title: Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study.
abstract: OBJECTIVE
  Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters.
  
  
  METHODS
  A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons.
  
  
  RESULTS
  Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo.
  
  
  CONCLUSIONS
  This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.
authors.affiliation: Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA University of California, San Diego, La Jolla, CA rrhenry@outlook.com.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX.
authors.forename: Julio
authors.initials: J
authors.lastname: Rosenstock
authors.affiliation: Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA University of California, San Diego, La Jolla, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Edelman
authors.affiliation: Center for Metabolic Research, VA San Diego Healthcare System, San Diego, CA University of California, San Diego, La Jolla, CA.
authors.forename: Sunder
authors.initials: S
authors.lastname: Mudaliar
authors.affiliation: Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
authors.forename: Alexandros-Georgios
authors.initials: AG
authors.lastname: Chalamandaris
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Sreeneeranj
authors.initials: S
authors.lastname: Kasichayanula
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Allyson
authors.initials: A
authors.lastname: Bogle
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Nayyar
authors.initials: N
authors.lastname: Iqbal
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: James
authors.initials: J
authors.lastname: List
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Griffen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001786:Blood Glucose / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006442:Glycated Hemoglobin / Q000187:drug effects; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin