Influence of Simvastatin on Apolipoprotein B-100 (apoB-100) Secretion (SVS)

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: NCT00905541
Recruitment Status : Completed
First Posted : May 20, 2009
Last Update Posted : May 20, 2009
Information provided by:
University Hospital, Bonn

Brief Summary:
3-Hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) decrease apolipoprotein B-100-containing lipoproteins by increasing their fractional catabolic rates through low-density lipoproteins (LDL) receptor-mediated uptake. Their influence on hepatic secretion of these lipoproteins is controversial. The current study investigates whether simvastatin influences lipoprotein secretion.

Condition or disease Intervention/treatment Phase
Hypercholesterolemia Drug: simvastatin Not Applicable

Detailed Description:

3-Hydroxy-3 methylglutaryl (HMG) coenzyme A-reductase inhibitors (statins) have an established role in the treatment of hypercholesterolemia. Their efficacy in reducing cardiovascular morbidity and mortality in secondary and primary prevention has been demonstrated in large prospective trials. HMG-CoA-reductase inhibitors inhibit competitively the rate-limiting enzyme of endogenous cholesterol biosynthesis. As a consequence, the intracellular pool of free cholesterol decreases and low-density lipoprotein (LDL) receptors are up-regulated, leading to an increased receptor-mediated clearance of LDL from plasma. This mechanism is responsible for a large proportion of their cholesterol-lowering effect. However, a statin-induced decrease in lipoprotein production has also been proposed as a mechanism for their lipid-lowering effects. The underlying mechanisms in vivo, however, that would mediate such an effect, are not fully understood. Except for their pronounced cholesterol-lowering properties, statins have also a modest effect (about 15 to 20%) in decreasing triglyceride concentrations. In subjects with high intra-abdominal fat stores, an increased flux of free fatty acids to the liver produces an increased rate of hepatic triglyceride synthesis, which in turn leads to increased very low-density lipoprotein (VLDL) production, since the latter is partly determined by the intracellular availability of triglycerides. This is also found in subjects with type 2 diabetes mellitus and there are a number of studies showing that in this pathophysiologic state statins are able to decrease lipoprotein production. Interestingly, in obese individuals it has been shown that statins increase the catabolism of apoB-100-containing lipoproteins but do not alter their rates of production or secretion.

In the present study we focus on subjects with near normal body weight (mean body mass index 25 +- 3 kg/m2) and normal serum triglyceride concentrations to investigate, in the fasting state, whether statins influence hepatic lipoprotein production. Since recent evidence suggests that the supply of cholesterol available for incorporation into nascent lipoprotein particles also exerts a regulatory influence on apoB secretion by the liver, we investigate in addition the acute inhibitory effects of a high bolus dose of simvastatin in order to stimulate LDL receptor expression to a maximum degree.

The main goal of the present study is to determine the influence of simvastatin on apoB-100 appearance rates and lipoprotein kinetics in fasting non-obese subjects with moderate hypercholesterolemia. For this purpose, each subject will be investigated with three turnover protocols: once without treatment, once during chronic simvastatin treatment at a standard dosage, and once during chronic simvastatin treatment after an additional acute-on-chronic high bolus dose of simvastatin.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Influence of Simvastatin on apoB-100 Secretion in Non-Obese Subjects With Moderate Hypercholesterolemia: A Stable Isotope Study
Study Start Date : November 1998
Actual Primary Completion Date : March 1999
Actual Study Completion Date : March 2000

Resource links provided by the National Library of Medicine

Drug Information available for: Simvastatin

Arm Intervention/treatment
No Intervention: No treatment
Phase A: No treatment
Experimental: simvastatin chronic
Phase B: 40 mg/day simvastatin
Drug: simvastatin
40 mg/day

Experimental: simvastatin acute-on-chronic
Phase C: 80 mg simvastatin acute-on-chronic
Drug: simvastatin
80 mg simvastatin acute-on-chronic

Primary Outcome Measures :
  1. apoB-100 kinetic parameters [ Time Frame: One year ]

Secondary Outcome Measures :
  1. Lipoprotein concentrations [ Time Frame: One year ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Hypercholesterolemia

Exclusion Criteria:

  • Obesity
  • Treatment with lipid-lowering drugs

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): NCT00905541

University of Bonn
Bonn, Germany
Sponsors and Collaborators
University Hospital, Bonn
Principal Investigator: Heiner K. Berthold, MD, PhD University of Bonn

Responsible Party: Heiner K. Berthold, MD, PhD, University of Bonn Identifier: NCT00905541     History of Changes
Other Study ID Numbers: SVS0001
First Posted: May 20, 2009    Key Record Dates
Last Update Posted: May 20, 2009
Last Verified: May 2009

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