Ezetimibe and Vascular Endothelial Function

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular diseases that has been managed mostly with 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) that suppress de novo cholesterol synthesis in the liver. Statins also have beneficial pleiotropic effects on the atherosclerotic process that are independent of their ability to lower lipid values. However, the levels of low-density lipoprotein cholesterol (LDL-C) in most hypercholesterolemic patients at high risk for cardiovascular disease do not reach the goals proposed by guidelines even when prescribed with statins. Ezetimibe is a new lipid-lowering agent that blocks the intestinal absorption of dietary and biliary cholesterol and reduces LDL-C levels, especially when combined with statins. However, its effect on cardiovascular events remains unknown. We reviewed the effects of ezetimibe on cardiovascular diseases, in particular, vascular endothelial function, which is initially impaired during the atherogenetic process and an important predictor of cardiovascular events. Increasing evidence suggests that ezetimibe improves endothelial function and nitric oxide availability, and reduces inflammation as well as oxidative stress. However, this mechanism has not been clarified and limited, large trials and cohort studies have not shown that this agent prevents cardiovascular events. Ezetimibe has just recently become commercially available, which might explain the paucity of evidence regarding its benefits and effects on cardiovascular morbidity and mortality.

Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice

“…Ezetimibe is a pharmacological inhibitor of NPC1L1, a cholesterol transporter that is highly expressed in the apical membrane of enterocytes and the canalicular membrane of hepatocytes. The main mechanism of ezetimibe's beneficial effects is inhibiting intestinal and hepatic cholesterol absorption through NPC1L1, thereby lowering cholesterol 127 . Interestingly, recent studies have shown that ezetimibe could inhibit oxidative stress, urokinase-type plasminogen activator receptor (uPAR) expression, or IL-6 secretion in human umbilical vein endothelial cells (HUVECs) 128,129 , and have direct vasodilatory effects on rat mesenteric resistance arteries 130 .…”

Do antilipidemic agents reduce blood pressure?

“…Many studies reported that ezetimibe improves vascular endothelial dysfunction [65][66][67][68] , although whether the effect was as good as 69) , superior to 70) , or weaker than 71,72) the effect of statins is controversial. However, the inhibitory effect of simvastatin on SNA was not observed with ezetimibe 17) .…”

The Effect of Ezetimibe on Plasma Viscosity, Fibrinogen and Lipid Profile

“…340 flow in the circulation. Elevated PV may contribute to tissue damage by impairing microcirculatory flow due to shear stress damage at the blood-endothelial interface [10][11][12][13][14].…”