LDL Receptor Under Ezetimibe and Simvastatin
Condition: Healthy Men
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to investigate the effects of the two lipid -lowering drugs,
      ezetimibe and simvastatin, on lipid metabolism in humans. In specific, the study will
      investigate in blood cells whether the enzyme that controls cholesterol synthesis, HMG-CoA
      reductase, and the receptor that takes up cholesterol from the blood, the LDL receptor, are
      changed during treatment with the aforementioned drugs.
    

Detailed description: 
      Ezetimibe decreases serum total and LDL cholesterol levels by blocking cholesterol absorption
      in the intestine, causing a compensatory increase in cholesterol synthesis. The exact
      underlying regulatory mechanisms of the ezetimibe-induced increase in cholesterol synthesis
      and decrease in serum LDL cholesterol are not known. In addition, it has never been
      investigated whether changes in LDL receptor expression contribute to the LDL-lowering effect
      of ezetimibe, as is the case with other agents causing a decrease in cholesterol absorption
      such as the plant stanols.

      In the present study, we plan to examine changes in LDL receptor and HMG-CoA reductase mRNA
      concentrations during ezetimibe treatment. For comparison, effects of simvastatin and the
      combined administration of the two will be investigated. Since mRNA expression profiles
      provide information about effects at the transcriptional but not necessarily at the
      translational level, we will also analyze changes in the LDL receptor protein at the cell
      surface of mononuclear blood cells. As a functional marker for HMG-CoA reductase activity the
      ratio of serum lathosterol to cholesterol concentration will be used since it correlates with
      HMG-CoA reductase activity and serves also as a marker of total cholesterol synthesis.

      In this regard it has been shown that plant sterols, which also act by blocking intestinal
      cholesterol absorption, increase cholesterol synthesis, decrease LDL synthesis, increase LDL
      receptor mRNA levels as well as LDL receptor protein concentrations but have no significant
      effect on HMG-CoA reductase expression or activity in peripheral blood mononuclear cells. Aim
      of this prospective ran-domized parallel study is to examine changes in HMG-CoA reductase
      activity/expression and in LDL receptor expression/protein concentration in mononuclear blood
      cells under treatment with ezetimibe.

      For this purpose 3 parallel groups of 20 healthy men will be formed. One group will be
      treated with ezetimibe (10 mg/day), one with 40 mg/day of simvastatin and another with
      ezetimibe (10 mg/day) plus simvastatin (40 mg/day). Each treatment period will last for 2
      weeks. Blood drawing will be per-formed at baseline (before the initiation of treatment) and
      at the end of the 2 weeks. (storing of the samples at -80°). The measurements involved in
      this study include the determination of the lipopro-tein concentrations in serum, isolation
      of the mononuclear cells, measurement of LDL receptor mRNA from the peripheral blood
      mononuclear cells, measurement of HMG-CoA reductase mRNA levels in peripheral blood
      mononuclear cells, measurement of the LDL-receptor protein concentrations on the surface of
      peripheral blood mononuclear cells. Furthermore, the serum latosterol to cholesterol
      con-centrations will be measured as a surrogate marker of the HMG-CoA reductase activity.
    

Intervention name(s): ezetimibe; simvastatin; ezetimibe plus simvastatin
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Simvastatin; Ezetimibe
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Diagnostic