title: Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.
abstract: OBJECTIVE
  There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin.
  
  
  METHODS
  The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.
  
  
  RESULTS
  Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.
  
  
  CONCLUSIONS
  Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.
authors.affiliation: The George Institute for Global Health, The University of Sydney and the Royal Prince Alfred Hospital, Sydney, Australia bneal@georgeinstitute.org.au.
authors.forename: Bruce
authors.initials: B
authors.lastname: Neal
authors.affiliation: The George Institute for Global Health, The University of Sydney and the Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: The Royal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Fulcher
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Kirk
authors.initials: K
authors.lastname: Ways
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Mehul
authors.initials: M
authors.lastname: Desai
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Wayne
authors.initials: W
authors.lastname: Shaw
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: George
authors.initials: G
authors.lastname: Capuano
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Maria
authors.initials: M
authors.lastname: Alba
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Joel
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Frank
authors.initials: F
authors.lastname: Vercruysse
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Gary
authors.initials: G
authors.lastname: Meininger
authors.affiliation: University of Oxford, Oxford, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Matthews
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects; D006442:Glycated Hemoglobin / Q000187:drug effects; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D020896:Hypovolemia / Q000139:chemically induced; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000139:chemically induced; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000139:chemically induced; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D000068896:Canagliflozin; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes