Use of SGLT2i versus DPP4i 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

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 (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i).

Research Design and Methods: Retrospective cohort of U.S. Veterans > 18 years old with diabetes who received care from the Veterans Health Administration from 10/01/2000 to 12/31/2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP4i medications as addition 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 SGLT2i and DPP4i in a propensity-score weighted cohort, with a competing risk of death and allowing for events to occur up to 90 days or 360 days after stopping SGLT2i.

Results: The weighted cohort included 76,072 SGLT2i vs 75,833 DPP4i use episodes. The median age was 69 years old, HbA1c was 8.4 [7.5, 9.4], and the diabetes duration was 10.1 [6.6, 14.6] years. There were 874 and 780 PAD events among SGLT2i and DPP4i users, respectively, for an event rate of 11.2 (10.5-11.9) and 10.0 (9.4-10.6) per 1000 person-years (aHR 1.18 [1.08, 1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 [1.06, 1.26]).

Conclusion: SGLT2i as an add-on therapy was associated with increased cause specific hazard of PAD surgeries compared to DPP4i.