Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium-dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus

Abstract

Aims/introduction: In the present dose-response study, we evaluated the efficacy and safety of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose cotransporter 2, in Japanese patients with type 2 diabetes mellitus.

Materials and methods: A total of 361 patients from 39 Japanese centers were randomized to receive either once-daily oral ipragliflozin (12.5, 25, 50 or 100 mg) or a placebo for 12 weeks.

Results: All ipragliflozin-treated groups had clinically significant, dose-dependent decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose levels compared with placebo-treated groups. The adjusted mean difference in HbA1c change from baseline to the end of treatment between the placebo and 12.5, 25, 50, and 100 mg ipragliflozin groups were -0.61%, -0.97%, -1.29%, and -1.31%, respectively (P < 0.001). Reductions in HbA1c levels were similar between obese and non-obese patients, and were larger in patients with baseline HbA1c ≥8.4% than in those with HbA1c <8.4%. Furthermore, bodyweight significantly (P < 0.001) and dose-dependently decreased among ipragliflozin-treated groups compared with the placebo group. The incidence of adverse events was similar across all groups. However, mild increases in hematocrit and blood urea nitrogen were found in ipragliflozin treated groups.

Conclusions: Once-daily administration of ipragliflozin was dose-dependently effective in glycemic control without major adverse effects. Ipragliflozin was equally effective between obese and non-obese patients, and led to weight loss in both groups. Ipragliflozin was safe and well-tolerated in Japanese patients with type 2 diabetes mellitus. This trial was registered with ClinicalTrials.gov (no. NCT00621868).

Keywords: Hyperglycemia; Oral antidiabetic drugs; Sodium‐dependent glucose co‐transporter 2.

Figures

Figure 1

Study diagram of patient enrolment and treatment protocol.

Figure 2

Subgroup analyses by treatment experience, body mass index (BMI) level and baseline glycated hemoglobin (HbA1c) levels. Effects did not differ between drug‐naïve and drug‐treated patients, or between patients with BMI of ≥25 kg/m2 and BMI <25 kg/m2 (P = 0.106 and P = 0.228, respectively). Reductions in HbA1c values were greater in patients with HbA1c levels ≥8.4% than in those with HbA1c levels <8.4% (P < 0.001). CI, confidence interval; PLA, placebo; SE, standard error.

Figure 3

(a) Dose‐dependent effects of ipragliflozin on mean changes in bodyweight levels from baseline over the study period. The values (means ± standard deviation) at each point are described in the figure. *P < 0.001 (compared with baseline by t‐test). (b) Changes in body weight from baseline to the end of treatment in drug‐naïve (n = 188) and drug‐treated patients (n = 172). Data are expressed as means ± standard error (SE). *P < 0.001 (compared with placebo by analysis of covariance). EOT, end of treatment.