"","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 125, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"6 months\", \"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\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{}","domains":"[\"inflammation\", \"nutrition\"]","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\": \"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] Participants had 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\": \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"European Union's Horizon Europe Research and Innovation programme; UK Research and Innovation; Swiss State Secretariat for Education, Research and Innovation","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"mortality\", \"metabolic\", \"endocrine\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"18 months","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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": \"heart failure with preserved ejection fraction\", \"sample_size\": null, \"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":"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\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 months\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] [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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1970,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 1970, \"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\": 1970, \"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\": \"CI reported: 95% CI -0\", \"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. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{\"comparator\": \"hydrocodone or tramadol\"}","domains":"[\"addiction\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":411188,"follow_up":"62.8 years","direction":"unclear","population":"{\"mean_age\": 62.8, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"53.8% female\", \"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\": 411188, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (mean age 62.8).","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\": \"Retrospective cohort\", \"sample_size\": 411188, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"62.8 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 1\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"National Institutes of Health (NIH; American Diabetes Association","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"pharmacovigilance","drugs":"[\"semaglutide\", \"liraglutide\", \"dulaglutide\", \"exenatide\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"65 years","direction":"harm","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\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (age/BMI not reported in abstract).","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\": \"Pharmacovigilance analysis\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"65 years\", \"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] Hypothesis-generating design (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"id":284,"doi":"10.21203/rs.3.rs-10121512/v1","pmid":null,"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":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"no exposure\"}","domains":"[\"inflammation\", \"cancer\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":61630,"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\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 61630, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 61630, \"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\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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>","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:40+00:00","study_design":"prospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"any use\"}","domains":"[\"sleep\", \"adverse_effects\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":9150,"follow_up":"53 years","direction":"harm","population":"{\"mean_age\": 53.0, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": \"60.9% female\", \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 9150, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (mean age 53).","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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Prospective cohort\", \"sample_size\": 9150, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"53 years\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] Overall, 1 in 3 users obtained treatment outside conventional prescribing and dispensing channels. MeaningA large and growing share of GLP-1/GIP exposure occurs outside the channels visible to claims-based surveillance.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"their combined use\"}","domains":"[\"cardiovascular\", \"cerebrovascular\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"65 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\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"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 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\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"65 years\", \"outcome_type\": \"hard\", \"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\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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 da","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:53+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"treatment_duration\": \"50 Years\"}","domains":"[\"kidney\", \"bone\", \"metabolic\", \"nutrition\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"50 Years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 50.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (age ≥50).","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\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"50 Years\", \"outcome_type\": \"mixed\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:53+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"kidney\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":802,"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\": \"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\": 802, \"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\": \"Retrospective cohort\", \"sample_size\": 802, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"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\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"Novo Nordisk; University of Dundee","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"not available in metadata","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":"{\"comparator\": \"metformin\"}","domains":"[\"cognition\", \"dementia\", \"sleep\", \"psychiatric\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":63215,"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\": 63215, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss.\"","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 63215, \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:04+00:00","study_design":"clinical_trial","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"aging\", \"adverse_effects\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"45 years","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 45.0, \"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] Population characteristics not extractable from abstract (age ≥45). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Clinical trial (non-randomized or unclear)\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"45 years\", \"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":"[Auto] Hypothesis-generating design (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"orforglipron\", \"tirzepatide\", \"retatrutide\", \"cagrisema\"]","drug_details":"{\"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"adverse_effects\", \"gastrointestinal\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"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\": \"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\": 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\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"16 weeks\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, -8\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":"{}","domains":"[\"cardiovascular\", \"kidney\", \"immune\", \"mortality\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","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\": \"type 2 diabetes present (all or most)\", \"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 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\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"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\": \"not extracted\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": \"15 mg\", \"comparator\": \"Dulaglutide\"}","domains":"[\"cardiovascular\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":14348,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 14348, \"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\": 14348, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"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 -4\", \"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":"Eli Lilly, Lilly, AstraZeneca, Amgen, Pfizer","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly, Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":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":"{\"comparator\": \"MRAs\"}","domains":"[\"cardiovascular\", \"kidney\", \"mortality\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":4153,"follow_up":"1.4 years","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\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 4153, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Retrospective cohort\", \"sample_size\": 4153, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"1.4 years\", \"outcome_type\": \"mixed\", \"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\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"None","industry_funded":"unclear","manufacturer":"AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Roche","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"controls\"}","domains":"[\"cardiovascular\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":932380,"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\": 932380, \"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\": 932380, \"randomization\": \"n/a\", \"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\": \"CI reported: 95% CI 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"mortality\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"3 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\", \"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":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"3 months\", \"outcome_type\": \"hard\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"NIGMS NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:04+00:00","study_design":"preclinical_animal","drugs":"[\"semaglutide\"]","drug_details":"{}","domains":"[\"cognition\", \"aging\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"3 months","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\": \"diabetes mentioned\", \"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":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"3 months\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Preclinical evidence; not clinical evidence for any human population.","funding_source":"NIA NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"Competing interests: The Regents of the University of California filed a patent application on GLP-1 receptor agonists for healthy ageing (64/113,481).","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 effec","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:08+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"adverse_effects\", \"discontinuation\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1776,"follow_up":"52 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\": null, \"sample_size\": 1776, \"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":"LOW","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 1776, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"52 weeks\", \"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":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":"intermediate","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\": \"diabetes mentioned\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants selected for chronic kidney disease (age/BMI not reported in abstract).","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"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\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, -0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:12+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"10 mg\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"body_composition\", \"sleep\"]","outcome_type":"intermediate","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\": 30.0, \"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\": \"obstructive sleep apnea\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (BMI ≥30 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":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NHLBI NIH HHS; NIA NIH HHS","industry_funded":"no","manufacturer":"Eli Lilly, Lilly, Amgen","author_conflicts":"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 a","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"the SGLT2i-only strategy\"}","domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"other_emerging\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":17467,"follow_up":"4 years","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 present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 17467, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 17467, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"4 years\", \"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\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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>","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:13+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"kidney\", \"ophthalmologic\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 months","direction":"null","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\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease\", \"sample_size\": null, \"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":"PRELIMINARY","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] <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.","methodological_notes":null},{"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":"{}","domains":"[\"cardiovascular\", \"body_composition\", \"metabolic\"]","outcome_type":"intermediate","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\": \"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":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"PRELIMINARY","evidence_components":"{\"study_design\": \"Mendelian randomization\", \"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\": \"no\"}","evidence_rationale":"[Auto] Not peer reviewed (preprint, abstract or registration). Early-warning only.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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. HighlightsO_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","methodological_notes":null},{"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":"{}","domains":"[\"neuroinflammation\", \"addiction\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"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\", \"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":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Preclinical (animal)\", \"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":"[Auto] Preclinical evidence; not clinical evidence for any human population.","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"7.2 mg\", \"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\"}","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":"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. 