LDL Receptor Under Ezetimibe and Simvastatin

Healthy Men Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00317993
• Other study ID #: EZE04-003
• Status: Completed
• Phase: Phase 4
• First received: April 24, 2006
• Last updated: December 2, 2014
• Start date: April 2004
• Est. completion date: July 2004

Study information

• Verified date: December 2014
• Source: University of Cologne
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: July 2004
• Est. primary completion date: July 2004
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Healthy Men

Intervention

Drug:
• ezetimibe

• simvastatin

• ezetimibe plus simvastatin

Locations

Country	Name	City	State
Germany	Medizinische Klinik II und Poliklinik für Innere Medizin	Cologne

Sponsors (2)

Lead Sponsor	Collaborator
University of Cologne	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HMG-CoA reductase activity
Primary	HMG-CoA reductase mRNA expression
Primary	LDL receptor mRNA expression
Primary	LDL receptor protein