Sodium Glucose Cotransporter-2 Inhibitor Treatment and the Risk of Diabetic Ketoacidosis in Denmark: A Retrospective Cohort Study of Five Years of Use

Abstract

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with increased risk of diabetic ketoacidosis (DKA) in both people with type 1 and type 2 diabetes mellitus. Few studies using data from high-quality registries exist that attempt to determine the real- world impact of the increasing use of this drug.

Objective: The aim of this study was to investigate the incidence and risk of DKA in connection with SGLT2i treatment in Denmark between 2013-2017.

Methods: A nationwide retrospective cohort of people with type 2 diabetes mellitus using SGLT2i or glucagon-like peptide-1 receptor agonists (GLP1-RA) was established and analysed using both Cox-proportional hazard regression and Kaplan-Meier survival analysis.

Results: The 37,058 individuals included in the cohort, were made up of SGLT2i (10,923), GLP1- RA (18,849), SGLT2i+insulin (2,069), and GLP1-RA+insulin (10,178) users. The incidence rate (IR) of DKA was 0.84 (95% CI 0.49-1.44) and 0.53 (95% CI 0.36-0.77) for the SGLT2i and GLP1-RA groups, respectively. There was no statistically significant increase in the risk for DKA with SGLT2i use (HR 1.02, 95% CI, 0.44-2.36). However, for the SGLT2i+insulin and GLP1- RA+insulin groups, IRs were 3.47 (95% CI 1.92-6.27) and 0.97 (95% CI 0.68-1.37) respectively, and the risk was statistically significantly higher (HR 5.42, 95% CI 2.16-13.56).

Conclusion: We observed no significant increase in the risk of DKA for SGLT2i users compared to GLP1-RA. However, a significantly higher IR of DKA was observed with concomitant insulin use, and the risk of DKA was considerably higher for the SGLT2 group using insulin.

Keywords: Kaplan- Meier; Sodium-glucose cotransporter 2 inhibitors; diabetic ketoacidosis; hyperglycaemia; insulin; retrospective cohort.