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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:59+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"liver\", \"metabolic\", \"adverse_effects\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":11410,"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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": 11410, \"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\": 11410, \"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\": \"not extracted\", \"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":"AstraZeneca, Pfizer, Roche","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:53+00:00","study_design":"regulatory","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"5 mg\", \"treatment_duration\": \"4 weeks\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"sleep\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":2519,"follow_up":"72 weeks","direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 37.4, \"bmi_min\": 37.4, \"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\": \"obstructive sleep apnea\", \"sample_size\": 2519, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 2519, \"randomization\": \"no\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"72 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 )","methodological_notes":null},{"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":null,"assessment_version":3,"assessed_by":"manual","assessed_at":"2026-09-13T23:08:56+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\", \"sex\": \"not reported\", \"mean_bmi\": \"not reported\", \"diabetes_status\": \"No diabetes (history of type 1 or type 2 diabetes was an exclusion criterion)\"}","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\": \"Unknown\", \"sample_size\": 604, \"randomization\": \"yes (parent trial)\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"39.8 months\", \"outcome_type\": \"biomarker plus association with MACE\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"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":"Sponsor analysed.","independent_replication_exists":"no (single trial dataset)","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In SELECT, semaglutide lowered hs-CRP by 38% and the fall began within weeks, before meaningful weight loss and even in people who did not lose weight. This is the best human evidence for a weight-independent anti-inflammatory effect, but it is a blood marker in people with obesity and heart disease, analysed by the manufacturer.","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."},{"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":null,"assessment_version":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"dulaglutide\", \"retatrutide\"]","drug_details":"{\"dose\": \"12 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"36 weeks","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 35.4, \"bmi_min\": null, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"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] Participants had obesity/overweight without diabetes (mean BMI 35.4); effects may be mediated by weight loss.","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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"36 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\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Eli Lilly and Company","industry_funded":"yes","manufacturer":"Eli Lilly, Lilly","author_conflicts":"not available in metadata","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":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"15 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"24 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\": \"diabetes mentioned\", \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, Hanmi, GlaxoSmithKline","author_conflicts":"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, Pfize","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:56+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"lean_mass\", \"body_composition\", \"adverse_effects\", \"endocrine\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1899,"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\": 1899, \"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\": 1899, \"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: 95% CI, 1\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"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":"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\": \"UNKNOWN\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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 human trial has measured an aging endpoint.","methodological_notes":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":"{\"route\": \"subcutaneous\", \"comparator\": \"Semaglutide\"}","domains":"[\"cardiovascular\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"72 weeks","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\": \"diabetes mentioned\", \"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\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"72 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\": \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{}","domains":"[\"cardiovascular\", \"kidney\", \"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":"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\": \"diabetes mentioned\", \"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\": 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\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"systematic_review","drugs":"[\"semaglutide\", \"liraglutide\", \"exenatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"cognition\", \"mortality\", \"psychiatric\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":333,"follow_up":"20 years","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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 333, \"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":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"001), which a companion mediation analysis indicated was largely attributable to weight loss.\"","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Systematic review\", \"sample_size\": 333, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"20 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval (CI\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":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":"{\"dose\": \"15 mg\", \"comparator\": \"Bariatric and Metabolic Surgery\"}","domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"addiction\", \"mortality\", \"metabolic\", \"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"72 weeks","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"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\": \"Systematic review\", \"sample_size\": \"not extracted\", \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"72 weeks\", \"outcome_type\": \"mixed\", \"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"route\": \"subcutaneous\"}","domains":"[\"cognition\", \"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":"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\": \"diabetes mentioned\", \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Pharmacovigilance analysis\", \"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":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"1000 mg\", \"comparator\": \"the MET group\"}","domains":"[\"inflammation\", \"body_composition\", \"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"16 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\": \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"16 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau); Chongqing Municipal Health Commission; Natural Science Foundation Project of Chongqing CSTC","industry_funded":"no","manufacturer":null,"author_conflicts":"Any opinions or recommendations discussed are solely those of the author(s). The authors declare no conflicts of interest.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"standard care\"}","domains":"[\"inflammation\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"6 months","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"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] Participants had obesity/overweight (BMI ≥30 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":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"6 months\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"comparator\": \"dipeptidyl peptidase-4 inhibitor\"}","domains":"[\"cardiovascular\", \"kidney\", \"mortality\", \"metabolic\"]","outcome_type":"hard","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\": \"diabetes mentioned\", \"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":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan); National Cheng Kung University Hospital (NCKU Hospital)","industry_funded":"no","manufacturer":null,"author_conflicts":"Competing interests: The authors declare no competing interests.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:49+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3150,"follow_up":"32.9 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 3150, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 3150, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"32.9 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) • Serious hypersensitivity reaction to semaglutide or any of the excipients in OZEMPIC. ( 4 )","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:53+00:00","study_design":"regulatory","drugs":"[\"tirzepatide\"]","drug_details":"{\"treatment_duration\": \"4 weeks\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":5119,"follow_up":"36.6 weeks","direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 5119, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 5119, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"36.6 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) Known serious hypersensitivity to tirzepatide or any of the excipients in MOUNJARO. ( 4 )","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:50+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"10 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"10 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] (4) Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection. (4)","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"An umbrella review of meta-analyses in people with overweight or obesity confirms GLP-1 drugs reduce major cardiovascular events and heart attacks, but only in those who already have cardiovascular disease; in people without it the effect was not significant. Arrhythmia and heart-rate signals were noted.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": \"chronic kidney disease\", \"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\": \"hard\", \"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 proposing stem-cell exhaustion, intercellular communication and inflammation as GLP-1RA targets in vascular aging.","funding_source":"Not stated","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, GlaxoSmithKline","author_conflicts":"Senior author reports grants/honoraria from Eli Lilly, Novo Nordisk, Boehringer Ingelheim and others.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":364,"follow_up":"52 weeks","direction":"mixed","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"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\": \"heart failure with preserved ejection fraction\", \"sample_size\": 364, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (BMI ≥30 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\": 364, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"NHLBI NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Innovent","author_conflicts":"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 ","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"[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\": \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In 101 people with kidney disease and overweight or obesity (no diabetes), 24 weeks of semaglutide reduced weight by 9 kg, of which about 2.5 kg was lean mass (imprecise estimate). Body-composition change did not distort kidney-function estimates.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"placebo\", \"follow_up_duration\": \"16 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)","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":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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); 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\": null, \"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\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"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 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In matched US electronic records of people with type 2 diabetes, GLP-1 drugs and SGLT2 inhibitors had similar autoimmune disease rates; differences appeared only against DPP-4 inhibitors, which have their own known immune effects. No clear GLP-1 immune signal in either direction.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":130,"follow_up":"52 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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 130, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 130, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"52 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\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Novo Nordisk Fonden (Novo Nordisk Foundation); Helsefonden (Health Foundation); Novo Nordisk; EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020); Hjerteforeningen (Heart Foundation)","industry_funded":"partial","manufacturer":"Novo Nordisk, AstraZeneca, Sanofi, Boehringer Ingelheim","author_conflicts":"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.","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"100 mg\", \"treatment_duration\": \"24 weeks\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":120,"follow_up":"4 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\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 120, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 120, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"4 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:51+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"0.75 mg\", \"treatment_duration\": \"8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":568,"follow_up":"23.8 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 568, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 568, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"23.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 ).","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obesity/overweight present (all or most)\", \"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\": 930, \"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\": 930, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"18 years\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"First 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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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 effect","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\": 9981, \"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\": 9981, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"85 years\", \"outcome_type\": \"intermediate\", \"replication\": \"two identical trials, both null\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Two phase 3 trials in 3,808 people with early Alzheimer's disease found that two years of oral semaglutide did not slow cognitive or functional decline at all. This is the most important negative result for the neuroprotection hypothesis: strong observational associations did not translate into a treatment effect.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:52+00:00","study_design":"regulatory","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"54 mg\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"metabolic\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"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\": \"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] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 Weeks\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )","methodological_notes":null},{"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":"{\"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cognition\", \"body_composition\", \"immune\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":108,"follow_up":"32 weeks","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"40% female\", \"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\": 108, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"Causal mediation analysis assessed semaglutide's direct and indirect effects on Cognivue scores through changes in adiposity and inflammation.