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1. Scope

Covered:

  • Use of GLP-1 RAs and the dual GIP/GLP-1 agonist tirzepatide (referred to collectively as “GLP-1–based therapies” where evidence is class-wide) for cardiometabolic risk reduction, weight management, glycaemic/prediabetes control and related metabolic endpoints in adults.
  • Longevity-relevant secondary signals: frailty progression, body composition/lean mass, and dementia risk.
  • Practical selection, dosing, monitoring, safety and clinic scenarios adjunctive to conventional primary/secondary care.

Not covered:

  • Paediatric use, type 1 diabetes, and detailed management of established type 2 diabetes (defer to ADA/NICE diabetes pathways).
  • Surgical (metabolic/bariatric) management, and non-incretin anti-obesity agents except for brief comparison.
  • Compounded/unlicensed “grey-market” semaglutide/tirzepatide, which should not be used.

Key framing: In a longevity clinic, most metabolic-health use outside licensed obesity/overweight-with-comorbidity or T2D indications is off-label. No GLP-1 RA is licensed for “anti-ageing”, lifespan extension, or use in metabolically healthy normal-weight adults. Genuine hard-outcome benefit (mortality, MACE) is established in populations with diabetes, established cardiovascular disease and/or obesity — not in low-risk, normal-weight individuals.

2. Background and pathophysiology

Biological rationale. GLP-1 is an incretin released post-prandially that suppresses appetite via the hypothalamus, delays gastric emptying, augments glucose-dependent insulin secretion, and suppresses glucagon (Elmaleh-Sachs et al., JAMA, 2023). Cardiometabolic ageing is driven by chronic low-grade inflammation, insulin resistance, visceral/ectopic adiposity, oxidative stress and mitochondrial dysfunction; type 2 diabetes accelerates biological ageing through these same pathways (Park et al., Diabetes Care/ADA, 2026). GLP-1 RAs act on several of these upstream drivers, giving mechanistic plausibility as “gerotherapeutics” (Forman et al., JACC, 2023).

Human mechanistic evidence (robust):

  • Consistent reductions in body weight, waist circumference, visceral adipose tissue, HbA1c, fasting glucose, systolic blood pressure, triglycerides and hs-CRP; improvement in hepatic steatosis (Ndumele et al., AHA/ACC/ADA/ASN, 2026; Sawicka-Gutaj et al., Int J Obes, 2026; Abushamat et al., Clin Gastroenterol Hepatol, 2024).
  • Improved muscle quality (reduced intramuscular fat infiltration) on MRI substudies despite modest reductions in muscle volume (Gonzalez-Rellan & Drucker, JAMA, 2025).

Preclinical only (mechanistic plausibility, not proven in humans):

  • In animal models GLP-1 agonists reduce oxidative stress, improve mitochondrial function, inhibit cellular senescence and modulate mTOR/nutrient-sensing signalling (Forman et al., JACC, 2023). These effects have not been demonstrated to translate into slowed ageing in humans and should be presented to patients as hypothesis-generating only.

Flag: Do not infer “senolytic”, “anti-senescence” or lifespan benefits in humans from these preclinical data. No robust human data link GLP-1 RAs to validated ageing-clock (epigenetic) endpoints.

3. Evidence base and grading

Study types available: Multiple large placebo-controlled cardiovascular outcome trials (CVOTs; e.g. LEADER, SUSTAIN-6, REWIND, PIONEER-6, SELECT, AMPLITUDE-O); large weight-loss RCT programmes (STEP, SURMOUNT, SCALE); numerous systematic reviews/meta-analyses and umbrella reviews; and observational cohorts for longevity-adjacent endpoints (frailty, dementia).

