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.