No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects

Valentin Demmel, Anne Sandberg-Schaal, Jacob B Jacobsen, Georg Golor, Jonas Pettersson, Anne Flint, Valentin Demmel, Anne Sandberg-Schaal, Jacob B Jacobsen, Georg Golor, Jonas Pettersson, Anne Flint

Abstract

Introduction: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia.

Methods: In a parallel design, 168 healthy subjects were randomized to the treatment or placebo arms, of whom 166 were treated with subcutaneous semaglutide (N = 83; escalated to a supratherapeutic dose of 1.5 mg) or placebo (N = 83). The subjects (60% males) had a mean age of 38.2 years and body mass index of 25.1 kg/m2. To assess QT assay sensitivity, subjects in the placebo group received a single 400 mg moxifloxacin dose as positive control, and placebo in a crossover fashion. The primary endpoint was the time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from 11 electrocardiogram recordings from 0 to 48 h after the last 1.5 mg dose. Similar assessments were made for the therapeutic 0.5 and 1.0 mg semaglutide dose levels.

Results: No QTcI prolongation occurred with any semaglutide dose; the upper limits of two-sided 90% confidence intervals of the placebo-subtracted ΔQTcI were < 10 ms at all doses and time points. Exposure-response analysis showed no dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed. The semaglutide safety profile was similar to that of other GLP-1 receptor agonists.

Conclusion: Based on investigations of QT/QTc, no concern with regard to ventricular arrhythmias was raised as semaglutide did not prolong the cardiac repolarization duration in healthy subjects.

Trial registration: ClinicalTrials.gov identifier: NCT 02064348.

Funding: Novo Nordisk.

Trial registration: ClinicalTrials.gov NCT02064348.

Keywords: Cardiac repolarization; Drug safety; GLP-1 analog; GLP-1 receptor agonist; QT interval; Semaglutide.

Figures

Fig. 1
Fig. 1
Trial design. ECG Electrocardiogram, PK pharmacokinetics
Fig. 2
Fig. 2
Time-matched mean placebo-subtracted ΔQTcI (ΔΔQTcI) for each semaglutide dose (0.5, 1.0 and 1.5 mg) over the 48-h post-dose period. Data are mean baseline-adjusted and placebo-subtracted QTcI with error bars representing the corresponding two-sided 90% confidence intervals. The dotted line corresponds to the ΔΔQTcI interval threshold of regulatory concern (< 10 ms). QTcl QT interval corrected individually for heart rate, ΔQTcI time-matched change from baseline in the QTcI
Fig. 3
Fig. 3
Placebo-corrected ΔQTcI interval versus semaglutide plasma concentration assessed at steady state at each dose. The QTcI intervals are individually placebo-corrected by subtracting the estimated placebo mean at each time point

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