Incretins and Preservation of Endothelial Function

The endothelium is critical for multiple processes occurring on both sides of the vascular wall including regulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It is frequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelial dysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia, hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by synthetic glucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or by hyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improve endothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduit arteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitric oxide production. Additional studies are necessary to confirm improvement of endothelial function after prolonged treatment with incretin based medications as well as the cardiovascular benefit of these agents.