Comparative Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Dipeptidyl Peptidase 4 Inhibitors and Sulfonylureas on the Risk of Diabetic Ketoacidosis
Research Design and Methods
We conducted a new-user active comparator cohort study design. We examined two pairwise comparisons: 1) SGLT2 inhibitors vs. DPP4 inhibitors and 2) SGLT2 inhibitors vs. sulfonylureas. The main outcome was diabetic ketoacidosis present on hospital admission. We adjusted for confounders via propensity score matching. We used Cox proportional-hazards regression with a robust variance estimator to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) while adjusting for calendar time.
Results: In cohort 1 (n= 85,125 for SGLT2 inhibitors and n= 85,125 for DPP-4 inhibitors), the incidence rates of diabetic ketoacidosis per 1000 person-years were 6.0 and 4.3 for SGLT2 inhibitors and DPP4 inhibitors, respectively. In cohort 2 (n= 72,436 for SGLT2 inhibitors and n= 72,436 for sulfonylureas), the incidence rates of diabetic ketoacidosis per 1000 person-years were 6.3 and 4.5 for SGLT2 inhibitors and sulfonylureas, respectively. In Cox proportional-hazards models, the use of SGLT2 inhibitors was associated with a higher rate of diabetic ketoacidosis compared to DPP4 inhibitors (adjusted HR (aHR), 1.63; 95% CI 1.36–1.96) and sulfonylureas (aHR, 1.56; 95% CI 1.30–1.87).
Conclusions: In this comparative safety study using real-world data, patients with type 2 diabetes who were newly prescribed SGLT2 inhibitors had a higher rate of diabetic ketoacidosis compared to DPP4 inhibitors and sulfonylureas. Clinicians should be vigilant about this association.