GLP1 ‐ 1RAs improve walking distance and reduce amputation in people with type 2 diabetes and peripheral artery disease: A systematic review and meta‐analysis of randomised controlled trials and cohort studies

Abstract 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 2 = 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 2 = 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.