title: A novel and selective sodium-glucose cotransporter-2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  To assess the efficacy, safety and tolerability of different doses of tofogliflozin, a novel, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  In a 12-week, multicentre, multinational, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study, patients with inadequate glycaemic control from diet and exercise alone, or from diet and exercise plus a stable dose of metformin, were randomized to one of five doses of tofogliflozin (2.5, 5, 10, 20, or 40 mg) or placebo. The primary efficacy endpoint was absolute change at week 12 from baseline in glycated haemoglobin (HbA1c), minus the change in the placebo group.
  
  
  RESULTS
  Statistically significant dose-dependent reductions in HbA1c were shown in all treated groups except the 2.5-mg dose group, with a maximum reduction of 0.56% (placebo-subtracted) at the 40-mg dose, along with increased urinary glucose excretion. Metformin treatment had no substantial influence on tofogliflozin efficacy. Dose-dependent reductions in fasting plasma glucose and body weight were observed, and glucose intolerance was improved, with a trend towards blood pressure reduction. Slight increases were observed for mean ketone bodies with no abnormal change in ketone body ratio. No deaths or treatment-related serious adverse events were reported. The incidence of adverse events was similar in the placebo (37.9%) to that in the tofogliflozin group (35.9-46.3%). Withdrawal because of adverse events was rare (≤2 patients per treatment group), with similar rates of withdrawal in the placebo and tofogliflozin groups.
  
  
  CONCLUSIONS
  A once-daily dose of tofogliflozin for 12 weeks was an effective, safe and well-tolerated treatment for T2DM.
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Cynshi
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: A D
authors.initials: AD
authors.lastname: Christ
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Boerlin
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Beyer
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Beck
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Ciorciaro
authors.affiliation: F. Hoffman-La Roche AG, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects*; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000628:therapy* / Q000652:urine; D003927:Diet, Diabetic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005081:Exercise Therapy; D005215:Fasting / Q000097:blood; D005260:Female; D005960:Glucosides / Q000008:administration & dosage*; D006442:Glycated Hemoglobin / Q000187:drug effects; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007659:Ketones / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007659:Ketones; D008687:Metformin; C517652:hemoglobin A1c protein, human; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
keywords: SGLT2 inhibitor; drug development; phase I-II study; type 2 diabetes