Semaglutide and major adverse cardiovascular events in patients with and without DM: a systematic review and meta-analysis

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, particularly in patients with type 2 diabetes mellitus (T2DM) and obesity. Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown promising effects on cardiovascular outcomes. This systematic review and meta-analysis aimed to evaluate semaglutide's effect on major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, in patients with and without T2DM. A comprehensive search of MEDLINE, Embase, Cochrane CENTRAL, and Web of Science databases followed PRISMA guidelines. Randomized controlled trials (RCTs) published up to January 2025 were included. Data from 11 high-quality RCTs, involving over 25,000 participants, were analyzed using a random-effects model. The pooled odds ratio (OR) for MACE was 0.68 (95% CI: 0.52–0.91, p < 0.01), indicating a significant 32% reduction in cardiovascular risk with semaglutide compared to placebo or active comparators. Sensitivity analyses confirmed the robustness of these findings, with ORs ranging between 0.630 and 0.761 across sequential exclusions. Moderator analysis revealed significant positive associations for age (slope = 0.025, p = 0.000), HbA1c (slope = 0.155, p = 0.002), and blood pressure, while body weight (slope = -0.126, p = 0.005), LDL, and total cholesterol were inversely associated. As confirmed by Egger’s regression and fail-safe N analyses, minimal publication bias was observed. These findings highlight semaglutide’s multifactorial benefits in reducing cardiovascular risk, which are driven by weight loss, blood pressure reduction, and metabolic improvements. Semaglutide represents a powerful intervention for cardiovascular risk management in patients with and without diabetes.