Outcome-by-outcome summary

OutcomeEvidence statementCertainty (GRADE)Strength of recommendationNotes on limitations
All-cause mortalityMeta-analysis of 21 RCTs (n=99,599) IRR 0.88 (0.84–0.92), NNT 121 (Galli et al., JACC, 2025)HighStrong — in populations studied (T2D, established CVD, obesity)Populations enriched for high risk; indirect for low-risk longevity clients
MACE (CV death/MI/stroke)IRR 0.87 (0.83–0.91), NNT 66; pooled CVOT HR ~0.85 (Galli 2025; Marx et al., ESC, 2023)HighStrong — high cardiometabolic riskLarger absolute benefit with established ASCVD
CV mortalityIRR 0.87 (0.81–0.92), NNT 170 (Galli 2025)HighStrongConsistent, low heterogeneity
Heart failure hospitalisation~15% reduction; larger effect in obesity (Galli 2025)HighStrong (conditional in non-obese)—
Weight loss (non-diabetic obesity/overweight)Tirzepatide up to −17.8%, semaglutide up to −13.9%, liraglutide up to −5.8% placebo-subtracted (Moiz et al., Ann Intern Med, 2025; Liu et al., AJCN, 2023)HighStrong — obesity/overweight + comorbidityWeight regain on discontinuation
Glycaemic control / prediabetes → normoglycaemia66–93% relative slowing of progression to T2D; regression to normoglycaemia OR ~4.6 (Nauck et al., Lancet, 2026; Wang et al., 2023)Moderate–HighConditional (surrogate; benefit reverses off-drug)Effect partly reverses after washout
Lipids / BP / hs-CRP / hepatic steatosis (MASH)Consistent improvement; semaglutide licensed for MASH F2–F3 (FDA; Ndumele et al., 2026)Moderate (surrogates) / High for MASH histologyConditional; Strong for licensed MASHMostly surrogate endpoints
Frailty progression (older T2D)Medicare cohort: slower frailty progression vs DPP-4i, independent of CV benefit (Park et al., ADA, 2026)Low (observational)Only in research / expert-consensusNo RCT with frailty endpoint
Dementia / cognitive declineRCT meta-analysis OR 0.55 (0.35–0.86) for GLP-1 RA; supportive cohort data; dedicated Alzheimer’s RCTs (evoke) reportedLow–ModerateOnly in researchPost-hoc/observational; not an indication
Muscle/lean-mass preservation~25–40% of lost weight may be fat-free mass; muscle-volume loss largely proportional to total loss; CRF improvement not demonstrated (Liu et al., JCEM, 2025; Neeland et al., 2024)ModerateMitigation (resistance exercise + protein) — expert-consensusLong-term functional implications unknown

Cross-cutting GRADE considerations:

  • Risk of bias: CVOT and weight-loss RCTs generally low risk; longevity endpoints (frailty, dementia) rely on observational/post-hoc data (downgraded).
  • Inconsistency: Low heterogeneity for mortality/MACE (I²≈0%); high heterogeneity for some weight and prediabetes analyses.
  • Indirectness: Major limitation for longevity practice — pivotal trials enrolled higher-risk populations (T2D, BMI ≥27–30 with comorbidity, established CVD), not metabolically healthy or normal-weight adults.
  • Imprecision: Narrow CIs for hard outcomes; wider for agent-specific and longevity endpoints.
  • Publication bias: Largely industry-sponsored programmes; interpret agent-superiority claims cautiously.

4. Patient selection and indications

Who may benefit (align with licensed/guideline populations wherever possible):

  • On-label (UK): Adults with obesity (BMI ≥30) or overweight (BMI ≥27) with ≥1 weight-related comorbidity (e.g. hypertension, dyslipidaemia, prediabetes, MASLD, OSA), as adjunct to reduced-calorie diet and increased physical activity; and adults with T2D. Semaglutide (Wegovy) additionally licensed to reduce MACE in adults with established CVD plus overweight/obesity, and for MASH with F2–F3 fibrosis.
  • High cardiometabolic-risk middle-aged adults with central adiposity, insulin resistance, atherogenic dyslipidaemia or prediabetes — strongest expected benefit-to-harm ratio.
  • Older adults: may derive cardiometabolic benefit and possibly slower frailty progression (observational only), but require careful muscle-mass and nutrition safeguards.

Poor candidates / caution:

  • Athletic or lean individuals seeking “performance/longevity optimisation” at normal BMI: No robust human evidence of benefit; net harm plausible from lean-mass loss and reduced fat-free mass. Off-label and not recommended outside research.
  • Pre-existing sarcopenia/frailty without a muscle-preservation plan.

Exclusions / specialist input required:

  • Personal/family history of medullary thyroid carcinoma or MEN-2 (absolute for the class).
  • History of pancreatitis; active significant gastrointestinal dysmotility/gastroparesis.
  • Pregnancy, planned pregnancy, breastfeeding.
  • Concurrent insulin/sulfonylurea (hypoglycaemia risk — needs dose adjustment).

Regulatory/ethical status in a longevity clinic:

  • Use within licensed indications = guideline-based, adjunctive to conventional care.
  • Use for metabolic/longevity optimisation in non-licensed populations (e.g. normal-weight, “biological-age reduction”) = off-label/experimental, and should be only within research frameworks or, at most, as carefully consented adjunctive care with explicit documentation of the absence of hard-outcome evidence.
  • Do not prescribe compounded/unlicensed product; verify MHRA-licensed supply.

