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OBJECTIVE: To examine long-term efficacy/safety of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, added to ongoing insulin therapy in Japanese patients with type 2 diabetes. METHODS: We conducted a 36-week, open-label extension of ipragliflozin therapy following a 16-week, randomized, placebo-controlled, double-blind period (treatment periods II and I, respectively). Prior to the open-label period, patients taking insulin with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo or 50 mg once-daily ipragliflozin. Oral antidiabetic drugs other than DPP-4 inhibitors were discontinued 4 weeks before screening. Following treatment period I, all patients received open-label ipragliflozin 50 mg, with the possibility of a dose increase to 100 mg at week 24 if HbA1c was ≥ 7.0% at week 20. Efficacy endpoints were changes in HbA1c, fasting plasma glucose (FPG), self-monitored blood glucose, bodyweight, and metabolic hormones. Drug-related treatment-emergent adverse events (TEAEs) were monitored for safety. RESULTS: Of 175 patients randomized to ipragliflozin, 168 entered treatment period II, 121 (69%) of whom completed this period. The mean ± standard deviation changes in HbA1c, FPG, and bodyweight from baseline (start of treatment period I) to the end of treatment were - 0.83 ± 0.72%, - 31.5 ± 41.2 mg/dL, and - 1.34 ± 1.80 kg, respectively. Between weeks 8 and 32, HbA1c was lower in patients taking a DPP-4 inhibitor than in those without. The most common drug-related TEAE was hypoglycemia; no drug-related TEAEs not already reported for ipragliflozin were observed. CONCLUSIONS: Ipragliflozin was well tolerated, effective, and reduced bodyweight over a period of 52 weeks in patients treated with insulin with/without a DPP-4 inhibitor. CLINICALTRIALSGOV IDENTIFIER: NCT02175784.
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INTRODUCTION: Few data are available regarding ipragliflozin treatment in combination with glucagon-like peptide-1 (GLP-1) receptor agonists. The aim of this study was to evaluate the efficacy and safety of ipragliflozin in combination with GLP-1 receptor agonists in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM). METHODS: This multicenter study (consisting of three periods: a 4-week washout period, a 6-week observation period, and a 52-week open-label treatment period) included patients aged ≥ 20 years who received a stable dose/regimen of a GLP-1 receptor agonist either solely or in combination therapy with a sulfonylurea for ≥ 6 weeks, with glycosylated hemoglobin (HbA1c) of ≥ 7.5% and a fasting plasma glucose (FPG) of ≥ 126 mg/dL. Ipragliflozin treatment was given at a fixed dose of 50 mg/day for 20 weeks, followed by 50 or 100 mg/day for 32 weeks. Changes from baseline in glycemic control and other parameters were examined; safety was also assessed. RESULTS: The mean changes in HbA1c and body weight from baseline to end of treatment were - 0.92% and - 2.69 kg, respectively, in all ipragliflozin-treated patients (n = 103). Overall, sustained reductions from baseline were observed for HbA1c, FPG, self-monitored blood glucose, and body weight during the 52-week treatment. The dose increase of ipragliflozin to 100 mg/day resulted in better glycemic control and weight reduction for patients in whom the 50-mg dose was insufficient. Overall, 46.6% (48/103) of patients experienced drug-related adverse events. The most common drug-related treatment-emergent adverse events were pollakiuria (9.7%), hypoglycemia (8.7%), constipation (6.8%), and thirst (5.8%). CONCLUSION: Combined therapy with ipragliflozin and GLP-1 receptor agonists/sulfonylureas was significantly efficacious in reducing glycemic parameters in patients with T2DM with inadequate glycemic control, and no major safety concerns were identified. The results from this study suggest that ipragliflozin can be recommended as a well-tolerated and effective add-on therapy to a GLP-1 receptor agonist for the treatment of T2DM. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT02291874). FUNDING: Astellas Pharma Inc., Tokyo, Japan.
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AIMS: To examine the efficacy and safety of add-on ipragliflozin in Japanese patients with type 2 diabetes in the early stage of insulin therapy. METHODS: Patients treated with insulin (bolus component <30% of total daily dose) with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo (n = 87) or ipragliflozin (n = 175) for 16 weeks. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline. Secondary endpoints included changes in fasting plasma glucose (FPG) and metabolic hormones. Safety endpoints were also examined. RESULTS: The changes in HbA1c were 0.27% and -0.79% (2.9 and -8.7 mmol/mol) in the placebo and ipragliflozin groups, respectively (baseline: 8.62% vs 8.67% [70.8 vs 71.2 mmol/mol]), corresponding to an adjusted mean difference of -1.07% (95% confidence interval -1.24, -0.91) or -11.7 mmol/mol (-13.5, -9.9), p < .001. Ipragliflozin reduced FPG and serum C-peptide levels and body weight (all p < .001), and increased serum adiponectin levels (p = .022). There was a statistically significant interaction for use/non-use of a DPP-4 inhibitor × treatment group for the change in HbA1c (p = .042). Hypoglycaemia was the only treatment-related adverse event reported in >5% of patients (14.9% vs 29.1%). Events consistent with urinary tract infection (placebo 1.1% vs ipragliflozin 2.3%) or genital infection (0.0% and 4.0%, respectively) occurred in <5% of patients. CONCLUSION: Ipragliflozin was well tolerated and effective in insulin-treated patients, especially when used with a DPP-4 inhibitor.
