The aggressive low density lipoprotein lowering controversy

Abstract

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.

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

“…These data suggest that the LDL target set by NCEP guidelines may be too high. [1][2][3][4][5] Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.…”

Following the mevalonate pathway to bone heal alley

“…By acting on the rate-limiting step of the pathway, and by the fact that their primary target organ is the liver, less been demonstrated that statins, and in particular simvastatin, exert beneficial effects beyond their ability of lowering cholesterol. For instance, in the 4S study, simvastatin was shown to be efficacious in secondary prevention of ischemic heart disease, an effect not satisfactorily accounted for by solely a lowering of cholesterol (Pedersen 1998, Gotto and Grundy 1999, Hay et al 1999, Jonsson et al 1999, Pedersen 1999, Velasco 1999, Forrester et al 2000, Pedersen et al 2000, Doggrell 2001, Tonkin 2001, Wilhelmsen et al 2001, Liao 2002, Ong 2002, Pedersen and Tobert 2004. This and other findings have spurred research into what other effects statins can effectuate on the body.…”

Low-Density Lipoprotein Lowering and Atherosclerosis Progression

“…For the clinician, the important questions remains how to initiate and titrate lipid-lowering therapy with statins: to a specific LDL-C target or to a specific % change in LDL-C, or should the decision be solely based on pretreatment LDL levels or pretreatment estimated clinical risk? 16 The recent data from the very large Heart Protection Study (HPS) using 40 mg of simvastatin/d shows that the magnitude of proportional risk reduction is the same whether the baseline LDL-C levels are Ͻ116, 116 to 135, or over 135 mg/dL in patients at high risk, indirectly raising questions about the "more" (LDL-C lowering) means "less" (atherosclerosis progression or clinical events) hypothesis. 6 Furthermore, in the HPS, the response of patients to simvastatin was assessed in the prerandomization phase of the study, and the magnitude of relative risk reduction was not related to the magnitude of LDL-C reduction observed during this prerandomization phase.…”