<p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of cardiometabolic diseases, extending their therapeutic applications far beyond glycemic control in type 2 diabetes (T2D) and obesity. This editorial synthesizes key milestones, from the discovery of glucagon-like peptide-1 (GLP-1) to recent clinical trials highlighting the pleiotropic effects of GLP-1RAs in addressing the interconnected spectrum of cardiometabolic conditions, with a focus on cardiovascular, renal, and hepatic benefits. In addition, as GLP-1RAs continue to reshape the management of cardiometabolic disease and global public health, we discuss future challenges to better elucidate their mechanisms of cardiometabolic protection and maximize their therapeutic potential.</p> Graphical abstract <p></p>