The long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: a systematic review and meta-analysis

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for the management of type 2 diabetes and obesity, yet their long-term cardiovascular effects in high-risk populations continue to be actively evaluated. Given emerging evidence of both metabolic and direct cardiovascular actions, a comprehensive synthesis of cardiovascular outcome trial data is required to clarify the efficacy and safety of this drug class. Methods We conducted a systematic review and meta-analysis of randomised, placebo-controlled cardiovascular outcome trials evaluating GLP-1RAs in adults at high cardiovascular risk. Searches of PubMed, Embase (via OVID), and the Cochrane Library were performed for studies published between January 2015 and May 2025, in accordance with PRISMA 2020 guidelines. Eligible trials included ≥ 3,000 participants with a minimum follow-up of 12 months. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for heart failure, and adverse events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using GRADE. Results Eleven cardiovascular outcome trials comprising 91,490 participants were included, with a mean follow-up of 2.7 years. GLP-1RA treatment was associated with a significant reduction in MACE compared with placebo (HR 0.86, 95% CI 0.81–0.92). Meta-analysis also demonstrated significant reductions in cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. GLP-1RAs did not materially increase the risk of severe hypoglycaemia or acute pancreatitis, while gastrointestinal adverse effects were consistently more frequent. Conclusions GLP-1 receptor agonists significantly reduce major cardiovascular events and mortality in high-risk populations, with a favourable long-term safety profile. These findings support the broader integration of GLP-1RAs into cardiovascular risk reduction strategies beyond glycaemic control. Graphical Abstract