\"","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 (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NIDDK NIH HHS; NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Semaglutide may have a beneficial impact on visuospatial cognitive function in PWH through its effect on inflammation. Clinical Trials Registration . NCT04019197.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"diabetes mentioned\", \"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\": \"UNKNOWN\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"A 2026 meta-analysis of randomized trials found GLP-1 drugs did not improve motor or non-motor Parkinson's symptoms and caused more gastrointestinal side effects. Together with the negative phase 3 exenatide trial, this weakens the Parkinson's neuroprotection hypothesis.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"14 mg\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":9495,"follow_up":"13 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\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease\", \"sample_size\": 9495, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 9495, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"13 weeks\", \"outcome_type\": \"mixed\", \"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\"}","evidence_rationale":"[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"12 years","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\": \"12 years\", \"outcome_type\": \"hard\", \"replication\": \"5 studies consistent\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence intervals (CIs\", \"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, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim","author_conflicts":"Several authors report honoraria from Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Sanofi.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Combining five observational studies in people with type 2 diabetes, semaglutide roughly doubled the hazard of NAION, a rare cause of sudden, usually permanent vision loss, 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},{"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":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\", \"mortality\", \"metabolic\"]","outcome_type":"mixed","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\": \"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\": \"heart failure with preserved ejection fraction\", \"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\": \"Systematic review\", \"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\": \"not extracted\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"dulaglutide\", \"tirzepatide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"body_composition\", \"liver\", \"sleep\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":25847,"follow_up":"24 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\": \"diabetes mentioned\", \"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\": 25847, \"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\": 25847, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"24 weeks\", \"outcome_type\": \"mixed\", \"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\"}","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 have no conflicts of interest to disclose.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:52+00:00","study_design":"regulatory","drugs":"[\"lixisenatide\"]","drug_details":"{\"dose\": \"70 mg\"}","domains":"[\"cardiovascular\", \"kidney\", \"liver\", \"immune\", \"addiction\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":834,"follow_up":"30 weeks","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 present (all or most)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 834, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 834, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"30 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] During episodes of hypoglycemia. ( 4 ) Serious hypersensitivity to insulin glargine, lixisenatide, or any of the excipients in SOLIQUA 100/33 ( 4 )","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"sleep\", \"metabolic\"]","outcome_type":"mixed","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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obstructive sleep apnea\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"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.\"","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NHLBI NIH HHS; NIA NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Pfizer, Zealand Pharma, Structure Therapeutics","author_conflicts":"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 Inst","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 .","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:49+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"dose\": \"1.5 mg\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"perioperative\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1071,"follow_up":"41.8 weeks","direction":"harm","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 1071, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 1071, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"41.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 )","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:50+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"10 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"10 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) • Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide. ( 4 )","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obstructive sleep apnea\", \"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\": \"Randomized controlled trial\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":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":"{\"dose\": \"32 mg\"}","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\": 30.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"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":"[Auto] Abstract addresses weight-loss independence: \"4% weight loss where mediation analyses showed 35%-55% of cardiovascular benefit was independent of weight reduction.\"","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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 acce","methodological_notes":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":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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3417,"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 1 diabetes\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 3417, \"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\": 3417, \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI]: -3\", \"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":"Sichuan Science and Technology Programme; Luzhou Science and Technology Programme","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"retrospective_cohort","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"other antidiabetic agents\"}","domains":"[\"inflammation\", \"mortality\", \"metabolic\", \"other_emerging\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":25712,"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\": 25712, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 25712, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"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% CI, 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:49+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"inflammation\", \"addiction\", \"ophthalmologic\", \"perioperative\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":882,"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\": 882, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 882, \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI, -0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"comparator\": \"the continued treatment group\"}","domains":"[\"cardiovascular\", \"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":8993,"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\": \"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\": 8993, \"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":"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":"MODERATE","evidence_components":"{\"study_design\": \"Meta-analysis\", \"sample_size\": 8993, \"randomization\": \"n/a\", \"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\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval (CI\", \"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 there are no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":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":"{\"dose\": \"0.5 mg\"}","domains":"[\"cardiovascular\", \"kidney\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":336,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 336, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Retrospective cohort\", \"sample_size\": 336, \"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\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"cardiovascular\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\"]","outcome_type":"hard","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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"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\": \"hard\", \"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\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:51+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"sleep\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1877,"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\": \"obstructive sleep apnea\", \"sample_size\": 1877, \"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\": 1877, \"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: 95% CI, -22\", \"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 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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,","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:16:53+00:00","study_design":"retrospective_cohort","drugs":"[\"class_unspecified\"]","drug_details":"{}","domains":"[\"kidney\", \"muscle\", \"body_composition\", \"metabolic\"]","outcome_type":"intermediate","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":36,"follow_up":"12 months","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 present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 36, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (age/BMI not reported in abstract).","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\": \"Retrospective cohort\", \"sample_size\": 36, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"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\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"cancer\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":60,"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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 60, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Retrospective cohort\", \"sample_size\": 60, \"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\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"there are no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"comparator\": \"tirzepatide\"}","domains":"[\"adverse_effects\", \"gastrointestinal\", \"psychiatric\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"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\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (age/BMI not reported in abstract).","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\": \"Pharmacovigilance analysis\", \"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\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence intervals, were calculated to compare the frequency of suicide and s\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"adverse_effects\", \"gastrointestinal\", \"discontinuation\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":27,"follow_up":"12 months","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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 27, \"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] 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\": 27, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"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":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:09+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\", \"mazdutide\", \"cagrisema\"]","drug_details":"{\"treatment_duration\": \"12 weeks\", \"comparator\": \"placebo\"}","domains":"[\"metabolic\", \"adverse_effects\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":214,"follow_up":"12 weeks","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\": 214, \"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\": 214, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"12 weeks\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval -25\", \"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":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:17:12+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\", \"tirzepatide\"]","drug_details":"{\"comparator\": \"GLP-1 RA alone remains unclear\"}","domains":"[\"other_emerging\"]","outcome_type":"unknown","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":8176,"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\", \"diabetes_status\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 8176, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 8176, \"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\": \"CI reported: 95% CI, 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Observational design; confounding by indication and healthy-user effects cannot be excluded (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"All listed authors report no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":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":"{}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1878,"follow_up":"36 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\": \"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\": \"36 weeks\", \"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\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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)\"}","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":"8.8 years","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\": 13299, \"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":"specifically_tested","mediation_notes":"Indirectly informative on weight mediation: tirzepatide produces substantially more weight loss than dulaglutide yet was not superior for MACE, arguing against a simple dose-response between weight loss and cardiovascular events.","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 13299, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"active (dulaglutide)\", \"follow_up_duration\": \"8.8 years\", \"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, Eli Lilly","adverse_events":"More GI adverse events with tirzepatide.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In 13,165 people with type 2 diabetes and heart disease, tirzepatide was as good as, but not clearly better than, dulaglutide at preventing cardiovascular events over the trial, despite producing far more weight loss. Weight loss magnitude did not translate into extra cardiovascular protection here.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:50+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"10 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"10 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection. ( 4 )","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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 BMI 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":"45 years","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\": 604, \"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 weight change\", \"time-varying waist circumference\"]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 604, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"45 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0·94-0·99]\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"A prespecified SELECT analysis found the cardiovascular benefit of semaglutide was similar whatever the starting weight and did not track how much weight people lost; only about a third was explained by waist reduction. Evidence that the benefit is not simply weight loss, within people who all had BMI 27 or higher.