State of the research: 2026-09

# Research-state review — 2026-09 Generated 2026-09-13T14:18:53+00:00 from the local evidence database. Every statement below cites a record number; open the record for provenance, funding and the full assessment. Auto-classified records are labelled as unreviewed in the database. > Scope reminder: this review assesses evidence about GLP-1 receptor agonists and related incretin therapies. It does not assess whether any therapy would benefit a specific person, and it does not recommend treatment. ## Claim status overview | Claim | Status | Trend | Change since last synthesis | |---|---|---|---| | GLP-1 receptor agonists reduce alcohol and other substance use. | PRELIMINARY_SIGNAL | strengthening | new | | GLP-1 receptor agonists slow biological aging or extend healthspan in humans. | MECHANISTIC_ONLY | stable | new | | GLP-1 receptor agonists slow clinical progression of Alzheimer's disease. | NOT_SUPPORTED | weakening | new | | GLP-1 receptor agonist treatment reduces bone mineral density. | PRELIMINARY_SIGNAL | stable | new | | GLP-1 receptor agonists increase the risk of thyroid cancer in humans. | CONTRADICTORY | weakening | new | | GLP-1 receptor agonists reduce the incidence of obesity-associated cancers. | PRELIMINARY_SIGNAL | unclear | new | | The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss. | PROBABLE | strengthening | new | | GLP-1 receptor agonists reduce cardiovascular events in people without obesity or established cardiovascular disease. | INSUFFICIENT_EVIDENCE | stable | new | | Incretin therapies improve outcomes in heart failure with preserved ejection fraction and obesity. | ESTABLISHED | stable | new | | GLP-1 receptor agonist therapy provides a net clinical benefit to healthy normal-weight adults aged 55-75. | INSUFFICIENT_EVIDENCE | stable | new | | GLP-1 receptor agonist treatment reduces the risk of developing dementia. | CONTRADICTORY | weakening | new | | Stopping GLP-1 therapy leads to regain of most lost weight and reversal of cardiometabolic improvements. | ESTABLISHED | stable | new | | GLP-1 receptor agonists cause serious gastrointestinal and biliary adverse events. | ESTABLISHED | stable | new | | GLP-1 receptor agonists reduce systemic inflammation independent of weight loss. | PLAUSIBLE_UNPROVEN | strengthening | new | | GLP-1 receptor agonists protect kidney function in people without diabetes. | PROBABLE | strengthening | new | | GLP-1-induced weight loss causes clinically meaningful loss of muscle mass or function. | PLAUSIBLE_UNPROVEN | stable | new | | Semaglutide improves liver histology in MASH with fibrosis. | ESTABLISHED | stable | new | | Semaglutide increases the risk of non-arteritic anterior ischaemic optic neuropathy (NAION). | EVIDENCE_OF_HARM | strengthening | new | | GLP-1 receptor agonists reduce osteoarthritis pain through mechanisms beyond weight loss. | INSUFFICIENT_EVIDENCE | stable | new | | GLP-1 receptor agonists slow progression of Parkinson's disease. | CONTRADICTORY | weakening | new | | GLP-1 receptor agonists increase suicidal ideation or suicide. | NOT_SUPPORTED | weakening | new | | GLP-1 receptor agonists alter the risk of autoimmune disease. | PRELIMINARY_SIGNAL | unclear | new | ## Inflammation - **Records:** 19 (human studies: 15). Evidence levels: MODERATE 4, LOW 9, VERY_LOW 2, PRELIMINARY 2, NOT_RATED 2. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 12, VERY_INDIRECT 4, UNKNOWN 3. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (Circulation, 2026; PMID 42610271; record #40) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation specifically_tested, industry funded: yes - Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (The New England journal of medicine, 2023; PMID 37622681; record #3) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation likely, industry funded: yes - Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (The New England journal of medicine, 2024; PMID 38912654; record #5) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation likely, industry funded: yes **Strongest contradictory or null evidence:** - 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 (Frontiers in endocrinology, 2026; PMID 42698481; record #94) — LOW, Retrospective cohort, direction mixed - 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 (Diabetes, obesity & metabolism, 2023; PMID 36306151; record #25) — LOW, Randomized controlled trial, direction mixed - 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 (Journal of diabetes and its complications, 2026; PMID 42679726; record #112) — LOW, Randomized controlled trial, direction mixed **Claims in this domain:** - GLP-1 receptor agonists reduce systemic inflammation independent of weight loss. → **PLAUSIBLE_UNPROVEN** (strengthening). Biomarker reductions (CRP/hs-CRP, MCP-1, adiponectin) are consistent across trials in obesity and type 2 diabetes. Two lines of evidence suggest partial weight-independence: hs-CRP fell within 4-8 weeks in SELECT, before major weight loss and among non-losers; liraglutide but not diet lowered MCP-1 at matched weight loss (small trial). No study exists in normal-weight people, and CRP is a biomarker, not a clinical outcome. **Unresolved questions:** - Are the anti-inflammatory effects of GLP-1 receptor agonists independent of weight loss, and do they occur in people without excess adiposity? (open) - Is there clinically meaningful neuroprotection (dementia, Parkinson's) in humans? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Cardiovascular - **Records:** 71 (human studies: 56). Evidence levels: HIGH 8, MODERATE 21, LOW 22, PRELIMINARY 5, NOT_RATED 15. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 50, UNKNOWN 19, VERY_INDIRECT 2. