title: Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes.
abstract: BACKGROUND
  This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.
  
  
  METHODS
  Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.
  
  
  RESULTS
  Canagliflozin increased UGE dose-dependently (,80-120 g/day with canagliflozin $100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ,4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.
  
  
  CONCLUSIONS
  Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00963768.
authors.forename: Sue
authors.initials: S
authors.lastname: Sha
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Atalanta
authors.initials: A
authors.lastname: Ghosh
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.forename: Marcus
authors.initials: M
authors.lastname: Hompesch
authors.forename: Sabine
authors.initials: S
authors.lastname: Arnolds
authors.forename: Linda
authors.initials: L
authors.lastname: Morrow
authors.forename: Heike
authors.initials: H
authors.lastname: Spitzer
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D000068896:Canagliflozin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006029:Glycosuria / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016482:Urinalysis
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin