Comparative Safety of Sodium–Glucose Cotransporter 2 Inhibitors Versus Dipeptidyl Peptidase 4 Inhibitors and Sulfonylureas on the Risk of Diabetic Ketoacidosis

<b>Objective: </b>To assess the association of sodium-glucose co-transporter-2 (SGLT2) inhibitors with diabetic ketoacidosis compared to dipeptidyl peptidase-4 (DPP4) inhibitors and sulfonylureas in patients with type 2 diabetes. <p><b>Research Design and Methods </b></p> <p>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<b> </b>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. </p> <p><b>Results:</b> 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). </p> <p><b>Conclusions</b>: 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. </p>