title: Influence of Renal Function on the 52-Week Efficacy and Safety of the Sodium Glucose Cotransporter 2 Inhibitor Luseogliflozin in Japanese Patients with Type 2 Diabetes Mellitus.
abstract: OBJECTIVE
  To evaluate the influence of renal function on the efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin (TS-071) in Japanese patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Study 1 was a 52-week, Phase III study to evaluate the efficacy and safety of 2.5 mg/d luseogliflozin (or increased to 5 mg/d) in patients with T2DM with moderate renal impairment. During the initial 24 weeks, efficacy and safety of luseogliflozin were compared with placebo. Study 2 was a pooled analysis of four 52-week, Phase III studies of luseogliflozin, including Study 1, to evaluate the efficacy and safety of luseogliflozin in patients with various degrees of renal function. Patients were stratified into 3 groups by baseline estimated glomerular filtration rate (eGFR): normal renal function (≥90 mL/min/1.73 m(2)), mild impairment (≥60 to <90 mL/min/1.73 m(2)), and moderate impairment (≥30 to <60 mL/min/1.73 m(2)). Patients with moderate impairment were further divided into those with mild-moderate (≥45 to <60 mL/min/1.73 m(2)) and moderate-severe (≥30 to <45 mL/min/1.73 m(2)). In both studies, efficacy end points included changes in glycated hemoglobin (HbA1c) level, fasting plasma glucose (FPG) level, and body weight. The safety end points included adverse events (AEs) and laboratory parameters.
  
  
  RESULTS
  In Study 1, HbA1c, FPG, and body weight significantly decreased at Week 24 in patients treated with luseogliflozin compared with patients treated with placebo, with the decrease in these parameters also observed with luseogliflozin at Week 52. The incidence of AEs was similar between groups. In Study 2, 1030 patients were included (normal, 275; mildly impaired, 598; and moderately impaired, 157). At Week 52, HbA1c, FPG, and body weight were significantly decreased from baseline in all groups. In between-group comparisons, the decreases in HbA1c and body weight were significantly smaller in patients with moderate impairment than in those with normal function; however, the HbA1c-lowering efficacy was reduced by nearly half, whereas the efficacy of body weight lowering was not so much diminished in the moderate impairment group. Furthermore, a scatter plot showed that changes in HbA1c were more influenced by baseline HbA1c than by baseline eGFR. The incidence of AEs during 52 weeks was similar among all groups, with the majority being mild.
  
  
  CONCLUSIONS
  Luseogliflozin improved glycemic control and reduced body weight in all eGFR groups, and its efficacy on HbA1c lowering was reduced in those with moderate renal impairment. Luseogliflozin was well tolerated and safe, with no significant safety issues identified, regardless of baseline eGFR. The study is registered with Clinical Trials Information/JapicCTI of the Japan Pharmaceutical Information Center, and the study registry identification numbers are JapicCTI-111507, JapicCTI-111508, JapicCTI-111509, and JapicCTI-111543.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan. Electronic address: haneda@asahikawa-med.ac.jp.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.affiliation: Kansai Electric Power Hospital, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Department of Internal Medicine, Kawasaki Medical University, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
authors.affiliation: Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Chiba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Yachiyo Hospital, Aichi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.affiliation: Taisho Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Kakiuchi
authors.affiliation: Taisho Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Taisho Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Taisho Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Samukawa
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000150:complications / Q000503:physiopathology*; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors; D013012:Sorbitol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D051247:Sodium-Glucose Transport Proteins; D013012:Sorbitol; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol
keywords: Japanese; glomerular filtration rate; luseogliflozin; renal impairment; sodium glucose cotransporter 2 inhibitor; type 2 diabetes mellitus