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials (The lancet. Diabetes & endocrinology, 2025; PMID 39608381; record #34) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - 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 (The lancet. Diabetes & endocrinology, 2021; PMID 34425083; record #13) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England journal of medicine, 2023; PMID 37952131; record #1) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes **Strongest contradictory or null evidence:** - Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (The New England journal of medicine, 2025; PMID 41406444; record #59) — HIGH, Randomized controlled trial, direction mixed - Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis (PeerJ, 2026; PMID 42729958; record #121) — MODERATE, Meta-analysis, direction harm - Tirzepatide and the Incidence of Atrial Fibrillation in Adults With Overweight or Obesity: An Updated Meta-Analysis of Randomized Controlled Trials (Journal of the American Heart Association, 2026; PMID 42714458; record #138) — MODERATE, Meta-analysis, direction null **Claims in this domain:** - The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss. → **PROBABLE** (strengthening). In SELECT (obesity + CVD, no diabetes) MACE reduction was consistent across baseline weight categories and showed no linear relationship with early weight loss; an estimated 33% of benefit was mediated via waist reduction. Class-wide CVOTs in type 2 diabetes show similar relative reductions with modest weight loss. This supports mechanisms beyond adiposity in people who already have obesity and atherosclerotic disease; it does not show benefit in people without excess adiposity. - GLP-1 receptor agonists reduce cardiovascular events in people without obesity or established cardiovascular disease. → **INSUFFICIENT_EVIDENCE** (stable). No outcome trial has enrolled such a population. REWIND included T2D participants without prior CVD (benefit similar), but all had diabetes. The umbrella review found no significant MACE benefit in those without baseline CVD. - Incretin therapies improve outcomes in heart failure with preserved ejection fraction and obesity. → **ESTABLISHED** (stable). STEP-HFpEF (symptoms, 6-minute walk, CRP) and SUMMIT (CV death or worsening HF, HR 0.62) in people with BMI >= 30. Not applicable to HFpEF without obesity; SELECT HF subgroup analysis also positive. **Unresolved questions:** - Are the cardiovascular effects independent of obesity? (partially_answered) - Is there an effective dose for non-weight indications below weight-loss doses? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Kidney - **Records:** 50 (human studies: 30). Evidence levels: HIGH 4, MODERATE 6, LOW 16, VERY_LOW 1, PRELIMINARY 3, NOT_RATED 20. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 27, UNKNOWN 23. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials (The lancet. Diabetes & endocrinology, 2025; PMID 39608381; record #34) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - 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 (The lancet. Diabetes & endocrinology, 2021; PMID 34425083; record #13) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (The New England journal of medicine, 2025; PMID 40162642; record #35) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes **Strongest contradictory or null evidence:** - Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (The New England journal of medicine, 2016; PMID 27633186; record #11) — MODERATE, Randomized controlled trial, direction mixed - Safety and Glycemic Efficacy of Perioperative Liraglutide in Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (Cardiology in review, 2026; PMID 42693519; record #181) — MODERATE, Meta-analysis, direction null - Cardiorenal Protection in Type 2 Diabetes: A Systematic Review Comparing Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors (Cureus, 2026; PMID 42724505; record #130) — MODERATE, Systematic review, direction mixed **Claims in this domain:** - GLP-1 receptor agonists protect kidney function in people without diabetes. → **PROBABLE** (strengthening). FLOW established kidney protection in type 2 diabetes with CKD. In SELECT (no diabetes, obesity + CVD) a composite kidney endpoint was reduced (HR 0.78) and eGFR decline was slower; a meta-analysis found effects consistent with the diabetes trials. Evidence in normal-weight people without CVD does not exist. Body-composition changes did not distort GFR estimates in the small SMART trial. **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Dementia - **Records:** 8 (human studies: 8). Evidence levels: HIGH 1, LOW 5, VERY_LOW 1, PRELIMINARY 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 6, PARTIAL 2. Records rated DIRECT or PARTIAL: 2. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis (JAMA neurology, 2025; PMID 40193122; record #22) — LOW, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss (npj metabolic health and disease, 2026; PMID 42680805; record #195) — LOW, Retrospective cohort, applicability INDIRECT, mediation specifically_tested, industry funded: unclear - GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias (JAMA neurology, 2025; PMID 40193118; record #21) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: no **Strongest contradictory or null evidence:** - 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 (Lancet (London, England), 2026; PMID 41865758; record #37) — HIGH, Randomized controlled trial, direction null - Mapping the effectiveness and risks of GLP-1 receptor agonists (Nature medicine, 2025; PMID 39833406; record #20) — LOW, Retrospective cohort, direction mixed - Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial (Nature medicine, 2026; PMID 41326666; record #38) — LOW, Randomized controlled trial, direction mixed **Claims in this domain:** - GLP-1 receptor agonist treatment reduces the risk of developing dementia. → **CONTRADICTORY** (weakening). Large observational cohorts in type 2 diabetes and a meta-analysis of RCT secondary outcomes suggest lower dementia incidence, but confounding by indication and healthy-user effects are plausible. The two phase 3 evoke trials found no slowing of progression in established early Alzheimer's disease, and ELAD (liraglutide) missed its primary endpoint. Prevention in cognitively normal people has not been tested in a randomized trial. **Unresolved questions:** - Is there clinically meaningful neuroprotection (dementia, Parkinson's) in humans? