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Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,592 patients

M. Galli, S. Benenati, C. Laudani, Beatrice Simeone, Gianmarco Sarto, L. Ortega-Paz, E. Rocco, Marco Bernardi et al.

Journal of the American College of Cardiology, 2025

99,592 participants · 76 citations

Abstract

BACKGROUND

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant cardiovascular (CV) benefits particularly in patients with diabetes mellitus (DM), 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 RCTs 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 pre-specified subgroups based on the GLP-1 RA used. Pre-specified subgroups according to DM, kidney function, obesity or heart failure (HF) were also performed. Main outcomes comprised mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). GRADE and trial sequential analyses were performed to evaluate certainty and conclusiveness of findings, respectively.

RESULTS

A total of 21 trials encompassing 99,592 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…

How strong is the evidence?

Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 99,592 participants or records.

How the five levels of evidence work. The level is assigned automatically from the abstract and can be wrong, so check the paper.

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