LDL Receptor Under Ezetimibe and Simvastatin

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”

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.

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(s) in this Clinical Trial

• Drug: ezetimibe
• Drug: simvastatin
• Drug: ezetimibe plus simvastatin

Primary Measures

• HMG-CoA reductase activity
• HMG-CoA reductase mRNA expression
• LDL receptor mRNA expression
• LDL receptor protein

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

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 60 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Investigator: University of Cologne Other

Overall Clinical Trial Officials and Contacts

Ioanna Gouni-Berthold, MD Principal Investigator Medizinische Klinik II und Poliklinik für Innere Medizin  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00317993

Study ID Number: EZE04-003

ClinicalTrials.gov Identifier: NCT00317993

Health Authority: Germany: Federal Institute for Drugs and Medical Devices