Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co-transporter 2 inhibitors versus other antihyperglycemic agents: An observational study of four US administrative claims databases

Abstract

Purpose: To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs).

Methods: Patients were identified from four large US claims databases using broad (all T2DM patients) and narrow (intended to exclude patients with type 1 diabetes or secondary diabetes misclassified as T2DM) definitions of T2DM. New users of SGLT2i and seven groups of comparator AHAs were matched (1:1) on exposure propensity scores to adjust for imbalances in baseline covariates. Cox proportional hazards regression models, conditioned on propensity score-matched pairs, were used to estimate hazard ratios (HRs) of DKA for new users of SGLT2i versus other AHAs. When I² <40%, a combined HR across the four databases was estimated.

Results: Using the broad definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (HR [95% CI]: 1.53 [1.31-1.79]), DPP-4i (1.28 [1.11-1.47]), GLP-1 receptor agonists (1.34 [1.12-1.60]), metformin (1.31 [1.11-1.54]), and insulinotropic AHAs (1.38 [1.15-1.66]). Using the narrow definition of T2DM, new users of SGLT2i had an increased risk of DKA versus sulfonylureas (1.43 [1.01-2.01]). New users of SGLT2i had a lower risk of DKA versus insulin and a similar risk as thiazolidinediones, regardless of T2DM definition.

Conclusions: Increased risk of DKA was observed for new users of SGLT2i versus several non-SGLT2i AHAs when T2DM was defined broadly. When T2DM was defined narrowly to exclude possible misclassified patients, an increased risk of DKA with SGLT2i was observed compared with sulfonylureas.

Keywords: SGLT2 inhibitor; diabetic ketoacidosis; type 2 diabetes.

Figure 1

Hazard ratio of DKA for new users of SGLT2 inhibitors versus comparator AHAs. Abbreviations: AHA, antihyperglycemic agent; CCAE, IBM^® MarketScan^® Commercial Database; CI, confidence interval; DKA, diabetic ketoacidosis; DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; HR, hazard ratio; MDCD, IBM^® MarketScan^® Multi‐State Medicaid Database; MDCR, IBM^® MarketScan^® Medicare Supplemental Database; Optum, Optum^© De‐identified Clinformatics^® Data Mart Database; SGLT2, sodium glucose co‐transporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione

Figure 2

Hazard ratio of DKA for new users of SGLT2 inhibitors versus comparator AHAs with censoring at the initiation of non‐index AHAs and discontinuation of the index AHA. Abbreviations: AHA, antihyperglycemic agent; CCAE, IBM^® MarketScan^® Commercial Database; CI, confidence interval; DKA, diabetic ketoacidosis; DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; HR, hazard ratio; MDCD, IBM^® MarketScan^® Multi‐State Medicaid Database; MDCR, IBM^® MarketScan^® Medicare Supplemental Database; Optum, Optum^© De‐identified Clinformatics^® Data Mart Database; SGLT2, sodium glucose co‐transporter 2; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione. *Either no cases in the target and/or comparator cohort or number of cases were too few for the model to converge