Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,599 Patients
- PMID: 40892610
- DOI: 10.1016/j.jacc.2025.08.027
Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,599 Patients
Abstract
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant cardiovascular (CV) benefits, particularly in patients with diabetes mellitus, but the safety and efficacy of different GLP-1 RAs across diverse populations remain insufficiently defined.
Objectives: Previous meta-analyses of GLP-1 RAs have been limited by restricted populations, omission of recent trials, or incomplete safety synthesis; this study integrates the latest evidence across 21 randomized controlled trials and diverse populations using advanced meta-analytic methods.
Methods: Randomized controlled trials comparing GLP-1 RAs vs controls or placebo were included. Analyses were conducted in prespecified subgroups based on the GLP-1 RA used. Prespecified subgroups according to diabetes mellitus, kidney function, obesity, or heart failure were also performed. Main outcomes comprised mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE) and serious adverse events. GRADE (Grading of Recommendations Assessment, Development and Evaluation) and trial sequential analyses were performed to evaluate certainty and conclusiveness of findings, respectively.
Results: A total of 21 trials encompassing 99,599 patients were included. Eight different GLP-1 RAs were used (lixisenatide, liraglutide, exenatide, semaglutide, efpeglenatide, dulaglutide, albiglutide, and tirzepatide), each administered at therapeutic doses and compared vs placebo or controls. Mean follow-up duration was 2.4 years. We found conclusive, high-certainty evidence that GLP-1 RAs reduced all-cause death (incidence rate ratio [IRR]: 0.88; 95% CI: 0.84-0.92; needed to treat [NNT] = 121), CV death (IRR: 0.87; 95% CI: 0.81-0.92; NNT = 170), and MACE (IRR: 0.87; 95% CI: 0.83-0.91; NNT = 66), compared with controls. GLP-1 RAs reduced serious adverse events (-9%), myocardial infarction (-15%), acute kidney failure (-9%), heart failure (-15%), and infections (-10%), but increased gastrointestinal (+63%) and gallbladder (+26%) disorders. There were no differences in stroke, pancreatitis, or neoplasm between groups. Results were mostly consistent across subgroups. Analysis by GLP-1 RA type revealed potential differences in efficacy and safety profiles.
Conclusions: GLP-1 RAs reduce mortality and MACE in high-risk populations, highlighting benefits beyond glycemic control. These come at increased gastrointestinal and gallbladder risks. Variation in efficacy and tolerability supports tailoring GLP-1 RA therapy to individual patient characteristics and treatment goals. (PROSPERO [GLP-1 RAs Reduce Mortality and Cardiovascular Events Across the Spectrum of Treated Patients: A Systematic Review and Meta-Analysis]; CRD420251032222).
Keywords: GLP-1 receptor agonists; cardiovascular effects; efficacy; mortality; safety.
Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures Dr Galli has received consulting fees from Genomadix; is the principal investigator of the following active grant: Sapienza University of Rome (Grant protocol n. RG1241910F5A1A50); and is an associate editor at European Heart Journal. Dr Federici has received consulting fees or honoraria from Amgen, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck Sharp and Dohme, Novartis, Novo Nordisk, and Sanofi. Dr Mehran has received institutional research funding from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, RenalPro, Shockwave, Vivasure, and Zoll; has received personal fees from Cine-Med Research and WebMD; has equity <1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); serves on scientific advisory board for the American Medical Association, American College of Cardiology (board of trustees member), Society for Cardiovascular Angiography and Interventions (Women in Innovations committee member), and an associate editor at JAMA; and is unpaid faculty of the Cardiovascular Research Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Sciarretta has received honoraria for speeches and/or advisory board participation from Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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