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Cardiovascular outcome trials (CVOT) with glucagon-like peptide-1 receptor agonists (GLP-1 RA) have had variable results to date: with two CVOTs being positive and two concluding neutrality/safety results for primary cardiovascular outcome. Mechanistic insights delving into the pathophysiologic mechanisms that may link certain GLP-1 RA to cardioprotection may help define the application of this medication class in clinical practice based on the evidence of the CVOT data. We discuss the various mechanisms that have been postulated from animal and preclinical human studies to help explain the benefits observed in CVOTs with GLP-1 RA.Cardiovascular benefits of GLP-1 may be dependent on the complex interactions of this incretin hormone with the atherosclerotic pathways, either through its direct actions on the cardiovascular system or indirectly through intermediary actions on metabolism, energy transfer, inflammation or thrombosis. An indirect metabolic action of GLP-1 RA, via an initial step of achieving glucose homeostasis or balancing inter-organ energy metabolism, leading to favorable downstream effects on the inflammation-thrombosis pathways, finally impacting atherosclerosis, appears compelling.In addition to their metabolic benefits, specific GLP-1 RA medications offer cardiovascular protection in high-risk type 2 diabetes. Further mechanistic studies and clinical trials in lower cardiovascular risk populations may help cement the place of this class of medications across the spectrum of type 2 diabetes.