Aims
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising effects in reducing cardiovascular events in patients with obesity and heart failure (HF) with preserved ejection fraction (HFpEF) irrespective of concomitant diabetes. However, the exact mechanisms underlying its cardioprotective actions remain unclear. Our study investigates the direct effects of semaglutide on human cardiomyocytes, focusing on calcium (Ca) and sodium (Na) handling and its potential to improve myocardial contractility.

Methods and results
Human left ventricular cardiomyocytes were isolated from non-failing (NF) hearts, patients with aortic stenosis and a HFpEF-like phenotype (AS), and those with end-stage HF with reduced ejection fraction (HFrEF). Late Na current (INa), sarcoplasmic reticulum (SR) Ca leak, and contractility were assessed in isolated cardiomyocytes treated with semaglutide. CaMKII inhibitor autocamtide-2-related inhibitory peptide and GLP-1 receptor antagonist exendin 9–39 (Ex-9-39) were used to elucidate signalling pathways. Semaglutide reduced late INa in AS and HFrEF cardiomyocytes to levels comparable to NF. Additionally, semaglutide decreased diastolic SR Ca leak and improved systolic Ca transients and contractility in AS and HFrEF tissue. These effects were mediated through GLP-1 receptor agonism and were comparable to CaMKII inhibition. In multicellular preparations, semaglutide differentially improved myocardial contractility in AS and HFrEF in a dose-dependent manner.

Conclusion
Semaglutide directly modulates ion homeostasis in human cardiomyocytes, reducing proarrhythmic diastolic SR Ca leak and enhancing systolic function, which may explain its observed clinical benefits. These findings provide mechanistic insights into the cardioprotective effects of semaglutide and suggest its potential therapeutic use in H