Cardiovascular Actions of Incretin-Based Therapies
Open accessAbstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9–36), a cardioactive metabolite generated by DPP-4–mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9–36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9–36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.
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DPP4 inhibitors, by blocking DPP-4, raise the amounts of intact GLP-1 but reduce the level of GLP-1 (9-36) and increase other peptides degraded by DPP-4, many of which directly affect the heart and vasculature.
“DPP4i, by blocking DPP-4, raise the amounts of intact GLP-1 but reduce the level of GLP-1 (9-36) and increase other peptides degraded by DPP-4, many of which directly affect the heart and vasculature.138,139”
From The effect of <scp>GLP</scp> ‐1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta‐analysis (2025) · cites this paper as [138]
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References 136 · Cited by 358
Research works printed but not linked: 3
- [20]20. Ban K, Kim H, Cho J, Diamandis E, Backx PH, Drucker DJ, Husain M. Glp-1(9-36) protects cardiomyocytes and endothelial cells from ischemia- reperfusion injury via cytoprotective pathways independent of the glp-1 receptor. Endocrinology. 2010;151:1520-1531.
- [47]47. Hsieh J, Longuet C, Baker CL, Qin B, Federico LM, Drucker DJ, Adeli K. The glucagon-like peptide 1 receptor is essential for postprandial lipopro- tein synthesis and secretion. Diabetologia. 2010;53:552-561.
- [129]129. Serre V, Dolci W, Scrocchi LA, Drucker DJ, Efrat S, Thorens B. Exendin-(9-39) as an inverse agonist of the murine glp-1 receptor. Implications for basal intracellular camp levels and β cell glucose com- petence. Endocrinology. 1998;139:4448-4454.
- Authors
- Ussher, J. R., & Drucker, D. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Venue
- Circulation Research
- Published
- 2014-05-23
- Volume
- 114
- Issue
- 11
- Pages
- 1788-1803
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2150012656
- Cited by
- 358
- References
- 136
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 20 · 2023: 16 · 2022: 20 · 2021: 27 · 2020: 31 · 2019: 25 · 2018: 41 · 2017: 41 · 2016: 53 · 2015: 31 · 2014: 15
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sanofi
- Heart and Stroke Foundation of Canada
- Novo Nordisk
- Alberta Innovates
- Canadian Institutes of Health Research
- Banting and Best Diabetes Centre, University of Toronto
- 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 › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- incretin-based therapy, GLP-1 receptor agonists, DPP-4 inhibitors, type 2 diabetes, cardiovascular effects, GLP-1 signaling, cardioprotection, coronary vasculature, diabetic heart, cardioactive peptides
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Animals, Blood Glucose, Cardiovascular System, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Disease Models, Animal, Enzyme Inhibitors, Humans, Treatment Outcome, Receptors, Glucagon, Dipeptidyl Peptidase 4, Lipid Metabolism, Mice, Incretins
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