Objective: To evaluate the effect of sotagliflozin (SOTA), a dual SGLT 1 and 2 inhibitor, on beta-hydroxybutyrate (BHB) over 52 weeks in adults with type 1 diabetes (T1D) on insulin therapy.
Methods: Analyses were performed on pooled data from two, 52-week, placebo-controlled studies in 1575 adult patients with T1D on optimized insulin therapy, who were randomly assigned 1:1:1 to placebo (PBO), SOTA 200 mg, and SOTA 400 mg. Descriptive statistics were performed on serum BHB using results from scheduled visits at baseline and Weeks 4, 12, 24, and 52. A 2-sample Wilcoxon rank sum test was performed to test the distribution of change in BHB from baseline between SOTA and placebo. The proportion of patients experiencing ≥1 measurement meeting predefined limits of DKA risk based on BHB levels (≥0.6 mmol/L “ketonemia” and ≥1.5 mmol/L “impending DKA”) was assessed.
Results: Median baseline BHB was 0.13 (IQR 0.10, 0.20), 0.13 (IQR 0.10, 0.22), and 0.14 mmol/L (IQR 0.10, 0.23) in the PBO, SOTA 200-mg, and SOTA 400-mg groups, respectively. While the median change in BHB was 0 mmol/L with PBO, median BHB increased from baseline by 0.03 to 0.05 mmol/L with SOTA, and generally remained stable over 52 weeks (p<0.001 vs. PBO at each time point). Per the predefined limits of DKA risk based on BHB levels, a BHB level ≥0.6 mmol/L was experienced by 19.8, 46.9, and 45.5% and a BHB level ≥1.5 mmol/L in 2.1, 6.3, and 8.2% of patients on PBO, SOTA 200 mg, and SOTA 400 mg, respectively. Approximately 2/3 of the BHB ≥0.6 mmol/L events were observed by Week 16 and ∼2/3 of the BHB ≥1.5 mmol/L events were observed by Week 24.
Conclusion: Treatment with SOTA was associated with small increases in BHB over time, which on average remained well below the clinically important level of 0.6 mmol/L. Although the DKA incidence was <4% overall on SOTA, the proportions of patients with ≥1 BHB measurement ≥0.6 mmol/L (∼45-47%) or ≥1.5 mmol/L (∼6-8%) suggest many BHB elevations were recognized and managed without progression to DKA.
A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M.J. Davies: Employee; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.