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Narative Review Volume 19 Issue 3
Endothelial dysfunction as the mechanistic bridge between GLP-1 receptor agonism and cardiovascular protection: a narrative review
Ney Carter do Carmo Borges
Received: August 14, 2026 | Published: September 1, 2026
Citation: Borges NCC. Endothelial dysfunction as the mechanistic bridge between GLP-1 receptor agonism and cardiovascular protection: a narrative review. J Cardiol Curr Res. 2026;19(3):98-111. DOI: 10.15406/jccr.2026.19.00650
Abstract
Background: Endothelial dysfunction is the shared substrate of obesity, type 2 diabetes, and atherosclerotic cardiovascular disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events (MACE) by a margin that glycemic and weight effects do not fully account for, which has directed attention toward the vessel wall itself. Objective: To appraise the preclinical and clinical evidence that GLP-1 RAs act directly on the vascular endothelium, and to define how much of the observed cardiovascular benefit this can reasonably explain. Methods: Narrative review of PubMed/MEDLINE, Embase, and Web of Science through early 2026, prioritizing cardiovascular outcome trials, randomized studies of vascular function, network meta-analyses, and mechanistic work in human endothelial cells and atherosclerosis-prone animal models. Findings: In experimental systems, GLP-1 RAs increase eNOS phosphorylation at Ser1177 and nitric oxide availability through AMPK/Akt and cAMP/PKA signaling; they lower NOX4-derived reactive oxygen species, endoplasmic reticulum stress, and NLRP3 inflammasome activity; they suppress ICAM-1, VCAM-1, and E-selectin via NF-κB inhibition; and they restore the number and functional capacity of endothelial progenitor cells. In patients, network meta-analyses show improvement in flow-mediated dilation exceeding that achieved with sulfonylureas or lifestyle modification, and coronary microvascular imaging studies report parallel gains in myocardial perfusion, although individual trials are not uniform. A modest, partly independent blood pressure-lowering effect has also been described. Across outcome trials, benefit is reproducible for human GLP-1 analogues and persists in a population without diabetes. A prespecified mediation analysis of SELECT attributed roughly one third of the MACE benefit to reduction in waist circumference, leaving the majority unexplained by adiposity. SURPASS-CVOT adds a complementary observation: tirzepatide was metabolically superior to dulaglutide yet not superior for MACE. Conclusions: Endothelial protection is a coherent and probably contributory mechanism of GLP-1 RA cardioprotection. It is not yet an established one. The principal unresolved questions concern GLP-1 receptor expression in human endothelium and the translational validity of in vitro work performed at supraphysiologic concentrations — a caution echoed by independent 2025–2026 syntheses of this literature, not merely a position specific to this review.
Keywords: vascular endothelium, endothelial dysfunction, glucagon-like peptide-1, GLP-1 receptor agonists, nitric oxide, atherosclerosis, cardiovascular outcomes
©2026 Borges. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.