Abstract Body (Do not enter title and authors here): Introduction:
Tirzepatide has demonstrated superior glycemic and cardiovascular benefits compared to traditional GLP-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes. Peripheral arterial disease (PAD) is a common and serious complication in this population; however, the comparative effectiveness of tirzepatide versus GLP-1 RAs in patients with both type 2 diabetes and PAD remains underexplored.

Research Questions:
Does tirzepatide offer greater clinical benefits than GLP-1 RAs in patients with type 2 diabetes and PAD?

Methods:
We conducted a retrospective cohort study using data from the Global Collaborative Network TriNetX, covering the period from January 2022 to January 2025. Patients with diabetes and PAD were identified based on ICD-10 codes. Two cohorts were established based on treatment with tirzepatide or GLP-1 RAs. Propensity score matching was employed to balance baseline characteristics, including demographics, comorbidities, laboratory data, and concurrent medications.

Results:
After propensity score matching, 3,018 patients were included in each group, with no significant differences in baseline characteristics. Over a one-year follow-up, patients treated with tirzepatide exhibited a significantly lower risk of adverse outcomes compared to those receiving GLP-1 RAs. These included all-cause mortality (HR 0.58, 95% CI: 0.429–0.785, P = 0.0004), major adverse cardiovascular events (MACE) (HR 0.769, 95% CI: 0.679–0.872, P < 0.0001), major adverse limb events (MALE) (HR 0.742, 95% CI: 0.621–0.887, P = 0.001), amputation (HR 0.558, 95% CI: 0.369–0.843, P = 0.005), and vascular intervention (HR 0.784, 95% CI: 0.649–0.947, P = 0.0146). In contrast, there was no significant difference in the risk of ischemic stroke (HR 1.025, 95% CI: 0.695–1.513, P= 0.8993).

Conclusion:
In patients with type 2 diabetes and PAD, tirzepatide was associated with significantly better clinical outcomes compared to GLP-1 RAs. Further prospective studies are warranted to confirm these benefits and assess long-term safety.