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Alzheimer's disease - **Records:** 6 (human studies: 5). Evidence levels: HIGH 1, LOW 2, VERY_LOW 2, PRELIMINARY 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 3, VERY_INDIRECT 1, PARTIAL 2. Records rated DIRECT or PARTIAL: 2. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias (JAMA neurology, 2025; PMID 40193118; record #21) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: no - 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 (Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024; PMID 39445596; record #43) — VERY_LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: no **Strongest contradictory or null evidence:** - 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 (Lancet (London, England), 2026; PMID 41865758; record #37) — HIGH, Randomized controlled trial, direction null - Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial (Nature medicine, 2026; PMID 41326666; record #38) — LOW, Randomized controlled trial, direction mixed **Claims in this domain:** - GLP-1 receptor agonists slow clinical progression of Alzheimer's disease. → **NOT_SUPPORTED** (weakening). Two adequately powered phase 3 trials (evoke, evoke+) were negative on the primary clinical endpoint; ELAD phase 2b was negative on its primary endpoint. **Unresolved questions:** - Is there clinically meaningful neuroprotection (dementia, Parkinson's) in humans? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Parkinson's disease - **Records:** 3 (human studies: 3). Evidence levels: HIGH 1, MODERATE 1, LOW 1. - **Applicability to healthy normal-weight adults 55-75:** PARTIAL 3. Records rated DIRECT or PARTIAL: 3. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Trial of Lixisenatide in Early Parkinson's Disease (The New England journal of medicine, 2024; PMID 38598572; record #9) — LOW, Randomized controlled trial, applicability PARTIAL, mediation unlikely, industry funded: no **Strongest contradictory or null evidence:** - 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 (Lancet (London, England), 2025; PMID 39919773; record #8) — HIGH, Randomized controlled trial, direction null - Efficacy and safety of GLP-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis of randomized clinical trials (Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2026; PMID 42105060; record #51) — MODERATE, Meta-analysis, direction null **Claims in this domain:** - GLP-1 receptor agonists slow progression of Parkinson's disease. → **CONTRADICTORY** (weakening). A phase 2 trial of lixisenatide showed less motor progression at 12 months, but the largest and longest trial (exenatide, phase 3, 96 weeks) found no benefit, and a 2026 meta-analysis of RCTs found no consistent benefit. **Unresolved questions:** - Is there clinically meaningful neuroprotection (dementia, Parkinson's) in humans? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Cognition - **Records:** 11 (human studies: 9). Evidence levels: HIGH 2, MODERATE 1, LOW 4, VERY_LOW 4. - **Applicability to healthy normal-weight adults 55-75:** VERY_INDIRECT 2, INDIRECT 4, UNKNOWN 2, PARTIAL 3. Records rated DIRECT or PARTIAL: 3. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis (JAMA neurology, 2025; PMID 40193122; record #22) — LOW, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss (npj metabolic health and disease, 2026; PMID 42680805; record #195) — LOW, Retrospective cohort, applicability INDIRECT, mediation specifically_tested, industry funded: unclear - GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias (JAMA neurology, 2025; PMID 40193118; record #21) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: no **Strongest contradictory or null evidence:** - 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 (Lancet (London, England), 2026; PMID 41865758; record #37) — HIGH, Randomized controlled trial, direction null - 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 (Lancet (London, England), 2025; PMID 39919773; record #8) — HIGH, Randomized controlled trial, direction null - Neuropsychiatric Effects of Glucagon-Like Peptide-1 Receptor Agonists in Schizophrenia-Spectrum Disorders: A Systematic Review (Cureus, 2026; PMID 42725235; record #128) — MODERATE, Systematic review, direction mixed **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Osteoarthritis - **Records:** 3 (human studies: 3). Evidence levels: MODERATE 2, PRELIMINARY 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 3. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis (The New England journal of medicine, 2024; PMID 39476339; record #7) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation likely, industry funded: yes **Strongest contradictory or null evidence:** - none recorded **Claims in this domain:** - GLP-1 receptor agonists reduce osteoarthritis pain through mechanisms beyond weight loss. → **INSUFFICIENT_EVIDENCE** (stable). STEP 9 showed large pain reduction in people with obesity (mean BMI 40) alongside 13.7% weight loss. Weight loss itself relieves knee OA pain, and no analysis separated the two. No data in normal-weight people with OA. **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Rheumatoid / inflammatory disease - **Records:** 3 (human studies: 3). Evidence levels: LOW 2, VERY_LOW 1. - **Applicability to healthy normal-weight adults 55-75:** UNKNOWN 1, INDIRECT 2. