Thomas Danne1, Bertrand Cariou2, Phillip Banks3, Michael Brandle4, Helmut Brath5, Edward Franek6, Jake A Kushner7, Pablo Lapuerta3, Darren K McGuire8, Anne L Peters9, Sangeeta Sawhney3, Paul Strumph3. 1. Department of Diabetes, Endocrinology, and Clinical Research, Children's and Youth Hospital Auf der Bult, Hannover Medical School, Hannover, Germany danne@hka.de. 2. L'institut du thorax, Department of Endocrinology, CHU Nantes, CIC 1413, INSERM, Nantes, France. 3. Lexicon Pharmaceuticals, Inc., The Woodlands, TX. 4. Department of Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland. 5. Diabetes Outpatient Clinic, Health Center South, Vienna, Austria. 6. Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland. 7. Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX. 8. Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX. 9. University of Southern California Keck School of Medicine, Los Angeles, CA.
Abstract
OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS: At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were -0.37% and -0.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (-0.87 mmol/L; P = 0.008), weight (-2.92 kg; P < 0.001), and total daily insulin dose (-8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS: In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).
RCT Entities:
OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS: At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were -0.37% and -0.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (-0.87 mmol/L; P = 0.008), weight (-2.92 kg; P < 0.001), and total daily insulin dose (-8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS: In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).
Authors: Bruce A Perkins; Julio Rosenstock; Jay S Skyler; Lori M Laffel; David Z Cherney; Chantal Mathieu; Christianne Pang; Richard Wood; Ona Kinduryte; Jyothis T George; Jan Marquard; Nima Soleymanlou Journal: Diabetes Care Date: 2019-06-08 Impact factor: 19.112
Authors: Thomas Danne; Bertrand Cariou; John B Buse; Satish K Garg; Julio Rosenstock; Phillip Banks; Jake A Kushner; Darren K McGuire; Anne L Peters; Sangeeta Sawhney; Paul Strumph Journal: Diabetes Care Date: 2019-03-04 Impact factor: 19.112
Authors: Tamara Y Milder; Sophie L Stocker; Dorit Samocha-Bonet; Richard O Day; Jerry R Greenfield Journal: Eur J Clin Pharmacol Date: 2019-08-03 Impact factor: 2.953
Authors: John B Buse; Satish K Garg; Julio Rosenstock; Timothy S Bailey; Phillip Banks; Bruce W Bode; Thomas Danne; Jake A Kushner; Wendy S Lane; Pablo Lapuerta; Darren K McGuire; Anne L Peters; John Reed; Sangeeta Sawhney; Paul Strumph Journal: Diabetes Care Date: 2018-06-24 Impact factor: 19.112