Tirzepatide and major adverse limb events: Insights from a multicenter real-world analysis in PAD and diabetes patients

Aims: Peripheral artery disease (PAD) is a major diabetic complication and a leading cause of amputation. While GLP-1 receptor agonists (GLP-1 RAs) provide cardiovascular and limb protection, the impact of tirzepatide, a dual GLP-1/GIP receptor agonist, on major adverse limb events (MALEs) remains unclear. This study assessed tirzepatide's association with MALE risk in patients with PAD and diabetes using real-world data. Methods: This retrospective cohort study analyzed 8,046 propensity score-matched PAD patients with diabetes (4,023 on tirzepatide, 4,023 controls) from the TriNetX database. The primary outcome was MALEs, with secondary outcomes including all-cause mortality, acute stroke, acute myocardial infarction (AMI), and major adverse cardiovascular events (MACEs). Cox models and Kaplan-Meier curves were used for analysis. Results: Tirzepatide significantly reduced MALE risk (HR: 0.44, 95 % CI: 0.33-0.59, p < 0.001) and was associated with lower mortality, stroke, and MACEs. AMI risk was similar between groups (HR: 0.85, p = 0.29). Subgroup analyses confirmed consistent findings, except in those with prior stroke. Conclusions: Tirzepatide significantly lowered MALE risk in PAD patients with diabetes, suggesting a potential therapeutic role. Further prospective studies are needed to validate these findings.