Introduction:

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue in development for once-weekly treatment of type 2 diabetes. QT interval prolongation is a biomarker for ventricular tachyarrhythmia. It is a regulatory requirement to test for prolongation of the QT interval for most new drugs with systemic exposure.

Purpose:

The objective of this thorough QT (TQT) study was to confirm that treatment with semaglutide does not result in an unacceptable prolongation of cardiac repolarisation, compared with placebo.

Methods:

In this parallel-design TQT study, healthy subjects (N=168, 60% males, mean age 38.2 years, mean body mass index 25.1 kg/m²) were randomised to semaglutide treatment over 16 weeks (once-weekly dosing, escalated to a supra-therapeutic dose of 1.5 mg) or placebo. To assess QT assay sensitivity, subjects in the placebo group received moxifloxacin (400 mg; single oral dose), as a positive control, and placebo in a crossover fashion. The primary endpoint was time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from the ECG recordings obtained at 11 time points, from pre-dose up to 48 hours after the last dose of semaglutide (1.5 mg) or placebo. Similar ΔQTcI assessments were conducted for 0.5 and
1.0 mg doses as secondary endpoints. Data were analysed in a linear mixed model for repeated measurements where all 11 time-matched sampling time points were entered as dependent variables, with treatment as fixed factor and baseline measurements as covariate. Heart rate was also assessed.

Results:

No unacceptable prolongation of QTcI occurred at semaglutide 1.5 mg, or at 0.5 and 1.0 mg doses (upper limits of two-sided 90% confidence intervals [CIs] of placebo-subtracted change from baseline QTcI (ΔΔQTcI) <10 ms at all doses and time points; mean ΔΔQTcI for semaglutide 1.5 mg ranged from –6.56 to –3.16 ms; Figure). An exposure–response analysis did not show a dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed (lower limits of 95% CIs of placebo-subtracted QTcI >5 ms following moxifloxacin administration). Heart rate increased with semaglutide at all doses compared with baseline and placebo. No new safety or tolerability issues were identified with semaglutide.

Conclusions:

Semaglutide treatment did not result in a prolongation of the QTcI interval in healthy subjects. It was well tolerated, with a safety profile similar to that observed with other GLP-1 receptor agonists.

 Figure. ΔΔQTcI interval (ms) at semaglutide steady state. Data are mean baseline-adjusted and placebo-subtracted QTcI with bars representing the corresponding two-sided 90% CIs.