Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes

Abstract

David R Powell, Deon Doree, Sabrina Jeter-Jones, Zhi-Ming Ding, Brian Zambrowicz, Arthur Sands Lexicon Pharmaceuticals, The Woodlands, TX, USA Purpose: Oral agents are needed that improve glycemic control without increasing hypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may meet this need, because this compound lowers blood glucose through the insulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. We examined the effect of sotagliflozin on glycemic control and rate of hypoglycemia measurements in T1D mice maintained on a low daily insulin dose, and compared these results to those from mice maintained in better glycemic control with a higher daily insulin dose alone. Materials and methods: Nonobese diabetes-prone mice with cyclophosphamide-induced T1D were randomized to receive one of four daily treatments: 0.2 U insulin/vehicle, 0.05 U insulin/vehicle, 0.05 U insulin/2 mg/kg sotagliflozin or 0.05 U insulin/30 mg/kg sotagliflozin. Insulin was delivered subcutaneously by micro-osmotic pump; the day after pump implantation, mice received their first of 22 once-daily oral doses of sotagliflozin or vehicle. Glycemic control was monitored by measuring fed blood glucose and hemoglobin A1c levels. Results: Blood glucose levels decreased rapidly and comparably in the 0.05 U insulin/sotagliflozin-treated groups and the 0.2 U insulin/vehicle group compared to the 0.05 U insulin/vehicle group, which had significantly higher levels than the other three groups from day 2 through day 23. A1c levels were also significantly higher in the 0.05 U insulin/vehicle group compared to the other three groups on day 23. Importantly, the 0.2 U insulin/vehicle group had, out of 100 blood glucose measurements, 13 that were <70 mg/dL compared to one of 290 for the other three groups combined. Conclusion: Sotagliflozin significantly improved glycemic control, without increasing the rate of hypoglycemia measurements, in diabetic mice maintained on a low insulin dose. This sotagliflozin-mediated improvement in glycemic control was comparable to that achieved by raising the insulin dose alone, but was not accompanied by the increased rate of hypoglycemia measurements observed with the higher insulin dose. Keywords: insulin, glucose, hypoglycemia, hemoglobin A1c