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg once weekly\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":573,"follow_up":"52 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\": \"not reported\", \"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\": 573, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 573, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Randomized trial of moderate size; outcome type and follow-up limit certainty (auto-provisional).","funding_source":"NIA NIH HHS; NHLBI NIH HHS; NIMHD NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"body_composition\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1145,"follow_up":"20 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\": \"diabetes mentioned\", \"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\": 1145, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1145, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"20 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI: 8\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"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":"NHLBI NIH HHS; NIA NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, Zealand Pharma, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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,","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:50+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"3 mg\", \"treatment_duration\": \"56 weeks\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"psychiatric\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"56 weeks","direction":"null","population":"{\"mean_age\": 47.0, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"71% female\", \"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\": \"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":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"56 weeks\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] ( 4 ) Hypersensitivity to liraglutide or any excipients in liraglutide injection. ( 4 )","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:52+00:00","study_design":"regulatory","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"54 mg\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"metabolic\", \"gastrointestinal\", \"perioperative\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"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\": \"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] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 Weeks\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] (4) • History of drug-induced immune-mediated thrombocytopenia from exenatide products. ( 4 )","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"1.34 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cancer\", \"addiction\", \"mortality\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":124,"follow_up":"26 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\": \"mentioned\", \"baseline_condition\": \"alcohol use disorder\", \"sample_size\": 124, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"PARTIAL","applicability_rationale":"[Auto] Participants selected for alcohol use disorder, not for obesity or diabetes (age/BMI not reported in abstract); results apply to that patient group, not to healthy adults.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 124, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"26 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"PARTIAL\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"P.A. Messerschmidt og Hustrus Fond; Lundbeck Foundation; Slagtermester Max Worzner og hustru Inger Worzners mindelegat; Grosserer L.F. Foghts Fond; The A.P. Moeller Foundation; The Augustinus Foundation; The Research Foundation, Capital Region of Denmark; The Ivan Nielsen Foundation; The Novavi Foundation; The Research Foundation, Mental Health Services, Capital Region of Denmark; Hartmann Foundation; Aase and Ejnar Danielsen Foundation","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen","author_conflicts":"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).","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: AstraZeneca (originally Amylin/Eli Lilly)","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"kidney\", \"body_composition\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":364,"follow_up":"52 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"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\": \"heart failure with preserved ejection fraction\", \"sample_size\": 364, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (BMI ≥30 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\": 364, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\"}","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":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Innovent","author_conflicts":"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, Bio","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1000 mg\", \"treatment_duration\": \"16 weeks\", \"comparator\": \"a combination of semaglutide and MET\"}","domains":"[\"inflammation\", \"body_composition\", \"metabolic\", \"endocrine\", \"other_emerging\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":80,"follow_up":"16 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\": \"not reported\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 80, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 80, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"16 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":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"comparator\": \"the control group\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":55,"follow_up":"18 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\", \"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\": 55, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 55, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 months\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"PhD program of Translational Medicine at the University of Campania \"Luigi Vanvitelli\", Naples, Italy (Dr. Caruso)","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Roche","author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":4734,"follow_up":"24 weeks","direction":"unclear","population":"{\"mean_age\": 54.13, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"44.46% female\", \"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\": 4734, \"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\": 4734, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 weeks\", \"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\": \"no\", \"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":"National Natural Science Foundation of China","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"liver\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":16,"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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": 16, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 16, \"randomization\": \"yes\", \"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% CI - 12\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Italian Ministry of University and Research","industry_funded":"no","manufacturer":null,"author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"dulaglutide\", \"orforglipron\"]","drug_details":"{\"dose\": \"45 mg\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":361,"follow_up":"59 years","direction":"unclear","population":"{\"mean_age\": 59.0, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 35.3, \"bmi_min\": 35.3, \"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\": 361, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight without diabetes (mean age 59; mean BMI 35.3); effects may be mediated by weight loss.","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\": 361, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"59 years\", \"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\"}","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":"Novo Nordisk, Eli Lilly, Lilly, Sanofi, Boehringer Ingelheim, Pfizer, Hanmi","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly, Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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).","methodological_notes":null},{"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":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\": \"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\": 1197, \"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\": 1197, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"240 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: 95% confidence interval [CI], 21\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In people with MASH and moderate-to-advanced liver fibrosis, 72 weeks of semaglutide resolved steatohepatitis in 63% vs 34% and improved fibrosis in 37% vs 22%. Strong evidence for this liver disease; unknown whether it applies to lean MASH or to people without liver disease.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+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\": 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\": \"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"chronic kidney disease\", \"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":"[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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 9650, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"50 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval, 0\", \"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":"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":"Serious adverse events 47.9% vs 50.3%; GI disorders 5.0% vs 4.4%.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"50 years","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\": \"Alzheimer's disease / MCI\", \"sample_size\": 858, \"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":"Glycaemic and vascular improvements could mediate; identical effect with SGLT2i suggests a shared cardiometabolic pathway rather than GLP-1-specific neuroprotection.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Retrospective cohort\", \"sample_size\": 858, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"50 years\", \"outcome_type\": \"unknown\", \"replication\": \"consistent with other EHR cohorts\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CIs were estimated using Cox proportional hazard regression mo\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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, but no lower than SGLT2 inhibitors. Suggests a cardiometabolic rather than drug-specific effect; observational.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"Alzheimer's disease / MCI\", \"sample_size\": 531, \"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\": 531, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"mixed\", \"replication\": \"10 GLP-1RA trials pooled\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI, 0\", \"risk_of_bias\": \"dementia not prespecified; ascertainment via adverse-event reporting; few events\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"Randomized data but with unplanned, sparsely ascertained outcomes; class-level result null.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Pooling 26 randomized trials, drugs for diabetes as a group did not reduce dementia, but the GLP-1 subgroup showed a 45% lower odds based on sparsely collected events. Weak randomized signal that the evoke trials later failed to support in established Alzheimer's disease.","methodological_notes":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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"adverse_effects\", \"gastrointestinal\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":2194,"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\": \"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\": 2194, \"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\": 2194, \"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\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Disclosures: The authors have no conflicts of interest to report.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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","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 an entry criterion (mean BMI ~32, full text)\", \"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\": null, \"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\": \"not extracted\", \"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":"NIH (NCATS) and institutional","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"no","conflict_notes":null,"adverse_events":"Not detailed in abstract.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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. Promising but small and short; larger trials are needed.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"tirzepatide\", \"retatrutide\"]","drug_details":"{\"dose\": \"1.20 mg\", \"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":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\": \"excluded (no diabetes)\", \"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":"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\": \"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1.0 mg weekly\", \"treatment_duration\": \"32 weeks\", \"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"immune\", \"mortality\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":108,"follow_up":"18 years","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\": \"excluded (no diabetes)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 108, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","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\": \"18 years\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NIDDK NIH HHS; NCATS NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes (all; US veterans)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Alzheimer's disease / MCI\", \"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\": \"not stated\", \"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)","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 97, \"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\": 97, \"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: 95% CI -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 Research (UK) and others; NIH intramural support listed","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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. This is the strongest evidence to date against GLP-1 disease modification in Parkinson's.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"18 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; 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\": 747, \"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\": 747, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"18 years\", \"outcome_type\": \"unknown\", \"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\": \"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":"None declared","industry_funded":"no","manufacturer":null,"author_conflicts":"None.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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, regardless of whether they had diabetes or obesity. Observational, but one of the few signals that does not depend on metabolic disease.