Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a 36-week, open-label extension of a 16-week, randomized, placebo-controlled, double-blind study

Abstract

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.

Keywords: Dipeptidyl peptidase-4 inhibitor; Insulin; Ipragliflozin; Sodium–glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus.

Conflict of interest statement

HI has served on the scientific advisory board of Astellas Pharma Inc.; received lecture or consulting fees from Astellas Pharma Inc., MSD, Sanofi, Mitsubishi Tanabe Pharma, Boehringer Ingelheim Japan, and Novartis Pharma; and received grants/research support from Astellas Pharma Inc., Ono Pharmaceutical, Boehringer Ingelheim Japan, AstraZeneca, Sanofi, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Daiichi-Sankyo, Novo Nordisk Pharma, Kyowa Hakko Kirin, and MSD. SY, IN, SA, and TS are employees of Astellas Pharma Inc., Japan.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.Informed consent or substitute for it was obtained from all patients for being included in the study. The study was approved by the institutional review board at each participating site.

Figures

Fig. 1

Patient disposition. The boxes indicate the treatment and dose received for treatment period I/from weeks 16 to 24/from weeks 24 to 52. *Some patients discontinued for more than one reason. †Ipragliflozin dose was maintained at 50 mg once daily after visit 10 (week 24). Note: the first 50 in 50/50/50 or 50/50/100 refers to the dose administered in treatment period I. ‡Ipragliflozin dose was increased to 100 mg once daily from visit 10 (week 24). §Discontinued before the decision was made whether to increase the ipragliflozin dose at week 24 (visit 10). FAS full analysis set, SAS safety analysis set

Fig. 2

Time-course of HbA1c from baseline to the end of treatment (with last observation carried forward) in all patients (a), all patients with/without DPP-4i (b), stratified by ipragliflozin dose (50/50/50 and 50/50/100 mg) used in treatment period II (c) and by ipragliflozin dose and DPP-4i use (d and e). Data are shown as the mean ± standard deviation (full analysis set). The number of patients at each timepoint is shown below the x-axis. DPP-4i dipeptidyl peptidase-4 inhibitor, EOT end of treatment, LOCF last observation carried forward

Fig. 2

Time-course of HbA1c from baseline to the end of treatment (with last observation carried forward) in all patients (a), all patients with/without DPP-4i (b), stratified by ipragliflozin dose (50/50/50 and 50/50/100 mg) used in treatment period II (c) and by ipragliflozin dose and DPP-4i use (d and e). Data are shown as the mean ± standard deviation (full analysis set). The number of patients at each timepoint is shown below the x-axis. DPP-4i dipeptidyl peptidase-4 inhibitor, EOT end of treatment, LOCF last observation carried forward

Fig. 3

Time-course of FPG from baseline to the end of treatment (with last observation carried forward) in all patients (a) and in patients stratified by ipragliflozin dose (50/50/50 and 50/50/100 mg) used in treatment period II (b). Data are shown as the mean ± standard deviation (full analysis set) for all patients who received ipragliflozin in both treatment periods. The number of patients at each timepoint is shown below the x-axis. EOT end of treatment, FPG fasting plasma glucose, LOCF last observation carried forward

Fig. 4

Change in bodyweight from baseline to the end of treatment (with last observation carried forward) in all patients (a) and in patients stratified by ipragliflozin dose (50/50/50 and 50/50/100 mg) used in treatment period II (b). Data are shown as the mean ± standard deviation (full analysis set) for all patients who received ipragliflozin in both treatment periods. The number of patients at each timepoint is shown below the x-axis. EOT end of treatment, LOCF last observation carried forward