Dose-dependent glycometabolic effects of sotagliflozin on type 1 diabetes over 12 weeks: The inTandem4 trial

Aims: To assess the dose-related effects of sotagliflozin, a novel dual inhibitor of sodium-glucose co-transporters-1 and -2, in type 1 diabetes (T1D). Materials and methods: In this 12-week, multicentre, randomized, double-blind, placebo-controlled dose-ranging trial, adults with T1D were randomized to once-daily placebo (n = 36) or sotagliflozin 75 mg (n = 35), 200 mg (n = 35) or 400 mg (n = 35). Insulin was maintained at baseline doses. The primary endpoint was least squares mean (LSM) change in glycated haemoglobin (HbA1c) from baseline. Other endpoints included proportion of participants with ≥0.5% HbA1c reduction and assessments of 2-hour postprandial glucose (PPG), weight, and urinary glucose excretion (UGE). Results: From a mean baseline of 8.0% ± 0.8% (full study population), placebo-adjusted LSM HbA1c decreased by 0.3% (P =.07), 0.5% (P <.001) and 0.4% (P =.006) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively, at week 12. In the placebo and sotagliflozin 75 mg, 200 mg and 400 mg groups, 33.3%, 37.1%, 80.0% and 65.7% of participants achieved an HbA1c reduction ≥0.5%. Placebo-adjusted PPG decreased by 22.2 mg/dL (P =.28), 28.7 mg/dL (P =.16) and 50.2 mg/dL (P =.013), UGE increased by 41.8 g/d (P =.006), 57.7 g/d (P <.001) and 70.5 g/d (P <.001), and weight decreased by 1.3 kg (P =.038), 2.4 kg (P <.001) and 2.6 kg (P <.001) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively. One case of severe hypoglycaemia occurred in each sotagliflozin group and one case of diabetic ketoacidosis (DKA) occurred with sotagliflozin 400 mg. Conclusions: Combined with stable insulin doses, sotagliflozin 200 mg and 400 mg improved glycaemic control and weight in adults with T1D. Sotagliflozin 400 mg reduced PPG levels. UGE increased with all sotagliflozin doses. Rates of severe hypoglycaemia and DKA were low (NCT02459899).