Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy

Aim: An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methods: Experiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findings: LG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during beta-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. Significance: LG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than beta-blockade.

Automated summary

This study investigated the mechanism and potential means to mitigate the positive chronotropy induced by Liraglutide. It was found that the direct effect of Liraglutide on the sino-atrial node, independent of adrenergic cascade, contributes to the increased heart rate. If blockers are suggested to be more effective than beta-blockers in mitigating LG-induced positive chronotropy.