5. Assessment and baseline work-up

History & examination:

  • Weight history, dietary pattern, physical activity/resistance-training status, alcohol; cardiometabolic and thyroid history; personal/family MTC or MEN-2; pancreatitis; gallstones; mental-health history (mood/anxiety — see safety); eating-disorder screen.
  • BMI, waist circumference, blood pressure, resting heart rate. Consider grip strength / gait speed / SARC-F in older adults (frailty and sarcopenia baseline).

Baseline investigations:

  • HbA1c and fasting glucose; fasting lipid profile; U&E/eGFR; LFTs; TFTs if indicated.
  • Consider hs-CRP and a non-invasive liver fibrosis score (e.g. FIB-4) where MASLD/MASH suspected.
  • Body composition where feasible (DXA or bioimpedance) to track fat vs lean mass — expert-consensus, particularly valuable in longevity practice and in older/lean patients.
  • Pregnancy test in those who could become pregnant.

Risk stratification:

  • Benefit-likely / harm-low: obesity or overweight-plus-comorbidity, prediabetes, high cardiometabolic risk — strongest case.
  • Intermediate: older multimorbid adults — benefit possible but monitor muscle/nutrition/frailty.
  • Benefit-uncertain / harm-relatively-higher: normal-weight, lean, or frail patients without a muscle-preservation strategy.

Baseline documentation for meaningful follow-up: weight, BMI, waist circumference, BP, HR, HbA1c, lipids, LFTs, eGFR, body composition if measured, functional/frailty measures in older adults, and explicit off-label consent where relevant.

6. Dosing regimens and practical implementation

All regimens require slow titration to limit gastrointestinal effects. Doses below reflect licensed weight-management/diabetes ranges; use in unlicensed populations is off-label.

Semaglutide (subcutaneous, weekly — Wegovy for weight; Ozempic for T2D):

  • Weight-management titration: 0.25 mg weekly → escalate at ~4-weekly intervals through 0.5, 1.0, 1.7 mg → maintenance 2.4 mg weekly.
  • Placebo-subtracted weight loss ~13–15% at ~68 weeks (STEP programme; Elmaleh-Sachs et al., 2023).

Tirzepatide (subcutaneous, weekly — Mounjaro; dual GIP/GLP-1):

  • Start 2.5 mg weekly × 4 weeks → 5 mg → escalate by 2.5 mg at ≥4-week intervals to a maintenance of 5–15 mg as tolerated.
  • Greatest weight efficacy of current agents (~18–20% placebo-subtracted; superior to semaglutide in SURMOUNT-5) (Nauck et al., 2026; Rodriguez et al., JAMA Intern Med, 2024).

Liraglutide (subcutaneous, daily — Saxenda 3.0 mg for weight):

  • Titrate 0.6 mg/day weekly increments to 3.0 mg/day; more modest weight loss (~5–6% placebo-subtracted).

Oral semaglutide (Rybelsus for T2D; higher-dose oral formulation licensed for weight in some regions): take fasting with ≤120 mL water, ≥30 min before food/other medication.

Dose–response: Weight loss is non-linear and dose-dependent; higher maintenance doses give greater weight/metabolic effect but more GI adverse events and potentially greater lean-mass loss (Liu et al., AJCN, 2023).

Non-pharmacological co-prescription (integral, not optional):

  • Resistance training ≥2–3 sessions/week plus adequate protein intake (~1.2–1.6 g/kg/day) to mitigate fat-free-mass loss — expert-consensus/mechanistic (Locatelli et al., Diabetes Care, 2024).
  • Structured intensive behavioural therapy amplifies and sustains benefit (WHO, JAMA, 2025).

Regimens supported by robust human data: licensed titrations above for weight/T2D/CVD/MASH. Regimens requiring caution (weaker basis): use for pure “longevity optimisation”, micro-dosing regimens, and combination with experimental muscle-preserving agents (myostatin/activin inhibitors — investigational, phase 2 only; Gonzalez-Rellan & Drucker, 2025).

7. Monitoring, safety and follow-up

Monitoring plan:

  • Clinical: weight, waist, BP, HR, GI tolerance, mood, hydration/oral intake at each visit; muscle/functional status and nutrition in older adults.
  • Laboratory: HbA1c and lipids at baseline and ~3–6-monthly initially; LFTs and eGFR periodically; body composition (DXA/BIA) at baseline and ~6–12-monthly if tracked.
  • Longevity biomarkers: hs-CRP and FIB-4 where relevant. Avoid over-reliance on commercial “ageing clocks” — no robust evidence links GLP-1-induced biomarker change to clinical longevity.

Suggested intervals: review at ~4 weeks during titration, then 3-monthly in year 1, then 6–12-monthly once stable. Reassess ongoing need and response (e.g. ≥5% weight loss) periodically.

