Among the frequently cited arguments in favor of low targets for LDL are, first, the fact that coronary heart disease (CHD) rates correlate with average plasma cholesterol levels within and between countries, with the lowest rates shown by people with a total cholesterol lower than 150 mg/dl [2, 3]. Second, secondary prevention trials have shown a direct correlation between degree of LDL lowering and the extent of angiographic or clinical benefits [4, 5]. Finally, the incomplete successes of the statin trials might have been amplified had larger proportions of study subjects reached their LDL goal. On the contrary, the proponents of a less aggressive approach to LDL management question the safety of very low LDL levels [6], cite data from statin trials showing reduced or absent benefits in patients with baseline low LDL [7] or in any patients after the initial 25% drop in LDL [8, 9,10], and invoke the possibility that the impressive results obtained with statins are partly due to direct effects of the drug on the vascular wall and are therefore somewhat independent of LDL changes [11].

Before emphasizing the basis for our position, we think it necessary to state what we do not consider valid arguments against aggressively low LDL goals. First, there is danger in achieving LDL levels between 50 and 75 mg/dl. Although LDL is an important vehicle to transport vitamin A and vitamin E as well as cholesterol to tissues, data from subjects with the heterozygous form of hypobetalipoproteinemia clearly indicate the safety of low LDL [12,13]. Untoward effects of low LDL may become evident for concentrations below 25 mg/dl [14], a value that is rarely reached with statin therapy in common high risk patients. Second, a small reduction in LDL may be just as good as a larger one. It is undeniable that, particularly in high risk patients, LDL reductions to extremely low levels should decrease the atherogenic pressure more than more moderate interventions would. The difference between benefits achieved with one approach versus the other may, however, be too small too justify aggressive interventions, as clinical trials have indicated that up to 85% of the preventive effect of lipid lowering is collected after the initial 25% drop in LDL from baseline [15]. Finally, LDL reduction is not a therapeutic objective at all in some high risk patients. Although data showing significant clinical benefits in high risk patients with low HDL and low LDL treated with gemfibrozil are available [16], it is unquestionable that the mediator of risk in low HDL conditions is the level of the atherogenic lipoproteins. It is also unquestionable that LDL and remnant reduction in these patients represent the best approach to reducing the cholesterol/high-density lipoprotein (HDL) ratio as well as CHD risk.