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Introduction: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat (VF) accumulation in Japanese individuals. Therefore, this study aimed to analyze the efficacy and safety of 52 weeks of orlistat administration in Japanese individuals., Methods: Orlistat 60 mg was administered orally three times daily for 52 weeks to Japanese participants with excessive VF accumulation and without dyslipidemia, diabetes mellitus, and hypertension (metabolic diseases). Participants were also counseled to improve their diet and to maintain exercise habits. We defined excessive VF accumulation as a waist circumference (WC) of ≥ 85 cm for males and ≥ 90 cm for females, which corresponds to a VF area of 100 cm 2 . Adverse reactions, clinical laboratory tests, VF, WC, body weight (BW), etc., were monitored throughout the study period., Results: VF, WC, and BW were significantly reduced at week 52 from baseline; the mean ± standard error rate of change was - 21.52% ± 1.89%, - 4.89% ± 0.45%, and - 5.36% ± 0.56%, respectively, and continued to reduce throughout the 52 weeks; these significantly reduced at whole term compared with baseline. Most adverse reactions were defecation-related symptoms such as oily spotting and flatus with discharge (flatus with small amounts of stool or oil) due to the pharmacologic effects of the lipase inhibitor. These symptoms were mostly mild, reversible, and recognizable by the participants; none were serious or severe. No participants discontinued by medical judgment about adverse reactions, and the drug could be administered continuously., Conclusion: VF, WC, and BW were reduced from week 4 to week 52, indicating the effect of long-term orlistat administration. Moreover, it was well tolerated with an acceptable safety profile. Long-term administration of orlistat may be efficacious in reducing VF accumulation with safety when used in combination with diet and exercise., Trial Registration: This study is registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-184004)., Funding: Funding for this study was provided by Taisho Pharmaceutical Co., Ltd.

Introduction: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat accumulation in Japanese subjects. Therefore, this comparative, placebo-controlled, double-blind, randomized study aimed to evaluate the efficacy and safety of orlistat in Japanese participants with excessive visceral fat accumulation and without dyslipidemia, diabetes mellitus, and hypertension ("metabolic diseases")., Methods: The study population included Japanese participants with excessive visceral fat accumulation (waist circumference ≥ 85 cm in males and ≥ 90 cm in females, which corresponds to a visceral fat area of 100 cm 2 ) and without metabolic diseases. Following a 12-week observation term, participants were randomized to the orlistat 60 mg group (n = 100) or placebo group (n = 100). Both drugs were administered orally three times daily for 24 weeks. Participants were also counseled to improve their diet and to maintain exercise throughout the study. Visceral fat area, subcutaneous fat area, waist circumference, body weight, body mass index, adverse reactions, laboratory tests, and blood pressure were regularly assessed., Results: Visceral fat area, waist circumference, and body weight were significantly reduced in the orlistat group (mean ± standard error, - 13.50 ± 1.52%, - 2.51 ± 0.25%, and - 2.79 ± 0.30%, respectively) compared to the placebo group (- 5.45 ± 1.50%, - 1.55 ± 0.26%, and - 1.22 ± 0.28%, respectively) at the last assessment. The main adverse reactions were defecation-related symptoms including oily spotting and flatus with discharge, resulting from the pharmacological effects of orlistat. Most adverse reactions were mild, and none were serious or severe., Conclusion: Orlistat administration reduced visceral fat area, waist circumference, and body weight in Japanese participants with excessive visceral fat and without metabolic diseases. In addition, safety was confirmed with a tolerable profile. Orlistat may be useful to reduce excessive visceral fat accumulation when used in combination with diet and exercise., Trial Registration: Japan Pharmaceutical Information Center identifier, JapicCTI-184005., Funding: Taisho Pharmaceutical Co., Ltd.

Introduction: In 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., Methods: Thirty-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., Results: Baseline 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., Conclusions: Luseogliflozin 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., Funding: Taisho Pharmaceutical Co., Ltd, Tokyo, Japan., Trial Registration: JapicCTI-142548.

Introduction: We investigated the impact of reduced renal function on 24-h glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM) treated with luseogliflozin., Methods: In 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 m(2) 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 m(2)): 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)., Results: The 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., Conclusion: This 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 Registration: JapicCTI-142548., Funding: Taisho Pharmaceutical Co., Ltd.