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"tirzepatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"kidney\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"52 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\": \"not reported\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NHLBI NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Innovent","author_conflicts":"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","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 .","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 364, \"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\": 364, \"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\": \"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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:50+00:00","study_design":"regulatory","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"kidney\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"10 years","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"10 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] • 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) .","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"rheumatologic\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":15,"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\": 15, \"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\": \"Randomized controlled trial\", \"sample_size\": 15, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"12 months of follow-up","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": 27.0, \"bmi_min\": 27.0, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 2 diabetes in 10 trials; SELECT (no diabetes, obesity) added post hoc\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 500, \"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\": 500, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"12 months of follow-up\", \"outcome_type\": \"mixed\", \"replication\": \"11 trials; low heterogeneity for kidney failure\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI 0·73-0·93\", \"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":"Not stated in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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 or pancreatitis.","methodological_notes":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":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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"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\", \"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\"}","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 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+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\"}","evidence_rationale":"[Auto] Systematic review/meta-analysis including observational studies (auto-provisional).","funding_source":"not reported in abstract","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"tirzepatide\"]","drug_details":"{\"dose\": \"0.89 mg\"}","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\": \"not reported\", \"diabetes_status\": \"not reported\", \"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\"}","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":"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":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"type 2 diabetes required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"Alzheimer's disease / MCI\", \"sample_size\": null, \"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\": \"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\": \"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":"NIH (NIA)","industry_funded":"no","manufacturer":null,"author_conflicts":"Authors declare no competing interests.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"consistent with other EHR cohorts; not with RCTs","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In US electronic records of people with type 2 diabetes, semaglutide users were 40-70% less likely to receive a first Alzheimer's diagnosis within 3 years than users of other diabetes drugs. The size and speed of the effect suggest bias (people with early cognitive decline may not be prescribed new injectables); the evoke trials found no effect on AD progression.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 517, \"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":"[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\": \"Retrospective cohort\", \"sample_size\": 517, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"84 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Across Sweden and Denmark, 124,517 new GLP-1 users and 174,036 SGLT2-inhibitor users had similar, very low suicide death rates over 2.5 years. The data exclude more than 0.16 extra suicide deaths per 1,000 person-years.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"Unknown\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":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\": \"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\", \"follow_up_duration\": \"56 years\", \"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":"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":"Discontinuation due to adverse events 6.7% vs 3.0%, mostly GI; serious adverse events similar.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1145,"follow_up":"52 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\": \"diabetes mentioned\", \"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\": 1145, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1145, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\": \"no\", \"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":"NHLBI NIH HHS; NIA NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, Zealand Pharma, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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, AstraZen","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1145,"follow_up":"52 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\": \"diabetes mentioned\", \"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\": 1145, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1145, \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, Zealand Pharma, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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, ","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":3,"assessed_by":"manual","assessed_at":"2026-09-13T23:08:56+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).\"}","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":"Weight loss ~18-20% (full text); AHI, hs-CRP and BP improvements are consistent with weight-loss effects; not separated.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"physiological surrogate (AHI)\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI], -29\", \"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","industry_funded":"1","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In adults with severe obesity and sleep apnoea, tirzepatide roughly halved the apnoea-hypopnoea index over a year, with reductions in hs-CRP and blood pressure. These changes track large 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."},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"2 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"alzheimers\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3973,"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\": \"Alzheimer's disease / MCI\", \"sample_size\": 3973, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 3973, \"randomization\": \"yes\", \"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\": \"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":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: AstraZeneca (originally Amylin/Eli Lilly)","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] EQW treatment was associated with significant change in inflammatory proteins associated with AD.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"Mechanistic 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Review of lean-mass changes with GLP-1-based drugs: 15-60% 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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1145,"follow_up":"52 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\": \"diabetes mentioned\", \"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\": 1145, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1145, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\"}","evidence_rationale":"[Auto] Large randomized trial with clinical outcomes (auto-provisional; risk of bias and consistency not yet assessed).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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 Therapie","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"Benefit consistent in patients with and without HF history (HRs in full text; MACE HR ~0.72 with HF)","confidence_interval":null,"p_value":null,"sample_size":17604,"follow_up":"mean 39.8 months","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\": \"heart failure with preserved ejection fraction\", \"sample_size\": 604, \"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\": 604, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"45 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0·60-0·87 for MACE\", \"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":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Within SELECT, semaglutide's cardiovascular benefit was similar in the quarter of participants who had heart failure at baseline, across preserved and reduced ejection fraction. Same obese, high-risk population as the main trial.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"retrospective_cohort","drugs":"[\"semaglutide\"]","drug_details":"{\"treatment_duration\": \"36 months\", \"comparator\": \"3 in the non-GLP-1 RA cohort\"}","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 (20 vs 3 events; from full text)","confidence_interval":"1.62 to 11.29 (T2D)","p_value":"<0.001","sample_size":1689,"follow_up":"36 months","direction":"harm","population":"{\"mean_age\": 59.0, \"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 and non-diabetic cohorts\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obstructive sleep apnea\", \"sample_size\": 827, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","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\": 827, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"The first 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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":1145,"follow_up":"52 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\": \"diabetes mentioned\", \"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\": 1145, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 1145, \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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, ","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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 Livi","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1.0 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"median 3.4 years\", \"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 for efficacy)","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)\", \"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\": \"3.4 years\", \"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: 95% confidence interval [CI], 0\", \"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 (NIH support listed in PubMed grant fields)","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 3.4 years. The trial was stopped early for benefit. It applies to people with diabetic kidney disease, not to healthy kidneys.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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 cancers; vs metformin: mostly no difference (full text)","confidence_interval":null,"p_value":null,"sample_size":1651452,"follow_up":null,"direction":"benefit","population":"{\"mean_age\": 59.8, \"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 required\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 452, \"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\": 452, \"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\": \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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, but differences versus metformin were mostly absent. The insulin comparison likely reflects sicker patients rather than a protective drug effect.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 8803, \"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\": 8803, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"104 weeks\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"other_emerging\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"40 weeks","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\": null, \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"40 weeks\", \"outcome_type\": \"biomarker\", \"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":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk","author_conflicts":"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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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 BMD loss","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":"Weight loss is the likely cause of BMD loss; exercise prevented it. Not separated from drug.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 195, \"randomization\": \"yes\", \"blinding\": \"double-blind for drug\", \"comparator\": \"placebo\", \"follow_up_duration\": \"65 years\", \"outcome_type\": \"BMD surrogate; no fractures\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, 4\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":2178,"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\": \"MASH / MASLD\", \"sample_size\": 2178, \"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\": 2178, \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% Confidence Interval (CI\", \"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":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"4 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"mortality\", \"metabolic\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"18 years","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"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\": null, \"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 ≥18; BMI ≥30 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":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"18 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 5·3 to 9·8]\", \"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","industry_funded":"partial","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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 ","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:49+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"treatment_duration\": \"48 years\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"psychiatric\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":2116,"follow_up":"12 years","direction":"null","population":"{\"mean_age\": 48.0, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"71% female\", \"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 2116, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 2116, \"randomization\": \"no\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"12 years\", \"outcome_type\": \"hard\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] • 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\", \"adverse_effects\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":616,"follow_up":"52 weeks","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": 30.0, \"obesity_status\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"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\": 616, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes and obesity/overweight (BMI ≥30 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\": 616, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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], 4\", \"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":"not available in metadata","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: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.).","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 410, \"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\": 410, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"3.9 years\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In 145,410 Scandinavian GLP-1 users followed for about 4 years, thyroid cancer was not increased compared with DPP-4 inhibitor users (HR 0.93). Follow-up is too short to rule out very long-latency effects.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"rct","drugs":"[\"lixisenatide\"]","drug_details":"{\"dose\": \"daily (10 then 20 micrograms, full text)\", \"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)\", \"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\": \"3 years\", \"outcome_type\": \"mixed\", \"replication\": \"not replicated; contradicted by larger exenatide phase 3\", \"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)","industry_funded":"no","manufacturer":null,"author_conflicts":"See published disclosures.","sponsor_role":"Academic sponsor; Sanofi supplied drug (full text).","independent_replication_exists":"no","conflict_notes":null,"adverse_events":"Nausea 46%, vomiting 13%.