GLP-1 and the cardiovascular system

Journal of Clinical Investigation, vol. 136

Abstract

The incretin hormone glucagon-like peptide-1 (GLP-1) exerts potent effects on glucose metabolism, prompting the development of therapeutic strategies that enhance activity of the GLP-1 receptor (GLP-1R) pathway. Inhibitors of dipeptidyl peptidase 4 (DPP-4) prolong the half-life of endogenous GLP-1 and typically achieve reductions in HbA1c of 0.5%-0.8%. However, large-scale cardiovascular (CV) outcomes trials (CVOTs) with DPP-4 inhibitors demonstrated CV safety but did not show a reduction in CV events. A second incretin-based therapeutic approach was the development of GLP-1R agonists (GLP-1RAs). Various GLP-1RAs, including liraglutide, semaglutide, and dulaglutide, demonstrated a reduction in CV outcomes in large CVOTs. Initially, these medications were only available as injectable agents for subcutaneous administration, but recent technological advancements have enabled the development of orally available GLP-1RAs. A third incretin-based approach is tirzepatide, a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR), which achieves greater HbA1c reduction and weight loss compared with GLP-1RAs alone. Ongoing large-scale CVOTs will determine its effects on hard cardiovascular endpoints. This Review summarizes the effects of GLP-1 and GLP-1RAs in the CV system as well as clinical data of GLP-1RAs in individuals with CV disease or high CV risk.

Authors 3

1. Florian Kahles Aachen Department of Internal Medicine I (Cardiology)

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen, Aachen, Germany

2. Andreas L. Birkenfeld

   King's College London · University of Tübingen · Helmholtz Munich · German Center for Diabetes Research

   Affiliation as printed

   Department of Internal Medicine IV, Diabetology, Endocrinology and Nephrology, Eberhard-Karls University Tübingen, Tübingen, Germany

   German Center for Diabetes Research (DZD), Neuherberg, Germany

   Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, Tübingen, Germany

   School of Cardiovascular and Metabolic Medicine and Sciences, Faculty of Life Sciences and Medicine, Kings College London, London, United Kingdom

3. Nikolaus Marx Aachen Department of Internal Medicine I (Cardiology)

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen, Aachen, Germany