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Comparative outcomes for tirzepatide versus glucagon-like peptide-1 receptor agonists in patients with inflammatory bowel disease: a national propensity matched study (Intestinal research, 2026; PMID 42717572; record #76) — LOW, Retrospective cohort, applicability UNKNOWN, mediation unknown, industry funded: unclear **Strongest contradictory or null evidence:** - Mapping the effectiveness and risks of GLP-1 receptor agonists (Nature medicine, 2025; PMID 39833406; record #20) — LOW, Retrospective cohort, direction mixed - Autoimmune Disease Risk With GLP-1RA, DPP-4i, and SGLT2i Treatment in Patients With Diabetes (ACR open rheumatology, 2026; PMID 42415363; record #53) — VERY_LOW, Retrospective cohort, direction mixed **Claims in this domain:** - GLP-1 receptor agonists alter the risk of autoimmune disease. → **PRELIMINARY_SIGNAL** (unclear). A TriNetX target-trial emulation found no difference between GLP-1RA and SGLT2i; DPP-4i differed in both directions for specific diseases. Hypothesis-generating only. **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Muscle / sarcopenia - **Records:** 9 (human studies: 5). Evidence levels: MODERATE 2, LOW 3, NOT_RATED 4. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 5, VERY_INDIRECT 1, UNKNOWN 3. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - none recorded **Strongest contradictory or null evidence:** - Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial (Nature medicine, 2026; PMID 42260100; record #47) — LOW, Randomized controlled trial, direction mixed - Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART Trial (Clinical journal of the American Society of Nephrology : CJASN, 2026; PMID 42308057; record #46) — LOW, Randomized controlled trial, direction mixed - Low baseline HbA1c and reduced eGFR are associated with relatively unfavorable body recomposition after SGLT2 inhibitor therapy in type 2 diabetes (Frontiers in endocrinology, 2026; PMID 42723833; record #175) — LOW, Retrospective cohort, direction harm **Unresolved questions:** - What happens to lean mass and muscle function in normal-weight users? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Lean-mass loss - **Records:** 11 (human studies: 8). Evidence levels: HIGH 1, MODERATE 5, LOW 2, NOT_RATED 3. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 8, UNKNOWN 3. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Once-Weekly Semaglutide in Adults with Overweight or Obesity (The New England journal of medicine, 2021; PMID 33567185; record #42) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation not_applicable, industry funded: yes - Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined (The New England journal of medicine, 2021; PMID 33951361; record #27) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation not_applicable, industry funded: partial **Strongest contradictory or null evidence:** - Treatment strategies for functional hypogonadism in obese men: a systematic review and network meta-analysis (The journal of sexual medicine, 2026; PMID 42704281; record #204) — MODERATE, Meta-analysis, direction mixed - Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial (JAMA network open, 2024; PMID 38916894; record #26) — MODERATE, Randomized controlled trial, direction harm - Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial (Nature medicine, 2026; PMID 42260100; record #47) — LOW, Randomized controlled trial, direction mixed **Claims in this domain:** - GLP-1-induced weight loss causes clinically meaningful loss of muscle mass or function. → **PLAUSIBLE_UNPROVEN** (stable). Lean-mass loss accompanies weight loss with these drugs (roughly 15-60% of weight lost across studies), including in trials adding myostatin inhibition to preserve it. Whether this translates into reduced strength, function or fracture risk is not established; reviews argue it is often proportionate to weight loss. Data in normal-weight or older adults, who have less fat to lose and higher sarcopenia risk, are absent. **Unresolved questions:** - What is the risk-benefit balance in normal-weight adults aged 55-75? (open) - What happens to lean mass and muscle function in normal-weight users? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Bone - **Records:** 7 (human studies: 6). Evidence levels: MODERATE 2, LOW 3, VERY_LOW 1, PRELIMINARY 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 5, UNKNOWN 1, VERY_INDIRECT 1. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (Clinical spine surgery, 2026; PMID 42683541; record #184) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial (JAMA network open, 2024; PMID 38916894; record #26) — MODERATE, Randomized controlled trial, direction harm - Vagal activity related events and glucagon-like peptide-1 receptor agonists (European heart journal. Cardiovascular pharmacotherapy, 2026; PMID 42709513; record #202) — LOW, Retrospective cohort, direction null - Preoperative GLP-1 receptor agonist use and outcomes after total hip arthroplasty: a matched cohort study (Hip international : the journal of clinical and experimental research on hip pathology and therapy, 2026; PMID 42725550; record #199) — LOW, Retrospective cohort, direction harm **Claims in this domain:** - GLP-1 receptor agonist treatment reduces bone mineral density. → **PRELIMINARY_SIGNAL** (stable). In S-LiTE, liraglutide alone was associated with lower hip and spine BMD than exercise alone after a year of weight maintenance; combining exercise with liraglutide preserved BMD. Fracture outcomes are not available. Effect likely reflects weight loss rather than a direct drug effect, but this was not separated. **Unresolved questions:** - What is the risk-benefit balance in normal-weight adults aged 55-75? (open) - What happens to lean mass and muscle function in normal-weight users? (open) - What happens with use measured in decades rather than years? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Liver / MASH - **Records:** 8 (human studies: 5). Evidence levels: HIGH 1, MODERATE 2, LOW 2, VERY_LOW 2, NOT_RATED 1. - **Applicability to healthy normal-weight adults 55-75:** VERY_INDIRECT 2, INDIRECT 4, UNKNOWN 2. