title: Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results.
abstract: BACKGROUND
  Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690.
  
  
  RESULTS
  The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis-related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful.
  
  
  CONCLUSIONS
  Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.
authors.affiliation: Senior Director and Clinical Leader, Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Keith
authors.initials: K
authors.lastname: Usiskin
authors.forename: Irina
authors.initials: I
authors.lastname: Kline
authors.forename: Albert
authors.initials: A
authors.lastname: Fung
authors.forename: Cristiana
authors.initials: C
authors.lastname: Mayer
authors.forename: Gary
authors.initials: G
authors.lastname: Meininger
mesh_terms: D000068896:Canagliflozin; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D007677:Kidney Function Tests; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D012737:Sex Factors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; D008055:Lipids; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin