Combination Treatment With Ipragliflozin and Metformin: A Randomized, Double-Blind, Placebo-Controlled Study in Patients With Type 2 Diabetes Mellitus

Abstract Background Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM). Objectives The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin. Methods Thirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid) were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n = 18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements, and vital signs were assessed throughout the study. The PK properties of metformin and ipragliflozin were determined in plasma. The geometric mean ratio and its 90% CI for the maximum plasma concentration and AUC0–10 were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day −1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours (UGE0–24 ). Results All the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients (16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving metformin + placebo. No hypoglycemic events (blood glucose level