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
Highlights
Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment
No relevant interactions with the human ether-a-go-go related gene-mediated potassium current were measured in transfected human embryonic kidney cells (HEK293 cells), and empagliflozin doses of ≥10 μM had no effect on action potential configuration or contractile function of guinea pig papillary muscle
The aim of this study was to confirm the absence of QT effects with therapeutic and supratherapeutic doses of empagliflozin compared with moxifloxacin as a positive control and placebo, using a new five-period crossover study design, utilising two placebo periods instead of one
Summary
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. The sodium glucose cotransporter 2 (SGLT2) plays an important role in glucose homeostasis, being responsible for around 90% of renal glucose reabsorption [1], and its inhibition represents a novel approach for the treatment of type 2 diabetes mellitus (T2DM). Empagliflozin is a potent and highly selective SGLT2 inhibitor that has been shown to reduce plasma glucose levels in patients with T2DM with a low risk of hypoglycaemia [6,8,9]. No relevant interactions with the human ether-a-go-go related gene (hERG)-mediated potassium current were measured in transfected human embryonic kidney cells (HEK293 cells), and empagliflozin doses of ≥10 μM had no effect on action potential configuration or contractile function of guinea pig papillary muscle (unpublished data)
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