Mechanisms
Simvastatin lowers cholesteryl ester transfer by reducing CETP concentration itself, not by altering HDL (Atherosclerosis 1993)
Original title: Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects
In twelve normolipidemic subjects, six weeks of simvastatin reduced esterified cholesterol transfer from HDL to VLDL and LDL by 23%. Recombination experiments using an isotopic transfer assay isolated the mechanism: when HDL from treated subjects was combined with VLDL/LDL and CETP fractions from untreated control plasma, simvastatin had no effect, indicating the drug did not alter HDL-dependent transfer, consistent with only minor simvastatin-induced changes to HDL structure. Conversely, when control HDL and VLDL/LDL were combined with CETP fractions from treated subjects, transfer activity was clearly reduced after simvastatin. The reduction in transfer activity correlated with the reduction in CETP concentration, which itself correlated with the fall in apo B-containing lipoprotein concentration, confirming that simvastatin lowers cholesteryl ester transfer specifically by lowering plasma CETP activity.
Original abstract
Hyperlipidemic patients often have an accelerated esterified cholesterol transfer (ECT) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). We investigated the effect of simvastatin on ECT in twelve normolipidemic subjects. After 6 weeks of simvastatin administration, ECT was decreased by 23%. To determine the mechanism of action of simvastatin, we measured ECT in different recombination experiments, using an isotopic assay in which the transfer of labelled EC from HDL to VLDL/LDL was determined. When HDL of the treated subjects were incubated with VLDL/LDL and CETP fractions isolated from control plasma, no effect of simvastatin was observed, indicating that the drug did not alter the HDL-dependent ECT. This might be expected since simvastatin induced only minor modifications of HDL structure. When HDL and VLDL/LDL of control plasma were incubated with CETP fractions of the treated subjects, a clear reduction of ECT occurred after simvastatin administration. The decrease of plasma transfer activity was correlated to that of CETP concentration and accounted for the simvastatin-induced lowering of ECT. The diminution of plasma CETP was correlated to that of the apo B-containing lipoproteins concentration. This finding confirms previous reports suggesting a relationship between LDL level and CETP activity. In conclusion, our work shows that simvastatin administration results in a decrease of ECT and that this effect occurs through a lowering of plasma CETP activity.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.