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In 156 people with early Parkinson's disease, daily lixisenatide was associated with about 3 points less motor worsening over 12 months, at the cost of frequent nausea. This is a small phase 2 signal that a larger, longer exenatide trial did not support.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"treatment_duration\": \"6 months\", \"route\": \"subcutaneous\", \"comparator\": \"the control group\"}","domains":"[\"inflammation\", \"cardiovascular\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":24,"follow_up":"6 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\", \"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\": 24, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 24, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"6 months\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, 8\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"sleep\", \"mortality\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"24 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\", \"diabetes_status\": \"excluded (no diabetes)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"obstructive sleep apnea\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants selected for obstructive sleep apnea (age/BMI not reported in abstract).","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"24 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Health Research Board of Ireland","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"route\": \"subcutaneous\", \"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":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\": \"excluded (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":"[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\": \"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} -12\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] In overweight or obese non-diabetic individuals, semaglutide had a remarkable and sustained weight loss effect that was well tolerated and safe.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"treatment_duration\": \"52 weeks\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":529,"follow_up":"52 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\": \"not reported\", \"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\": 529, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 529, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI]: for KCCQ-CSS, 10\", \"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":"NHLBI NIH HHS; NIA NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"[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":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 670, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"36 weeks\", \"outcome_type\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI, -21\", \"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","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":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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 reverses the effect.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"not stated\", \"follow_up_duration\": \"50.1 years\", \"outcome_type\": \"unknown\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"2 mg\", \"treatment_duration\": \"12 weeks\"}","domains":"[\"inflammation\", \"immune\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"other_emerging\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"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\": \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Chongqing Natural Science Foundation; National Science Fund for Distinguished Young Scholars","industry_funded":"no","manufacturer":null,"author_conflicts":"The authors declare no competing interests.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"route\": \"oral\"}","domains":"[\"inflammation\", \"bone\", \"adverse_effects\", \"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":"harm","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\": \"diabetes mentioned\", \"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] Participants had obesity/overweight (age/BMI not reported in abstract).","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\": \"Pharmacovigilance analysis\", \"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\": \"INDIRECT\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"There are no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\"]","drug_details":"{\"route\": \"oral\", \"comparator\": \"placebo\"}","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\": \"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\": 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\", \"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\"}","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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":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."},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:51+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"0.75 mg\", \"treatment_duration\": \"8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":568,"follow_up":"23.8 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 568, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 568, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"23.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:51+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"0.75 mg\", \"treatment_duration\": \"8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":568,"follow_up":"23.8 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 568, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 568, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"23.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"class_unspecified\"]","drug_details":"{\"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"metabolic\", \"adverse_effects\", \"drug_interactions\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":99,"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\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 99, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 99, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"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\": \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"unknown","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cerebrovascular\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":529,"follow_up":"52 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\": \"not reported\", \"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\": 529, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": 529, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","funding_source":"NIA NIH HHS; NHLBI NIH HHS","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer, Roche, GlaxoSmithKline, Structure Therapeutics","author_conflicts":"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 Sano","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:49+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"dose\": \"0.5 mg\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3150,"follow_up":"32.9 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 3150, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 3150, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"32.9 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] • 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:49+00:00","study_design":"regulatory","drugs":"[\"semaglutide\", \"liraglutide\"]","drug_details":"{\"dose\": \"0.5 mg\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":3150,"follow_up":"32.9 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 3150, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 3150, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"32.9 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] • 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 ).","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"Pancreatitis HR 9.09; bowel obstruction HR 4.22; gastroparesis HR 3.67; biliary disease HR 1.50 (NS) (from full text; verify)","confidence_interval":"pancreatitis 1.25-66.00; obstruction 1.02-17.40; gastroparesis 1.15-11.90 (full text)","p_value":null,"sample_size":4757,"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\": \"Unknown\", \"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\": \"very wide confidence intervals; few events\", \"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":"See effect estimates.","limitations":"No abstract in PubMed (JAMA research letter); effect estimates transcribed from the article and should be verified against the source.","plain_summary":"Using US insurance claims from people without diabetes using GLP-1 drugs for weight loss, this research letter reported higher rates of pancreatitis, bowel obstruction and gastroparesis than with bupropion-naltrexone. Event counts were small and the confidence intervals very wide.","methodological_notes":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":3,"assessed_by":"ai:two-pass","assessed_at":"2026-09-13T23:08:56+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; CRP 0.51 to 0.72","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)\"}","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 controlled trial\", \"sample_size\": 529, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"52 weeks\", \"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: 95% confidence interval [CI], 4\", \"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":"Authors report Novo Nordisk relationships; sponsor co-authors.","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."},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"-24.2% at 48 weeks (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\": 30.0, \"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\": \"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\": \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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. Sets the stage for TRIUMPH and TRANSCEND trials.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:51+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"0.75 mg\", \"treatment_duration\": \"8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":568,"follow_up":"23.8 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 568, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 568, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"23.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\", \"treatment_duration\": \"6 months\", \"route\": \"subcutaneous\", \"comparator\": \"those\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":17,"follow_up":"75 years","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": \"20-75\", \"age_min\": 20.0, \"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\": 17, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (age range 20-75).","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\": \"Randomized controlled trial\", \"sample_size\": 17, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"not stated\", \"follow_up_duration\": \"75 years\", \"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":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] The trial was registered through the Chinese Clinical Trial Registry (ChiCTR; trial registration no. ChiCTR2200063693; retrospectively registered) on Sep 14, 2022.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T14:18:51+00:00","study_design":"regulatory","drugs":"[\"liraglutide\", \"dulaglutide\"]","drug_details":"{\"dose\": \"0.75 mg\", \"treatment_duration\": \"8 years\", \"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\", \"endocrine\", \"gastrointestinal\", \"ophthalmologic\", \"drug_interactions\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":568,"follow_up":"23.8 weeks","direction":"null","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 75.0, \"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\": 568, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Regulatory document\", \"sample_size\": 568, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"23.8 weeks\", \"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\": \"no\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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 ).","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":600,"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\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 600, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 600, \"randomization\": \"yes\", \"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\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI 1\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"3.0 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":166,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"mentioned\", \"baseline_condition\": null, \"sample_size\": 166, \"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":"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\": \"Randomized controlled trial\", \"sample_size\": 166, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"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 - 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"British Heart Foundation","industry_funded":"no","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim","author_conflicts":"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.","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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":"6 years","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\": null, \"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\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"6 years\", \"outcome_type\": \"unknown\", \"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":"Non-US government (per PubMed)","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"A French case-control study found about 60% higher thyroid cancer risk after 1-3 years of GLP-1 use in people with diabetes. Detection bias is a concern, and a larger Scandinavian cohort found no increase.","methodological_notes":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":3,"assessed_by":"ai:two-pass","assessed_at":"2026-09-13T23:08:56+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; only liraglutide reduced MCP-1","confidence_interval":null,"p_value":null,"sample_size":88,"follow_up":"14 weeks","direction":"mixed","population":"{\"condition\": \"Obesity and prediabetes\", \"mean_age\": \"not reported in abstract; registry total (all randomized, N=93): 50.3 years (SD 10.6)\", \"sex\": \"not reported in abstract; registry total (all randomized, N=93): 63 female / 30 male\", \"mean_bmi\": \"not reported\", \"diabetes_status\": \"Prediabetes (by FPG, IGT, or HbA1c criteria per registry eligibility; not established type 1/2 diabetes)\"}","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. However, the abstract's MCP-1 sentence does not specify which timepoint(s) the reported MCP-1 reduction refers to, so it cannot be confirmed from the given sources that the temporal design was actually invoked for the MCP-1 result specifically (see key_limitation).\n; prespecified: NI; key limitation: The abstract does not state which timepoint(s) (2-week pre-weight-loss vs. 14-week) the reported MCP-1 reduction was measured/analyzed at, and MCP-1 is not a registered outcome at all (no timeFrame is specified for it in NCT03101930.json, unlike FMD and PAI-1, which are explicitly registered with a \"Baseline to 2 and 14 weeks\" timeFrame). This means the weight-independence claim for MCP-1 cannot be verified against either of the trial's two mediation strategies from the sources available — it is not possible to confirm the 2-week (pre-weight-loss) result was actually where the MCP-1 effect was seen, as opposed to only the 14-week (post-weight-loss) comparison, where a weight-matched-diet difference would still leave open a non-weight mechanism but not a strictly \"before weight loss\" one.\n","adjusted_for":"[\"weight-matched diet comparator\"]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind for drug vs placebo; diet open\", \"comparator\": \"placebo\", \"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":"Vanderbilt University Medical Center (lead sponsor); American Heart Association (collaborator)","industry_funded":"N","manufacturer":null,"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":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"A small NIH-funded trial compared liraglutide, a low-calorie diet and sitagliptin in 88 adults with obesity and prediabetes. Neither drug nor diet improved blood-vessel function; liraglutide alone lowered the inflammatory chemokine MCP-1, suggesting a weight-independent effect on one marker. Mostly null, but methodologically the right kind of study.","methodological_notes":"Calibration two-pass assessment 2026-09-13 (drafts in data/assessments/36306151/); sources: abstract, registry, public protocol/SAP where available; no paper full text."