Tirzepatide versus other anti-diabetic agents for the prevention of diabetic foot complications in patients with type 2 diabetes

Background Diabetic foot complications affect up to 25% of patients with type 2 diabetes (T2D) and represent a major cause of morbidity. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist - tirzepatide (TZP) has demonstrated superior glycemic control compared with semaglutide however, evidence regarding its effects on diabetic foot complications (DFCs) remains limited. Methods We conducted a retrospective cohort study using the TriNetX network. Adults with T2D initiating TZP, sulfonylurea (SU), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium–glucose cotransporter-2 inhibitors (SGLT2is), and glucagon-like peptide-1 receptor agonists (GLP-1RAs) between January 2022 and July 2025 were included. Propensity score matching created balanced cohorts for four comparisons. The primary outcome was the risk of DFC - a composite of ulcers, infections, critical limb ischemia, and revascularization or amputation. Results After matching, four cohorts included 141,002 patients per arm (TZP vs. SU), 131,449 patients per arm (TZP vs. DPP-4i), 146,321 patients per arm (TZP vs. SGLT2i), and 97,457 patients per arm (TZP vs. GLP-1RA). Compared with SU, TZP was associated with reduced diabetic foot complications (HR, 0.80; 95% CI, 0.76–0.84). Similar reductions were observed versus DPP-4i (HR, 0.83; 95% CI, 0.78–0.87) and SGLT2i (HR, 0.88; 95% CI, 0.83–0.92). No difference was found versus GLP-1RA (HR, 0.97; 95% CI, 0.91–1.03). Conclusion TZP was associated with a reduction in diabetic foot complications compared with SU, DPP-4i, and SGLT2i, with outcomes similar to GLP-1RA. These findings suggest tirzepatide may be a valuable option for patients at risk of ulceration or amputation.