Key result
GLP-1 receptor agonists reduced all-cause mortality (IRR 0.88; 95% CI 0.83-0.92), CV mortality (IRR 0.86), and MACE (IRR 0.87; 95% CI 0.83-0.91) compared with placebo or standard care.
Why the study?
Do GLP-1 receptor agonists reduce mortality and cardiovascular events across diverse patient populations compared to placebo or standard care?
Meta-Analysis
Do GLP-1 receptor agonists reduce mortality and cardiovascular events across diverse patient populations compared to placebo or standard care?
Effect estimate: IRR 0.87 (95% CI 0.83-0.91)
GLP-1 receptor agonists provide consistent and significant reductions in mortality and major adverse cardiovascular events across diverse patient populations, though they are associated with increased risks of gallbladder disorders and pancreatitis.
Warrants broader GLP-1RA use in cardiometabolic risk management; reinforces class-wide mortality and MACE benefits across populations and agents.
Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with significant cardiovascular (CV) benefits in patients with type 2 diabetes mellitus (DM). However, the efficacy and safety among different agents across diverse patient populations remain inadequately defined. Purpose We conducted a systematic review, along with pairwise and network meta-analysis, to assess the safety and efficacy of GLP-1 RAs across various patient subgroups and to explore potential variances in outcomes among different GLP-1 RA agents. Methods A systematic search was conducted to identify randomized controlled trials comparing GLP-1 RAs vs placebo or standard care. Primary endpoints comprised mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). Secondary outcomes included myocardial infarction (MI), stroke, heart failure (HF) hospitalization, pancreatitis, infections, gastrointestinal (GI) disorders, and neoplasms. Incident Rate Ratios (IRRs) with 95% confidence intervals (CI) using the random-effects model with inverse variance weighting were calculated. All analyses were run according to a pre-specified subgroup based on the specific GLP-1 RA used. Sensitivity analyses included patients with diabetes mellitus (DM), chronic kidney disease (CKD), obesity or reduced ejection fraction (EF). A Bayesian network meta-analysis including ranking of treatments was performed to explore the comparative effects of different GLP-1 RAs. Results A total of 19 trials encompassing 6967 patient-year and using eight different GLP1-RAs (Lixisenatide, Liraglutide, Exenatide, Semaglutide, Efpeglenatide, Dalaglutide Albiglutide, and Tirzepatide) were included. Mean follow-up duration was 2.2 years. GLP-1 RA reduced all-cause (IRR 0.88, 95% CI 0.83–0.92) and CV (IRR 0.86, 95% CI 0.80–0.92; Figure 1) mortality, MACE (IRR 0.87, 95% CI 0.83–0.91; Figure 2) and SAE (IRR 0.92, 95% CI 0.90–0.94), compared with placebo. GLP-1 RAs reduced MI (-10%), stroke (-10%), HF (-12%), but increased gallbladder disorders (+32%) and pancreatitis (+17%) with no difference in GI disorder, infections, and neoplasms. At treatment ranking, efpeglenatide, liraglutide and semaglutide ranked as the best treatments for all-cause and CV mortality, while efpeglenatide, albiglutide and semaglutide as the best treatments for MACE and SAE. Semaglutide ranked as the safest treatment for gallbladder disorders while lixisenatide, liraglutide and efpeglenatide as the safest treatments for pancreatitis. Results were consistent across the spectrum of patients with DM, CKD, obesity or reduced EF. Conclusions These findings underscore the significant prognostic and cardiovascular effects of GLP-1 receptor agonists across various patient groups. The identification of agent-specific risk-benefit profiles highlights the value of individualized treatment approaches guided by cardiovascular risk and patient tolerance.Figure 1:Forest plots for CV death Figure 2:Forest plots for MACE
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Galli et al. (2025) conducted a meta-analysis in Type 2 diabetes mellitus, chronic kidney disease, obesity, or reduced ejection fraction. GLP-1 receptor agonists vs. Placebo or standard care was evaluated on Mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE), and serious adverse events (SAEs) (IRR 0.87, 95% CI 0.83-0.91). GLP-1 receptor agonists reduced all-cause mortality (IRR 0.88; 95% CI 0.83-0.92), CV mortality (IRR 0.86), and MACE (IRR 0.87; 95% CI 0.83-0.91) compared with placebo or standard care.
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