Effects of Atorvastatin on the Different Phases of Atherogenesis

Abstract

Molecular differences among the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) give rise to some important differences in their properties, including their anti-atherogenic and anti-inflammatory actions (among the so-called pleiotropic effects) - differences that may help to account for variation in clinical efficacy and safety among the available drugs of this class.

The question of whether the clinical benefit of statins such as atorvastatin in reducing cardiovascular events in individuals with elevated cholesterol levels results from direct anti-atherogenic effects in addition to cholesterol-lowering-dependent effects cannot be conclusively answered at present. However, the available evidence suggests that these actions should be considered further, especially in some clinical situations such as acute coronary syndrome where an anti-inflammatory effect could conceivably have a greater role. In the case of atorvastatin, various direct anti-atherogenic effects have been demonstrated. These effects include modification of endothelial dysfunction, inflammatory processes and lipid oxidation, and a possible direct effect on the composition of atheromatous plaques, which together may have a positive influence on the development of atherosclerosis and its subsequent progression (e.g. on the reduction of carotid intima media thickness and regression of atheromas noted in studies with intensive atorvastatin therapy [80 mg/day]). In terms of its effects on endothelial function, improvements in flow-mediated endothelium-dependent vasodilatation have been observed as early as 2 weeks after starting atorvastatin treatment. This effect does not appear to be quantitatively correlated with lowering of low-density lipoprotein-cholesterol (LDL-C) as greater improvements in endothelial function versus ezetimibe/simvastatin have been noted with atorvastatin despite comparable reductions in LDL-C. Atorvastatin has also been shown to reduce levels of the inflammatory marker C-reactive protein; in comparative studies, this effect proved to be superior to that of simvastatin or pravastatin and equivalent to that of rosuvastatin. In other studies, atorvastatin has been found to inhibit the in vitro oxidation of LDL — an effect that appears to be due mainly its active hydroxy metabolite — and to reduce various oxidative stress markers in hypercholesterolaemic patients. In addition, there is evidence that atorvastatin is able to modify the composition of atherosclerotic plaques and their inflammatory status via a series of effects, mostly involving tissue factors.