Effects of Ezetimibe on Postprandial Hyperlipidemia and Endothelial Function
Condition: Metabolic Syndrome
MeSH terms: Metabolic Syndrome; Hyperlipidemias; Hyperlipoproteinemias; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      In the present study the investigators are researching the effects of the cholesterol
      absorption inhibitor ezetimibe on postprandial lipemia and postprandial endothelial function
      in patients with the metabolic syndrome. The lipid-lowering effect of high-dose statin
      monotherapy on fasting lipids is equal to the combination therapy of low-dose statin and
      ezetimibe.
    

Detailed description: 
      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.

      AIMS In the present study we propose to investigate the effects of the cholesterol absorption
      inhibitor ezetimibe on postprandial lipemia and (postprandial) endothelial function in
      patients with the metabolic syndrome. High-dose statin monotherapy has the same
      lipid-lowering effect (on fasting lipids) as the combination therapy of low dose statin and
      ezetimibe. The latter may reduce postprandial lipemia more effectively and may therefore have
      beneficial effects on postprandial endothelial dysfunction.

      Ezetimibe is unlikely to have a direct vascular effect and therefore any observed change in
      vascular function is due to a change in postprandial lipemia. As secondary objective of the
      study, this enables us to differentiate between direct and indirect effects of statin therapy
      on postprandial endothelial function comparing modulation of postprandial endothelial
      function by monotherapy simvastatin with combination therapy of simvastatin and ezetimibe.

      Hypothesis With comparable reduction in fasting plasma lipids, combination therapy of
      low-dose statin and ezetimibe reduces postprandial lipemia better than high-dose statin
      monotherapy. This leads to better postprandial endothelial function in patients with the
      metabolic syndrome.

      Objectives

        1. To determine the effects of combination therapy of low-dose statin and ezetimibe on
           postprandial hyperlipidemia compared to high-dose statin monotherapy.

        2. To determine the effects of combination therapy of low-dose statin and ezetimibe on
           postprandial endothelial (dys-)function compared to high-dose statin monotherapy.
    

Intervention name(s): simvastatin and ezetimibe
Intervention type(s): Drug
Intervention MeSH terms: Simvastatin; Ezetimibe; Ezetimibe, Simvastatin Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Metabolic syndrome