Study Mentions Concerns of Diabetic Ketoacidosis When Starting SGLT2 Inhibitors

Prior data had indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors could be linked to diabetic ketoacidosis, a serious complication of diabetes. The recently published results of a claims analysis seem to confirm the association between initiating SGLT2 inhibitor therapy and experiencing diabetic ketoacidosis.

According to a study recently published in the New England Journal of Medicine (NEJM), the FDA issued a warning to patients in May 2015 after case studies showed patients were at higher risk of diabetic ketoacidosis. More recently, a report published in Diabetes Care indicated that rates of diabetic ketoacidosis, while rare, were elevated for patients taking SGLT2 inhibitors to treat type 2 diabetes.

Diabetic ketoacidosis, which can be life-threatening, occurs when insulin levels are low, provoking the body to burn fatty acids, which causes the presence of acetic ketone bodies. Meanwhile, SGLT2 inhibitors “decrease plasma glucose by blocking the reabsorption of glucose at the proximal tubule,” the NEJM study explained.

The researchers conducting that study used a large commercial claims database to collect a sample of adults who had initiated therapy with either an SGLT2 inhibitor or a dipeptidyl peptidase 4

(DPP4) inhibitor, another medication for diabetes that has not been linked to diabetic ketoacidosis. They examined the records for evidence of hospitalizations for diabetic ketoacidosis up to 180 days after initiating therapy.

Over 50,000 patients were identified in the SGLT2 inhibitor group, who tended to be younger, more likely to receive insulin, and have fewer comorbid conditions than the more than 90,000 patients in the DPP4 inhibitor group. The study authors performed an unadjusted comparison analysis, then used propensity-score matching to account for 46 different patient characteristics.

In the unadjusted comparison, patients starting SGLT2 inhibitor therapy were around twice as likely as the DPP4 inhibitor group to experience diabetic ketoacidosis (hazard ratio [HR], 2.1). The rate of diabetic ketoacidosis was 4.9 occurrences per 1000 person-years in the SGLT2 inhibitor group, compared with 2.3 occurrences per 1000 person-years in the DPP4 inhibitor group.

After matching for propensity scores, there was still a higher risk of diabetic ketoacidosis among the SGLT2 inhibitor patients than the DPP4 inhibitor patients (HR, 2.2). The authors wrote that these findings confirmed that “shortly after initiation, SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis as were DPP4 inhibitors, although cases of diabetic ketoacidosis leading to hospitalization were infrequent.”

Similar to the conclusions of other studies investigating the link between SGLT2 inhibitors and diabetic ketoacidosis, the study authors recommended clinicians use extra caution when prescribing SGLT2 inhibitors to patients with diabetes and be aware of the signs of the complication.

“The increased risk of diabetic ketoacidosis with SGLT2 inhibitors is among the factors to be considered at the time of prescribing and throughout therapy if patients present with symptoms suggestive of diabetic ketoacidosis,” they wrote.