Differential Effect of GLP-1RA and SGLT2 Inhibitors on Lower Extremity Amputation Outcomes in Type 2 Diabetes

Introduction and Objective: Patients with diabetes mellitus are at increased risk of lower extremity amputations (LEAs), a severe complication affecting morbidity and quality of life. This study evaluates the association between glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus sodium-glucose cotransporter-2 inhibitors (SGLT2i) and risk of LEAs in patients with type 2 diabetes (T2D). Methods: We conducted a retrospective cohort study using TriNetX, a federated electronic health records network, including adults with T2D who initiated GLP-1 RA or SGLT2i after May 2013. Outcomes included incident diabetic foot ulcer (DFU), major LEA, and minor LEA. Propensity score matching (1:1 ratio) adjusted for demographics, comorbidities, medications, and laboratory values. Results were reported as hazard ratio (HR) with 95% confidence intervals (CIs). Results: The matched cohort included 106,649 patients receiving GLP-1 RA and 106,649 patients receiving SGLT2i. Compared with SGLT2i, GLP-1 RA cohort was associated with a lower risk of major (HR 0.73, 95% CI 0.60-0.90) and minor LEA (HR 0.86, 95% CI 0.74-0.99) at 3 years, but no differences in DFU risk. Conclusion: In this real-world study, GLP-1 RA treatment was linked to a reduced risk of amputations compared with SGLT2i in T2D. Prospective studies are needed to confirm these findings and guide glucose-lowering therapy for at-risk patients. Disclosure: A.T. Hong: None. I.Y. Luu: None. F. Lin: None. L. Shin: None. C. Hsu: None. D.G. Armstrong: None. T. Tan: None.