Future GLP-1 receptor co-agonists and their cardiac effects

Abstract Agonists at glucagon-like-peptide-1 receptors (GLP-1R) are becoming approved drugs to treat not only type 2 diabetes and obesity but also cardiac diseases such as coronary heart disease, myocardial infarction and heart failure. Agonism at the GLP-1R can be combined with agonism at additional receptors (co-agonists) to obtain drugs which are more potent to induce weight loss. Therefore, new co-agonists were developed that not solely stimulate GLP-1R. We discuss here the known (for tirzepatide and retatrutide) or predicted contractile effects of such co-agonists on isolated cardiac preparations of experimental animals, mainly in mice and compare these results with data in isolated human cardiac preparations. We point out where preclinical studies in mice may be misleading in order to study cardiac effects of the drugs of interest in the human heart and as potential drugs for heart diseases. We address in some detail which additional receptors are or might be involved, the receptor expression of such additional receptors in the heart of various experimental animals. We will discuss not only receptor agonists but also a receptor antagonist (AMG133). We identify research needs and controversies in the literature. We make suggestions for further preclinical research and what improvements in drug design for treatment may lie ahead.