Impact of semaglutide on limb events: a meta-analysis of randomized controlled trials

Abstract Aims 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, 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 and results Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 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. Semaglutide significantly reduced the risk of LEs compared with 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 and 2.4 mg, respectively); and regardless of background SGLT2 inhibitor use. Meta-regression showed no significant effect modification by age, body mass index, HbA1c, follow-up duration, or sodium-glucose co-transporter 2 inhibitors use. Conclusion This meta-analysis suggests that semaglutide is associated with a significant reduction in major LEs across diverse populations and treatment settings, supporting a potential protective effect on limb-related vascular safety. Lay summary This meta-analysis evaluates whether semaglutide can reduce the risk of peripheral artery disease (PAD) complications in people with diabetes or obesity. By analysing data from 19 randomized controlled trials involving over 51 000 participants, the findings highlight semaglutide’s potential role in lowering the risk of amputations, revascularizations, and disease progression, beyond its established benefits on weight loss and glycaemic control. Key findings:Semaglutide reduced the risk of PAD-related events by about 30% compared with other treatments.The protective effect was consistent across patient subgroups, formulations (oral or injectable), and irrespective of concomitant SGLT2 inhibitor use.