The aim of the present study was to determine the effects of luseogliflozin on 24‐h glucose levels, assessed by continuous glucose monitoring, and on pharmacodynamic variables measured throughout the day. In this double‐blind, placebo‐controlled, crossover study, 37 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized into two groups. Patients in each group first received luseogliflozin then placebo for 7 days each, or vice versa. After 7 days of treatment, the mean 24‐h glucose level was significantly lower with luseogliflozin than with placebo [mean (95% confidence interval) 145.9 (134.4–157.5) mg/dl vs 168.5 (156.9–180.0) mg/dl; p < 0.001]. The proportion of time spent with glucose levels ≥70 to ≤180 mg/dl was significantly greater with luseogliflozin than with placebo [median (interquartile range) 83.2 (67.7–96.5)% vs 71.9 (46.9–83.3)%; p < 0.001] without inducing hypoglycaemia. The decrease in glucose levels was accompanied by reductions in serum insulin levels throughout the day.

This randomized, double‐blind, placebo‐controlled, crossover study was the first to determine the effects of luseogliflozin in combination with a low‐carbohydrate diet (LCD) on 24‐h glucose variability, assessed by continuous glucose monitoring (CGM). A total of 18 Japanese patients with type 2 diabetes were randomized into two groups, in which patients first received luseogliflozin 2.5 mg once daily then placebo for 8 days each, or vice versa. Patients took luseogliflozin or placebo with a normal‐carbohydrate diet (NCD) on day 7 and with the LCD on day 8. CGM was performed on both days. Luseogliflozin significantly reduced glucose exposure in terms of the area under the curve over the course of 24 h when administered with the NCD (difference vs placebo: −555.6 mg/dl·h [1 mg/dl = 0.0556 mmol/l]; p < 0.001) or with the LCD (−660.7 mg/dl·h; p < 0.001). No hypoglycaemia was observed over 24 h with either diet. Although glucose levels were lower with the LCD than with the NCD in the placebo treatment period, luseogliflozin with the LCD improved glycaemic control throughout the day to nearly the same extent as luseogliflozin with the NCD, without inducing hypoglycaemia.

IntroductionWe investigated the impact of reduced renal function on 24-h glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM) treated with luseogliflozin.MethodsIn this double-blind, placebo-controlled, crossover study, 37 Japanese patients with T2DM [glycated hemoglobin (HbA1c) 7.0–10.0%] and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 were randomized into two groups in which patients first received luseogliflozin then placebo, or vice versa, for 7 days each. Twenty-four-hour glucose variability was measured on day 7 in each period and was compared among patients divided into three groups according to their baseline eGFR (mL/min/1.73 m2): normal (≥90; n = 13; normal group), normal-to-mildly reduced renal function (≥75 to <90; n = 12; normal–mild group), and mild-to-moderately reduced renal function (<75; n = 9; mild–moderate group).ResultsThe mean [95% confidence interval (CI)] placebo-subtracted 24-h cumulative urinary glucose excretion (g) was 82.1 (72.7, 91.5), 82.5 (73.4, 91.5), and 62.2 (51.2, 73.3); the placebo-subtracted 24-h mean glucose concentration (mg/dL) was −24.39 (−32.53, −16.26), −28.28 (−39.35, −17.22), and −11.53 (−23.93, 0.86); and the placebo-subtracted peak postprandial glucose (mg/dL) was −26.9 (−46.9, −6.9), −38.1 (−59.6, −16.6), and 1.5 (−25.5, 28.4) in the normal, normal–mild, and mild–moderate groups, respectively. The mean lowest glucose concentrations (placebo vs. luseogliflozin, mg/dL) decreased to similar levels in the normal (115.4 vs. 93.4), normal–mild (121.0 vs. 97.9), and mild–moderate (104.0 vs. 91.1) groups.ConclusionThis post hoc subanalysis revealed that although mild-to-moderately reduced renal function attenuated the glucose-lowering effects of luseogliflozin on peak postprandial glucose, it did not attenuate the effects of luseogliflozin on fasting glucose. These findings may explain the smaller increase in urinary glucose excretion in these patients relative to patients with normal renal function or normal-to-moderately reduced renal function. Further studies may be needed to examine these findings in large populations of patients with T2DM and reduced renal function.Trial registrationJapicCTI-142548.FundingTaisho Pharmaceutical Co., Ltd.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0291-z) contains supplementary material, which is available to authorized users.

IntroductionIn our previous study investigating effects of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, on 24-h glycemic variability by continuous glucose monitoring (CGM), luseogliflozin elicited parallel downward shifts in fasting and postprandial glucose levels. However, further review of individual patients’ data revealed that postprandial hyperglycemia was not reduced in some patients, while preprandial glucose was ameliorated in most patients. Therefore, we divided patients into two groups according to their postprandial glucose responses and conducted a post hoc subanalyses to elucidate which factors contributed to the differential effects of luseogliflozin.MethodsThirty-four Japanese type 2 diabetic patients in our previous randomized, double-blind, placebo-controlled, crossover study with 7-day luseogliflozin administration were divided into postprandial glucose responders (PGR, n = 23, ameliorated peak glucose) and postprandial glucose non-responders (PGNR; n = 11, non-ameliorated peak glucose). Baseline characteristics, variations in CGM-measured 24-h glucose levels, and other pharmacodynamic variabilities were compared.ResultsBaseline characteristics did not differ significantly between groups. Placebo-subtracted peak glucose was significantly lowered in PGR and significantly increased in PGNR (−43.8 and 17.9 mg/dL; both p < 0.05). Luseogliflozin significantly lowered “lowest glucose” (defined as the lowest level measured throughout a 24-h period) similarly in PGR and PGNR (−19.2 and −24.0 mg/dL; both p < 0.05), significantly reduced the mean amplitude of glucose excursions in PGR (−15.50 mg/dL; p < 0.05), and increased the area under the curve for plasma glucagon over 24 h in PGNR (median difference vs. placebo: 240 pg/mL h; p < 0.05). Luseogliflozin increased urinary glucose excretion (UGE) and decreased serum insulin by similar magnitudes in both groups.ConclusionsLuseogliflozin diminished glucose fluctuations in most patients by lowering peak glucose to a greater extent than lowest glucose. Luseogliflozin may also lower lowest glucose in patients whose peak glucose was not ameliorated despite increasing UGE. The glucagon increase in PGNR might explain its hypoglycemic effect on postprandial glucose.FundingTaisho Pharmaceutical Co., Ltd, Tokyo, Japan.Trial RegistrationJapicCTI-142548.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0350-5) contains supplementary material, which is available to authorized users.