Aim To assess the efficacy and safety of once‐daily ipragliflozin 50 mg versus placebo in Japanese people with type 1 diabetes mellitus (T1DM) inadequately controlled with insulin. Materials and methods We conducted a multicentre, double‐blind, parallel‐group, placebo‐controlled phase 3 study. Participants (N = 175) were randomized (2:1) to receive once‐daily ipragliflozin 50 mg (n = 115) or placebo (n = 60), combined with insulin, for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c); key secondary endpoints included change in insulin dose and body weight. Treatment‐emergent adverse events (TEAEs) were evaluated. Results The ipragliflozin group demonstrated a significant decrease in HbA1c from baseline to end of treatment versus the placebo group: adjusted mean difference (AMD) −3.8 mmol/mol (95% confidence interval [CI] −6.2, −1.5) or − 0.36% (95% CI −0.57, −0.14; P = 0.001). Significant reductions in total daily insulin dose (AMD −7.35 IU [95% CI −9.09, −5.61]; P < 0.001) and body weight (AMD −2.87 kg [95% CI −3.58, −2.16]; P < 0.001) were observed for the ipragliflozin group versus placebo. Two serious TEAEs occurred (major hypoglycaemia and abdominal abscess); both were in the placebo group. All other TEAEs were mild or moderate in severity. Four cases of study discontinuation occurred; three in the placebo group and one in the ipragliflozin group. No diabetic ketoacidosis was reported for any participant in this study. Conclusions Daily ipragliflozin 50 mg in combination with insulin significantly reduced HbA1c, daily insulin dose and body weight versus placebo in people with T1DM. No safety concerns were identified after 24 weeks of treatment. Overall, once‐daily ipragliflozin 50 mg was both efficacious and well tolerated.
AimTo evaluate the efficacy and safety of ipragliflozin vs placebo as add‐on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).MethodsThis double‐blind, placebo‐controlled, multi‐centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).ResultsIn total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; P < .0001). More ipragliflozin‐treated patients than placebo‐treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference −1.64 mmol/L, −1.50 μU/mL, −1.72 kg, and −0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.ConclusionsIpragliflozin as add‐on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.
Aim To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium‐glucose co‐transporter‐2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus. Materials and methods We conducted a multicentre, double‐blind, placebo‐controlled, parallel‐group study. Patients were randomized to receive 25, 50, or 100 mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration‐time curve 24 hours postdose (AUC24h), maximum plasma concentration (Cmax), and renal clearance. Key pharmacodynamic endpoints included 24‐hour urinary glucose excretion, mean plasma glucose AUC0‐24h, and mean renal glucose clearance. Changes in total, basal, and bolus insulin dosages were recorded. Adverse events (AEs) were monitored for safety. Results Dose‐dependent increases were observed in AUC24h and Cmax on days 1 and 14 for 25‐, 50‐, and 100‐mg ipragliflozin. The mean plasma glucose AUC0‐24h was lower than that of placebo and the mean renal glucose clearance increased in a dose‐dependent manner from baseline, but remained unchanged in the placebo group. The mean (standard deviation) change from baseline in total daily insulin dose was greater in the ipragliflozin 25‐, 50‐, and 100‐mg groups (−14.77 ± 14.04%, −18.40 ± 12.49% and −19.25 ± 16.77%, respectively), than placebo (−4.51 ± 16.28%). Most AEs were mild in severity; no patients discontinued the study because of treatment‐emergent AEs. Conclusions The pharmacokinetic and pharmacodynamic properties of ipragliflozin in Japanese patients with type 1 diabetes mellitus were confirmed. Increases in urinary glucose excretion lead to dose‐dependent decreases in plasma glucose. Concomitant insulin dose decreased with ipragliflozin treatment. No clinically relevant safety concerns were identified.
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.
Introduction: The aim of the present study was to assess the long-term (52-week) efficacy and safety of ipragliflozin in insulin-treated Japanese patients with type 1 diabetes mellitus and inadequate glycemic control. Materials and Methods: In this 28-week, open-label extension of a multicenter, randomized, placebo-controlled, 24-week phase III study, ipragliflozin recipients continued treatment (50 mg, once daily), and placebo recipients were switched to once-daily 50 mg ipragliflozin at the start of the extension period. The ipragliflozin dose could be increased to 100 mg if warranted. The primary end-point was change in glycated hemoglobin; secondary end-points were change in insulin dose and bodyweight. Safety outcomes were monitored as treatment-emergent adverse events. Results: A total of 53 (placebo switched to ipragliflozin) and 108 (ipragliflozin) patients completed the open-label extension (treatment period 2), with 24 and 44 patients, respectively, receiving dose increases. From baseline to end of treatment, the overall mean change (standard deviation [SD]) in glycated hemoglobin was -0.33% (0.72; -3.7 mmol/ mol [7.9]), with changes in basal, bolus and total insulin doses of -3.76 IU (SD 3.85 IU), -2.51 IU (SD 7.08 IU) and -6.27 IU (SD 8.16 IU), respectively. No serious drug-related treatment-emergent adverse events or deaths were reported. Treatment-emergent adverse events leading to study discontinuation occurred in zero and three (2.6%) patients in the placebo switched to ipragliflozin and ipragliflozin groups, respectively; all were considered drug-related. There were no cases of severe hypoglycemia or diabetic ketoacidosis, and no safety concerns related to dose increase. Conclusions: The efficacy and safety of 50 mg, once-daily ipragliflozin in insulin-treated type 1 diabetes mellitus patients were confirmed in this long-term, open-label extension study. No safety concerns were attributed to a dose increase to 100 mg.
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