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Certain GLP\u20101 receptor monoagonists are indicated for treatment of type 2 diabetes, obesity, and metabolic dysfunction\u2013associated 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\u20101 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\u2010dose exogenous glucagon has acute chronotropic, inotropic, and hypertensive effects. Clinical studies of GCGR\/GLP\u20101 receptor dual agonists (eg, mazdutide, survodutide) have generally found that they increased heart rate to a similar extent as GLP\u20101 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\u2010compound differences may reflect different potencies for activating the GCGR and GLP\u20101 receptors. Cardiovascular effects of GCGR signaling by dual agonists should be clarified per compound by ongoing clinical trials, notably the cardiovascular outcomes trial SYNCHRONIZE\u2010CVOT (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.<\/jats:p>","DOI":"10.1161\/jaha.126.049727","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:15:04Z","timestamp":1785496504000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Cardiovascular Effects of Glucagon Receptor Signaling Alone and Combined With Glucagon\u2010Like Peptide\u20101 Receptor Signaling in Multiagonists: A Narrative Review With a Translational Focus"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5871-1265","authenticated-orcid":false,"given":"Pamela R.","family":"Kushner","sequence":"first","affiliation":[{"name":"University of California Irvine Medical Center","place":["Orange, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5547-5084","authenticated-orcid":false,"given":"Erin D.","family":"Michos","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001184"},{"key":"e_1_3_2_3_2","volume-title":"World Obesity Atlas","author":"World Obesity Federation","year":"2023","unstructured":"World Obesity Federation . 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