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 AUC(0-10) 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 (UGE(0-24)). 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 <54 mg/L [to convert to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios for C-max and AUC(0-10) of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03-1.19) and 1.18 (90% CI, 1.08-1.28), respectively. After ipragliflozin treatment, UGE(0-24) on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g) and at baseline (3.3 g). Conclusions: Combination treatment for 14 days with ipragliflozin and metforrnin was well tolerated in patients with T2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd) to metformin therapy did not result in a clinically relevant change in the PK properties of metformin. ClinicalTrials.gov identifier: NCT01302145. (Clin Ther. 2012;34:1761-1771) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.