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis (The New England journal of medicine, 2025; PMID 40305708; record #6) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes - Comparative Efficacy of Promising Targets in the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Steatohepatitis: A Systematic Review and Network Meta-analysis (Journal of clinical and translational hepatology, 2026; PMID 42724131; record #214) — MODERATE, Meta-analysis, applicability UNKNOWN, mediation unknown, industry funded: unclear - Association of GLP-1 Receptor Agonists Versus Other Antidiabetic Medications With Cardiovascular, Renal, and Liver Outcomes in Patients With Type 2 Diabetes (Diabetes, obesity & metabolism, 2026; PMID 42712110; record #141) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - 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 (Cureus, 2026; PMID 42677221; record #169) — MODERATE, Systematic review, direction mixed **Claims in this domain:** - Semaglutide improves liver histology in MASH with fibrosis. → **ESTABLISHED** (stable). ESSENCE part 1 (n=800 analysed): steatohepatitis resolution 62.9% vs 34.3%, fibrosis improvement 36.8% vs 22.4% at 72 weeks. Participants had MASH and mostly obesity; benefit may be partly weight mediated. Clinical outcomes (cirrhosis, decompensation) awaited in part 2. **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Immune function - **Records:** 15 (human studies: 7). Evidence levels: MODERATE 2, LOW 3, VERY_LOW 1, PRELIMINARY 1, NOT_RATED 8. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 4, UNKNOWN 10, VERY_INDIRECT 1. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - none recorded **Strongest contradictory or null evidence:** - Safety and Glycemic Efficacy of Perioperative Liraglutide in Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (Cardiology in review, 2026; PMID 42693519; record #181) — MODERATE, Meta-analysis, direction null - Cardiorenal Protection in Type 2 Diabetes: A Systematic Review Comparing Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors (Cureus, 2026; PMID 42724505; record #130) — MODERATE, Systematic review, direction mixed - Mapping the effectiveness and risks of GLP-1 receptor agonists (Nature medicine, 2025; PMID 39833406; record #20) — LOW, Retrospective cohort, direction mixed **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Cancer - **Records:** 26 (human studies: 9). Evidence levels: HIGH 2, LOW 3, VERY_LOW 2, PRELIMINARY 2, NOT_RATED 17. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 9, UNKNOWN 17. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (The lancet. Diabetes & endocrinology, 2021; PMID 34425083; record #13) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Impact of GLP-1 receptor agonists on patients with intraductal papillary mucinous neoplasms: Study protocol for a multicentric cohort study (PloS one, 2026; PMID 42715243; record #225) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: unclear - Associations Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Cancer Risk: A Systematic Review and Meta-Analysis (Cancer control : journal of the Moffitt Cancer Center, 2026; PMID 42677883; record #168) — LOW, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - 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 (JAMA internal medicine, 2022; PMID 35344001; record #39) — HIGH, Meta-analysis, direction harm - Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study (BMJ (Clinical research ed.), 2024; PMID 38683947; record #18) — LOW, Retrospective cohort, direction null - GLP-1 Receptor Agonists and the Risk of Thyroid Cancer (Diabetes care, 2023; PMID 36356111; record #19) — VERY_LOW, Case-control, direction harm **Claims in this domain:** - GLP-1 receptor agonists increase the risk of thyroid cancer in humans. → **CONTRADICTORY** (weakening). Rodent C-cell tumours underlie the boxed warning. A French case-control analysis found increased thyroid and medullary cancer with 1-3 years' use, but a larger Scandinavian active-comparator cohort found no increase (HR 0.93, upper CI 1.31). Detection bias is a concern in the positive study; follow-up remains short for a slow-growing cancer. - GLP-1 receptor agonists reduce the incidence of obesity-associated cancers. → **PRELIMINARY_SIGNAL** (unclear). A large EHR cohort in type 2 diabetes found lower incidence of 10 of 13 obesity-associated cancers versus insulin, with weaker or null results versus metformin. Observational, susceptible to confounding by indication and surveillance differences; no randomized cancer-outcome data. **Unresolved questions:** - What happens with use measured in decades rather than years? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Addiction / reward - **Records:** 9 (human studies: 7). Evidence levels: MODERATE 1, LOW 6, VERY_LOW 1, NOT_RATED 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 4, VERY_INDIRECT 1, UNKNOWN 2, PARTIAL 2. Records rated DIRECT or PARTIAL: 2. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (Addiction (Abingdon, England), 2025; PMID 39415416; record #56) — LOW, Retrospective cohort, applicability PARTIAL, mediation unlikely, industry funded: no - Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial (JAMA psychiatry, 2025; PMID 39937469; record #23) — LOW, Randomized controlled trial, applicability PARTIAL, mediation unlikely, industry funded: no **Strongest contradictory or null evidence:** - 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 (Cureus, 2026; PMID 42677221; record #169) — MODERATE, Systematic review, direction mixed - Mapping the effectiveness and risks of GLP-1 receptor agonists (Nature medicine, 2025; PMID 39833406; record #20) — LOW, Retrospective cohort, direction mixed - Impact of GLP-1 Dose Intensity on Perioperative and Long-Term Fusion Outcomes Following ACDF (The spine journal : official journal of the North American Spine Society, 2026; PMID 42705550; record #230) — LOW, Retrospective cohort, direction null **Claims in this domain:** - GLP-1 receptor agonists reduce alcohol and other substance use. → **PRELIMINARY_SIGNAL** (strengthening). A small phase 2 RCT (n=48, 9 weeks, low doses) reduced laboratory alcohol self-administration, craving and drinks per drinking day. Large observational cohorts show lower opioid overdose and alcohol intoxication rates. No phase 3 trial has reported; the RCT population was young and not selected for weight. **Unresolved questions:** - Is there an effective dose for non-weight indications below weight-loss doses? