ABSTRACT
HMG-CoA reductase inhibitors (statins) were originally developed to achieve a simple objective: to lower plasma cholesterol concentrations by inhibiting the rate-limiting enzyme in the pathway of cholesterol synthesis in the liver. They do this effectively, decreasing cholesterol synthesis and causing consequent up-regulation of hepatic LDL receptor activity. Their affinity for the active site of HMG-CoA reductase and their elimination half-lives largely determine differences in their efficacy in achieving this. It was anticipated that this would retard the development of atheromatous plaque, which might even regress through lipid loss, rendering plaque less occlusive and less vulnerable to disruption and thrombosis. Over the past decade, however, a number of diverse biological effects of HMG-CoA reductase inhibition by statins have been described in experimental systems, both in vitro and in vivo, that are difficult to explain on the basis of cholesterol lowering. These ancillary or pleiotropic effects (from the Greek for ‘more’) have been invoked to explain a number of phenomena that were not expected when statins were first introduced for the treatment of hypercholesterolaemia.
