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

OBJECTIVETo assess the association of sodium-glucose cotransporter 2 (SGLT2) inhibitors with diabetic ketoacidosis compared with dipeptidyl peptidase 4 (DPP-4) inhibitors and sulfonylureas in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSWe conducted a new-user active comparator cohort study to examine two pairwise comparisons: 1) SGLT2 inhibitors versus DPP-4 inhibitors and 2) SGLT2 inhibitors versus sulfonylureas. The main outcome was diabetic ketoacidosis present on hospital admission. We adjusted for confounders through propensity score matching. We used Cox proportional hazards regression with a robust variance estimator to estimate hazard ratios (HRs) and corresponding 95% CIs while adjusting for calendar time. RESULTSIn cohort 1 (n = 85,125 for SGLT2 inhibitors and n = 85,125 for DPP-4 inhibitors), the incidence rates of diabetic ketoacidosis per 1,000 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 1,000 person-years were 6.3 and 4.5 for SGLT2 inhibitors and sulfonylureas, respectively. In Cox proportional hazards regression models, the use of SGLT2 inhibitors was associated with a higher rate of diabetic ketoacidosis compared with DPP-4 inhibitors (adjusted HR [aHR] 1.63; 95% CI 1.36, 1.96) and sulfonylureas (aHR 1.56; 95% CI 1.30, 1.87). CONCLUSIONSIn 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 with DPP-4 inhibitors and sulfonylureas. Clinicians should be vigilant about this association.

Automated summary

This study examined the association of SGLT2 inhibitors with diabetic ketoacidosis in patients with type 2 diabetes compared to DPP-4 inhibitors and sulfonylureas. The results showed that patients newly prescribed SGLT2 inhibitors had a higher rate of diabetic ketoacidosis compared to the other two drug classes. Clinicians should be cautious about this association when prescribing SGLT2 inhibitors.