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Biological aging - **Records:** 9 (human studies: 4). Evidence levels: MODERATE 2, LOW 1, VERY_LOW 2, NOT_RATED 4. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 2, UNKNOWN 4, VERY_INDIRECT 3. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Diabetes, Adiposity, and Functional Phenotypes in HFpEF: A Systematic Review of Recent Treatment-Response Evidence (Cureus, 2026; PMID 42729808; record #123) — MODERATE, Systematic review, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - none recorded **Claims in this domain:** - GLP-1 receptor agonists slow biological aging or extend healthspan in humans. → **MECHANISTIC_ONLY** (stable). Reviews describe mitochondrial, senescence and vascular-aging mechanisms and cite aged-mouse multi-omic data. No human trial has a prespecified aging endpoint; no epigenetic-clock or healthspan outcome trial exists. Mortality reductions in CVOTs occurred in high-risk diabetic or cardiovascular populations. **Unresolved questions:** - Is chronic GLP-1 receptor agonist use beneficial, neutral or harmful in metabolically healthy people? (open) - Do GLP-1 receptor agonists affect biological aging in humans? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Mortality - **Records:** 30 (human studies: 29). Evidence levels: HIGH 7, MODERATE 9, LOW 10, PRELIMINARY 3, NOT_RATED 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 23, UNKNOWN 6, VERY_INDIRECT 1. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials (The lancet. Diabetes & endocrinology, 2025; PMID 39608381; record #34) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - 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 (The lancet. Diabetes & endocrinology, 2021; PMID 34425083; record #13) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England journal of medicine, 2023; PMID 37952131; record #1) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes **Strongest contradictory or null evidence:** - Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (The New England journal of medicine, 2025; PMID 41406444; record #59) — HIGH, Randomized controlled trial, direction mixed - Neuropsychiatric Effects of Glucagon-Like Peptide-1 Receptor Agonists in Schizophrenia-Spectrum Disorders: A Systematic Review (Cureus, 2026; PMID 42725235; record #128) — MODERATE, Systematic review, direction mixed - Safety and Glycemic Efficacy of Perioperative Liraglutide in Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (Cardiology in review, 2026; PMID 42693519; record #181) — MODERATE, Meta-analysis, direction null **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Metabolic health - **Records:** 49 (human studies: 27). Evidence levels: HIGH 1, MODERATE 11, LOW 12, VERY_LOW 2, PRELIMINARY 3, NOT_RATED 20. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 20, VERY_INDIRECT 2, UNKNOWN 27. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Once-Weekly Semaglutide in Adults with Overweight or Obesity (The New England journal of medicine, 2021; PMID 33567185; record #42) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation not_applicable, industry funded: yes - Comparative Efficacy of Promising Targets in the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Steatohepatitis: A Systematic Review and Network Meta-analysis (Journal of clinical and translational hepatology, 2026; PMID 42724131; record #214) — MODERATE, Meta-analysis, applicability UNKNOWN, mediation unknown, industry funded: unclear - Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials (Cardiovascular diabetology. Endocrinology reports, 2026; PMID 42681675; record #166) — MODERATE, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - 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 (Clinical obesity, 2026; PMID 42670242; record #262) — MODERATE, Meta-analysis, direction mixed - Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension (Diabetes, obesity & metabolism, 2022; PMID 35441470; record #29) — MODERATE, Randomized controlled trial, direction harm - 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 (Diabetes, obesity & metabolism, 2026; PMID 42723273; record #244) — MODERATE, Umbrella review, direction mixed **Unresolved questions:** - Is chronic GLP-1 receptor agonist use beneficial, neutral or harmful in metabolically healthy people? (open) - Is there an effective dose for non-weight indications below weight-loss doses? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Adverse effects / safety - **Records:** 68 (human studies: 57). Evidence levels: HIGH 4, MODERATE 19, LOW 19, VERY_LOW 11, PRELIMINARY 5, NOT_RATED 10. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 44, UNKNOWN 22, VERY_INDIRECT 1, PARTIAL 1. Records rated DIRECT or PARTIAL: 1. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials (The lancet. Diabetes & endocrinology, 2025; PMID 39608381; record #34) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - 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 (The lancet. Diabetes & endocrinology, 2021; PMID 34425083; record #13) — HIGH, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England journal of medicine, 2023; PMID 37952131; record #1) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes **Strongest contradictory or null evidence:** - 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 (JAMA internal medicine, 2022; PMID 35344001; record #39) — HIGH, Meta-analysis, direction harm - Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis (PeerJ, 2026; PMID 42729958; record #121) — MODERATE, Meta-analysis, direction harm - Treatment strategies for functional hypogonadism in obese men: a systematic review and network meta-analysis (The journal of sexual medicine, 2026; PMID 42704281; record #204) — MODERATE, Meta-analysis, direction mixed **Unresolved questions:** - What is the risk-benefit balance in normal-weight adults aged 55-75? (open) - What happens with use measured in decades rather than years? (open) - How large are rare irreversible harms (NAION, pancreatitis, obstruction) and are they dose-related? