The effects of lovastatin and simvastatin on the diurnal periodicity of plasma mevalonate concentrations in patients with heterozygous familial hypercholesterolemia

Abstract

Animal and human studies have shown that the biosynthesis of cholesterol exhibits diurnal periodicity with nocturnal increases in the level of cholesterol precursors. Dietary cholesterol, which increases the intracellular pool of cholesterol and plasma cholesterol levels, has been shown to blunt the nocturnal increases in cholesterol biosynthesis. Patients with heterozygous familial hypercholesterolemia (FH) have very high levels of plasma low-density lipoprotein cholesterol (LDL) due to their reduced ability to metabolize LDL particles. The present studies were carried out to determine whether diurnal variations in cholesterol synthesis occur in FH patients and to test the effects of 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase inhibitors on the diurnal cycle of cholesterol biosynthesis in these patients. Diurnal rates of cholesterol synthesis were assessed by measuring the plasma concentrations of mevalonate, an intermediate in the pathway of cholesterol biosynthesis. Female FH patients exhibited a diurnal pattern in plasma mevalonate levels similar to that previously reported in controls with peak values occurring at night. Treatment with lovastatin and simvastatin (40 mg b.i.d.) significantly reduced 24-h mean plasma mevalonate levels from baseline values. Administration of lovastatin in the evening reduced the nocturnal increases in mevalonate levels, and the administration of simvastatin completely abolished the nighttime rise. These results demonstrate that inhibition of cholesterol biosynthesis by lovastatin and simvastatin modifies the normal diurnal rhythm of cholesterol biosynthesis in female FH patients.