Trial Overview

Locations

Intervention

Outcome

Official Title

Influence of Simvastatin on apoB-100 Secretion in Non-Obese Subjects With Moderate Hypercholesterolemia: A Stable Isotope Study

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

Inclusion Criteria:

- Hypercholesterolemia

Exclusion Criteria:

- Obesity

- Treatment with lipid-lowering drugs