Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Diabetic Ketoacidosis Among Adults With Type 2 Diabetes: A Systematic Review and Meta-Analysis

Abstract

Objectives: The magnitude and precision regarding the risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear. Thus, we examined the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials.

Methods: Searches were performed in PubMed, Embase, CENTRAL and Google Scholar (from inception to April 15, 2019) without language restrictions, including conference proceedings and reference lists. Study selection consisted of randomized controlled trials and observational studies that quantified the rate of DKA with an SGLT2 inhibitor in comparison to other diabetes medications or placebo. Two independent investigators abstracted the study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung-Knapp-Sidik-Jonkman method. Absolute event rates and hazard ratios for DKA were extracted from each study.

Results: Seven randomized trials encompassing 42,375 participants and 5 cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1,000 person years. Four randomized trials were included in the meta-analysis and, compared with placebo or comparator medication, SGLT2 inhibitors had a 2.5-fold higher risk of DKA (relative risk [RR], 2.46; 95% confidence interval [CI], 1.16 to 5.21]; I²=0%; p=0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1,000 person years and a 1.7-fold higher rate of DKA compared with another diabetes medication (RR, 1.74; 95% CI, 1.07 to 2.83; I²=45%; p=0.12).

Conclusions: In adults with type 2 diabetes, SGLT2 inhibitors were found to increase the risk of DKA in both observational studies and large randomized clinical trials.

Keywords: SGLT2 inhibitors; canagliflozin; canagliflozine; dapagliflozin; dapagliflozine; diabetic ketoacidosis; diabète de type 2; d’acidocétose diabétique; empagliflozin; empagliflozine; inhibiteurs du SGLT2; type 2 diabetes.