Written by Peter Liu
Spoon Feed
A VA retrospective cohort study found higher procedure rates for peripheral artery disease (PAD) with SGLT2 vs. DPP-4 inhibitors.
SGLT2 inhibitor use is associated with increased PAD events
SGLT2 inhibitors offer clear benefits in diabetes, heart failure, chronic kidney disease, and MI, but carry risks – including UTI, euglycemic DKA, hypovolemia, and possibly PAD. A recent VA study of 150,000 veterans found SGLT2i use was associated with increased PAD-related surgical events vs. DPP-4i (aHR 1.18; 95%CI 1.08–1.29), with event rates of 11.2 vs. 10.0 per 1,000 person-years for SGLT2i and DPP-4i, respectively. This adds to growing but still controversial evidence linking SGLT2 inhibitors to elevated PAD risk.
These findings add to high-quality meta-analyses of RCTs that also conclude a significant cause-effect relationship between SGLT2 use and PAD risk, but results from individual trials remain mixed, and the specific association between SGLT2 inhibitors and amputation risk is even less certain. In their 2022 Guidelines, the ADA concludes that “longer-term studies… have not seen an imbalance in risk,” but cites studies that only evaluate amputation risk, which showed an unfavorable association for SGLT2 inhibitors that didn’t reach statistical significance but still raises eyebrows.
The American College of Cardiology, on the other hand, suggests caution in patients with a history of PAD, severe peripheral neuropathy, or diabetic foot ulcers when using SGLT-2 inhibitors, and careful monitoring and regular foot exams. This most recent VA study favors a more cautious approach.
How does this change my practice?
Due to the myriad cardiovascular, renal, and endocrine benefits of SGLT2 inhibitors, these medications still remain an important part of treatment for many patients with PAD, peripheral neuropathy, or diabetic foot ulcers. However, extra caution for PAD complications should be taken for such patients, including more frequent and thorough foot exams, and lower threshold to discontinue these agents if PAD complications are suspected.
Source
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 Mar 1;48(3):361-370. doi: 10.2337/dc24-1546. PMID: 39977627
