SGLT2 inhibitors tied to ketoacidosis, limb amputation in diabetics

An observational study of nearly 35,000 Scandinavian patients with type 2 diabetes (T2D) has found sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of prescription drugs approved by the FDA to lower blood sugar in adults with T2D, may almost double patients’ risks of lower limb amputation and diabetic ketoacidosis compared to glucagon-like peptide 1 (GLP1) receptor agonists.

In a paper published in The BMJ, senior researcher Bjorn Pasternak, MD, PhD, and colleagues said SGLT2 inhibitors, which include medications like canagliflozin, dapagliflozin and empagliflozin, are becoming an increasingly popular class of drugs for the treatment of T2D. SGLT2s lower blood glucose levels by encouraging glucose loss through the kidneys, but they’ve provoked concern in the past from the FDA.

“Case reports to the U.S. FDA Adverse Event Reporting System have indicated that SGLT2 inhibitors could cause diabetic ketoacidosis, acute kidney injury and serious urinary tract infection,” Pasternak and coauthors wrote. “SGLT2 inhibitors increase blood viscosity by inducing mild diuresis, which suggests that the risk of venous thromboembolism could be increased.”

The FDA is also investigating reports linking SGLT2s to acute pancreatitis, they said.

Pasternak and his team evaluated the potential risks of the drug class by comparing data from 17,213 diabetic patients in Sweden and Denmark who’d just started taking SGLT2 inhibitors to that of 17,213 diabetics taking GLP1 receptor agonists. All patients were 35 or older, with no previous prescriptions for either of the study drugs.

The researchers looked for outcomes including limb amputation, bone fracture, ketoacidosis, acute kidney injury, urinary tract infection and venous thromboembolism during an average 270 day follow-up period. After adjusting for factors like disease history, socioeconomic status and other medications, the team found the use of SGLT2 inhibitors was associated with a twofold increased risk of both lower limb amputation and diabetic ketoacidosis compared to GLP1 receptor agonists.

There was no significant link between SGLT2 inhibitors and elevated risk for bone fracture, acute kidney injury, serious UTI, thromboembolism or acute pancreatitis.

Pasternak et al. said since their results are observational, they can’t rule out residual or unmeasured confounding factors that could have affected their study outcomes.

“In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern,” the authors wrote.