CLINICAL QUESTION: Do sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as add-on therapy for diabetes, increase the risk of amputations, stent placement, or revascularization surgeries compared with dipeptidyl peptidase 4 (DPP-4) inhibitors?
BACKGROUND: Early studies of SGLT-2 inhibitors suggested an increased risk of lower extremity amputation, though more recent studies did not come to the same conclusion. Given this conflicting evidence, uncertainty remains about the use of SGLT-2 inhibitors in patients with increased risk for peripheral artery disease (PAD).
STUDY DESIGN: A retrospective cohort study
SETTING: Veterans Health Administration
SYNOPSIS: 151,905 high-risk U.S. veterans with type 2 diabetes (median age, 68 years; median diabetes duration, 10 years; average hemoglobin A1c, 8.4%) were evaluated for risk of PAD-related surgical events (amputation, stent placement, or revascularization) between users of SGLT-2 inhibitors and DPP-4 inhibitors. The study found that SGLT-2 inhibitor use, predominantly empagliflozin, was associated with a higher risk of PAD-related surgical events compared to DPP-4 inhibitors (adjusted hazard ratio, 1.18;95% CI, 1.08 to 1.29), with the increased risk being consistent across both amputations and revascularizations. Limitations included short median follow-up (approximately 0.7 years), potential residual confounding, and a demographically narrow sample (mostly older white men), limiting generalizability. These findings add to ongoing concerns about PAD risk with SGLT-2i’s, reinforcing the importance of individualized risk-benefit assessment, particularly in patients with high baseline PAD risk.
BOTTOM LINE: The addition of SGLT-2 inhibitors as add-on therapy for diabetes is associated with an increased risk of amputations, stent placement, or revascularization surgeries compared to DPP-4 inhibitors, underscoring the need for a better risk-stratified approach to SGLT-2 inhibitor prescribing with respect to risks of PAD and cardiovascular benefit.
CITATION: Griffin KE, et al. Use of SGLT-2i 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. Diabetes Care. 2025;48(3):361-370. doi: 10.2337/dc24-1546.
Dr. Khan
Dr. Petullo
Drs. Khan and Petullo are clinical assistant professors in the division of hospital medicine at The Ohio State University Wexner Medical Center in Columbus, Ohio.