Adverse effects:

  • Common (mild–moderate, mostly during titration): nausea (~25–60%), vomiting (~5–15%), diarrhoea, constipation, dyspepsia; dropout ~4–8% (Brown et al., Lancet, 2021; Rosen & Ingelfinger, NEJM, 2026). Manage with slower titration, smaller meals, dose hold/reduction.
  • Gallbladder/biliary disease: ~1.5× risk vs placebo, higher with higher dose/longer duration and rapid weight loss (Rosen & Ingelfinger, 2026).
  • Hypoglycaemia: only with concomitant insulin/sulfonylurea — reduce those agents proactively.
  • Lean-mass loss: monitor; mitigate with resistance training + protein.
  • Perioperative aspiration risk from delayed gastric emptying — follow current anaesthetic guidance on withholding around surgery/endoscopy.
  • Serious but rare: pancreatitis (no consistent excess in long-term RCTs but discontinue if suspected); diabetic retinopathy worsening (semaglutide signal in SUSTAIN-6, linked to rapid glucose lowering); DKA if insulin abruptly reduced in T2D.
  • Observational signals warranting vigilance, not proven causal: psychiatric outcomes (anxiety/depression) and GI dysmotility/obstruction in a multicentre cohort (Park et al., Diabetes Obes Metab, 2026) — RCT data have not shown increased psychiatric events; counsel and monitor mood.
  • Not substantiated: thyroid cancer and pancreatic cancer are not associated in systematic reviews (Bracchiglione et al., Cochrane, 2025).

Actions for abnormal findings: hold/slow-titrate for intolerable GI effects; discontinue and investigate for suspected pancreatitis or significant biliary disease; ophthalmology referral for retinopathy concern; reduce insulin/sulfonylurea for hypoglycaemia; stop for pregnancy.

Interactions: delayed gastric emptying may alter absorption of oral drugs; caution with insulin/sulfonylureas; oral semaglutide has strict administration requirements.

Special populations: avoid in pregnancy/breastfeeding (discontinue ≥2 months before planned conception per label guidance for semaglutide); use with caution and monitoring in significant renal/hepatic impairment (dehydration from GI losses can worsen renal function); in frailty/extremes of age prioritise muscle and nutrition and use lower targets.

8. Contraindications and cautions

Absolute:

  • Personal/family history of medullary thyroid carcinoma or MEN-2.
  • Prior serious hypersensitivity to the agent.
  • Pregnancy and breastfeeding.

Relative / specialist input:

  • History of pancreatitis or symptomatic gallstone disease.
  • Gastroparesis or significant GI dysmotility.
  • Proliferative/unstable diabetic retinopathy (particularly semaglutide).
  • Significant renal or hepatic impairment; history of eating disorder; concurrent insulin/sulfonylurea.

Harm likely to outweigh benefit with current evidence:

  • Metabolically healthy, normal-weight or lean/athletic adults using the drug purely for “longevity” — no demonstrated hard-outcome benefit and real risks (GI, lean-mass loss, cost, unknown long-term effects).
  • Frail older adults without a concurrent resistance-exercise/nutrition strategy.

9. Practical management scenarios

Scenario A — Middle-aged adult with multiple cardiometabolic risk factors

Example: 52-year-old, BMI 33, prediabetes, hypertension, atherogenic dyslipidaemia.

  • Recommendation: OFFER (guideline-based/on-label). Strong recommendation — high-certainty benefit for weight, glycaemia and (in high-risk/established-CVD subsets) MACE and mortality.
  • Assessment: full cardiometabolic work-up (Section 5), exclude contraindications.
  • Shared decision-making: discuss expected ~13–20% weight loss (agent-dependent), GI effects, weight regain on stopping, need for long-term therapy and lifestyle co-treatment.
  • Initiation: semaglutide 2.4 mg or tirzepatide (titrate as Section 6) + reduced-calorie diet, resistance training, protein target.
  • Monitoring: 4-weekly during titration, then 3-monthly; track weight, BP, HbA1c, lipids.
  • Escalate/stop: if <5% weight loss at an adequate maintenance dose/duration, reassess; refer to specialist weight service for alternative therapy/bariatric surgery consideration.

Scenario B — Older, frail patient with multimorbidity

Example: 78-year-old, BMI 31, T2D, hypertension, reduced gait speed.

