Sodium-Glucose Cotransporter-2 Inhibitors and Diabetic-Ketoacidosis in T2DM Patients: An Updated Meta-Analysis and a Mendelian Randomization Analysis.

Summary

Across 80,235 participants in 22 RCTs, SGLT2 inhibitors doubled DKA risk overall (RR 2.32), with signal concentrated at higher HbA1c, in CKD, and high ASCVD-risk trials, but not significantly in heart failure trials. Mendelian randomization supported a genetic association with DKA liability.

Key Findings

• SGLT2 inhibitors increased DKA risk versus controls across 22 RCTs (RR 2.32; 95% CI 1.64–3.27).
• Risk elevation was significant at HbA1c >7.9% and in CKD or high ASCVD risk trials, but not significant in heart failure trials.
• Mendelian randomization supported a genetic association between SGLT2i use and DKA risk.

Clinical Implications

Consider enhanced patient education and ketone monitoring in T2DM patients with high HbA1c, CKD, or high ASCVD risk starting SGLT2 inhibitors; risk appears lower in heart failure populations.

Limitations

• DKA is a rare outcome; event adjudication and reporting may vary across trials.
• MR relies on instrument validity assumptions and reflects lifetime exposure proxies rather than trial-like interventions.

Future Directions

Develop risk scores integrating HbA1c, renal function, and ASCVD status to personalize SGLT2i safety monitoring; assess preventive strategies (e.g., sick-day rules, ketone education) in high-risk T2DM subgroups.