Use of SGLT2i Versus DPP-4i as an Add-On Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes

Abstract

OBJECTIVE To compare the risk of composite peripheral artery disease (PAD) surgical outcome, including peripheral revascularization and amputation procedures, between new users of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP-4is). RESEARCH DESIGN AND METHODS This retrospective cohort study of U.S. veterans age ≥18 years with diabetes who received care from the Veterans Health Administration was performed from 1 October 2000 to 31 December 2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP-4i medications as an add-on to metformin, sulfonylurea, or insulin treatment alone or in combination was evaluated for an association with PAD surgical procedure for peripheral revascularization and amputation. A Cox proportional hazards model for time-to-PAD event analysis compared the risk of a PAD event between SGLT2is and DPP-4is in a propensity score–weighted cohort with a competing risk of death and allowance for events to occur up to 90 days or 360 days after stopping SGLT2is. RESULTS The weighted cohort included 76,072 SGLT2i vs. 75,833 DPP-4i use episodes. The median age was 69 years, HbA1c was 8.4% (interquartile range [IQR] 7.5–9.4%), and the median diabetes duration was 10.1 (IQR 6.6–14.6) years. There were 874 and 780 PAD events among SGLT2i and DPP-4i users, respectively, for an event rate of 11.2 (95% CI 10.5–11.9) and 10.0 (9.4–10.6) per 1,000 person-years (adjusted hazard ratio [aHR] 1.18 [95% CI 1.08–1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 (95% CI 1.06–1.26). CONCLUSIONS SGLT2i as an add-on diabetes therapy was associated with an increased cause-specific hazard of PAD surgeries compared with DPP-4i.