title: The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study.
abstract: BACKGROUND
  Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters.
  
  
  METHODS
  A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power.
  
  
  METHODS
  single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1-4 hours after dosing.
  
  
  RESULTS
  Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18-52] years) were randomised. The placebo-corrected MCfB in QTcN 1-4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2-4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis.
  
  
  CONCLUSIONS
  Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01195675.
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Tobias
authors.initials: T
authors.lastname: Brand
authors.forename: Sreeraj
authors.initials: S
authors.lastname: Macha
authors.forename: Kerstin
authors.initials: K
authors.lastname: Breithaupt-Groegler
authors.forename: Gudrun
authors.initials: G
authors.lastname: Simons
authors.forename: Beate
authors.initials: B
authors.lastname: Walter
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D005858:Germany; D005960:Glucosides / Q000009:adverse effects* / Q000493:pharmacokinetics; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D024841:Fluoroquinolones; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin; D000077266:Moxifloxacin