Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality.

Hypercholesterolemia and dyslipidemia are independent risk factors for cardiovascular disease and death. Statins are the drugs of choice to decrease plasma cholesterol and have other beneficial actions beyond lipid-lowering leading to substantial improvements in cardiovascular morbidity and mortality. However, evaluation of the effects of statins to reduce overall morbidity and mortality must integrate metabolic consequences of statin therapy with its lipid-lowering effect. Indeed, reduction in LDL-cholesterol to target level achieved by statins does not completely eliminate risk of cardiovascular disease and may elevate metabolic risk factors that contribute to dysregulation of metabolic homeostasis. This may lead to increased incidence of diabetes and its cardiovascular complications that are explained, in part, by reciprocal relationships between insulin resistance and endothelial dysfunction. Genetic factors may determine 40-60% of total cholesterol levels and 70% of the efficacy of statin treatments. Metabolic and cardiovascular phenotypes that are either genetically determined or environmentally acquired are also important determinants of responses to specific statins. Moreover, differences between biological outcomes of specific statins or increasing dosages of statins result in differential metabolic actions due to off-target or unknown mechanism that have important implications for the use of statins to reduce overall morbidity and mortality. In this review, we discuss differential cardiovascular and metabolic pleiotropic actions of specific statins that interact in a context-dependent manner with patient phenotypes and genotypes. These important considerations may influence progression of atherosclerosis, risk of diabetes, and modulation of insulin resistance that help determine overall morbidity and mortality in patients undergoing statin therapy.