Introduction: We investigated the possibilities of drug-drug interactions between luseogliflozin, a sodium-glucose co-transporter-2 inhibitor, and oral antidiabetic drugs (OADs) in healthy Japanese males., Methods: We conducted six independent studies to investigate potential drug-drug interactions between 5 mg luseogliflozin and the following OADs usually used in Japan: 1 mg glimepiride, 250 mg metformin, 30 mg pioglitazone, 50 mg sitagliptin, 50 mg miglitol, or 0.6 mg voglibose (0.2 mg before each meal). Twelve subjects were enrolled in each study. The glimepiride, metformin, sitagliptin, and miglitol studies were randomized, open-label, single-dose, three-way crossover studies. The pioglitazone and voglibose studies were open-label studies, where a single dose of luseogliflozin was added to multiple doses of pioglitazone or voglibose. The endpoints were the area under the curve from 0 to 24 h (AUC0-24 h) or to infinity (AUCinf) and the maximum concentration (Cmax) of each drug administered alone or in combination., Results: The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for Cmax of luseogliflozin in the pioglitazone and miglitol studies were beyond the reference range for bioequivalence (0.80-1.25) (miglitol: 0.851 [0.761, 0.952]; pioglitazone: 1.16 [1.04, 1.30]). However, the 90% CIs for AUC0-24 h were within the reference range. The 90% CIs of the GMRs for Cmax and AUC0-24 h of pioglitazone were beyond the reference range (Cmax 0.884 [0.746, 1.05]; AUC0-24 h 0.896 [0.774, 1.04]), but the 90% CIs for the active metabolites of pioglitazone were within the reference range. For the other combinations tested, the 90% CIs and GMRs for luseogliflozin and the individual OADs were within the reference range., Conclusion: No clinically meaningful interactions were observed between luseogliflozin and six commonly used OADs in Japan, although there were some changes in the pharmacokinetics of pioglitazone co-administered with luseogliflozin and for luseogliflozin co-administered with miglitol or pioglitazone., Funding: Taisho Pharmaceutical Co., Ltd.

Introduction: Luseogliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, promotes urinary glucose excretion (UGE) and reduces plasma glucose concentrations. Luseogliflozin was approved for use in Japan after favorable pharmacokinetic, pharmacodynamic, and safety profiles were reported in healthy Japanese subjects and patients with type 2 diabetes mellitus (T2DM) in clinical development studies. We aimed to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple doses of luseogliflozin administered once daily for 7 days in Japanese patients with T2DM., Methods: We conducted a randomized, placebo-controlled, single-blind, parallel-group, clinical pharmacology study at the P-One Clinic, Keikokai Medical Corporation (Tokyo, Japan) between August 2009 and November 2009. Forty Japanese patients with T2DM were randomly assigned to receive once-daily 0.5, 1, 2.5 or 5 mg luseogliflozin or placebo for 7 days. We assessed the pharmacokinetics, pharmacodynamics (including changes in UGE and plasma glucose concentrations), and safety of luseogliflozin., Results: The plasma concentrations of luseogliflozin and its active metabolite, M2, were dose proportional, without accumulation. 24-h UGE was greater in all luseogliflozin groups versus placebo. Least-squares mean differences in 24-h UGE on Day 7 increased dose dependently in the luseogliflozin groups, with values of 49.2, 66.5, 89.4, and 101 g/day at 0.5, 1, 2.5, and 5 mg, respectively. On Day 7, the areas under the concentration-time curves for post-meal plasma glucose and the mean plasma glucose for 0-16 h were significantly lower in all luseogliflozin groups versus placebo. Seven patients had mild adverse events (AEs); all were resolved. No AEs led to study discontinuation., Conclusion: Once-daily administration of luseogliflozin for 7 days increased 24-h UGE in a dose-dependent manner, reduced plasma glucose concentrations, and was well tolerated in Japanese patients with T2DM. The pharmacokinetic and pharmacodynamic profile of luseogliflozin observed in this study supports its once-daily dosing regimen., Funding: Taisho Pharmaceutical Co., Ltd.

Introduction: Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, inhibits reabsorption of glucose in the proximal renal tubule. It was developed for the treatment of type 2 diabetes mellitus., Methods: For this first human study of luseogliflozin, randomized, single-blind, placebo-controlled, single ascending dose (1-25 mg) and multiple ascending dose (5 or 10 mg/day, 7 days) trials were conducted in healthy male Japanese subjects to investigate safety, pharmacokinetics, and pharmacodynamics., Results: There were no serious adverse events, adverse events leading to discontinuation, or episodes of hypoglycemia. After administration of a single oral dose of luseogliflozin, its maximum plasma level (C max) and area under the concentration-time curve increased in a dose-dependent manner, and no food effects were observed on pharmacokinetics. The mean time taken to reach C max (T max) ranged from 0.667 to 2.25 h. The mean plasma half-life of luseogliflozin (T 1/2) after multiple dosing for 7 days ranged from 9.14 to 10.7 h, and no detectable accumulation of luseogliflozin was observed. Urinary glucose excretion increased in a dose-dependent manner, ranging from 18.9 to 70.9 g (single-dose study)., Conclusion: Luseogliflozin was well tolerated and showed favorable pharmacokinetic and pharmacodynamic profiles in healthy male Japanese subjects.