SGLT2 inhibitors associated with increased risk of amputations, diabetic ketoacidosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with an increased risk of lower-limb amputation and diabetic ketoacidosis compared to glucagon-like peptide-1 (GLP-1) receptor agonists, but rates of other serious adverse events were similar, a study found.

To assess the association between the use of SGLT2 inhibitors and serious adverse events, researchers conducted a register-based cohort study in Sweden and Denmark from July 2013 to December 2016. The study assessed all patients ages 35 years and older who filled a first prescription for either an SGLT2 inhibitor or a GLP-1 receptor agonist during the study period.

Researchers used a matched cohort of 17,213 patients on SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) compared to an equal number of patients taking GLP-1 receptor agonists. Hospital records provided rates of seven serious adverse events: lower-limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis. Results were published by BMJ on Nov. 14.

Use of SGLT2 inhibitors compared with GLP-1 receptor agonists was associated with an increased risk of lower-limb amputation (incidence rate, 2.7 vs. 1.1 events per 1,000 person-years; hazard ratio [HR], 2.32; 95% CI, 1.37 to 3.91) and diabetic ketoacidosis (1.3 vs. 0.6 events per 1,000 person-years; HR, 2.14; 95% CI, 1.01 to 4.52).

Use of SGLT2 inhibitors was not associated with significantly increased risk of bone fracture (15.4 vs. 13.9 events per 1,000 person-years; HR, 1.11; 95% CI, 0.93 to 1.33), acute kidney injury (2.3 vs. 3.2 events per 1,000 person-years; HR, 0.69; 95% CI, 0.45 to 1.05), serious urinary tract infection (5.4 vs. 6.0 events per 1,000 person-years; HR, 0.89; 95% CI, 0.67 to 1.19), venous thromboembolism (4.2 vs. 4.1 events per 1,000 person-years; HR, 0.99; 95% CI, 0.71 to 1.38) or acute pancreatitis (1.3 vs. 1.2 events per 1,000 person-years; HR, 1.16; 95% CI, 0.64 to 2.12).

The study authors noted that the twofold increased risk of diabetic ketoacidosis matches an analysis of insurance claims in the U.S., as well as other studies. They wrote, “Viewed together, a relatively coherent picture of an increased risk of diabetic ketoacidosis associated with the use of SGLT2 inhibitors has emerged, although the absolute risk increase seems small.”