Clinical Significance of Statin Pleiotropic Effects

Abstract

The word “pleiotropic” usually is applied to genetics, referring to the multiple actions of a single gene. Regarding drug therapy for dyslipidemia, however, the term has become synonymous with clinical benefits beyond the effects of the drug on lipoproteins. HMG-CoA reductase inhibitors (statins), as the most widely prescribed drugs in the world, have been extensively evaluated for effects independent of lipid alterations. Mice and rats are relatively good models to evaluate potential pleiotropic effects of HMG-CoA reductase inhibitors because statins do not lower circulating cholesterol concentrations in these species. Statin administration results in greater nitric oxide bioavailability, increased ability to recruit endothelial progenitor cells, inhibition of cardiac hypertrophy, and reductions in the size and severity of strokes.1 Despite a failure to lower blood cholesterol, however, these drugs may influence cell membrane lipid levels. In rodent models, statins have been shown to decrease mitogen-activated protein kinase activation, enhance nitric oxide synthase expression, and reduce LOX-1 transcription by reducing oxidized low-density lipoprotein (LDL) uptake in endothelial cell membranes.2 Accordingly, the pleiotropic effects in animals may not be independent of the cellular uptake of lipids. See p 2356 In humans, the purported clinical benefits of statins have ranged from improved bone density to reduced occurrence of Alzheimer disease, as well as enhanced cardiovascular benefits beyond blood lipid modification. Numerous studies have demonstrated that statins improve endothelial function, most likely by increasing nitric oxide bioavailability and reducing oxidant stress. Statins also may …