Cardiovascular Effects of Glucagon Receptor Signaling Alone and Combined With Glucagon-Like Peptide-1 Receptor Signaling in Multiagonists: A Narrative Review With a Translational Focus.

Cardio-kidney-metabolic diseases including obesity, metabolic dysfunction-associated liver disease, and type 2 diabetes have reached pandemic prevalence, fueling the search for new treatments for these conditions, given their associated complications, notably cardiovascular disease. Dual agonists of the glucagon and glucagon-like peptide (GLP-1) receptors are promising. Certain GLP-1 receptor monoagonists are indicated for treatment of type 2 diabetes, obesity, and metabolic dysfunction-associated steatotic liver disease; and for reducing cardiovascular events in type 2 diabetes or obesity and cardiorenal events in people with type 2 diabetes and chronic kidney disease. GCGR (glucagon receptor)/GLP-1 receptor dual agonists may have additional efficacy, given emerging evidence that glucagon regulates energy balance and lipid metabolism as well as glucose homeostasis. However, putative cardiac effects of glucagon highlight cardiovascular safety considerations for dual agonists. Although unequivocal evidence that the GCGR is expressed in the human heart is lacking, high-dose exogenous glucagon has acute chronotropic, inotropic, and hypertensive effects. Clinical studies of GCGR/GLP-1 receptor dual agonists (eg, mazdutide, survodutide) have generally found that they increased heart rate to a similar extent as GLP-1 receptor monoagonists (which are cardioprotective despite such chronotropic effects). Mazdutide and survodutide also reduced blood pressure and hyperglycemia. However, at least 1 other dual agonist was discontinued, partly due to unacceptably large increases in heart rate and prolongation of the corrected QT interval. These between-compound differences may reflect different potencies for activating the GCGR and GLP-1 receptors. Cardiovascular effects of GCGR signaling by dual agonists should be clarified per compound by ongoing clinical trials, notably the cardiovascular outcomes trial SYNCHRONIZE-CVOT (A Study to Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity) and thorough corrected QT study of survodutide.