Clinical features modifying the cardiovascular benefits of GLP-1 receptor agonists: a systematic review and meta-analysis

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D), but heterogeneity exists across cardiovascular outcome trials (CVOTs). A comprehensive search of PubMed, EMBASE, and Cochrane Library was conducted through November 2024. Eligible CVOTs compared GLP-1 RAs with placebo in T2D patients. The primary outcome was MACE, defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed using I², τ², and R². Meta-regression analyses evaluated the influence of baseline covariates on cardiovascular benefits of GLP-1 RAs, contingent upon the detection of moderate to substantial heterogeneity (I² ≥ 30%). Sensitivity analyses and GRADE assessments were also performed. Ten trials (67 769 patients; 34 536 receiving GLP-1 RAs) were analyzed. GLP-1 RAs significantly reduced MACE compared with placebo (OR = 0.87, 95% CI: 0.81–0.93, P < 0.001, I² = 48.4%). Cardiovascular death (OR = 0.86, 95% CI: 0.79–0.94, P < 0.001, I² = 22.6%) and all-cause mortality (OR = 0.87, 95% CI: 0.82–0.94, P < 0.001, I² = 17.7%) were also reduced. Meta-regression revealed a greater cardiovascular benefit in patients with higher baseline body mass index (BMI; logOR = −0.098 per kg/m², P = 0.006, R² = 99.98%) and older age (logOR = −0.033 per year, P = 0.023, R² = 75.47%). Sensitivity analyses confirmed the robustness of these findings, with consistent effect sizes and no single trial unduly influencing the results. The certainty of evidence was rated as high for all outcomes based on GRADE criteria. GLP-1 RAs significantly reduce MACE, cardiovascular death, and all-cause mortality in T2D patients. Higher baseline BMI and older age were associated with greater cardiovascular benefit.