Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide proven cardiovascular benefits in type 2 diabetes mellitus (T2DM) and heart failure, but their effects in patients with peripheral artery disease (PAD) remain unclear. PAD is common in T2DM and increases the risk of adverse cardiovascular and limb outcomes. This meta-analysis assessed the impact of GLP-1 RAs on cardiovascular and limb-related outcomes in patients with T2DM and PAD. A systematic search of PubMed, Cochrane CENTRAL, ScienceDirect, and ClinicalTrials.gov was conducted through May 24, 2025. Primary outcomes included all-cause mortality (ACM) and cardiovascular mortality (CVM). Secondary outcomes were major adverse cardiovascular events (MACE), myocardial infarction, stroke, major adverse limb events (MALE), glycemic control (HbA1c), body weight, and adverse events. Pooled risk ratios and mean differences were calculated using random-effects models. Six randomized controlled trials, including 7,645 participants met the inclusion criteria. GLP-1 RAs significantly reduced ACM (RR 0.83, 95% CI 0.70 to 0.99, p = 0.04, I² = 0%), MACE (RR 0.86, 95% CI 0.76 to 0.98, p = 0.02, I² = 0%), and improved HbA1c (MD -0.72%, p = 0.02), with no significant effect on weight, major adverse limb events (MALE), CVM, myocardial infarction, or stroke. In conclusion, GLP-1 RAs lower MACE and ACM in patients with T2DM and PAD but do not clearly benefit limb-specific outcomes, highlighting the need for larger, PAD-focused trials to clarify their role in limb protection.
