Kenichi Kazuta

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.

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.

Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study.

This multicenter, double‐blind, placebo‐controlled study examined the efficacy and safety of ipragliflozin, a sodium‐glucose co‐transporter 2 inhibitor, in combination with metformin in Japanese patients with type 2 diabetes mellitus (T2DM). Patients were randomized in a 2 : 1 ratio to 50 mg ipragliflozin (n = 112) or placebo (n = 56) once daily for 24 weeks, followed by a 28‐week open‐label extension in which all patients received 50 or 100 mg ipragliflozin, while continuing metformin. The primary outcome was the change in glycated haemoglobin (HbA1c) from baseline to week 24. HbA1c decreased significantly in the ipragliflozin group (−0.87%; adjusted mean difference from placebo: −1.30%; p < 0.001). The overall incidence of treatment‐emergent adverse events was similar in both groups, although pollakiuria and constipation were more common in the ipragliflozin group; thus, ipragliflozin significantly improved glycaemic control and reduced body weight without major safety issues in Japanese patients with T2DM.

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study

AIMS Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. METHODS In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days -1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0-3h (AUC0-3h) and 0-24h (AUC0-24h). Pharmacokinetic characteristics included AUC0-24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax). RESULTS Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0-3h and AUC0-24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0-24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0-24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. CONCLUSIONS Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.

Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes stratified by body mass index: A subgroup analysis of five randomized clinical trials.

The influence of overweight/obesity on the clinical efficacy and safety of sodium‐glucose co‐transporter 2 inhibitors is unclear. We carried out a pooled analysis to examine the impact of body mass index on the efficacy and safety of ipragliflozin.

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.

Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials

To examine differential improvements among cardiovascular risk factors in response to treatment with ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients, we conducted a pooled analysis of six randomized, double-blind trials of Japanese T2DM patients who received ipragliflozin 50 mg/day or placebo and had patient-level data for cardiometabolic risk parameters. Risk factors included glycated hemoglobin (HbA1c), body weight, homeostatic model assessment for insulin resistance and beta-cell function (HOMA-R and HOMA-beta, respectively), systolic blood pressure, fasting serum insulin concentrations, and the concentration of uric acid, lipids, and liver enzymes from baseline to end of treatment (EOT; 12-24 weeks). The primary endpoint of each trial was the change in HbA1c from baseline to EOT. Changes in risk factors from baseline to EOT were compared between ipragliflozin-treated and placebo groups, and between two subgroups (high- and low-risk groups for each parameter). All parameters, except low-density lipoprotein cholesterol (LDL-C) and non high-density lipoprotein cholesterol (non HDL-C), improved significantly in the ipragliflozin group. Subgroup analysis revealed a significantly greater improvement in the high-risk group versus low-risk group in HbA1c, HOMA-R, HOMA-beta, aspartate transaminase, alanine transaminase, and gamma-glutamyltransferase, but not in any of the lipid parameters or blood pressure. Liver function improvement in the ipragliflozin group was significantly correlated with changes in body weight, HbA1c, HOMA-beta, and HOMA-R. This analysis demonstrated that, in Japanese T2DM patients, ipragliflozin 50 mg/day was associated with improvements in cardiometabolic risk factors, except for LDL-C and non HDL-C.

Effects of Ipragliflozin, a Selective Sodium–Glucose Co-Transporter 2 Inhibitor, on Blood Pressure in Japanese Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Six Randomized, Placebo-Controlled Clinical Trials

Background: Sodium-glucose co-transporter 2 inhibitors reduce systolic blood pressure (SBP) by 3–5 mmHg in patients with type 2 diabetes mellitus (T2DM) probably by exerting mild osmotic diuresis, body weight reduction and/or sodium excretion. Although ipragliflozin reduced SBP and diastolic blood pressure (DBP) in individual trials, larger-scale analyses are necessary to confirm the magnitudes of the reductions. Objective: To examine the effects of ipragliflozin on changes in SBP/DBP in Japanese T2DM patients, and identify factors associated with the changes in SBP/DBP. Methods: We conducted a pooled analysis of six Japanese randomized, placebo-controlled trials in which ipragliflozin was used as monotherapy (two trials) or in combination with other oral antidiabetic drugs (four trials, including one involving patients with renal impairment). We analyzed the associations between the changes in SBP/DBP and clinical characteristics. Results: Data of 993 patients (placebo, n = 367; 50 mg ipragliflozin, n = 626) were analyzed. The baseline to end-of-treatment changes in SBP and DBP (ipragliflozin vs. placebo) were −4.1 vs. −0.7 mmHg (−2.8 mmHg vs. placebo; P < 0.001) and −2.6 vs. −0.4 mmHg (−1.6 mmHg vs. placebo; P = 0.002), respectively. Patients with baseline SBP ≥140 mmHg showed a greater reduction in SBP (−5.5 mmHg vs. placebo; P = 0.003). Conclusions: Ipragliflozin induced mild SBP/DBP reduction in T2DM patients. The magnitude of reduction was greater in patients with high blood pressure.