  • Recommendation: CONSIDER with caution. Conditional recommendation. Potential cardiometabolic and possible frailty-progression benefit (observational only) balanced against sarcopenia and GI/dehydration risk.
  • Assessment: baseline frailty/sarcopenia measures (grip strength, gait speed, SARC-F), body composition, nutrition, renal function.
  • Shared decision-making: emphasise muscle-preservation plan; set conservative weight goals.
  • Initiation: lowest effective dose, slow titration; mandatory resistance exercise + adequate protein; dietitian involvement.
  • Monitoring: closer review of weight, muscle/function, nutrition, renal function and mood.
  • Escalate/stop: stop for excessive/unintended weight or muscle loss, functional decline, dehydration, or poor tolerance.

Scenario C — Adjunct to conventional therapy in a patient already under specialist care

Example: patient with established ASCVD/T2D or MASH already under cardiology/hepatology.

  • Recommendation: OFFER/CONTINUE as adjunct, in coordination with the specialist. Strong where licensed (e.g. semaglutide for CVD risk reduction or MASH F2–F3).
  • Assessment: confirm indication, existing regimen, and hypoglycaemia risk (insulin/sulfonylurea).
  • Shared decision-making & consent: align goals with specialist; document off-label status if outside licence.
  • Initiation: coordinate titration; pre-emptively down-titrate insulin/sulfonylurea.
  • Monitoring: shared monitoring plan; retinopathy surveillance with semaglutide in T2D.
  • Escalate/refer/stop: refer back to specialist for suspected pancreatitis, significant retinopathy progression, or unexplained deterioration.

Scenario D — Normal-weight adult requesting GLP-1 for “longevity optimisation”

  • Recommendation: RESTRICT TO RESEARCH / RECOMMEND AGAINST routine use. No robust human evidence of benefit at normal BMI; real risks (lean-mass loss, GI effects, cost, unknown long-term harms).
  • If pursued at all, only within a well-designed trial/registry with explicit informed consent and body-composition/functional monitoring.

10. Research gaps and future directions

  • Hard outcomes in low-risk/normal-weight and healthy-ageing populations: no RCTs show mortality/morbidity benefit outside T2D, obesity or established CVD. This is the central evidence gap for longevity practice.
  • Validated ageing biomarkers: no robust human data linking GLP-1-induced changes in inflammatory or epigenetic markers to clinical longevity outcomes.
  • Frailty and sarcopenia: frailty benefit is observational only (Park et al., ADA, 2026); RCTs with frailty/functional primary endpoints and muscle-preservation co-interventions (resistance exercise, myostatin/activin inhibitors — currently phase 2) are needed. Cardiorespiratory-fitness effects are unproven despite weight loss (Liu et al., JCEM, 2025).
  • Cognition/dementia: promising but not yet an indication; dedicated Alzheimer’s RCTs (oral semaglutide, evoke/evoke+) and further prevention trials will clarify (Cummings et al., Lancet, 2026; Seminer et al., JAMA Neurol, 2025).
  • Durability and discontinuation: weight and metabolic benefits reverse after stopping; optimal long-term/maintenance and de-escalation strategies are undefined.
  • Comparative and agent-specific effects, and long-term safety (psychiatric, GI dysmotility signals) require confirmation in prospective randomised data.

Where practice should be limited to trials/registries: any use for anti-ageing/longevity in metabolically healthy or normal-weight adults; micro-dosing; and combination with investigational muscle-preserving agents.

Footnote

This summary is adjunctive to, and does not replace, NICE appraisals and specialist pathways for obesity and type 2 diabetes. Confirm current MHRA licensing and NICE guidance before prescribing.

Key evidence anchors:

– Hard outcomes are high-certainty only in enriched populations. GRADE high-certainty meta-analytic data (21 RCTs, n=99,599) support reductions in all-cause mortality (IRR 0.88), CV mortality (IRR 0.87) and MACE (IRR 0.87), but these were derived from patients with T2D, established CVD and/or obesity — so the document repeatedly flags indirectness for low-risk longevity clients.[1][6][7]

– Weight/metabolic benefit is robust; longevity endpoints are not. Weight-loss efficacy is high-certainty in non-diabetic obesity/overweight, and prediabetes-to-normoglycaemia reversal is well supported, but these remain largely surrogate. Frailty (observational, Medicare cohort) and dementia (post-hoc/observational plus emerging RCTs) are explicitly graded low-to-moderate and marked research-only.[2][3][11][12][13][14][8][10][15][16]

– Safety qualifiers preserved intact: MTC/MEN-2 contraindication, pancreatitis and biliary risk, retinopathy signal with semaglutide, hypoglycaemia only with insulin/sulfonylurea, perioperative aspiration, and the observational psychiatric/GI-dysmotility signals versus reassuring RCT data on thyroid/pancreatic cancer.[17][18][19][20][21]

– Lean-mass caveat foregrounded for the longevity audience: ~25–40% of lost weight may be fat-free mass, with no demonstrated CRF gain — hence the mandatory resistance-exercise/protein co-prescription framed as expert-consensus.[9][22][23]

Two areas were deliberately conservative: the document recommends against routine use in metabolically healthy normal-weight adults (no hard-outcome data), and does not endorse commercial ageing-clock monitoring given the absence of validated linkage.

