Impact of Semaglutide on Limb Events: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Peripheral artery disease (PAD) is a prevalent and debilitating complication of diabetes and obesity, yet it remains underrecognized and undertreated. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have shown cardiovascular benefits, but their impact on peripheral vascular outcomes remains unclear. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the effect of semaglutide on limb events (LEs) in individuals with type 2 diabetes and/or overweight or obesity. METHODS: Following PRISMA guidelines, 19 randomized controlled trials encompassing 51,557 participants were included. Major limb events, prespecified and reported as safety outcomes in the original trials, were defined a priori as the primary outcome of this meta-analysis, comprising revascularizations, amputations, and PAD progression. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Semaglutide significantly reduced the risk of LEs compared to control interventions (OR 0.70; 95% CI 0.60-0.82; p < 0.0001), with no heterogeneity across studies (I² = 0%). Benefits were consistent across patient subgroups, in patients with diabetes (OR 0.70; 95% CI: 0.57-0.87; p = 0.001) or obesity (OR 0.71; 95% CI: 0.56-0.89; p = 0.003); oral formulation (0.71; 95% CI: 0.53-0.94; p = 0.02) or subcutaneous (0.68; 95% CI: 0.49-0.95; p = 0.02 and 0.71; 95% CI: 0.57-0.89; p = 0.003, for 1.0 mg and 2.4 mg, respectively); and regardless of background SGLT2 inhibitor use. Meta-regression showed no significant effect modification by age, BMI, HbA1c, follow-up duration, or SGLT2i use. CONCLUSIONS: This meta-analysis suggest that semaglutide is associated with a significant reduction in major limb events across diverse populations and treatment settings, supporting a potential protective effect on limb-related vascular safety.