title: Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial.
abstract: OBJECTIVE
  The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.
  
  
  METHODS
  This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N = 1,284) with type 2 diabetes aged ≥ 18 and ≤ 80 years who had inadequate glycaemic control (HbA1c ≥ 7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.
  
  
  RESULTS
  At week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (-0.79%, -0.94%, -0.17%, respectively; p < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (-0.73%, -0.88%,-0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (-0.12, 0.12) and -0.15% (-0.27, -0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: -3.7%, -4.2%, -1.2%, respectively; p < 0.001) and sitagliptin (week 52: -3.8%, -4.2%, -1.3%, respectively; p < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.
  
  
  CONCLUSIONS
  Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01106677 FUNDING: This study was supported by Janssen Research & Development, LLC.
authors.affiliation: Endocrinology and Internal Medicine Department, Universidad Autonóma de Nuevo León, Avenida Madero y Gonzalitos, S/N Col. Mitras Centro, 64460, Monterrey, Nuevo León, Mexico, drfernandolavalle@hotmail.com.
authors.forename: F J
authors.initials: FJ
authors.lastname: Lavalle-González
authors.forename: A
authors.initials: A
authors.lastname: Januszewicz
authors.forename: J
authors.initials: J
authors.lastname: Davidson
authors.forename: C
authors.initials: C
authors.lastname: Tong
authors.forename: R
authors.initials: R
authors.lastname: Qiu
authors.forename: W
authors.initials: W
authors.lastname: Canovatchel
authors.forename: G
authors.initials: G
authors.lastname: Meininger
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005215:Fasting; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects; D006442:Glycated Hemoglobin / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008055:Lipids; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D000068900:Sitagliptin Phosphate; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D001786:Blood Glucose; D000068896:Canagliflozin; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008055:Lipids; D008687:Metformin; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D013876:Thiophenes; D014230:Triazoles; C517652:hemoglobin A1c protein, human
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