Physician-authored summaries and commentary on the most important medical research, provided by the NEJM Group, a division of the Massachusetts Medical Society.
© Massachusetts Medical SocietyMay 2025
In a large retrospective study, SGLT-2 inhibitor use was associated with excess risk for peripheral artery revascularisation and amputation.
Some studies have suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors are associated with modest excess risk for adverse peripheral arterial disease (PAD) events (NEJM JW Gen Med 15 Sep 2018 and JAMA Intern Med 2018; 178: 1190-1198; NEJM JW Gen Med 1 Aug 2017 and N Engl J Med 2017; 377: 644-657). To examine this concern further, researchers conducted a retrospective study of US veterans with diabetes who were treated with metformin, insulin, sulfonylurea or combinations of them. About 76,000 patients who received additional treatment with SGLT-2 inhibitors (usually empagliflozin) were compared with 76,000 propensity matched patients who received add-on treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors. Median age was 69 years, and median diabetes duration was 10 years.
The composite primary outcome (i.e. amputation or peripheral artery revascularisation) occurred slightly more often in the SGLT-2 group than in the DPP-4 group (11.2 vs 10.0 events per 1000 person-years). In adjusted analysis, SGLT-2 inhibitor use was associated with significantly higher risks: adjusted hazard ratios were 1.18, 1.25 and 1.15 for the composite outcome, revascularisation and amputation, respectively.
Comment: These results support previous research that suggests a link between SGLT-2 inhibitors and adverse PAD events. Nevertheless, absolute risk for adverse events was low in this study, and cumulative four-year mortality was lower with SGLT-2 inhibitor use than with DPP-4 inhibitor use. The underlying mechanism for a link between SGLT-2 inhibitors and PAD remains unknown. I will discuss potential risks before prescribing SGLT-2 inhibitors, but for appropriately selected patients with stable PAD, cardiovascular and renal benefits probably will outweigh risks. However, avoiding SGLT-2 inhibitors seems prudent for patients with severe or progressively symptomatic PAD.
David S. Weisman, DO, FACP, Associate Professor of Medicine Clinician Educator, Georgetown University Medical Center, Washington, DC; Associate Program Director in Internal Medicine, MedStar Health, Baltimore, USA.
Griffin KE, et al. 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. Diabetes Care 2025; 48: 361–370.
This summary is taken from the following Journal Watch titles: General Medicine, Ambulatory Medicine.