 

Figure 2 Summary plot for GLP‐1RAs versus placebo and outcomes. Kunutsor SK, Zaccardi F, Balasubramanian VG, et al. Glycaemic Control and Macrovascular and Microvascular Outcomes in Type 2 Diabetes: Systematic Review and Meta-Analysis of Cardiovascular Outcome Trials of Novel Glucose-Lowering Agents. Diabetes, Obesity & Metabolism. 2024;26(5):1837-1849. doi:10.1111/dom.15500.

 

 

Figure 2 Risk of A, major adverse cardiovascular events (MACE) and all‐cause mortality. Mannucci E, Dicembrini I, Nreu B, Monami M. Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Outcomes in Patients With and Without Prior Cardiovascular Events: An Updated Meta-Analysis and Subgroup Analysis of Randomized Controlled Trials. Diabetes, Obesity & Metabolism. 2020;22(2):203-211. doi:10.1111/dom.13888.

 

 

Figure 1 Forest and network plots of cardiometabolic profiles for glucagon‐like peptide‐1 (GLP‐1) receptor mono‐agonist versus placebo in adults with overweight or obesity. Lu Y, Chen J, Guo Y, et al. Cardiometabolic Profiles of Oral and Subcutaneous Glucagon-Like Peptide-1 Receptor Mono-Agonists in Adults With Overweight or Obesity: A Systematic Review and Network Meta-Analysis. Diabetes, Obesity & Metabolism. 2026;28(7):5761-5766. doi:10.1111/dom.70742.

 

 

Figure 2 An analysis of the effect of Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) on weight, BMI, waist circumference and blood pressure (A) based on the change in weight; (B) based on the change in BMI; (C) based on the change in waist circumference; (D) based on the change in systolic blood pressure (SBP); (E) based on the change in diastolic blood pressure (DBP). Wang W, Wei R, Huang Z, et al. Effects of Treatment With Glucagon-Like Peptide-1 Receptor Agonist on Prediabetes With Overweight/Obesity: A Systematic Review and Meta-Analysis. Diabetes/Metabolism Research and Reviews. 2023;39(7):e3680. doi:10.1002/dmrr.3680.

 

 

Figure 4 Evidence maps of glucagon‐like peptide‐1 receptor agonist and their specific agents on various health outcomes. Yeo D, Jo Y, Jeong J, et al. Efficacy and Safety of Glucagon-Like Peptide 1 Receptor Agonists Across All Health Outcomes in Type 2 Diabetes: An Umbrella Review and Evidence Map of Randomised Controlled Trials. Diabetes, Obesity & Metabolism. 2026;28(2):1136-1149. doi:10.1111/dom.70298.

 

 

Figure 3 Effects of glucagon‐like peptide‐1 receptor agonists on gastrointestinal and other outcomes. Yeo D, Jo Y, Jeong J, et al. Efficacy and Safety of Glucagon-Like Peptide 1 Receptor Agonists Across All Health Outcomes in Type 2 Diabetes: An Umbrella Review and Evidence Map of Randomised Controlled Trials. Diabetes, Obesity & Metabolism. 2026;28(2):1136-1149. doi:10.1111/dom.70298.

 

 

Figure 1 Change in body composition at Week 72. Look M, Dunn JP, Kushner RF, et al. Body Composition Changes During Weight Reduction With Tirzepatide in the SURMOUNT-1 Study of Adults With Obesity or Overweight. Diabetes, Obesity & Metabolism. 2025;27(5):2720-2729. doi:10.1111/dom.16275.

 

 

Figure 3 Conceptual description of how changes in muscle volume z‐score with weight change relates to changes in muscle volume (in litres). Neeland IJ, Linge J, Birkenfeld AL. Changes in Lean Body Mass With Glucagon-Like Peptide-1-Based Therapies and Mitigation Strategies. Diabetes, Obesity & Metabolism. 2024;26 Suppl 4:16-27. doi:10.1111/dom.15728.

 

 

Figure 1 Association of Glucose-Lowering Therapy With All-Cause Dementia Seminer A, Mulihano A, O’Brien C, et al. Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis. JAMA Neurology. 2025;82(5):450-460. doi:10.1001/jamaneurol.2025.0360.

 

 

Figure 2 Inverse Probability of Treatment Weighting (IPTW)–Adjusted Cumulative Incidence of Alzheimer Disease and Related Dementias Within the 3 Study Cohorts Tang H, Donahoo WT, DeKosky ST, et al. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. JAMA Neurology. 2025;82(5):439-449. doi:10.1001/jamaneurol.2025.0353.

 

 

Figure 1 An analysis of the effect of Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) regressed from prediabetes and diagnosed with diabetes (A) based on regressed from prediabetes; (B) based on diagnosed with diabetes; analysis of the effect of GLP‐1RA on post‐treatment glucose and changes of fasting glucose; (C) based on post‐treatment glucose; (D) based on the change in fasting glucose. Wang W, Wei R, Huang Z, et al. Effects of Treatment With Glucagon-Like Peptide-1 Receptor Agonist on Prediabetes With Overweight/Obesity: A Systematic Review and Meta-Analysis. Diabetes/Metabolism Research and Reviews. 2023;39(7):e3680. doi:10.1002/dmrr.3680.

 

 

Figure 2 Forrest plot of meta‐analysis. Tsironikos GI, Tsolaki V, Zakynthinos G, et al. Effectiveness of GLP-1 RAs in Restoring Normoglycemia in Patients With Prediabetes: An Updated Systematic Review and Meta-Analysis. Diabetes/Metabolism Research and Reviews. 2026;42(1):e70114. doi:10.1002/dmrr.70114.

 

References

  1. Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,599 Patients. Galli M, Benenati S, Laudani C, et al. Journal of the American College of Cardiology. 2025;86(20):1805-1819. doi:10.1016/j.jacc.2025.08.027.
  2. The Weight-Loss Effect of GLP-1RAs Glucagon-Like Peptide-1 Receptor Agonists in Non-Diabetic Individuals With Overweight or Obesity: A Systematic Review With Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. Liu Y, Ruan B, Jiang H, et al. The American Journal of Clinical Nutrition. 2023;118(3):614-626. doi:10.1016/j.ajcnut.2023.04.017.
  3. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials. Moiz A, Filion KB, Toutounchi H, et al. Annals of Internal Medicine. 2025;178(2):199-217. doi:10.7326/ANNALS-24-01590.
  4. 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Ndumele CE, Rodriguez F, Dixon DL, et al. Journal of the American College of Cardiology. 2026;87(22S):e1889-e2007. doi:10.1016/j.jacc.2026.03.056.
  5. World Health Organization Guideline on the Use and Indications of Glucagon-Like Peptide-1 Therapies for the Treatment of Obesity in Adults. Celletti F, Farrar J, De Regil L. JAMA. 2025;:2842199. doi:10.1001/jama.2025.24288.
  6. 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients With Diabetes. Marx N, Federici M, Schütt K, et al. European Heart Journal. 2023;44(39):4043-4140. doi:10.1093/eurheartj/ehad192.
  7. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2026. American Diabetes Association Professional Practice Committee for Diabetes*. Diabetes Care. 2026;49(Suppl 1):S216-S245. doi:10.2337/dc26-S010.
  8. Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-Like Peptide 1 Receptor Agonists, and Frailty Progression in Older Adults With Type 2 Diabetes. Park CM, Thanapluetiwong S, Chen X, et al. Diabetes Care. 2026;49(1):147-151. doi:10.2337/dc25-1031.
  9. New Molecules and Indications for GLP-1 Medicines. Gonzalez-Rellan MJ, Drucker DJ. JAMA. 2025;334(14):1231-1234. doi:10.1001/jama.2025.14392.
  10. Cardioprotective Glucose-Lowering Agents and Dementia Risk. Seminer A, Mulihano A, O’Brien C, et al. JAMA Neurology. 2025;82(5):450-460. doi:10.1001/jamaneurol.2025.0360.
  11. Obesity Management in Adults. Elmaleh-Sachs A, Schwartz JL, Bramante CT, et al. JAMA. 2023;330(20):2000-2015. doi:10.1001/jama.2023.19897.
  12. Effects of treatment with Glucagon‐like peptide‐1 receptor agonist on prediabetes with overweight/obesity: A systematic review and meta‐analysis. Wang W, Wei R, Huang Z, et al. Diabetes/Metabolism Research and Reviews. 2023;39(7):e3680. doi:10.1002/dmrr.3680.
  13. Glucagon-Like Receptor Agonists and Next-Generation Incretin-Based Medications: Metabolic, Cardiovascular, and Renal Benefits. Nauck MA, Tuttle KR, Tschöp MH, Blüher M. Lancet (London, England). 2026;407(10531):892-908. doi:10.1016/S0140-6736(25)02105-1.
  14. Beyond Weight Loss: Multisystem Benefits of Obesity Medications. Savas M, Kuckuck S, Boon MR, van Rossum EFC. The Lancet. Diabetes & Endocrinology. 2026;14(8):678-692. doi:10.1016/S2213-8587(26)00100-2.
  15. 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. Cummings JL, Atri A, Sano M, et al. Lancet (London, England). 2026;407(10544):2167-2179. doi:10.1016/S0140-6736(26)00459-9.
  16. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. Tang H, Donahoo WT, DeKosky ST, et al. JAMA Neurology. 2025;82(5):439-449. doi:10.1001/jamaneurol.2025.0353.
  17. Semaglutide for Adults Living With Obesity. Bracchiglione J, Meza N, Franco JV, et al. The Cochrane Database of Systematic Reviews. 2025;10:CD015092. doi:10.1002/14651858.CD015092.pub2.
  18. GLP-1 Receptor Agonists. Rosen CJ, Ingelfinger JR. The New England Journal of Medicine. 2026;394(13):1313-1324. doi:10.1056/NEJMra2500106.
  19. GLP‐1 Receptor Agonists for Weight Loss and Risk of Major Safety Outcomes: A Multicentre Cohort Study. Park J, Kim JH, Kim YS, et al. Diabetes, Obesity & Metabolism. 2026;. doi:10.1111/dom.71065.
  20. SGLT2 Inhibitors and GLP-1 Receptor Agonists: Established and Emerging Indications. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. Lancet (London, England). 2021;398(10296):262-276. doi:10.1016/S0140-6736(21)00536-5.
  21. The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction: JACC State-of-the-Art Review. Newman JD, Vani AK, Aleman JO, et al. Journal of the American College of Cardiology. 2018;72(15):1856-1869. doi:10.1016/j.jacc.2018.07.071.
  22. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?. Locatelli JC, Costa JG, Haynes A, et al. Diabetes Care. 2024;47(10):1718-1730. doi:10.2337/dci23-0100.
  23. Incretin Receptor Agonism, Fat-Free Mass, and Cardiorespiratory Fitness: A Narrative Review. Liu Z, Weeldreyer NR, Angadi SS. The Journal of Clinical Endocrinology and Metabolism. 2025;110(10):2709-2717. doi:10.1210/clinem/dgaf335.
  24. Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta‐analysis of cardiovascular outcome trials of novel glucose‐lowering agents. Kunutsor SK, Zaccardi F, Balasubramanian VG, et al. Diabetes, Obesity & Metabolism. 2024;26(5):1837-1849. doi:10.1111/dom.15500.
  25. Glucagon‐like peptide‐1 receptor agonists and cardiovascular outcomes in patients with and without prior cardiovascular events: An updated meta‐analysis and subgroup analysis of randomized controlled trials. Mannucci E, Dicembrini I, Nreu B, Monami M. Diabetes, Obesity & Metabolism. 2020;22(2):203-211. doi:10.1111/dom.13888.
  26. Cardiometabolic Profiles of Oral and Subcutaneous Glucagon‐Like Peptide‐1 Receptor Mono‐Agonists in Adults With Overweight or Obesity: A Systematic Review and Network Meta‐Analysis. Lu Y, Chen J, Guo Y, et al. Diabetes, Obesity & Metabolism. 2026;28(7):5761-5766. doi:10.1111/dom.70742.
  27. Efficacy and safety of glucagon‐like peptide 1 receptor agonists across all health outcomes in type 2 diabetes: An umbrella review and evidence map of randomised controlled trials. Yeo D, Jo Y, Jeong J, et al. Diabetes, Obesity & Metabolism. 2026;28(2):1136-1149. doi:10.1111/dom.70298.
  28. Body composition changes during weight reduction with tirzepatide in the SURMOUNT ‐1 study of adults with obesity or overweight. Look M, Dunn JP, Kushner RF, et al. Diabetes, Obesity & Metabolism. 2025;27(5):2720-2729. doi:10.1111/dom.16275.
  29. Changes in lean body mass with glucagon‐like peptide ‐1‐based therapies and mitigation strategies. Neeland IJ, Linge J, Birkenfeld AL. Diabetes, Obesity & Metabolism. 2024;26 Suppl 4:16-27. doi:10.1111/dom.15728.
  30. Effectiveness of GLP‐1 RAs in Restoring Normoglycemia in Patients With Prediabetes: An Updated Systematic Review and Meta‐Analysis. Tsironikos GI, Tsolaki V, Zakynthinos G, et al. Diabetes/Metabolism Research and Reviews. 2026;42(1):e70114. doi:10.1002/dmrr.70114.