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

Arne Ring, Tobias Brand, Sreeraj Macha, Kerstin Breithaupt-Groegler, Gudrun Simons, Beate Walter, Hans J Woerle, Uli C Broedl, Arne Ring, Tobias Brand, Sreeraj Macha, Kerstin Breithaupt-Groegler, Gudrun Simons, Beate Walter, Hans J Woerle, Uli C Broedl

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.

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.

Figures

Figure 1
Figure 1
Patient flow (five-period crossover design).
Figure 2
Figure 2
Placebo-corrected QTcN CfB (A) and placebo-corrected heart rate CfB (B). Data are adjusted means and 90% confidence intervals (CIs) after administration of empagliflozin 25 mg, or 200 mg, or moxifloxacin 400 mg. Data from the full analysis set analysed: placebo (n=29); 25 mg empagliflozin group (n=28); 200 mg empagliflozin group (n=30); and 400 mg moxifloxacin group (n=29). CfB, change from baseline; HR, heart rate; QTcN, population heart rate-corrected QT interval.
Figure 3
Figure 3
Empagliflozin exposure-response relationships for placebo-corrected QTcN (A) and heart rate (B) changes from baseline. Placebo-corrected changes from baseline versus plasma concentrations of empagliflozin for empagliflozin 25 mg and empagliflozin 200 mg treatment groups. HR, heart rate; QTcN, population heart rate-corrected QT interval. Data from the full analysis set.

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