title: Dapagliflozin in patients with type 1 diabetes: A post hoc analysis of the effect of insulin dose adjustments on 24-hour continuously monitored mean glucose and fasting β-hydroxybutyrate levels in a phase IIa pilot study.
abstract: To investigate the effects of total daily insulin dose (TDD) reductions on 24-hour continuously monitored mean glucose and fasting β-hydroxybutyrate (a marker for diabetic ketosis/ketoacidosis [DKA]) levels, using patient-level data from a 14-day, pilot study of dapagliflozin in type 1 diabetes (T1DM).
  
  
  
  A post hoc exploratory correlation analysis was performed to determine the relationship between change in TDD and (1) 24-hour mean glucose, assessed by continuous glucose monitoring, and (2) fasting β-hydroxybutyrate, in 70 patients with T1DM receiving insulin and dapagliflozin (1, 2.5, 5 or 10 mg) or placebo. The pharmacodynamic effect of dapagliflozin was estimated as a virtual "insulin dose" using 24-hour urinary glucose excretion values and a recognized insulin-to-carbohydrate counting technique.
  
  
  
  Trends for correlations were observed between change in TDD and 24-hour glucose (day 7: r = -0.264, P = .056) and β-hydroxybutyrate (day 7: r = -0.187, P = .133; day 14: r = -0.274, P = .047). The pharmacodynamic effect of dapagliflozin 5 or 10 mg was estimated as equivalent to ~20% of baseline TDD. Higher mean and maximum β-hydroxybutyrate levels were observed on days 7 and 14 in patients with a TDD reduction >20% vs ≤20%.
  
  
  
  Over 14 days, decreasing the insulin dose diminished the glucose-lowering effect of dapagliflozin-insulin combination therapy and increased levels of β-hydroxybutyrate. While insulin dose adjustments should always be individualized, these analyses suggest that, as a general rule, TDD reduction in dapagliflozin-treated patients with T1DM should not exceed 20%, to ensure glycaemic control does not deteriorate and to mitigate the potential for an increased risk of DKA.
authors.affiliation: University of California, San Diego, California.|Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: State University of New York at Buffalo, Buffalo, New York.
authors.forename: Paresh
authors.identifier: 0000-0002-7055-2084
authors.initials: P
authors.lastname: Dandona
authors.affiliation: University of California, San Diego, California.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Pettus
authors.affiliation: University of California, San Diego, California.|Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Sunder
authors.initials: S
authors.lastname: Mudaliar
authors.affiliation: AstraZeneca, Gaithersburg, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Xu
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Lars
authors.identifier: 0000-0003-0784-8189
authors.initials: L
authors.lastname: Hansen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood*; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D015190:Blood Glucose Self-Monitoring / Q000379:methods; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005215:Fasting / Q000097:blood*; D005260:Female; D005947:Glucose / Q000032:analysis; D005960:Glucosides / Q000008:administration & dosage*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; C529054:dapagliflozin; D005947:Glucose; D020155:3-Hydroxybutyric Acid
keywords: antidiabetic drug; continuous glucose monitoring (CGM); dapagliflozin; glycaemic control; insulin therapy; type 1 diabetes; β-hydroxybutyrate