Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study

Glenn F Carlson, Conrad K P Tou, Shamik Parikh, Bruce K Birmingham, Kathleen Butler, Glenn F Carlson, Conrad K P Tou, Shamik Parikh, Bruce K Birmingham, Kathleen Butler

Abstract

Introduction: Dapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization.

Methods: The present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit. The study enrolled 50 healthy men who were randomized to receive sequences of single doses of dapagliflozin 150 mg, dapagliflozin 20 mg, moxifloxacin 400 mg, and placebo. The sequences were randomized based on the Williams design for a cross-over study to reduce the "carryover" effects from drug-to-drug even with sufficient washout periods. Digital 12-lead electrocardiograms were recorded at nine time points over 24 hours in each period. QT intervals were corrected for heart rate using a study-specific correction factor (QTcX) and Fridericia's formula.

Results: For dapagliflozin, the upper bound of the one-sided 95% confidence interval (CI) for time-matched, placebo-subtracted, baseline adjusted QTc intervals (ΔΔQTc) was <10 ms. ΔΔQTc was independent of dapagliflozin concentrations. No QTc thresholds >450 ms or QTc increases >30 ms were observed. Moxifloxacin increased the mean QTcX interval by 7.7 ms (lower bound 90% CI, 6.2 ms) over 1-4 hours after dosing, confirming assay sensitivity.

Conclusion: Dapagliflozin, at supratherapeutic doses, does not have a clinically significant effect on the QT interval in healthy subjects.

Figures

Figure 1
Figure 1
Placebo-subtracted (time-matched), baseline-adjusted least-squares (LS) mean difference in QTcX interval versus sample time.
Figure 2
Figure 2
Shift from baseline to the maximum observed QTcX interval by treatment
Figure 3
Figure 3
Mean individual QTcX intervals versus dapagliflozin (150 mg and 20 mg) plasma concentration
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3173598/bin/13300_2011_3_Fig1_HTML.jpg

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Source: PubMed

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