GLP-1RAs associated with improved walking distance in diabetes with PAD, but limb event evidence uncertain

AIMS: The aim of this systematic review and meta-analysis was to evaluate the effect of GLP-1RAs on functional walking distance and the risk of major adverse limb events (MALE) or lower extremity amputation (LEA) in people with type 2 diabetes and peripheral artery disease (PAD). MATERIALS AND METHODS: We searched many electronic databases up to 10 October 2025 for randomised controlled trials (RCTs) and cohort studies. We included studies enrolling adults with type 2 diabetes and PAD, comparing GLP-1RAs against placebo or other glucose-lowering drugs. The primary outcomes were walking distance, MALE, or LEA. Data were pooled using a random-effects model, with hazard ratios (HR) or risk ratios (RR). Risk of bias was assessed using RoB2 for RCTs and ROBINS-I for cohort studies; evidence certainty was evaluated using the GRADE approach. RESULTS: We included seven studies (3 RCTs, 4 cohorts) enrolling 107 092 participants. The meta-analysis of two RCTs with 847 participants demonstrated a significant improvement in walking distance with liraglutide or semaglutide (HR = 1.10, 95% CI 1.05-1.15, p < 0.001), with no heterogeneity (I = 0.0%) and moderate certainty of evidence. In the additional meta-analysis of two RCTs with 3592 participants, the incidence of MALE or LEA did not differ significantly between patients receiving exenatide or semaglutide and those receiving placebo. The meta-analysis of four cohort studies with 104 292 participants showed that GLP-1RAs reduced the risk of LEA (RR = 0.53, 95% CI 0.39-0.73, p < 0.001), with high heterogeneity (I = 85.96%), totally related to one study, and very low certainty of evidence. Subgroup analyses showed a significant difference (p < 0.001) between GLP-1RA therapies, with the strongest associations with LEA reduction for tirzepatide and semaglutide (55% and 54% risk reduction, respectively); there was no difference in the LEA outcome excluding from the analysis patients with type 2 diabetes and diabetic foot ulcers at baseline. CONCLUSIONS: This meta-analysis suggests that GLP-1RAs are associated with a significant improvement in functional walking distance and a reduction in the risk of LEA in people with type 2 and PAD. Further dedicated RCTs are needed to confirm these limb-specific benefits of GLP-1RAs.