title: Diabetic Ketoacidosis With Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes.
abstract: To assess the incidence of serious adverse events (AEs) of diabetic ketoacidosis (DKA) with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as an add-on to insulin in adults with type 1 diabetes.
  
  
  
  In this 18-week, randomized, double-blind, phase 2 study, patients (N = 351; HbA1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion received canagliflozin 100 or 300 mg or placebo once daily. The incidence of ketone-related AEs, defined as any event from a prespecified list of preferred terms (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, urine ketone body present), including serious AEs of DKA, was assessed based on AE reports.
  
  
  
  At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE.
  
  
  
  Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin. Mitigation strategies are needed for use in future clinical trials to reduce the risk of DKA with canagliflozin treatment in patients with type 1 diabetes.
authors.affiliation: Keck School of Medicine of the University of Southern California, Los Angeles, CA momofmax@mac.com.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Peters
authors.affiliation: Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA University of California, San Diego, La Jolla, CA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Payal
authors.initials: P
authors.lastname: Thakkar
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Cindy
authors.initials: C
authors.lastname: Tong
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Maria
authors.initials: M
authors.lastname: Alba
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D015992:Body Mass Index; D000068896:Canagliflozin / Q000008:administration & dosage / Q000009:adverse effects*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D016883:Diabetic Ketoacidosis / Q000139:chemically induced* / Q000175:diagnosis; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000008:administration & dosage; D007332:Insulin Infusion Systems; D008297:Male; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D007328:Insulin; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin