Metabolic & Cardiometabolic
GLP-1 receptor agonists decreases major adverse cardiovascular events
In plain terms: Do GLP-1 weight-loss/diabetes drugs actually lower the risk of heart attacks and strokes?
Strong support Metabolic & Cardiometabolic 💰 Industry COI noted
Part of: 💊 GLP-1 Drugs
RefutedContestedStrong support
consensus score 1.00
Yes — across multiple large randomized trials and meta-analyses they cut major cardiovascular events by roughly 12-20%, in people with diabetes and (per SELECT) in obesity without diabetes.
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: All trials, pooled (Meta-analysis)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
17 support 0 contradict 0 tested null 0 mixed · 17 sources, 15 independent groups · 4 superseded — pooled inside a review, counted once
What the evidence shows
GLP-1 receptor agonists cut major adverse cardiovascular events by 12 to 20 percent on randomised evidence: eight placebo-controlled trials in 60,080 people with type 2 diabetes, and SELECT, 17,604 people with heart disease and overweight but no diabetes (hazard ratio 0.80). Every trial enrolled people with diabetes or established heart disease; lower-risk groups rest on observational data.
The evidence (26)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Parekh RS, Inban P, Thai A, Agrawal A, Kudaiarov D, Tariq H 2026 · Dis Mon | observational | supports | low | Systematic review (PRISMA 2020) of GLP-1 receptor agonists in high-risk people with obesity plus cancer, diabetes or cardiovascular disease: 110 records screened, 8 included, narrative synthesis with no pooled estimate of its own. The cardiovascular outcome trials it summarises reported hazard ratios of 0.80 (0.72-0.90) and 0.74 (0.58-0.95) for major cardiovascular events. Semaglutide trials reported up to 15.2% weight loss versus 2.6% in controls. Venous thromboembolism, the review's own question, was reported by one study only: 1 event versus 3, not statistically significant. |
| Khera R, Aminorroaya A, Dhingra LS, Thangaraj PM, Pedroso Camargos A, Bu F, Ding X, Nishimura A, Anand TV, Arshad F, Blacketer C, Chai Y, Chattopadhyay S, Cook M, Dorr DA, Duarte-Salles T, DuVall SL, Falconer T, French TE, Hanchrow EE, Kaur G, Lau WCY, Li J, Li K, Liu Y, Lu Y, Man KKC, Matheny ME, Mathioudakis N, McLeggon JA, McLemore MF, Minty E, Morales DR, Nagy P, Ostropolets A, Pistillo A, Phan TP, Pratt N, Reyes C, Richter L, Ross JS, Ruan E, Seager SL, Simon KR, Viernes B, Yang J, Yin C, You SC, Zhou JJ, Ryan PB, Schuemie MJ, Krumholz HM, Hripcsak G, Suchard MA 2024 · J Am Coll Cardiol | observational | supports | high | LEGEND-T2DM, a target-trial emulation across ten health databases in four countries: 1,492,855 adults with type 2 diabetes and existing cardiovascular disease starting a second drug after metformin, 25,982 heart-attack/stroke/death events. Starters of a GLP-1 receptor agonist had lower risk than starters of a DPP-4 inhibitor (hazard ratio 0.83, 95% CI 0.70-0.98) or a sulfonylurea (0.72, 0.58-0.88), and lower heart-failure hospitalisation (0.76, 0.67-0.86 vs DPP-4i). GLP-1RAs and SGLT2 inhibitors did not differ. Every estimate was calibrated against 100 negative-control outcomes. |
| Abdul Nabi H, Dreher L, Al Osta S, Shamoun FE 2026 · Med Sci (Basel) | observational | supports | moderate | Retrospective Mayo Clinic cohort of 162,126 adults with thoracic aortic aneurysm diagnosed 2018-2026. The GLP-1 receptor agonist comparison used its own propensity-matched subset of 7,834 users and 7,834 non-users. Through 60 months, users had higher MACE-free survival (93.2% vs 89.3%; HR 0.62, 95% CI 0.56-0.70) and higher overall survival (97.5% vs 92.5%; HR 0.32, 95% CI 0.27-0.38); MACE was cardiovascular death, myocardial infarction or stroke. The authors note these associations are larger than in most randomised trials and may reflect residual selection or survivor bias. |
| Amorim Moreira Alves G, Teranishi M, Majumdar R, Khan F, Dodeja M, Teixeira de Castro Goncalves Ortega AC, Acerboni M, Perera Molligoda Arachchige AS, James F 2026 · Chronic Dis Transl Med | observational | supports | moderate | Narrative review restating cardiovascular outcome trial results, with no pooled estimate and no new data of its own: across LEADER, SUSTAIN-6 and REWIND, GLP-1 receptor agonists consistently reduced major adverse cardiovascular events, and SELECT showed a 20% MACE reduction in adults with obesity but without diabetes. Component figures cited are a roughly 22% reduction in cardiovascular death in LEADER, non-fatal stroke HR 0.61 in SUSTAIN-6, and a 15% reduction in all-cause mortality in LEADER. |
| Mahmoud AK, Sheashaa H, Killian M, Awad K, Ibrahim R, Mahmoud A, Farina J, Abdelnabi M, Kamel I, Horn B, Simper D, Lester SJ, Ayoub C, Arsanjani R 2026 · Int J Cardiol | observational | supports | moderate | Retrospective multicenter cohort of adults with lipoprotein(a) above 50 mg/dL plus obesity or type 2 diabetes; 3,310 GLP-1 receptor agonist users were propensity-matched one to one with non-users, out of 24,185 eligible patients. Over a median follow-up of about two years, GLP-1RA use was associated with lower all-cause mortality (HR 0.66, 95% CI 0.48-0.90), the primary outcome, and with fewer major adverse cardiovascular events, a secondary composite of myocardial infarction, ischemic stroke and coronary revascularization (HR 0.68, 95% CI 0.60-0.76). Treatment was not randomized. |
| Kosako Yost KC, Ghai MB, Aboona M, Ali Q, Rangan P, Gomez P, Nathan R, Wong M, Wijarnpreecha K, Nevah Rubin MI, Fallon M, Han MAT 2026 · Transplantation Direct | observational | supports | low | Retrospective single-centre chart review of 457 adults with type 2 diabetes who received a liver or liver-kidney transplant. The 33 taking a GLP-1 receptor agonist or an SGLT2 inhibitor were analysed as one combined group (13 on a GLP-1 drug, 16 on an SGLT2 inhibitor, 4 on both), so no separate result for GLP-1 drugs is reported. That combined group had fewer new cardiovascular events over 5 years (3 of 33 vs 110 of 424; adjusted subdistribution hazard ratio 0.24, 95% CI 0.059-0.99) and no graft failures or new dialysis. Adjusted mortality was not significantly lower. |
| Dai H, Lee YA, Natalie A, Jackson W, Pham A, Levine J, Radwan RM, Guo J, Bian J, Sheer AJ 2026 · J Am Heart Assoc | observational | supports | moderate | Target trial emulation in the OneFlorida+ electronic health record network (2014-2024): 13,204 adults with obesity and an autoimmune disease starting a GLP-1 receptor agonist, matched 1:1 to nonusers (mean BMI 37, 73.4% women). GLP-1RA use was associated with lower stroke or transient ischemic attack (HR 0.87, 95% CI 0.76-0.99), pulmonary embolism (HR 0.69), venous thromboembolism (HR 0.83) and all-cause mortality (HR 0.56, 0.47-0.66). Myocardial infarction and coronary revascularization were also primary outcomes, but no result is reported for either. Treatment was not randomized. |
| Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, Lam CSP, Lopes RD, McMurray JJV, Pratley RE, Rosenstock J, Gerstein HC 2021 · Lancet Diabetes Endocrinol 2021;9(10):653-662 | meta-analysis | supports | high | A meta-analysis of eight randomised placebo-controlled outcome trials in type 2 diabetes (60,080 patients; searched to June 2021, PROSPERO CRD42021259711) found GLP-1 receptor agonists cut major adverse cardiovascular events by 14% (hazard ratio 0.86, 95% CI 0.80-0.93; p<0.0001), with no significant difference across drug structural class or eight other subgroups. Death from any cause fell 12% (HR 0.88, 0.82-0.94), hospital admission for heart failure 11% (HR 0.89, 0.82-0.98) and a composite kidney outcome 21% (HR 0.79, 0.73-0.87). The authors report no funding for the analysis. |
| Raslan MA, Abdul Nabi H, Dreher L, Al Osta S, De Sousa Barzon Serra V, Ayoub C, El Masry H, Shamoun FE 2026 · Diagnostics (Basel) | observational | supports | low | Retrospective cohort of 32,279 adults with thoracic aortic aneurysm at three Mayo Clinic sites; 588 GLP-1 drug users were matched one-to-one to non-users, median follow-up 4.1 years. Over five years cardiovascular death was 1.9% on a GLP-1 drug vs 5.5% (hazard ratio 0.30, 95% CI 0.13-0.70), death from any cause 5.0% vs 14.5% (0.31, 0.19-0.50) and aortic dissection 0.9% vs 4.0% (0.19, 0.06-0.60). Only univariable Cox models were run, users had to stay on the drug a year to count, and their follow-up started later than non-users', so the authors call the findings hypothesis-generating. |