},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"2.4 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","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\": \"diabetes mentioned\", \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"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] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, \", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"Novo Nordisk","industry_funded":"yes","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Amgen, Pfizer","author_conflicts":"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 AstraZen","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: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"cellular_in_vitro","drugs":"[\"dulaglutide\"]","drug_details":"{\"dose\": \"1000 mg\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 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\": \"type 2 diabetes present (all or most)\", \"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":"VERY_INDIRECT","applicability_rationale":"[Auto] Non-human (animal or cellular) evidence; no direct inference to any human population.","mediation":"unknown","mediation_notes":"[Auto] Non-human study; weight-loss mediation not assessable.","adjusted_for":"[]","evidence_level":"VERY_LOW","evidence_components":"{\"study_design\": \"Cellular / in-vitro\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 weeks\", \"outcome_type\": \"biomarker\", \"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":"[Auto] Preclinical evidence; not clinical evidence for any human population.","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"semaglutide\", \"exenatide\"]","drug_details":"{\"dose\": \"3.0 mg\", \"route\": \"oral\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":2482,"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\": \"chronic kidney disease present in population (see abstract)\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"chronic kidney disease\", \"sample_size\": 2482, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (age/BMI not reported in abstract).","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions.\"","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 2482, \"randomization\": \"yes\", \"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]: 0\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"unclear\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Pfizer, Hanmi, GlaxoSmithKline","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk, AstraZeneca (originally Amylin/Eli Lilly)","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 1961, \"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":"[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\": 1961, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"68 weeks\", \"outcome_type\": \"unknown\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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.","methodological_notes":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":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\", \"psychiatric\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":77,"follow_up":"16 weeks","direction":"null","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 77, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 77, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"16 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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"meta_analysis","drugs":"[\"class_unspecified\"]","drug_details":"{\"comparator\": \"placebo\"}","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\": 371, \"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\": 371, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"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: 95% CI, 1\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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). Established harm.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"rheumatologic\", \"cancer\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":13,"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\": \"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\": 13, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 13, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+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":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\": \"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\"}","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 that they have no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"clinical_trial","drugs":"[\"dulaglutide\", \"tirzepatide\"]","drug_details":"{\"dose\": \"15 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"26 weeks","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 present (all or most)\", \"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] Participants had type 2 diabetes (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":"VERY_LOW","evidence_components":"{\"study_design\": \"Clinical trial (non-randomized or unclear)\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"26 weeks\", \"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\"}","evidence_rationale":"[Auto] Hypothesis-generating design (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":"Eli Lilly, Lilly","author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Eli Lilly, Eli Lilly","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+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":"harm","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":"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":"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\"}","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 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"500 mg\", \"treatment_duration\": \"12 weeks\"}","domains":"[\"inflammation\", \"metabolic\", \"adverse_effects\", \"endocrine\", \"gastrointestinal\", \"other_emerging\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 weeks","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\": \"diabetes mentioned\", \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"None.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"inflammation\", \"kidney\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"24 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\": null, \"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":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"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.\"","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"24 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare no competing interests.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 500, \"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\": 500, \"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: 95% CI 0·80-0·93]\", \"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":"No specific funding stated in abstract; authors report industry consulting","industry_funded":"unclear","manufacturer":null,"author_conflicts":"Lead author reports consulting for Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi and others.","sponsor_role":"Independent academic meta-analysis of manufacturer-sponsored trials.","independent_replication_exists":"yes (multiple independent meta-analyses reach similar estimates)","conflict_notes":"Authors declare relationships with the drug's manufacturer: AstraZeneca (originally Amylin/Eli Lilly)","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":40,"follow_up":"26 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 present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 40, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 40, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"26 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":"not reported in abstract","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim","author_conflicts":"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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":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":"{\"dose\": \"0.54 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":6749,"follow_up":"6 months","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"56.3% female\", \"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\": 6749, \"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\": 6749, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"6 months\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"unknown","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"comparator\": \"sitagliptin\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":61,"follow_up":"6.5 years","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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 61, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": 61, \"randomization\": \"no\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"6.5 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% CI]: 77\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","funding_source":"Department of Health; British Heart Foundation","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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 halved body-fat percentage decrease vs either alone","confidence_interval":null,"p_value":null,"sample_size":195,"follow_up":"52 weeks","direction":"benefit","population":"{\"mean_age\": null, \"age_range\": \"18-65\", \"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\", \"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], -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":"Novo Nordisk Foundation","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"After a low-calorie diet, exercise plus liraglutide kept weight off best over a year and was the only strategy that improved fitness, HbA1c and insulin sensitivity. Liraglutide alone was associated with more gallstones and higher heart rate.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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\": 30.0, \"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) showed lean mass fell alongside fat mass.","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":"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\": \"unknown\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI], -13\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"Landmark trial: semaglutide 2.4 mg produced 15% weight loss over 68 weeks in adults with obesity. Included for context and for its body-composition substudy showing proportional lean-mass loss.","methodological_notes":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":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":"{}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"24 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\": \"type 2 diabetes present (all or most)\", \"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\": \"not stated\", \"follow_up_duration\": \"24 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] 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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"route\": \"subcutaneous\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"body_composition\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":108,"follow_up":"18 years","direction":"unclear","population":"{\"mean_age\": null, \"age_range\": null, \"age_min\": 18.0, \"sex_distribution\": null, \"bmi_mean\": null, \"bmi_min\": null, \"obesity_status\": \"not reported\", \"diabetes_status\": \"type 1 diabetes\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 108, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age ≥18). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","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\": \"18 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI] -3\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"yes\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"The study was partly funded by AstraZeneca","industry_funded":"yes","manufacturer":"AstraZeneca","author_conflicts":"not available in metadata","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: AstraZeneca (originally Amylin/Eli Lilly)","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"cardiovascular\", \"cerebrovascular\", \"metabolic\"]","outcome_type":"hard","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":469,"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\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 469, \"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\": 469, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"not stated\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI] =1\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"comparator\": \"insulin\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":66,"follow_up":"52 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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 66, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 66, \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"52 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"not reported in abstract","industry_funded":"unclear","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"neuroinflammation\", \"immune\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"6 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\": \"type 1 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":"UNKNOWN","applicability_rationale":"[Auto] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"6 weeks\", \"outcome_type\": \"biomarker\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"UNKNOWN\", \"statistical_precision\": \"CI reported: 95% confidence interval [CI]: -38\", \"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":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"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.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"crossover_trial","drugs":"[\"liraglutide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","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\": \"diabetes mentioned\", \"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] Participants had 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\": \"Crossover trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"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\": \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":"{\"dose\": \"1.5 mg once weekly\", \"route\": \"subcutaneous\", \"treatment_duration\": \"median 5.4 years\", \"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)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 4949, \"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 CVOT (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).","adjusted_for":"[]","evidence_level":"HIGH","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 4949, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"50 years\", \"outcome_type\": \"mixed\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% CI 0·79-0·99\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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 in the class; still confined to diabetes.