Statin effects beyond lipid lowering—are they clinically relevant?

Currently, five different statins (simvastatin,pravastatin, lovastatin, fluvastatin, and atorvastatin) are approved for treatment of hypercholesterolemia in humans and two new compounds (rosuvastatin and NK-104) are under investigation.1,2 Despite differences in their pharmacokinetic profiles, all statins have at least onecharacteristic in common: they block the conversion of HMG-CoA to mevalonic acid with consecutive attenuation of the biosynthesis of cholesterol (Fig. 1), which is associated with a reduction in serum total and low-density lipoprotein (LDL) cholesterol of as much as 20–31 and 28–42% during chronic treatment.3 Because of these properties, statins have become the most widely prescribed lipid-lowering drugs in patients with elevatedserum cholesterol levels. Several large trialsdemonstrated that statins are not only safe and well tolerated but also significantly decrease cardiovascular morbidity and mortality in hypercholesterolemic patients in both primary and secondary prevention.4–8 However, the striking benefit achieved with statin treatment in patients with a wide range of cholesterol levels, which cannot be attributed to their cholesterol lowering effect alone, has raised the question about the possible presence of additional effects of statins beyond their impact on serum cholesterol levels. Indeed, in recent years a substantial quantity of data has accumulated showing that statins exert variouseffects on multiple targets, which are independent of their plasma cholesterol lowering properties. Fig. 1 The effect of statins on the mevalonate pathway. Statins inhibit conversion of HMG-CoA to mevalonate by competitive inhibition of the rate limiting enzyme HMG-CoA reductase. Herewith, statins not only inhibit the cellular production of cholesterol but also the biosynthesis of several intermediates of the mevalonate pathway (e.g. farnesylpyrophosphate and geranylgeranylpyrophosphate). These so-called isoprenoids are essential for the posttranslational modification of several proteins involved in important intracellular signaling pathways (e.g. the small GTP-binding proteins Ras and Rho). Many of these so-called pleiotropic effects have been shown to be secondary to the …