| McGuire DK, Marx N, Mulvagh SL, Deanfield JE, Inzucchi SE, Pop-Busui R, Mann JFE, Emerson SS, Poulter NR, Engelmann MDM, Ripa MS, Hovingh GK, Brown-Frandsen K, Bain SC, Cavender MA, Gislum M, David JP, Buse JB, SOUL Study Group 2025 · N Engl J Med | RCT | supports | high | SOUL randomised 9,650 people with type 2 diabetes plus atherosclerotic cardiovascular disease, chronic kidney disease or both to once-daily oral semaglutide (up to 14 mg) or placebo, double-blind, median follow-up 49.5 months. Major adverse cardiovascular events - cardiovascular death, non-fatal myocardial infarction or stroke - occurred in 579 of 4,825 (12.0%) on semaglutide versus 668 of 4,825 (13.8%) on placebo: hazard ratio 0.86, 95% CI 0.77 to 0.96, P=0.006. The confirmatory secondary outcomes, including a kidney composite, did not differ significantly. Novo Nordisk funded. |
| Caruso P, Di Martino N, Longo M, Scappaticcio L, Bellastella G, Maiorino MI, Esposito K, Giugliano D 2026 · Cardiovasc Diabetol | meta-analysis | supports | moderate | Meta-analysis of 12 studies (2 randomised trials, 10 matched cohorts, 13 arms, 418,282 participants) in adults with type 2 diabetes and peripheral artery disease. The primary outcome was major limb events (RR 0.73, 95% CI 0.65-0.82); major adverse cardiovascular events were a secondary outcome, RR 0.76 (95% CI 0.63-0.90), and all-cause mortality RR 0.67 (0.61-0.73). The paper does not report how many of the twelve studies contributed the cardiovascular estimate, so that figure does not rest on the full 418,282. Three authors report consultancy fees from GLP-1 drug makers. |
| Amr Ahmed, khulood Almutari 2026 · Research Square | meta-analysis | supports | low | Bayesian network meta-analysis of 93 studies (N>4,200,000) comparing recombinant zoster vaccine, SGLT2 inhibitors and GLP-1 receptor agonists for prevention of major adverse cardiovascular events and dementia in adults aged 50 and over. GLP-1 receptor agonists reduced MACE, NMA-HR 0.86 (95% CrI 0.80-0.92), ranking second of the three (SUCRA 0.71). The paper does not report how many of the 93 studies, or how many participants, contributed that GLP-1 estimate, and states that in the diabetic subgroup all three interventions performed comparably. Unreviewed preprint. |
| Dhamelia P, Khandekar N, Vallurupalli S, Saucedo J, Arthur J, Jadvani D, Beemidi V, Jain N 2026 · Cardiovasc Drugs Ther | observational | supports | moderate | TriNetX US database study of 37,768 adults with non-dialysis chronic kidney disease starting a GLP-1 receptor agonist, each matched to a similar non-user and followed up to 3 years (mean age 67, 63% diabetic, mean eGFR 49). Major adverse cardiovascular events, a secondary outcome, were lower among users (HR 0.58, 95% CI 0.56-0.59). The primary outcome, atrial fibrillation, fell from 12.4% to 6.9% (HR 0.59), and it is the atrial fibrillation result that held up in non-diabetics (HR 0.42) and non-obese patients (HR 0.63). Death was also lower (HR 0.52). |
| Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T, REWIND Investigators 2019 · Lancet | RCT | supports | high | REWIND randomised 9,901 adults aged 50+ with type 2 diabetes, with or without previous cardiovascular disease, to weekly dulaglutide 1.5 mg or placebo, median follow-up 5.4 years. The primary composite of non-fatal heart attack, non-fatal stroke or cardiovascular death occurred in 594 (12.0%) on dulaglutide vs 663 (13.4%) on placebo (hazard ratio 0.88, 95% CI 0.79-0.99; p=0.026). All-cause mortality did not differ (10.8% vs 12.0%; HR 0.90, 95% CI 0.80-1.01). Gastrointestinal adverse events were far more common on dulaglutide (47.4% vs 34.1%). Funded by Eli Lilly. ↩ SUPERSEDED — pooled in the review above, counted once |
