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Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action

Nature Reviews Cardiology volume 20, pages 463–474 (2023)Cite this article

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Abstract

Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders characterized by excess cardiovascular risk. Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists reduce body weight, glycaemia, blood pressure, postprandial lipaemia and inflammation — actions that could contribute to the reduction of cardiovascular events. Cardiovascular outcome trials (CVOTs) have demonstrated that GLP1R agonists reduce the rates of major adverse cardiovascular events in patients with T2DM. Separate phase III CVOTs of GLP1R agonists are currently being conducted in people living with heart failure with preserved ejection fraction and in those with obesity. Mechanistically, GLP1R is expressed at low levels in the heart and vasculature, raising the possibility that GLP1 might have both direct and indirect actions on the cardiovascular system. In this Review, we summarize the data from CVOTs of GLP1R agonists in patients with T2DM and describe the actions of GLP1R agonists on the heart and blood vessels. We also assess the potential mechanisms that contribute to the reduction in major adverse cardiovascular events in individuals treated with GLP1R agonists and highlight the emerging cardiovascular biology of novel GLP1-based multi-agonists currently in development. Understanding how GLP1R signalling protects the heart and blood vessels will optimize the therapeutic use and development of next-generation GLP1-based therapies with improved cardiovascular safety.

Key points

  • Cardiovascular outcome trials in individuals with type 2 diabetes mellitus demonstrate that glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists reduce the rates of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death.

  • A single, canonical GLP1R, expressed at low levels in the heart and blood vessels, mediates the major cardiovascular actions of GLP1R agonists.

  • GLP1R activation might reduce cardiovascular morbidity indirectly through reductions in glycaemia, blood pressure, inflammation, postprandial lipaemia and body weight.

  • GLP1R agonists increase heart rate and might not be beneficial in individuals with severe left ventricular dysfunction, reduced ejection fraction and/or a history of repeated hospitalization for heart failure.

  • New GLP1-based multi-agonist therapies seem to be substantially more effective than older GLP1R agonists in reducing body weight but their safety requires ongoing scrutiny in trials assessing outcomes in individuals with obesity.

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Fig. 1: Major cardiometabolic actions of GLP1.
Fig. 2: GLP1R agonists reduce MACE.
Fig. 3: Direct and indirect actions of GLP1R agonist-mediated cardioprotection.
Fig. 4: Distribution of mouse Glp1r and human GLP1R mRNA expression.
Fig. 5: Actions and potential mechanisms of GLP1R agonists in HF.

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Acknowledgements

J.R.U. is supported by a Project Grant from the Canadian Institutes for Health Research (CIHR), an End Diabetes Award from Diabetes Canada and a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). D.J.D. is supported by operating grants from the CIHR, a Banting and Best Diabetes Centre–Novo Nordisk Chair in Incretin Biology and a Sinai Health–Novo Nordisk Foundation Fund in Regulatory Peptides.

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Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

    John R. Ussher

  2. Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada

    John R. Ussher

  3. Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Daniel J. Drucker

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Correspondence to Daniel J. Drucker.

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Competing interests

D.J.D. is a consultant to Altimmune, Amgen, Kallyope, Merck, Novo Nordisk and Pfizer. Mount Sinai Hospital has received funding for investigator-initiated preclinical studies from Novo Nordisk and Pfizer. J.R.U. declares no competing interests.

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Ussher, J.R., Drucker, D.J. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol 20, 463–474 (2023). https://doi.org/10.1038/s41569-023-00849-3

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