Impact of GLP-1 receptor agonists on cardiovascular outcomes in patients with peripheral artery disease without diabetes: A propensity score-matched analysis

Peripheral artery disease (PAD) is associated with a high risk of cardiovascular events. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular benefit in patients with diabetes, their role in patients with PAD without diabetes is not well understood. This study aimed to assess the impact of GLP-1RA therapy on cardiovascular outcomes in nondiabetic PAD patients. We conducted a retrospective cohort study using the TriNetX U.S. collaborative network, identifying adults aged 18-89 with PAD and no history of diabetes from January 2014 to January 2024. Patients treated with GLP-1RAs were compared with untreated counterparts. A 1:1 greedy nearest neighbor propensity score matching was performed to balance baseline characteristics. The primary outcomes were 3-point major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, all-cause mortality; major adverse limb events (MALE) defined as limb-threatening ischemia, revascularization procedures, or major amputation. Cox regression and Kaplan-Meier analysis were used to assess outcomes over a 5-year follow-up period. After matching, 13,555 patients remained in each group with well-balanced covariates. GLP-1RA use was associated with lower risk of MACE (hazard ratio (HR): 0.61; 95% confidence interval (CI): 0.57-0.66; <i>p</i> < 0.001), all-cause mortality (HR: 0.40; 95% CI: 0.35-0.46; <i>p</i> < 0.001), and MALE (HR: 0.22; 95% CI: 0.17-0.28; <i>p</i> < 0.001). In a sensitivity analysis focusing on semaglutide use initiated post-2021, the benefits remained robust for both MACE (HR: 0.55; 95% CI: 0.50-0.60) and all-cause mortality (HR: 0.303; 95% CI: 0.25-0.36). In this large real-world cohort, GLP-1RA therapy was associated with significantly reduced cardiovascular and limb-related events in nondiabetic patients with PAD. These findings support the potential role of GLP-1RAs in cardiovascular risk reduction beyond diabetes and highlight the need for prospective randomized trials in this population.