New Study Takes Closer Look at SGLT2 Inhibitors and Amputation Risk

Do sodium-glucose cotransporter-2 (SGLT2) inhibitors increase amputation risk? A newly published study in the European Heart Journal involving over 2,722,000 patients found that the risk of lower limb amputation with the combination of SGLT-2 inhibitors and incretins was not higher in comparison to other anti-diabetes drugs.¹

This is in marked contrast to the highly publicized CANVAS study, which found that the SGLT2 inhibitor canagliflozin nearly doubled the risk of amputation.² Yet the new study from Paul and colleagues notes similar lower limb amputation rates for patients taking either canagliflozin, empagliflozin or dapagliflozin as a SGLT2 inhibitor.

Patients with preexisting peripheral arterial disease (PAD) had a fourfold higher risk of amputation, according to Paul and coworkers.¹ However, the researchers note that among patients who did not have PAD at the beginning of the study, the rate of PAD at a mean 1.8-year follow-up was lower in the SGLT2 inhibitor group and the glucagon-like peptide 1 receptor agonist (GLP-1RA) group in comparison to those treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor and other anti-diabetes drugs.

Deepak L. Bhatt, MD, MPH, a co-author of the new study, says these findings should allay some of the concerns over the use of SGLT2 inhibitors in regard to amputation risk.

“After the CANVAS trial, there was a great deal of concern about amputation risk with canagliflozin specifically and SGLT2 inhibitors in general. In our large observational analysis (not randomized), we found no relationship between SGLT2 inhibitors and amputation,” notes Dr. Bhatt, a Professor of Medicine at Harvard Medical School. “… I think our data are very reassuring and suggest that in patients in whom doctors choose to use SGLT2 inhibitors, there does not appear to be a detectable risk in amputation.”

David Swain, DPM, CWSP, says he was among the practitioners who had concerns about SGLT2 inhibitors and the potential amputation risk after the CANVAS trial was published.² He is encouraged by the new study findings but says long-term follow-up research may provide more clarity on these medications.

“I believe with the findings of this new study, the perception of (SGLT2 inhibitors) may shift so they are viewed as being slightly safer for use,” suggests Dr. Swain, who is board-certified in limb preservation and salvage, podiatric surgery and primary care in podiatric medicine by the American Board of Multiple Specialties in Podiatry. “As there are conflicting results between multiple studies, further long-term testing and research will need to be completed to better refute the perception of SGLT2 inhibitors as amputation-causing agents.”³

Dr. Bhatt says other major SGLT2 inhibitor trials after the CANVAS trial have not found any amputation concerns.⁴ However, he notes that doctors may have been more cautious about utilizing SGLT2 inhibitors after the CANVAS trial so it is possible that patients at the highest risk of amputation may not have been enrolled in subsequent clinical trials.

Paul and colleagues acknowledge that the CANVAS study patients were five years older on average, had a longer duration of diabetes and had a 46 percent higher prevalence of cardiovascular disease at baseline in comparison to the patient population in the new study.^1,2 Accordingly, Dr. Bhatt emphasizes caution with SGLT2 inhibitors when patients have more severe PAD.

“While I think it is likely okay to use SGLT2 inhibitors in patients with stable PAD, I would still be cautious in patients with critical limb-threatening ischemia (CLTI),” notes Dr. Bhatt, the Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital Heart and Vascular Center in Boston.

“Based on the conflicting results from multiple studies, I would still be careful with the use of these drugs, especially in older patients with known PAD,” adds Dr. Swain, who is affiliated with the First Coast Cardiovascular Institute, which has multiple office locations in Florida and Georgia.

In regard to future directions for research looking at SGLT2 inhibitors and other anti-diabetes medications and whether they have an impact on amputation rates, Dr. Bhatt says trials specifically looking at the use of these medications in patients with diabetes and PAD would be beneficial.

“(These trials) would be informative in terms of demonstrating what I think would be robust benefit and also providing a more comprehensive assessment of amputation risk,” suggests Dr. Bhatt.

Assuming it has not already been studied, Dr. Swain says it would be interesting to look at groups of patients who were previously on older anti-diabetes medications for years with no issues but began to have pathology after switching to SGLT2 inhibitors.

“I recently had a patient who developed her first foot ulcer within a month of switching to a SGLT2 inhibitor,” notes Dr. Swain.

Dr. Bhatt says SGLT2 inhibitors still have an essential role for many patients with type 2 diabetes.

“Other than issues of cost or a contraindication, I believe that most patients with type 2 diabetes should be on an SGLT2 inhibitor,” posits Dr. Bhatt. “This is especially true if they have heart failure or chronic kidney disease.”

While Dr. Swain maintains that more long-term research is needed, he says this new study shows that SGLT2 inhibitors “may not be as dangerous as previously thought.” He adds that the study’s finding of a fourfold greater amputation risk in patients with preexisting PAD is very troubling.¹

“The study highlights the known correlation of PAD to amputation risk and shows how badly we, as physicians, need better treatments and medications for PAD prevention,” claims Dr. Swain.

References

1. Paul SK, Bhatt DL, Montvida O. The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study. Eur Heart J. 2021;42(18):1728-1738.
2. Neal B, Perkovic V, Mahaffey KW. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
3. Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365. doi: 10.1136/bmj.k4365.
4. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139.