SGLT-2 inhibitors associated with increased risk for diabetic ketoacidosis

A cohort study found a threefold increase in the risk for diabetic ketoacidosis with sodium-glucose cotransporter-2 (SGLT-2) inhibitors compared to dipeptidyl peptidase-4 (DPP-4) inhibitors, with possible variation by severity or duration of diabetes.


In patients with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT-2) inhibitors are associated with an increased risk for diabetic ketoacidosis compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, a propensity-matched cohort study found.

Researchers used data from electronic health records in seven Canadian provinces and the U.K. to look at adult patients initiating therapy with an SGLT-2 inhibitor (alone or in combination with other antidiabetic drugs) or a DPP-4 inhibitor between Jan. 1, 2013, and June 30, 2018. Patients were excluded if they had a hospitalization or ED visit for diabetic ketoacidosis in the year before study cohort entry, initiated therapy with an SGLT-2 inhibitor and a DPP-4 inhibitor on the same date, or received a DPP-4 inhibitor after previously receiving an SGLT-2 inhibitor. The study outcome was diabetic ketoacidosis. Results were published online on July 28 by Annals of Internal Medicine.

Overall, 270,902 study patients with type 2 diabetes received an SGLT-2 inhibitor and 632,114 received a DPP-4 inhibitor. Of those, researchers matched 208,757 SGLT-2 inhibitor recipients (canagliflozin, 42.3%; dapagliflozin, 30.7%; empagliflozin, 27.0%) to 208,757 DPP-4 inhibitor recipients (164,032 unique patients, owing to matching with replacement). During a total of 370,454 person-years of follow-up (mean, 0.9 year), 521 patients were hospitalized with diabetic ketoacidosis (incidence rate, 1.41 per 1,000 person-years).

Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an almost threefold increase in the risk for diabetic ketoacidosis (incidence rates, 2.03 vs. 0.75 per 1,000 person-years; hazard ratio, 2.85 [95% CI, 1.99 to 4.08]). Hazard ratios for specific SGLT-2 inhibitors compared to DPP-4 inhibitors as a class were 1.86 (95% CI, 1.11 to 3.10) for dapagliflozin, 2.52 (95% CI, 1.23 to 5.14) for empagliflozin, and 3.58 (95% CI, 2.13 to 6.03) for canagliflozin. The association was not modified by age, sex, or whether a patient was a new user. However, the risk of diabetic ketoacidosis was lower among patients with prior receipt of insulin compared to those without (hazard ratios, 2.24 [95% CI, 1.40 to 3.61] vs. 3.96 [95% CI, 2.74 to 5.72]). “Thus, our results suggest that the risk for this adverse drug effect could be higher among patients with less advanced disease,” the study authors wrote.

They noted limitations of the study, such as its observational design and their lack of access to baseline laboratory data (e.g., HbA1c levels) for the majority of participants. They added that the results of some subgroup analyses (empagliflozin users, prevalent new users, and those with no prior insulin use) were mainly driven by site-specific findings in Ontario, which did not include patients younger than age 66 years.

The authors concluded, “Because the beneficial effects of SGLT-2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the following years, physicians should be aware of [diabetic ketoacidosis] as a potential adverse effect.”