3-Hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (
statins) are extremely effective at reducing
low-density lipoprotein (
LDL) cholesterol and have been demonstrated to reduce mortality and the risk of major cardiovascular events in a number of large primary and
secondary prevention studies. The linear relationship between
LDL-cholesterol and cardiovascular risk suggests
statins work solely by reducing
LDL-cholesterol, and that ancillary properties do not contribute to cardiovascular risk reduction. In recent years, however, a number of additional non-
lipid-lowering, or 'pleiotropic', effects of
statins have been suggested to contribute to their efficacy in
cardiovascular disease. The first data to suggest that
statins may have benefits beyond
lipid lowering came from the Heart Protection Study, in which
simvastatin reduced mortality and morbidity even in patients with 'normal'
LDL-cholesterol levels (2.6 mmol/L or 100 mg/dL). It has since been demonstrated, however, that cardiovascular risk remains high at this
LDL concentration, but is substantially reduced in those achieving levels below 2.0 mmol/L (77 mg/dL). Evidence for the pleiotropic effects of
statins in
heart failure comes largely from retrospective and subgroup analyses of large studies. When
statin therapy is compared with placebo, or when high-dose
statin therapy is compared with low-dose treatment, a lower incidence of
heart failure or hospitalization is observed. Despite promising retrospective data, however, two prospective studies of
rosuvastatin in the treatment of patients with New York Heart Association class II-IV
heart failure showed no impact on the primary endpoint and only one of the studies showed a lower rate of hospitalization favouring
rosuvastatin. A number of small studies has shown evidence for mechanisms of action of
statins outside of
LDL-cholesterol lowering, including improvements in endothelial function, halting or retardation of
atheroma development, reduction in
inflammation and antithrombotic effects. The linear relationship between
LDL-cholesterol lowering and reduction in
coronary heart disease risk, as well as a lack of conclusive evidence for other mechanisms of action raise the question of whether any
cholesterol-lowering agent is equally effective for reducing cardiovascular risk, but recent data from the
torcetrapib clinical trial programme suggest this is not the case. Future
cholesterol-lowering modalities must be able to demonstrate efficacy and good tolerability in large-scale clinical trials.