The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia

We have examined the influence of simvastatin, a competitive inhibitor of 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of ¹²⁵I‐labelled LDL by freshly isolated mononuclear leucocytes and the 24 h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day⁻¹) taken in a twice‐daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36·6%, 45·6% and 47·1% respectively on the three doses. High‐affinity degradation of ¹²⁵I‐LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day⁻¹ dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2‐¹⁴C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12–15 h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day⁻¹ of simvastatin compared with values at baseline. In contrast, the 24 h excretion of mevalonic acid in the urine fell by 16·9%, 31·4% and 31·9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increases in high‐affinity LDL receptor‐mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease. 1990 European Society for Clinical Investigation