title: Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.
abstract: BACKGROUND
  Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs.
  
  
  METHODS
  A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231)
  
  
  METHODS
  126 centers in Europe and North America from 30 April 2008 to 19 November 2009.
  
  
  METHODS
  808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs.
  
  
  METHODS
  Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks.
  
  
  METHODS
  The primary outcome was change in hemoglobin A(1c) from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods.
  
  
  RESULTS
  800 patients were analyzed. After 24 weeks, mean hemoglobin A(1c) decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, -0.40% [95% CI, -0.54% to -0.25%] in the 2.5-mg group, -0.49% [CI, -0.65% to -0.34%] in the 5-mg group, and -0.57% [CI, -0.72% to -0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%).
  
  
  CONCLUSIONS
  Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety.
  
  
  CONCLUSIONS
  Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.
  
  
  BACKGROUND
  AstraZeneca and Bristol-Myers Squibb.
authors.affiliation: University Hospital Aintree, Liverpool, United Kingdom. j.p.h.wilding@liverpool.ac.uk
authors.forename: John P H
authors.initials: JP
authors.lastname: Wilding
authors.forename: Vincent
authors.initials: V
authors.lastname: Woo
authors.forename: Norman G
authors.initials: NG
authors.lastname: Soler
authors.forename: Andrea
authors.initials: A
authors.lastname: Pahor
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sugg
authors.forename: Katja
authors.initials: K
authors.lastname: Rohwedder
authors.forename: Shamik
authors.initials: S
authors.lastname: Parikh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005831:Genital Diseases, Female / Q000139:chemically induced; D005832:Genital Diseases, Male / Q000139:chemically induced; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D015431:Weight Loss; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D051247:Sodium-Glucose Transport Proteins; C529054:dapagliflozin