Introduction and Objective: Peripheral artery disease (PAD) increases the risk for amputations and limb-threatening events in people with type 2 diabetes (T2D). Tirzepatide and injectable semaglutide are associated with improved limb outcomes. However, real-world comparative outcomes are unknown.Methods: This retrospective cohort study used the TriNetX real-world global database across 112 healthcare organizations with over 130 million patients. Adults 18 years or older with T2D and PAD initiating tirzepatide or injectable semaglutide were included. Propensity score matching (1:1) was performed on 54 covariates across demographics, cardiovascular risk factors, relevant medications, and laboratory measures. The study was conducted from May 13, 2022-December 10, 2025, with a six-month look-back for inclusion of baseline characteristics. Outcomes were evaluated following the index date where inclusion criteria were met. The primary outcome was a composite of major adverse limb events consisting of critical limb ischemia (CLI), amputation, or percutaneous transluminal angioplasty (PTA) or peripheral bypass. Kaplan-Meier analysis was performed with calculation of risk ratios and 95% confidence intervals for outcomes.Results: After matching, 24,274 people were included (N=12,137 in each cohort). Cohorts were well-balanced after matching. Tirzepatide was associated with a significantly lower risk of major adverse limb events versus injectable semaglutide (RR: 0.55, 95% CI: 0.46-0.65, P <0.001). Individual endpoints including CLI (RR: 0.50, 95% CI: 0.39-0.63, P <0.001), amputation (RR: 0.65, 95% CI: 0.45-0.92, P=0.015), and PTA or peripheral bypass (RR: 0.53, 95% CI: 0.43-0.64, P <0.001) all favored tirzepatide.Conclusion: In the real-world, among adults with T2D and PAD, tirzepatide was associated with significantly lower risks of major adverse limb events compared with injectable semaglutide. These findings suggest tirzepatide may offer improved limb-related protection in this high-risk population.
K. Cowart: Research Support; Ended; Abbott Diabetes, Sanofi. B. Ansong: None. R. White: Research Support; Ended; Abbott Diabetes.
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