LDL Receptor Under Ezetimibe and Simvastatin

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00317993
Recruitment Status : Completed
First Posted : April 25, 2006
Last Update Posted : December 3, 2014
Merck Sharp & Dohme Corp.
Information provided by:
University of Cologne

Brief 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.

Condition or disease Intervention/treatment Phase
Healthy Men Drug: ezetimibe Drug: simvastatin Drug: ezetimibe plus simvastatin Phase 4

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.

Study Type : Interventional  (Clinical Trial)
Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Diagnostic
Official Title: Effects of Ezetimibe and Simvastatin on LDL Receptor Protein Expression and on LDL Receptor and HMG-CoA Reductase mRNA Expression in Mononuclear Cells: a Randomized Controlled Study in Healthy Men
Study Start Date : April 2004
Actual Primary Completion Date : July 2004
Actual Study Completion Date : July 2004

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. HMG-CoA reductase activity
  2. HMG-CoA reductase mRNA expression
  3. LDL receptor mRNA expression
  4. LDL receptor protein

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • healthy male subjects
  • age between 18 and 60 years
  • body mass index between 18.5 and 30 kg/m2
  • LDL cholesterol smaller than 190 mg/dL
  • triglicerides smaller than 250 mg/dL
  • normal blood pressure

Exclusion Criteria:

  • intake of lipid-lowering drugs
  • excessive alcohol intake
  • liver disease
  • kidney disease
  • coronary heart disease
  • eating disorders
  • diabetes or other endocrine disorders
  • medications that interfere with lipid metabolism

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00317993

Medizinische Klinik II und Poliklinik für Innere Medizin
Cologne, Germany, 50924
Sponsors and Collaborators
University of Cologne
Merck Sharp & Dohme Corp.
Principal Investigator: Ioanna Gouni-Berthold, MD Medizinische Klinik II und Poliklinik für Innere Medizin

Publications automatically indexed to this study by Identifier (NCT Number): Identifier: NCT00317993     History of Changes
Other Study ID Numbers: EZE04-003
First Posted: April 25, 2006    Key Record Dates
Last Update Posted: December 3, 2014
Last Verified: December 2014

Additional relevant MeSH terms:
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors