Emerging views of statin pleiotropy and cholesterol lowering

Abstract

Over the past four decades, no class of drugs has had more impact on cardiovascular health than the 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or statins. Developed as potent lipid-lowering agents, statins were later shown to reduce morbidity and mortality of patients who are at risk for cardiovascular disease. However, retrospective analyses of some of these clinical trials have uncovered some aspects of their clinical benefits that may be additional to their lipid-lowering effects. Such 'pleiotropic' effects of statins garnered intense interest and debate over its contribution to cardiovascular risk reduction. This review will provide a brief background of statin pleiotropy, assess the available clinical evidence for and against their non-lipid-lowering benefits, and propose future research directions in this field.

Keywords: Cholesterol • HMG-CoA reductase inhibitors • Atherosclerosis • Inflammation.

Figure 1

Chemical structures of statins of major historical and clinical significance and their classifications by marketing generation and key chemical characteristics.

Figure 2

Flow chart of cholesterol biosynthesis and key enzymatic steps that are targeted by key classes of lipid-lowering drugs, with the statins’ target sites broken down by canonical lipid-lowering and pleiotropic effects.

Figure 3

Graphic correlation of percent reduction in major coronary events to percent LDL-C lowering based on published data from major secondary prevention trials. Notably, statin trials are distributed along a steeper line than non-statin trials, suggesting contribution from statins’ pleiotropic effects on CV outcomes beyond pure LDL-C lowering.