Why some patients respond poorly to statins and how this might be remedied.

Abstract

The advent of the statins, competitive inhibitors of HMG CoA reductase and thus of cholesterol synthesis, has revolutionized the treatment and prevention of coronary heart disease. The reduction in coronary heart disease events in dyslipidaemic subjects largely reflects the extent to which these drugs lower LDL cholesterol, although additional mechanisms have been proposed in normolipidaemic individuals. A meta-analysis of the five major statin trials showed an overall reduction in LDL cholesterol of 28%, which resulted in a 31% decrease in coronary heart disease events. The latter value is 10% less than expected from the decrease in LDL cholesterol that occurred, judging from the Proportional Hazards analysis of the Lipid Research Clinics Coronary Primary Prevention Trial (CPPT) where cholestyramine was used to lower LDL. This discrepancy may reflect differences in design and duration between the CPPT and statin trials but does not support the notion that statins reduce coronary heart disease events by actions (‘pleiotropic effects’) which are additional to their LDL-lowering properties. Hence any factors which adversely affect the latter would be expected to diminish the benefits of statin therapy in the prevention of coronary heart disease, at least in hypercholesterolaemic subjects.