GLP-1 Evidence

Not medical advice. A record of published research and our assessments of it. The limits

State of the research: 2026-09

Written Sep 13, 2026 · Generated from the database; every statement cites a record number.

01Review

Correction, 19 October 2026

This review was generated on 13 September 2026 and is kept below exactly as published. Since then, a check of every record against its source changed some of what it relies on:

  • Unreviewed records. Most of the records this review counts and cites had only an automatic assessment. A check found about a quarter of the automatically extracted details false or unsupported, so the collection no longer publishes those records' study tier, population match, direction, mediation or funding until a person or a two-pass review has assessed them. Where this review gives those details for such a record, treat them as unchecked.
  • Study facts. Sample sizes, follow-up periods, doses and summaries were corrected on many records, quote by quote against the source.
  • Claim statuses. "GLP-1 receptor agonist treatment reduces the risk of developing dementia" is now Plausible, unproven (trend unclear), not Contradictory: the evoke trials treated established Alzheimer's disease and do not test prevention. "The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss" stays Probable, with its trend now stable. The claim that GLP-1 drugs reduce inflammatory markers beyond weight loss stays Plausible, unproven, with its trend now weakening. Several claim rationales were corrected.

Each record page and claim page shows the current assessment. From November, the monthly review counts and cites reviewed records only.

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

ClaimStatusTrendChange since last synthesis
GLP-1 receptor agonists reduce alcohol and other substance use.PRELIMINARY_SIGNALstrengtheningnew
GLP-1 receptor agonists slow biological aging or extend healthspan in humans.MECHANISTIC_ONLYstablenew
GLP-1 receptor agonists slow clinical progression of Alzheimer's disease.NOT_SUPPORTEDweakeningnew
GLP-1 receptor agonist treatment reduces bone mineral density.PRELIMINARY_SIGNALstablenew
GLP-1 receptor agonists increase the risk of thyroid cancer in humans.CONTRADICTORYweakeningnew
GLP-1 receptor agonists reduce the incidence of obesity-associated cancers.PRELIMINARY_SIGNALunclearnew
The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss.PROBABLEstrengtheningnew
GLP-1 receptor agonists reduce cardiovascular events in people without obesity or established cardiovascular disease.INSUFFICIENT_EVIDENCEstablenew
Incretin therapies improve outcomes in heart failure with preserved ejection fraction and obesity.ESTABLISHEDstablenew
GLP-1 receptor agonist therapy provides a net clinical benefit to healthy normal-weight adults aged 55-75.INSUFFICIENT_EVIDENCEstablenew
GLP-1 receptor agonist treatment reduces the risk of developing dementia.CONTRADICTORYweakeningnew
Stopping GLP-1 therapy leads to regain of most lost weight and reversal of cardiometabolic improvements.ESTABLISHEDstablenew
GLP-1 receptor agonists cause serious gastrointestinal and biliary adverse events.ESTABLISHEDstablenew
GLP-1 receptor agonists reduce systemic inflammation independent of weight loss.PLAUSIBLE_UNPROVENstrengtheningnew
GLP-1 receptor agonists protect kidney function in people without diabetes.PROBABLEstrengtheningnew
GLP-1-induced weight loss causes clinically meaningful loss of muscle mass or function.PLAUSIBLE_UNPROVENstablenew
Semaglutide improves liver histology in MASH with fibrosis.ESTABLISHEDstablenew
Semaglutide increases the risk of non-arteritic anterior ischaemic optic neuropathy (NAION).EVIDENCE_OF_HARMstrengtheningnew
GLP-1 receptor agonists reduce osteoarthritis pain through mechanisms beyond weight loss.INSUFFICIENT_EVIDENCEstablenew
GLP-1 receptor agonists slow progression of Parkinson's disease.CONTRADICTORYweakeningnew
GLP-1 receptor agonists increase suicidal ideation or suicide.NOT_SUPPORTEDweakeningnew
GLP-1 receptor agonists alter the risk of autoimmune disease.PRELIMINARY_SIGNALunclearnew

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