SGLT-2 inhibitors up risk of diabetic ketoacidosis

Sodium–glucose cotransporter-2 (SGLT-2) inhibitors increase the risk for diabetic ketoacidosis (DKA) by almost threefold, with molecule-specific analyses suggesting a class effect, according to a study.

DKA was diagnosed in 521 patients during 370,454 person-years of follow-up (incidence rate per 1,000 person-years, 1.40, 95 percent confidence interval [CI], 1.29–1.53).

SGLT-2 inhibitors correlated with an increased risk for DKA when compared with dipeptidyl peptidase-4 (DPP-4) inhibitors (incidence rate, 2.03, 95 percent CI, 1.83–2.25 vs 0.75, 95 percent CI, 0.63–0.89; hazard ratio [HR], 2.85, 95 percent CI, 1.99–4.08). Molecule-specific HRs were 1.86 (95 percent CI, 1.11–3.10) for dapagliflozin, 2.52 (95 percent CI, 1.23–5.14) for empagliflozin, and 3.58 (95 percent CI, 2.13–6.03) for canagliflozin.

Such association was not modified by age and sex, but prior receipt of insulin appeared to lower the risk.

This population-based cohort study utilized electronic healthcare databases from seven Canadian provinces and the UK.  Using time-conditional propensity scores, a total of 208,757 new users of SGLT-2 inhibitors were matched 1:1 to users of DPP-4 inhibitors.

The investigators used Cox proportional hazards models to estimate site-specific HRs of DKA, comparing receipt of SGLT-2 inhibitors with that of DPP-4 inhibitors. Random effects models were used to pool results. Secondary analyses were stratified by age, sex, molecule, and prior insulin use.

The study was limited by unmeasured confounding and lack of available laboratory data for the majority of patients. In addition, molecule-specific analyses were carried out at a limited number of sites.