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

This study has been completed.
Sponsor:
Information provided by:
University Hospital, Bonn
ClinicalTrials.gov Identifier:
NCT00905541
First received: May 18, 2009
Last updated: NA
Last verified: May 2009
History: No changes posted
  Purpose

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 Intervention
Hypercholesterolemia
Drug: simvastatin

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University Hospital, Bonn:

Primary Outcome Measures:
  • apoB-100 kinetic parameters [ Time Frame: One year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Lipoprotein concentrations [ Time Frame: One year ] [ Designated as safety issue: No ]

Enrollment: 8
Study Start Date: November 1998
Study Completion Date: March 2000
Primary Completion Date: March 1999 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Hypercholesterolemia

Exclusion Criteria:

  • Obesity
  • Treatment with lipid-lowering drugs
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00905541

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

No publications provided

Responsible Party: Heiner K. Berthold, MD, PhD, University of Bonn
ClinicalTrials.gov Identifier: NCT00905541     History of Changes
Other Study ID Numbers: SVS0001
Study First Received: May 18, 2009
Last Updated: May 18, 2009
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Simvastatin
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014