ENHANCED CELLULAR-METABOLISM OF VERY-LOW-DENSITY LIPOPROTEIN BY SIMVASTATIN - A NOVEL MECHANISM OF ACTION OF HMG-COA REDUCTASE INHIBITORS

To test the possibility that HMG-CoA reductase inhibitors reduce LDL m ass by an increased VLDL catabolism, we determined the effect of simva statin therapy on cellular metabolism of VLDL in 18 patients with prim ary hypercholesterolaemia. Six months of simvastatin therapy was follo wed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cho lesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts w as similar to control VLDL. Six months after therapy was initiated, a remarkable 2-5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenou s recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased met abolic ratios of 60-70% and 45-95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19 % and increase of the phospholipid content of 13%. The data strongly i ndicate that simvastatin therapy stimulates VLDL:cell interactions and catabolism, possibly reflecting alterations of the physico-chemical p roperties of the particle. It is proposed that in addition to other pr eviously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to t he conversion to LDL.