The aggressive low density lipoprotein lowering controversy.

Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.