Semaglutide and the Heart: Focus on Their Love–Hate Relationship

Semaglutide, a recombinant DNA-derived long-acting GLP-1 receptor agonist, has emerged as a key player for patients with or without T2DM and obesity. It exerts pleiotropic effects by modulating glycemic regulation and energy homeostasis. Mechanistically, it stimulates glucose-dependent insulin secretion and suppresses glucagon while enhancing satiety through POMC/NPY modulation in the arcuate nucleus and delaying gastric emptying. Beyond its metabolic utility, semaglutide is cardioprotective, leveraging the PI3K/Akt and eNOS pathways to improve vasodilation, reduce reactive oxygen species (ROS), and stabilize atherosclerotic plaques by inhibiting pro-inflammatory cytokines like TNF-α. While it improves cardiac output via PKA-mediated inotropy, potential cardiotoxicity, including resting tachycardia and autonomic-driven arrhythmias, requires clinical vigilance, particularly regarding electrolyte imbalances in heart failure patients. Ultimately, its robust vasculoprotective profile reinforces its potential as a cornerstone in cardiovascular pharmacotherapy. Further research is needed to better understand the effects of semaglutide on cardiac function and pathologies as it advances as a cardiac drug. This review discusses multiple molecular targets of semaglutide on the heart.