Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

Heuvelman, Valerie D; Van Raalte, Daniël H; Smits, Mark M

doi:10.1093/cvr/cvz323

Cited by 106Diabetes Treatment and ManagementCardiovascular Function and Risk FactorsDiabetes, Cardiovascular Risks, and Lipoproteins

Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

Heuvelman, Valerie D, Van Raalte, Daniël H, Smits, Mark M·2020·Cardiovascular Research

DOI 10.1093/cvr/cvz323

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Abstract

Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.

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Short-acting GLP-1RAs predominantly affect postprandial glucose levels mainly by reducing gastric emptying speed.
“Furthermore, short-acting GLP-1RAs predominantly affect postprandial glucose levels, mainly by reducing gastric emptying speed, while long-acting GLP-1RAs more strongly affect fasting glucose levels through a combination of increased fasting insulin and reduced hepatic gluconeogenesis [14].”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [14]
Long-acting GLP-1RAs more strongly affect fasting glucose levels through increased fasting insulin and reduced hepatic gluconeogenesis.
“Furthermore, short-acting GLP-1RAs predominantly affect postprandial glucose levels, mainly by reducing gastric emptying speed, while long-acting GLP-1RAs more strongly affect fasting glucose levels through a combination of increased fasting insulin and reduced hepatic gluconeogenesis [14].”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [14]

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The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice
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Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance
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GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe?
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Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males
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Investigation of the haemodynamic effects of exenatide in healthy male subjects
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The effect of liraglutide on endothelial function in patients with type 2 diabetes
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Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients: an acute and 12-week randomised, double-blind, placebo-controlled trial
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No benefit of additional treatment with exenatide in patients with an acute myocardial infarction
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Generalizability of glucagon‐like peptide‐1 receptor agonist cardiovascular outcome trials to the overall type 2 diabetes population in the United States
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GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men
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Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus
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Glucagon‐like peptide‐1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men
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Ability of GLP-1 to decrease food intake is dependent on nutritional status
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The Role of Triglyceride in Cardiovascular Disease in Asian Patients with Type 2 Diabetes - A Systematic Review
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GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus
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Role of Vasopressin in the Regulation of Renal Sodium Excretion: Interaction with Glucagon‐Like Peptide‐1
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Authors: Heuvelman, V. D., Van Raalte, D. H., & Smits, M. M.
Affiliations: Amsterdam University Medical Centers (NL)
Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Location VUmc, De Boelelaan 1117, Room ZH 4A72, 1081 HV Amsterdam, The Netherlands
Corresponding author: Smits, Mark M
ORCID: Heuvelman, Valerie D
Smits, Mark M
Venue: Cardiovascular Research
Publisher: Oxford University Press (OUP)
Published: 2019-12-11
Volume: 116
Issue: 5
Pages: 916-930
ISSN: 0008-6363 (ISSN-L)
1755-3245
DOI: 10.1093/cvr/cvz323
OpenAlex: W2995527943
Cited by: 106
References: 137
Citations by year: 2026: 7 · 2025: 18 · 2024: 25 · 2023: 12 · 2022: 14 · 2021: 18 · 2020: 12
FWCI: 1.81
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations: Cardiovascular Research (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: GLP-1 receptor agonists, type 2 diabetes, cardiovascular outcomes, heart rate, blood pressure, microvascular function, lipids, inflammation, glucagon-like peptide-1, insulin secretion, glycemic control
MeSH terms: Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Blood Glucose, Cardiovascular Diseases, Cardiovascular System, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Risk Factors, Signal Transduction, Biomarkers, Treatment Outcome, Incretins

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Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

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