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Gastrointestinal - **Records:** 53 (human studies: 32). Evidence levels: HIGH 4, MODERATE 11, LOW 9, VERY_LOW 5, PRELIMINARY 3, NOT_RATED 21. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 26, UNKNOWN 26, PARTIAL 1. Records rated DIRECT or PARTIAL: 1. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England journal of medicine, 2023; PMID 37952131; record #1) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes - Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial (Lancet (London, England), 2019; PMID 31189511; record #12) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation possibly, industry funded: yes - Once-Weekly Semaglutide in Adults with Overweight or Obesity (The New England journal of medicine, 2021; PMID 33567185; record #42) — HIGH, Randomized controlled trial, applicability INDIRECT, mediation not_applicable, industry funded: yes **Strongest contradictory or null evidence:** - 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 (JAMA internal medicine, 2022; PMID 35344001; record #39) — HIGH, Meta-analysis, direction harm - Weight regain following discontinuation of glucagon-like peptide-1 receptor agonists in adults who are overweight or obese: a systematic review and meta-analysis (PeerJ, 2026; PMID 42729958; record #121) — MODERATE, Meta-analysis, direction harm - 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 (Clinical obesity, 2026; PMID 42670242; record #262) — MODERATE, Meta-analysis, direction mixed **Claims in this domain:** - GLP-1 receptor agonists cause serious gastrointestinal and biliary adverse events. → **ESTABLISHED** (stable). Gallbladder/biliary disease is increased in a meta-analysis of 76 RCTs (RR 1.37; higher with weight-loss doses, RR 2.29). Cohort data show increased pancreatitis, gastroparesis and bowel obstruction versus bupropion-naltrexone. The VA atlas adds drug-induced pancreatitis, nephrolithiasis and interstitial nephritis signals. GI intolerance drives discontinuation (16.6% vs 8.2% in SELECT). **Unresolved questions:** - How large are rare irreversible harms (NAION, pancreatitis, obstruction) and are they dose-related? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Psychiatric - **Records:** 11 (human studies: 9). Evidence levels: MODERATE 1, LOW 6, VERY_LOW 2, NOT_RATED 2. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 6, UNKNOWN 3, PARTIAL 2. Records rated DIRECT or PARTIAL: 2. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (Addiction (Abingdon, England), 2025; PMID 39415416; record #56) — LOW, Retrospective cohort, applicability PARTIAL, mediation unlikely, industry funded: no - Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss (npj metabolic health and disease, 2026; PMID 42680805; record #195) — LOW, Retrospective cohort, applicability INDIRECT, mediation specifically_tested, industry funded: unclear - Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial (JAMA psychiatry, 2025; PMID 39937469; record #23) — LOW, Randomized controlled trial, applicability PARTIAL, mediation unlikely, industry funded: no **Strongest contradictory or null evidence:** - Neuropsychiatric Effects of Glucagon-Like Peptide-1 Receptor Agonists in Schizophrenia-Spectrum Disorders: A Systematic Review (Cureus, 2026; PMID 42725235; record #128) — MODERATE, Systematic review, direction mixed - GLP-1 Receptor Agonist Use and Risk of Suicide Death (JAMA internal medicine, 2024; PMID 39226030; record #17) — LOW, Retrospective cohort, direction null - Association of semaglutide with risk of suicidal ideation in a real-world cohort (Nature medicine, 2024; PMID 38182782; record #16) — LOW, Retrospective cohort, direction null **Claims in this domain:** - GLP-1 receptor agonists increase suicidal ideation or suicide. → **NOT_SUPPORTED** (weakening). Pharmacovigilance reports prompted regulatory review. Two large cohorts (US EHR; Swedish/Danish registers with SGLT2i active comparator) found no increase in suicidal ideation or suicide death; the Nordic upper confidence limit excludes more than 0.16 extra deaths per 1,000 person-years. **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Ophthalmologic - **Records:** 18 (human studies: 6). Evidence levels: MODERATE 1, LOW 3, VERY_LOW 1, PRELIMINARY 1, NOT_RATED 12. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 5, UNKNOWN 13. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - none recorded **Strongest contradictory or null evidence:** - Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (The New England journal of medicine, 2016; PMID 27633186; record #11) — MODERATE, Randomized controlled trial, direction mixed - GLP1-RA Use and Risk of Non-arteritic Anterior Ischemic Optic Neuropathy in Patients with Type 2 Diabetes (Ophthalmology. Retina, 2026; PMID 42692107; record #236) — LOW, Retrospective cohort, direction harm - 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 (Frontiers in endocrinology, 2026; PMID 42698481; record #94) — LOW, Retrospective cohort, direction mixed **Claims in this domain:** - Semaglutide increases the risk of non-arteritic anterior ischaemic optic neuropathy (NAION). → **EVIDENCE_OF_HARM** (strengthening). A single-centre neuro-ophthalmology cohort first reported HR 4.28 (T2D) and higher in obesity; a 2026 meta-analysis of observational studies found HR ~2.2 with very low absolute risk (~1 extra case per 7,000 treated per year). The meta-analysis authors note consistency with regulatory communications. Observational evidence; causality not proven; rare but irreversible. **Unresolved questions:** - How large are rare irreversible harms (NAION, pancreatitis, obstruction) and are they dose-related? (open) **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Sleep - **Records:** 7 (human studies: 6). Evidence levels: MODERATE 2, LOW 2, PRELIMINARY 2, NOT_RATED 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 6, UNKNOWN 1. