Effects of Simvastatin and Pravastatin on the Composition of Lipoproteins

We investigated the effects of simvastatin and pravastatin, which are inhibitors of HMG-CoA reductase, on serum lipoproteins by administrating pravastatin (P) and simvastatin (S) to the same hypercholesterolemic patients. We then analyzed the mechanism by which simvastatin increases HDL-C. Ten mg of P was administrated daily to 28 outpatients with hypercholesterolemia for more than 16 weeks. These patients were then given daily 5mg doses of S for further 16 weeks in exchange for P. At the end of each administration period (at the time of cessation of the drug for pravastatin and at week 16 for simvastatin), sera were obtained to determine serum lipoproteins and apolipoproteins as well as blood chemistry and hematology. Total cholesterol (TC or C), low density lipoprotein (LDL)-C, and LDL-triglyceride (TG) were significantly decreased by treatment with P and S. S decreased TC and LDL-C significantly greater than P did, respectively. S also significantly dereased very low-density lipoprotein (VLDL)-TG and significantly increased HDL-C (determined by a precipitation method using phosphotungstic acid-dextran sulfate). Though apolipoproteins (apo) B, C-II, and E were significantly reduced by both statins, S reduced them significantly greater than P did. Only simvastatin significantly increased apo A-I and significantly decreased apo C-II. Though atherogenic indices such as the (TC-HDL-C)/HDL-C and apo B/apo A-I ratios, as well as the LDL-C/apo B ratio, were significantly reduced by both statins, S reduced these atherogenic indices significantly greater than P did. S significantly increased the apo A-I/apo A-II ratio and significantly decreased the apo E/(apo C-II+apo C-III) ratio. To determine the mechanism by which simvastatin increased HDL-C, the relationship between changes in HDL-C and various parameters were examined. Changes in HDL-C were found to be negatively correlated with baseline HDL-C levels, changes in VLDL-C/LDL-C, and changes in LDL-TG. However there were no correlations of changes in HDL-C with baseline TG, changes in VLDL-TG or changes in LDL-C. Changes in HDL-C also showed positive correlations with changes in apo A-I, the HDL-C/apo A-I ratio, and the apo A-I/apo A-II ratio, respectively. These results suggest that simvastatin should be capable of promoting VLDL catabolism aside form the enhanced clearance of LDL from the circulation. The results also indicate that during these processes, except for patients with extremely high serum HDL-C levels, the number of HDL particles might increase partly as a result of increased VLDL hydrolysis and partly as a result of other unknown mechanisms. The precise mechanism by which HDL is increased by S remains to be elucidated.