title: Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination.
  
  
  METHODS
  In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1:1:1:1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight.
  
  
  RESULTS
  Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (-0.52 vs. -0.30%, p = 0.0106 and -0.65% vs. -0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated.
  
  
  CONCLUSIONS
  Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen.
authors.affiliation: Clinic for Endocrinology, Diabetology, Angiology, Academic Teaching Hospital, Munich, Germany.
authors.forename: P-M
authors.initials: PM
authors.lastname: Schumm-Draeger
authors.forename: L
authors.initials: L
authors.lastname: Burgess
authors.forename: L
authors.initials: L
authors.lastname: Korányi
authors.forename: V
authors.initials: V
authors.lastname: Hruba
authors.forename: J E
authors.initials: JE
authors.lastname: Hamer-Maansson
authors.forename: T W A
authors.initials: TW
authors.lastname: de Bruin
mesh_terms: D000368:Aged; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005060:Europe; D005240:Feasibility Studies; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D049990:Membrane Transport Modulators / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013019:South Africa
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; D008687:Metformin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C517652:hemoglobin A1c protein, human; C529054:dapagliflozin
keywords: SGLT2 inhibitor; metformin; phase III study; type 2 diabetes