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - 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 (Frontiers in endocrinology, 2026; PMID 42676363; record #170) — MODERATE, Meta-analysis, applicability INDIRECT, mediation possibly, industry funded: unclear - Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (The New England journal of medicine, 2024; PMID 38912654; record #5) — MODERATE, Randomized controlled trial, applicability INDIRECT, mediation likely, industry funded: yes - Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss (npj metabolic health and disease, 2026; PMID 42680805; record #195) — LOW, Retrospective cohort, applicability INDIRECT, mediation specifically_tested, industry funded: unclear **Strongest contradictory or null evidence:** - GLP-1/GIP Uptake, Indication, and Access Pathways Among US Adults in the Understanding America Study (medrxiv (preprint), 2026; DOI 10.64898/2026.08.28.26361368; record #288) — PRELIMINARY, Prospective cohort, direction harm **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Other emerging indication - **Records:** 4 (human studies: 4). Evidence levels: LOW 3, PRELIMINARY 1. - **Applicability to healthy normal-weight adults 55-75:** INDIRECT 3, UNKNOWN 1. Records rated DIRECT or PARTIAL: 0. - **Confidence change since last synthesis:** first synthesis for this topic. **Strongest supporting evidence (benefit direction, by evidence level):** - Tirzepatide and the risk of asthma exacerbations in patients with type 2 diabetes (Frontiers in endocrinology, 2026; PMID 42712413; record #81) — LOW, Retrospective cohort, applicability INDIRECT, mediation possibly, industry funded: unclear **Strongest contradictory or null evidence:** - Association of Tirzepatide versus Semaglutide with Risk of Asthma Exacerbation in Patients with Asthma and Type 2 Diabetes: A US Multicenter Retrospective Cohort Study (Journal of asthma and allergy, 2026; PMID 42730051; record #272) — LOW, Retrospective cohort, direction null - 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 (preprint server, 2026; DOI 10.21203/rs.3.rs-10427939/v1; record #279) — PRELIMINARY, Retrospective cohort, direction mixed **Applicability note:** records rated DIRECT for the target population: 0. No direct evidence exists in this domain for healthy normal-weight older adults. ## Evidence shifts since previous synthesis - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: OZEMPIC, RYBELSUS (ORAL SEMAGLUTIDE) - label effective 2026-01-30 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Ozempic (SEMAGLUTIDE) - label effective 2026-07-30 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Ozempic (SEMAGLUTIDE) - label effective 2023-11-22 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: OZEMPIC (SEMAGLUTIDE) - label effective 2023-11-17 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: WEGOVY (SEMAGLUTIDE) - label effective 2024-04-23 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-11-13 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-10-16 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2025-01-30 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2026-07-27 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Liraglutide (LIRAGLUTIDE) - label effective 2026-01-30 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: TRULICITY (DULAGLUTIDE) - label effective 2023-08-05 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2026-06-16 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2023-12-12 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Trulicity (DULAGLUTIDE) - label effective 2023-12-09 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: TRULICITY (DULAGLUTIDE) - label effective 2023-05-03 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Byetta (EXENATIDE) - label effective 2025-09-02 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Exenatide (EXENATIDE) - label effective 2026-05-27 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Soliqua 100/33 (INSULIN GLARGINE AND LIXISENATIDE) - label effective 2026-03-18 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: MOUNJARO (TIRZEPATIDE) - label effective 2026-07-29 - [notable] regulatory_update: New or updated FDA label retrieved: FDA prescribing information: Zepbound, ZEPBOUND (TIRZEPATIDE) - label effective 2026-08-28 - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Normal-weight Diabetes: Adipocyte-directed Therapy With Pioglitazone or Tirzepatide - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Semaglutide for Helping Opioid Recovery - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Semaglutide for Post-Smoking Cessation Weight Management - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: GLP-1R Agonist Treatment for Opioid Use Disorder - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Cessation or Reduction of Alcohol Consumption in Veterans: A Randomized Controlled Trial for Alcohol Use Disorder (CRAVE) - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Mazdutide Plus LNG-IUS for Fertility-Sparing Treatment of AEH or Early Endometrial Cancer - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: A Clinical Trial to Evaluate The Effects of Semaglutide and Empagliflozin Combined to Automated Insulin Delivery on Diabetes Control in Adults Living With Type 1 Diabetes - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Effects of Semaglutide in HIV-Associated Lipohypertrophy - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: GLP-1 RA for Stage 1 Type 1 Diabetes - [notable] new_trial_non_obese_or_healthy: Registered trial in a non-obese or healthy population: Mirikizumab and Tirzepatide Administered in Adult Participants With Moderately to Severely Active Crohn's Disease and Obesity or Overweight