Isoprenoid metabolism and the pleiotropic effects of statins

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. Indeed, in animal studies many of the cholesterol-independent or pleiotropic effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol, synthesis. Thus, with the recent findings of the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.