title: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes.
abstract: OBJECTIVE
  In rodent models of diabetes, treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors improves beta cell function. This analysis assessed the effects of the SGLT2 inhibitor, canagliflozin, on model-based measures of beta cell function in patients with type 2 diabetes.
  
  
  METHODS
  Data from three Phase 3 studies were analysed, in which: (Study 1) canagliflozin 100 and 300 mg were compared with placebo as monotherapy for 26 weeks; (Study 2) canagliflozin 100 and 300 mg were compared with placebo as add-on to metformin + sulfonylurea for 26 weeks; or (Study 3) canagliflozin 300 mg was compared with sitagliptin 100 mg as add-on to metformin + sulfonylurea for 52 weeks. In each study, a subset of patients was given mixed-meal tolerance tests at baseline and study endpoint, and model-based beta cell function parameters were calculated from plasma glucose and C-peptide.
  
  
  RESULTS
  In Studies 1 and 2, both canagliflozin doses increased beta cell glucose sensitivity compared with placebo. Placebo-subtracted least squares mean (LSM) (SEM) changes were 23 (9) and 18 (9) pmol min(-1) m(-2) (mmol/l)(-1) with canagliflozin 100 and 300 mg, respectively (p < 0.002, Study 1), and 16 (8) and 10 (9) pmol min(-1) m(-2) (mmol/l)(-1) (p < 0.02, Study 2). In Study 3, beta cell glucose sensitivity was minimally affected, but the insulin secretion rate at 9 mmol/l glucose increased to similar degrees from baseline with canagliflozin and sitagliptin [LSM (SEM) changes 38 (8) and 28 (9) pmol min(-1) m(-2), respectively; p < 0.05 for both].
  
  
  CONCLUSIONS
  Treatment with canagliflozin for 6 to 12 months improved model-based measures of beta cell function in three separate Phase 3 studies.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01081834 (Study 1); NCT01106625 (Study 2); NCT01137812 (Study 3).
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA, DPolido1@its.jnj.com.
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology*; D004311:Double-Blind Method; D005260:Female; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D016018:Least-Squares Analysis; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage; D000068900:Sitagliptin Phosphate; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000008:administration & dosage; D013876:Thiophenes / Q000627:therapeutic use*; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005960:Glucosides; D011719:Pyrazines; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D013453:Sulfonylurea Compounds; D013876:Thiophenes; D014230:Triazoles; D000068896:Canagliflozin; D008687:Metformin; D000068900:Sitagliptin Phosphate