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Published on: February 26, 2019

Cardiovascular Effects of Glucagon Receptor Signaling Alone and Combined With Glucagon-Like Peptide-1 Receptor

Pamela R Kushner1, Erin D Michos2

  • 1Department of Family Medicine University of California Irvine Medical Center Orange CA USA.

Journal of the American Heart Association
|July 31, 2026
PubMed

Insights

Dual glucagon/GLP-1 receptor agonists show promise for cardio-kidney-metabolic diseases. Cardiovascular safety of these agents, including heart rate effects, requires careful evaluation in ongoing clinical trials.

Area of Science:

  • Endocrinology and Metabolism
  • Cardiovascular Medicine
  • Pharmacology

Background:

  • Cardio-kidney-metabolic diseases (CKMDs) like obesity, type 2 diabetes, and metabolic dysfunction-associated liver disease are prevalent globally.
  • Existing treatments for CKMDs have limitations, driving the search for novel therapeutic strategies.
  • Glucagon receptor (GCGR)/glucagon-like peptide-1 (GLP-1) receptor dual agonists are emerging as promising candidates for CKMDs.

Purpose of the Study:

  • To evaluate the potential efficacy and cardiovascular safety of GCGR/GLP-1 receptor dual agonists for treating CKMDs.
  • To explore the role of glucagon signaling in energy balance, lipid metabolism, and glucose homeostasis.
  • To address cardiovascular safety concerns associated with dual agonists, particularly regarding cardiac effects of glucagon.

Main Methods:

  • Review of clinical studies investigating GCGR/GLP-1 receptor dual agonists (e.g., mazdutide, survodutide).
  • Analysis of emerging evidence on glucagon's physiological roles and cardiac effects.
  • Examination of cardiovascular safety data, including heart rate, blood pressure, and QT interval changes.

Main Results:

  • GLP-1 receptor agonists are established treatments for type 2 diabetes, obesity, and related complications.
  • GCGR/GLP-1 receptor dual agonists have demonstrated potential for additional efficacy in managing glucose homeostasis, energy balance, and lipid metabolism.
  • Clinical studies show dual agonists generally increase heart rate similarly to GLP-1 receptor agonists, while reducing blood pressure and hyperglycemia; however, some compounds have shown safety concerns like significant heart rate increase and QT prolongation.

Conclusions:

  • GCGR/GLP-1 receptor dual agonists represent a promising therapeutic class for prevalent cardio-kidney-metabolic diseases.
  • Careful compound-specific evaluation of cardiovascular effects, including heart rate and QT interval, is crucial.
  • Ongoing clinical trials, such as SYNCHRONIZE-CVOT, are essential for clarifying the cardiovascular safety profile of these agents.
Keywords:
cardiovascular systemglucagonglucagon receptorsglucagon‐like peptide‐1 receptor agonists

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