Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study

Abstract

Objective: Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D).

Research design and methods: The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks of insulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks.

Results: From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline HbA1c ≥7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma glucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for basal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo.

Conclusions: In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941).

© 2018 by the American Diabetes Association.

Figures

Figure 1

Study design. After a 2-week screening period, insulin therapy was optimized for 6 weeks prior to randomization (R), and optimized insulin continued until the study conclusion at week 52. After a 2-week placebo run-in, patients were randomly assigned to double-blind (DB) treatment with sotagliflozin 200 or 400 mg or placebo for 52 weeks. Insulin optimization refers to the adjustment of insulin to meet standard-of-care glycemic targets starting 6 weeks prior to randomization, which continued for the entire study. An IDMC assessed standard-of-care adherence and provided feedback to the principal investigator if deviations from standard of care were observed prior to week 24; HbA1c was masked to study staff during this period. Between week 24 and 52, insulin optimization continued without input from the IDMC, and HbA1c values were unmasked. Safety was monitored for 30 days after the last dose of study medication.

Figure 2

Primary and other selected end points. Error bars represent SEM. A: LSM change from baseline in HbA1c over 52 weeks. Data between week −6 to week 0 depict arithmetic mean differences between screening and baseline HbA1c values to illustrate effect of insulin optimization. During the 24-week double-blind (DB) core treatment (CT) period, HbA1c levels were masked to study staff and an IDMC reviewed investigators’ insulin titration decisions and provided feedback. During the 28-week double-blind extension (EXT), HbA1c was unmasked and the IDMC did not review insulin titration. B: LSM percent change from baseline in total daily insulin dose (TDD) over 52 weeks. C: LSM change from baseline in weight over 52 weeks. PBO, placebo.

Figure 2

Primary and other selected end points. Error bars represent SEM. A: LSM change from baseline in HbA1c over 52 weeks. Data between week −6 to week 0 depict arithmetic mean differences between screening and baseline HbA1c values to illustrate effect of insulin optimization. During the 24-week double-blind (DB) core treatment (CT) period, HbA1c levels were masked to study staff and an IDMC reviewed investigators’ insulin titration decisions and provided feedback. During the 28-week double-blind extension (EXT), HbA1c was unmasked and the IDMC did not review insulin titration. B: LSM percent change from baseline in total daily insulin dose (TDD) over 52 weeks. C: LSM change from baseline in weight over 52 weeks. PBO, placebo.

Figure 3

Sotagliflozin inTandem1 interstitial glucose. 24-h CGM tracing consisting of interstitial glucose readings collected every 5 min. Solid lines represent mean values from each treatment group (light purple, placebo [n = 45]; light blue, sotagliflozin 200 mg [n = 44]; dark blue, sotagliflozin 400 mg [n = 47]); shaded areas represent ± 1 SEM. The figure shows data collected from midnight. Actual start time for 24-h readings may vary for each subject. Top of target CGM range = 10.0 mmol/L (180 mg/dL).