Risk of diabetic ketoacidosis with sodium-glucose cotransporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: A nationwide cohort study.

BACKGROUND

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have significantly improved glycemic control and reduced cardiovascular and renal risks in type 2 diabetes mellitus (T2DM). However, diabetic ketoacidosis (DKA), though rare, remains a serious safety concern. While previous studies have established an elevated DKA risk with SGLT2is, real-world evidence in Asian populations remains limited.

OBJECTIVES

This study evaluated the real-world risk of DKA associated with SGLT2i use compared to dipeptidyl peptidase-4 inhibitors (DPP4is) in patients with T2DM in Taiwan.

DESIGN

A nationwide population-based cohort study using Taiwan's National Health Insurance Research Database.

METHODS

This study included over 700,000 patients with T2DM who initiated SGLT2is or DPP4is between 2016 and 2020. A prevalent new-user design was applied, and inverse probability treatment weighting was used to balance baseline characteristics. DKA cases were identified using validated diagnostic codes from hospital admissions and emergency visits.

RESULTS

The incidence of DKA was higher in SGLT2i users (0.34 per 1000 person-years (PY)) than in DPP4i users (0.19 per 1000 PY), with an adjusted hazard ratio of 2.04 (95% CI: 1.64-2.54). Subgroup analyses revealed a consistently elevated DKA risk, particularly among men, older adults, and patients with advanced diabetes complications. Sensitivity analyses, including an E-value of 3.72, suggested minimal impact from unmeasured confounders.

CONCLUSION

SGLT2i use was associated with a twofold increased DKA risk compared to DPP4is in this Asian cohort. Although the absolute incidence was low, targeted monitoring is warranted in high-risk populations. The lower DKA incidence observed in Taiwan compared to Western studies suggests potential regional influences, necessitating further investigation. These findings contribute to the understanding of SGLT2i safety in Asian populations and inform clinical risk management strategies.