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Review
. 2022 Feb;179(4):659-676.
doi: 10.1111/bph.15462. Epub 2021 May 6.

Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor

Johanna Helmstädter  1 , Karin Keppeler  1 , Leonie Küster  1 , Thomas Münzel  1   2   3 , Andreas Daiber  1   2   3 , Sebastian Steven  1   2
Affiliations
Review

Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor

Johanna Helmstädter et al. Br J Pharmacol. 2022 Feb.

Abstract

Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long-acting glucagon-like peptide-1 (GLP-1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP-1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP-1 and receptor agonists, and the GLP-1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP-1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP-1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP-1 receptor-dependent versus independent effects secondary of GLP-1 metabolites. We conclude that the favourable cardiovascular profile of GLP-1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non-diabetic populations. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Keywords: GLP-1 metabolites; cardiovascular outcome trial; cardiovascular protection; diabetes mellitus; glucagon-like peptide-1 receptor.

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Conflict of interest statement

S.S. received lecture honorary by Novo Nordisk.

Figures

FIGURE 1
FIGURE 1
Glucagon like‐peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) release after food uptake and degradation by dipeptidyl peptidase‐4 (DPP‐4). From (Herman et al., 2007) with permission. © 2007 American Society for Clinical Pharmacology and Therapeutics
FIGURE 2
FIGURE 2
Transcripts per million (TPM) of the GLP1R gene in selected tissues related to the cardiovascular system (from GTEx Portal https://gtexportal.org/home/gene/GLP1R on 04/01/2021). The Genotype‐Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS). ©2020 The Broad Institute of MIT and Harvard
FIGURE 3
FIGURE 3
Proposed cellular targets and protective effects of GLP‐1 receptor agonists (GLP‐1RAs) and GLP‐1 split products in the vasculature. The benefits are likely mediated by a combination of GLP‐1 receptor‐dependent mechanisms on endothelial and smooth muscle cells (ECs, SMCs) and GLP‐1 receptor‐independent actions of GLP‐1 metabolites. The existence of a second, yet not discovered, GLP‐1 receptor has been proposed. The figure was created with BioRender (https://biorender.com) and by using elements from Servier Medical Art (https://smart.servier.com), which is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/)
See this image and copyright information in PMC

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