Intermolecular Differences of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Contribute to Distinct Pharmacologic and Pleiotropic Actions

Statin drugs inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and share the common mechanism of lowering circulating levels of low-density lipoprotein (LDL) cholesterol, a powerful indicator of risk for cardiovascular disease. Large clinical trials have documented the benefit of hypolipidemic therapy for both primary and secondary prevention of coronary artery disease and stroke. Recent clinical findings, including direct comparator studies, now indicate that certain statins may slow progression of disease at a rate and to an extent that cannot be solely attributed to LDL reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the biochemical basis for such differences among statins, this article reviews their physicochemical properties and pharmacology at the molecular level.