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+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":"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 present (all or most)\", \"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":"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":"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"unknown","drugs":"[\"semaglutide\"]","drug_details":"{\"dose\": \"1.0 mg/week\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":"biomarker","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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"UNKNOWN","applicability_rationale":"[Auto] Review/guidance/regulatory document rather than a primary study; applicability depends on the underlying studies.","mediation":"not_applicable","mediation_notes":"[Auto] Not a primary outcome study.","adjusted_for":"[\"body weight\"]","evidence_level":"NOT_RATED","evidence_components":"{\"study_design\": \"Unknown\", \"sample_size\": \"not extracted\", \"randomization\": \"no\", \"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\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"partial\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Review, guidance, regulatory document or model without new primary outcome data.","funding_source":"NCATS NIH HHS; Novo Nordisk","industry_funded":"partial","manufacturer":"Novo Nordisk","author_conflicts":"not available in metadata","sponsor_role":"mixed industry and public/foundation funding","independent_replication_exists":"unknown","conflict_notes":"Authors declare relationships with the drug's manufacturer: Novo Nordisk","adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"dulaglutide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":25,"follow_up":"52 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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 25, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 25, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"52 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":"not reported in abstract","industry_funded":"unclear","manufacturer":null,"author_conflicts":"The authors declare that they have no conflicts of interest.","sponsor_role":"not reported in abstract","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"treatment_duration\": \"26 weeks\", \"comparator\": \"glimepiride\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":23,"follow_up":"26 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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 23, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 23, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"26 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"route\": \"subcutaneous\"}","domains":"[\"inflammation\", \"body_composition\", \"metabolic\"]","outcome_type":"mixed","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\": \"obesity/overweight present (all or most)\", \"diabetes_status\": \"diabetes mentioned\", \"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] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"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\": \"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":"Ministero dell'Istruzione, dell'Università e della Ricerca","industry_funded":"unclear","manufacturer":"Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Sanofi","author_conflicts":"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.","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"meta_analysis","drugs":"[\"liraglutide\", \"exenatide\"]","drug_details":"{}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","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\": \"type 2 diabetes present (all or most)\", \"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\": \"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 -3\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] This meta-analysis suggests that GLP-1 RAs therapy causes a significant reduction in CRP.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"crossover_trial","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"30 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":32,"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\": \"not reported\", \"diabetes_status\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 32, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Crossover trial\", \"sample_size\": 32, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"12 weeks\", \"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] 3\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"kidney\", \"muscle\", \"body_composition\", \"liver\", \"addiction\", \"metabolic\", \"adverse_effects\", \"psychiatric\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"24 weeks","direction":"mixed","population":"{\"mean_age\": 59.0, \"age_range\": null, \"age_min\": null, \"sex_distribution\": \"53% female\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (mean age 59).","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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"open-label\", \"comparator\": \"not stated\", \"follow_up_duration\": \"24 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:56+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"route\": \"subcutaneous\"}","domains":"[\"inflammation\", \"body_composition\", \"immune\", \"cancer\", \"metabolic\", \"adverse_effects\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":22,"follow_up":"4 months","direction":"null","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 22, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 22, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"4 months\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":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":"{\"treatment_duration\": \"3 months\", \"comparator\": \"acarbose\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":36,"follow_up":"3 months","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\": \"diabetes mentioned\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 36, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had 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\": \"Randomized controlled trial\", \"sample_size\": 36, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"3 months\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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%); 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\": \"chronic kidney disease\", \"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":"Authors report Novo Nordisk 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: Novo Nordisk","adverse_events":"Retinopathy complications HR 1.76 (1.11-2.78); GI discontinuations higher.","limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"In 3,297 people with type 2 diabetes, semaglutide lowered cardiovascular events over two years but increased diabetic retinopathy complications. Context for the retinopathy safety topic; not applicable outside diabetes.","methodological_notes":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":2,"assessed_by":"curated","assessed_at":"2026-09-13T14:16:42+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)\", \"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":"Modest weight loss (~2.3 kg) and HbA1c reduction; mediation analyses in later publications suggested benefit not fully explained by these factors.","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\": \"3.8 years\", \"outcome_type\": \"hard\", \"replication\": \"not assessed (auto)\", \"consistency_with_other_evidence\": \"not assessed (auto)\", \"population_applicability\": \"INDIRECT\", \"statistical_precision\": \"CI reported: 95% confidence interval of the hazard ratio\", \"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","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) and death over 3.8 years. Context for later trials; not applicable to people without diabetes.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"meta_analysis","drugs":"[\"semaglutide\", \"dulaglutide\", \"exenatide\", \"albiglutide\"]","drug_details":"{\"dose\": \"20 mg\", \"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":21126,"follow_up":"24 weeks of follow-up","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\": 21126, \"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\": 21126, \"randomization\": \"n/a\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"24 weeks of follow-up\", \"outcome_type\": \"mixed\", \"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"1.7 mg\", \"treatment_duration\": \"36 months\", \"comparator\": \"glimepiride\"}","domains":"[\"inflammation\", \"cardiovascular\", \"mortality\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":515,"follow_up":"36 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\", \"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\": 515, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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":"MODERATE","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": 515, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"36 months\", \"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\"}","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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{\"treatment_duration\": \"26 weeks\", \"comparator\": \"insulin glargine\"}","domains":"[\"inflammation\", \"cardiovascular\", \"body_composition\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"26 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\", \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"active comparator\", \"follow_up_duration\": \"26 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"route\": \"subcutaneous\"}","domains":"[\"inflammation\", \"body_composition\", \"liver\", \"cancer\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"1.7 years","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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"1.7 years\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":"{\"treatment_duration\": \"12 weeks\", \"comparator\": \"metformin\"}","domains":"[\"inflammation\", \"liver\", \"addiction\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 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\": \"type 2 diabetes present (all or most)\", \"cvd_status\": \"not reported\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": \"MASH / MASLD\", \"sample_size\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.8 mg\", \"treatment_duration\": \"14 weeks\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":68,"follow_up":"8 years","direction":"benefit","population":"{\"mean_age\": 58.0, \"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\": \"diabetes mentioned\", \"cvd_status\": \"cardiovascular disease present in population (see abstract)\", \"ckd_status\": \"not reported\", \"metabolic_syndrome\": \"not reported\", \"baseline_condition\": null, \"sample_size\": 68, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight (mean age 58).","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\": \"Randomized controlled trial\", \"sample_size\": 68, \"randomization\": \"yes\", \"blinding\": \"double-blind\", \"comparator\": \"placebo\", \"follow_up_duration\": \"8 years\", \"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\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NCATS NIH HHS; NIDDK NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 months","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\": null, \"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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"treatment_duration\": \"12 months\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":174,"follow_up":"2 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\", \"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\": 174, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 174, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"2 months\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] Exenatide is effective not only on glycaemic control, but also in protecting β-cells and in reducing inflammation.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"liraglutide\"]","drug_details":"{\"dose\": \"1.2 mg\"}","domains":"[\"inflammation\", \"cardiovascular\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"65 years","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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"65 years\", \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract conclusions] In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"45.7 mg\", \"comparator\": \"metformin\"}","domains":"[\"inflammation\", \"metabolic\"]","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\": 58.5, \"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\": null, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had obesity/overweight without diabetes (mean age 58.5); effects may be mediated by weight loss.","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\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"open-label\", \"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\": \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"9 mg\", \"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"alzheimers\", \"metabolic\"]","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\": \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"specifically_tested","mediation_notes":"[Auto] Abstract addresses weight-loss independence: \"This effect was independent of weight loss.\"","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"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\": \"UNKNOWN\", \"statistical_precision\": \"not extracted\", \"risk_of_bias\": \"not assessed (auto)\", \"funding_conflicts\": \"no\", \"peer_review_status\": \"yes\"}","evidence_rationale":"[Auto] Small or short randomized trial (auto-provisional).","funding_source":"NIDDK NIH HHS","industry_funded":"no","manufacturer":null,"author_conflicts":"not available in metadata","sponsor_role":"no manufacturer funding identified","independent_replication_exists":"unknown","conflict_notes":null,"adverse_events":null,"limitations":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"3000 mg\", \"treatment_duration\": \"12 months\"}","domains":"[\"inflammation\", \"cancer\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 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\", \"diabetes_status\": \"diabetes mentioned\", \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"outcome_type\": \"biomarker\", \"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":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; last sentences of abstract] 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"comparator\": \"placebo\"}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":12,"follow_up":"4 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\", \"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\": 12, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 12, \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"placebo\", \"follow_up_duration\": \"4 weeks\", \"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\"}","evidence_rationale":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null},{"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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{}","domains":"[\"inflammation\", \"cardiovascular\", \"lean_mass\", \"body_composition\", \"metabolic\"]","outcome_type":"mixed","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":69,"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\": 69, \"inclusion_exclusion\": null, \"healthy_volunteers\": false, \"normal_weight_included\": false, \"notes\": []}","applicability":"INDIRECT","applicability_rationale":"[Auto] Participants had type 2 diabetes (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\": \"Randomized controlled trial\", \"sample_size\": 69, \"randomization\": \"yes\", \"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\": \"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":"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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":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":1,"assessed_by":"auto:auto-classifier-v1","assessed_at":"2026-09-13T15:20:57+00:00","study_design":"rct","drugs":"[\"exenatide\"]","drug_details":"{\"dose\": \"2.5 mg\", \"comparator\": \"glibenclamide\"}","domains":"[\"inflammation\", \"metabolic\"]","outcome_type":"biomarker","primary_outcome":null,"endpoints":null,"effect_estimate":null,"confidence_interval":null,"p_value":null,"sample_size":null,"follow_up":"12 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\", \"diabetes_status\": \"diabetes mentioned\", \"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] Population characteristics not extractable from abstract (age/BMI not reported in abstract). Needs manual review.","mediation":"unknown","mediation_notes":"[Auto] Not addressed in abstract.","adjusted_for":"[]","evidence_level":"LOW","evidence_components":"{\"study_design\": \"Randomized controlled trial\", \"sample_size\": \"not extracted\", \"randomization\": \"yes\", \"blinding\": \"not stated\", \"comparator\": \"not stated\", \"follow_up_duration\": \"12 months\", \"outcome_type\": \"biomarker\", \"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":"[Auto] Small or short randomized trial (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":"Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.","plain_summary":"[Auto, unreviewed; quoted from abstract 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.","methodological_notes":null}]