The Effects of Ezetimibe on Postprandial Hyperlipidemia and Endothelial Dysfunction in Patients With the Metabolic Syndrome.

In patients at high risk for future cardiovascular events, more intensive LDL cholesterol lowering with high doses statin therapy provides greater protection against death or major cardiovascular events than does a standard regimen. Intensive LDL cholesterol lowering can be achieved by high dose statin treatment or with combination therapy of lower doses statin and ezetimibe. However, it is unclear whether this combination therapy results in the same or more beneficial effects on cardiovascular prognosis.

The metabolic syndrome is a cluster of several vascular risk factors (as abdominal obesity, high blood pressure, hypertriglyceridemia, low HDL cholesterol and high fasting glucose). The underlying pathophysiology is still not fully clarified, but insulin resistance seems to be a main characteristic of this syndrome. Subjects with the metabolic syndrome are at increased risk for the development of cardiovascular morbidity and mortality and type II diabetes. The prevalence of the metabolic syndrome is high in patients with clinical manifestations of vascular diseases and is associated with more vascular damage in these patients.

Insulin resistance is linked to endothelial dysfunction and decreased nitric oxide bioavailability by several mechanisms including, inflammation (as reflected by elevated high sensitive C Reactive Protein (hs-CRP) plasma levels), disruption of insulin receptor signalling cascades, increased production of cytokines and activation of the renin angiotensin system. However, other studies do not support an association between insulin resistance and endothelial function, so this mechanism seems controversial.

In the postprandial state, insulin resistance is associated with hyperlipidemia. Postprandial hyperlipidemia may be an important determinant of endothelial dysfunction as well. Remnants of chylomicron and very low density lipoprotein metabolism impair endothelial dependent vasodilatation. In line with the hypothesis that endothelial function can be used as a surrogate endpoint for cardiovascular morbidity, therapeutic modulation of (postprandial) endothelial function may potentially contribute to prevention of cardiovascular disease in patients with the metabolic syndrome.

Statin therapy modulates (postprandial) endothelial function but it is not known whether this is an indirect effect of lipid-lowering or a direct vascular effect of statins influencing the stability and bioavailability of NOS.