The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study.

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. TREATMENTS: 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/INTERPRETATION: Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01195675.

Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects.

Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose-proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food.