| Peter K, Roka O, Sepp E, Warburton M, Zhang J, Cork SC 2026 · Cardiovasc Diabetol Endocrinol Rep 2026;12:36 | meta-analysis | supports | high | Meta-analysis of 11 placebo-controlled cardiovascular outcome trials (LEADER, SUSTAIN-6, SELECT, SOUL, REWIND and six others), 91,490 adults at high cardiovascular risk, median follow-up 2.7 years. GLP-1 receptor agonists cut major adverse cardiovascular events: HR 0.86 (95% CI 0.81-0.92), 4,386 events on drug vs 4,884 on placebo, I-squared 49%. Dropping the single pre-diabetes trial left HR 0.87 (0.82-0.93). Cardiovascular death fell in the 9 trials reporting it (HR 0.87, 0.80-0.94), all-cause death in the 8 reporting it (HR 0.87, 0.81-0.94). Publication bias was not tested statistically. |
| Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Køber L, Petrie MC, McMurray JJV 2019 · Lancet Diabetes Endocrinol 2019;7(10):776-785 | meta-analysis | supports | high | MA of 7 CVOTs (n=56,004): MACE HR 0.88 (12% reduction); CV death, stroke, MI, HF admission, kidney all lower. |
| Batista PG, Dos Santos Silva RRA, Montenegro MV, Malik M, Dandamudi M, de Oliveira JP, Molinari ME, de Lucena LA, Huntermann R, Giorgi J, Bacca COF 2026 · Am J Cardiovasc Drugs | meta-analysis | supports | moderate | Meta-analysis of 7 studies, 37,393 people with type 2 diabetes who had had a heart attack (9,556 on a GLP-1 receptor agonist). GLP-1 RA use was linked to fewer major adverse cardiovascular events (HR 0.69, 95% CI 0.56-0.84), though studies varied a lot (I2 55.6%) and the prediction interval, 0.44-1.06, includes no effect. Cardiovascular death (0.85), recurrent heart attack (0.82) and stroke (0.91) each showed no significant effect. Under a small-study sensitivity adjustment every endpoint lost significance (MACE P=0.13), and the authors call the findings exploratory. |
| Ritsinger V, Fagerström J, Nero H, Cars T, Svensson MK, Norhammar A 2026 · Diabetes Obes Metab | observational | supports | moderate | In three Swedish regions between 2013 and 2023, 9,652 adults aged 45 or over with obesity and established cardiovascular disease but no diabetes had a major adverse cardiovascular event rate of 21.7% over a mean 5.4 years, 2.3 times the rate among 48,260 matched people from the general population (HR 2.3, 95% CI 2.2-2.4). Nobody in this cohort was studied on semaglutide: the authors took the relative effect measured in the earlier SELECT trial and applied it to these risks, giving a modelled number needed to treat of 35 (95% CI 24-66). |
| Maggioni AP, Orso F, Lucci D, De Luca L, Colivicchi F 2026 · Int J Cardiol | observational | supports | low | Among 12,430 patients in two Italian cardiology registries (START and BRING-UP), 623 were excluded for severe kidney impairment or existing GLP-1 drug use, leaving 11,807: 8,682 without diabetes and 3,125 with. Of those without diabetes, 3,689 (42.5%) matched the SELECT trial profile — overweight or obese with established coronary disease; of those with diabetes, 3,059 (97.9%) matched the SOUL profile — aged 50 or over with cardiovascular disease. Overall 6,748 of 12,430 (54.3%) would qualify for semaglutide. The study counts who is eligible; it follows no one's cardiovascular outcomes. |
| Montenegro-Avila A, Montenegro-Cantillo A, Fuentes J, Cifuentes J, Giraldo-Gonzalez GC 2026 · Cardiovasc Endocrinol Metab | meta-analysis | supports | high | Meta-analysis of 7 placebo-controlled trials in 56,191 adults with type 2 diabetes at high cardiovascular risk. Cardiovascular death, heart attack or stroke combined fell 11% (hazard ratio 0.89, 95% CI 0.83-0.96), death from any cause 11% (0.89, 0.82-0.97), heart-failure admission 7% (0.93, 0.89-0.98). Fatal heart attack (0.92, 0.82-1.03) and fatal stroke (0.94, 0.77-1.14), from the 5 trials reporting them (43,107), were not significant, nor was cardiovascular death across all 7 (0.89, 0.78-1.01). Exenatide and lixisenatide pooled at 0.94 (0.87-1.02) vs 0.86 (0.80-0.92) for the other 5 drugs. |
| Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T, SUSTAIN-6 Investigators 2016 · N Engl J Med | RCT | supports | high | SUSTAIN-6 randomised 3,297 adults with type 2 diabetes (83% with existing cardiovascular or kidney disease) to weekly semaglutide or placebo for 104 weeks. Cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 6.6% on semaglutide vs 8.9% on placebo (HR 0.74, 95% CI 0.58-0.95). Nonfatal stroke fell significantly (1.6% vs 2.7%, HR 0.61); nonfatal heart attack fell by a similar proportion but not significantly (HR 0.74, 95% CI 0.51-1.08); cardiovascular deaths were similar. The trial was designed to test noninferiority, not superiority. ↩ SUPERSEDED — pooled in the review above, counted once |
| Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH, SELECT Trial Investigators 2023 · N Engl J Med | RCT | supports | high | SELECT randomised 17,604 adults aged 45 or older who had existing cardiovascular disease and a body-mass index of 27 or more but no diabetes to weekly subcutaneous semaglutide 2.4 mg or placebo, with a mean follow-up of 39.8 months. The primary composite of cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 569 patients (6.5%) on semaglutide versus 701 (8.0%) on placebo (hazard ratio 0.80, 95% CI 0.72-0.90; P<0.001). Adverse events forcing permanent discontinuation were twice as common on semaglutide (16.6% vs 8.2%). Funded by Novo Nordisk; NCT03574597. ↩ SUPERSEDED — pooled in the review above, counted once |
| Chen JJ, Tsai MH, Ho WY, Yen CL, Fang YW, Chen MT, Hsiao CC 2026 · Clin Kidney J | observational | supports | moderate | Retrospective TriNetX US cohort of dialysis patients with type 2 diabetes: 1688 starting a GLP-1 receptor agonist, propensity-matched to 1688 starting a DPP-4 inhibitor, followed up to 5 years. Major adverse cardiovascular events occurred in 31.2% vs 38.2% (HR 0.88, 95% CI 0.78-0.99). That composite was defined to include death, so the separately reported mortality drop (16.8% vs 22.5%, HR 0.84) sits inside it rather than beside it. Heart failure (HR 0.87), myocardial infarction (HR 0.84) and sepsis (HR 0.81) were also lower; atrial fibrillation and pneumonia were not. |
| Badve SV, Bilal A, Lee MMY, Sattar N, Gerstein HC, Ruff CT, McMurray JJV, Rossing P, Bakris G, Mahaffey KW, Mann JFE, Colhoun HM, Tuttle KR, Pratley RE, Perkovic V 2025 · Lancet Diabetes Endocrinol | meta-analysis | supports | high | Meta-analysis of 11 placebo-controlled randomised trials, 85,373 participants, registered PROSPERO CRD42024528864 and searched to March 2024. Among the 67,769 participants with type 2 diabetes, GLP-1 receptor agonists cut major adverse cardiovascular events by 13% (hazard ratio 0.87, 95% CI 0.81-0.93; I2=49.75%), all-cause death by 12% (0.88, 0.83-0.93) and a composite kidney outcome by 18% (0.82, 0.73-0.93). Adding SELECT, in people with obesity and heart disease but no diabetes, left the cardiovascular result similar (0.86, 0.80-0.92). |
| Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, LEADER Steering Committee, LEADER Trial Investigators 2016 · N Engl J Med | RCT | supports | high | LEADER randomised 9,340 adults with type 2 diabetes and high cardiovascular risk to liraglutide 1.8 mg daily or placebo on top of standard care, median follow-up 3.8 years. Cardiovascular death, non-fatal heart attack or non-fatal stroke hit 13.0% on liraglutide vs 14.9% on placebo (hazard ratio 0.87, 95% CI 0.78-0.97; P=0.01 for superiority). Cardiovascular death fell from 6.0% to 4.7% (HR 0.78, 0.66-0.93) and death from any cause from 9.6% to 8.2% (HR 0.85, 0.74-0.97); the non-fatal heart attack and stroke components were lower but not significantly. Funded by Novo Nordisk and the NIH. ↩ SUPERSEDED — pooled in the review above, counted once |
| Hasebe M, Su CY, Yabe D, Yoshiji S 2026 · Diabetes Obes Metab | meta-analysis | supports | high | Meta-analysis of eight placebo-controlled randomized trials (nine publications, 70,822 adults with type 2 diabetes or overweight/obesity; 70,534 with kidney-function-stratified data), searched to 29 April 2026 and including the SOUL trial. GLP-1 receptor agonists cut major adverse cardiovascular events by the same amount at every level of kidney function: hazard ratio 0.83 (95% CI 0.77-0.90) at eGFR >=60 and 0.83 (95% CI 0.74-0.93) below 60, ratio of hazard ratios 1.02 (95% CI 0.85-1.21). Absolute benefit was larger at lower eGFR: 2.6% vs 1.6%, number needed to treat 39 vs 62. |
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