Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (DBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared DBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with DBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and DBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and DBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.