Reduction of Serum LDL-C Levels: a Relationship to Clinical Benefits

The association between elevated serum cholesterol levels and cardiovascular risk was established several decades ago by studies such as the Framingham study and the Multiple Risk Factor Intervention Trial (MRFIT). Both primary and secondary prevention trials of cholesterol lowering, using HMG-CoA reductase inhibitors, have demonstrated clear benefits for lipid lowering in preventing both cardiovascular morbidity and mortality over a wide spectrum of coronary heart disease (CHD) risk. Even so, risk of events has been reduced by about 30% in these trials, leaving 70% of events occurring even in the presence of substantial cholesterol lowering. It is unknown whether further reduction of serum cholesterol levels will lower risk factors. The relationship between cholesterol lowering and cardiovascular risk, moreover, is not completely defined; it is unclear, at lower cholesterol levels, whether that relationship follows a threshold, a linear, or a curvilinear model. Early studies of low-density lipoprotein-cholesterol (LDL-C) lowering with HMG-CoA reductase inhibitors suggested that non-cardiovascular mortality might be increased at low serum LDL-C levels, however, these concerns have not been supported by subsequent clinical trials. Recent studies have shed further light on the potential benefits of lowering serum cholesterol levels beyond current guideline targets with HMG-CoA reductase inhibitors. More potent agents in development are likely to make such levels more readily achievable, as well as making guideline targets attainable for many of the large number of patients who currently fail to reach them.