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

Abstract

BackgroundEmpagliflozin 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.MethodsA 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.ResultsThirty 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/interpretationSingle doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers.Trial registrationClinicalTrials.gov: NCT01195675

Effect of sodium‐glucose co‐transporter‐2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes

“…the low QTc dispersion subgroup). These results are consistent with the results of a previous study that showed that empagliflozin did not prolong QTc interval in healthy participants [13]. Interestingly, QTc dispersion and T peak -T end were reduced by treatment with an SGLT2 inhibitor when these indices of ventricular repolarization were prolonged before the treatment.…”

“…A varied relationship between QT dispersion/QTc dispersion and cardiovascular mortality has been reported in the literature [5][6][7][8], but an association of longer QT dispersion with higher mortality has been shown by the finding that relative risks of mortality in people with QT dispersion ≥80 ms and in those with QT dispersion of 30-80 ms were 1.80-fold and 1.65-fold higher than the relative risk in people with QT dispersion of ≤ 30 ms [12]. These results are consistent with the results of a previous study that showed that empagliflozin did not prolong QTc interval in healthy participants [13]. Treatment with an SGLT2 inhibitor did not change heart rate or QTc interval.…”

Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies

“…In a randomized, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design has demonstrated that empagliflozin was not associated with QTc prolongation. This effect was consistent with single therapeutic (25 mg) and supratherapeutic (200 mg) doses of empagliflozin [49].…”

A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans

“…This lack of effect was also observed with supra-therapeutic doses up to 800 mg in a single rising dose study in healthy volunteers (Seman et al 2013). Moreover, neither a therapeutic (25 mg) nor a supra-therapeutic dose (200 mg) of empagliflozin affected mean change from baseline for heart rate-corrected QT interval in healthy volunteers (Ring et al 2013). …”