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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).

SUBMITTER: Kashiwagi A

PROVIDER: S-EPMC4210070 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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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.

Kashiwagi Atsunori A Kazuta Kenichi K Yoshida Satoshi S Nagase Itsuro I

Journal of diabetes investigation 20131128 4

<h4>Aims/introduction</h4>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.<h4>Materials and methods</h4>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.<h4>Results</h4>All ipragliflozin-treated groups ha ...[more]

PMID: 25411597

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Project description:BackgroundIn recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus.MethodsThe efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n?=?56) or tofogliflozin (10, 20, or 40 mg; n?=?58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24.ResultsOverall, 229 patients were included in the full analysis set (placebo: n?=?56; tofogliflozin 10 mg: n?=?57; tofogliflozin 20 and 40 mg: n?=?58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was -0.028% (-0.192 to 0.137) in the placebo group, compared with -0.797% (-0.960 to -0.634) in the tofogliflozin 10 mg group, -1.017% (-1.178 to -0.856) in the tofogliflozin 20 mg group, and -0.870% (-1.031 to -0.709) in the tofogliflozin 40 mg group (p?<?0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity.ConclusionsTofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study.Trial registrationThis study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).

Project description:IntroductionSodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM.MethodsThe time course of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in patients with T2DM following ipragliflozin treatment that had been observed in earlier clinical trials was modeled using empirical models combined with the maximum drug effect (Emax) model and disease progression model. As a predictive factor of drug effect, estimated ΔUGE was introduced into the Emax model, instead of ipragliflozin exposure. The developed models were used to simulate the time course of FPG and HbA1c following once-daily treatment with placebo or ipragliflozin at doses of 12.5, 25, 50 and 100 mg, and the changes at 52 weeks at the approved dose of 50 mg were summarized by renal function category.ResultsThe developed models that included UGE as a dependent variable of response were found to well describe observed time courses in FPG and HbA1c. Baseline blood glucose level and renal function had significant effects on the glucose-lowering effect of ipragliflozin, and these models enabled quantification of these impacts on clinical outcomes. Simulated median changes in HbA1c in T2DM patients with mild and moderate renal impairment were 25 and 63% lower, respectively, than those in T2DM patients with normal renal function. These results are consistent with the observed clinical data from a previous renal impairment study.ConclusionsEmpirical models established based on the effect of UGE well predicted the renal function-dependent long-term glucose-lowering effects of ipragliflozin in patients with T2DM.

Dataset Information

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.

Publications

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.

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