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The aggressive low density lipoprotein lowering controversy
J S Forrester1, C N Bairey-Merz, S Kaul
1Department of Medicine, Cedars-Sinai Medical Center, and University of California at Los Angeles School of Medicine, USA.
Insights
Aggressively lowering low-density lipoprotein (LDL) with statins offers cardiovascular benefits, but optimal targets remain unclear. Further research is needed to balance benefits against potential adverse events.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Clinical trials confirm cardiovascular benefits of statin-induced low-density lipoprotein (LDL) lowering.
- Unresolved questions persist regarding the relationship between LDL levels and cardiac events, optimal efficacy measures, and target LDL concentrations for therapy.
Purpose of the Study:
- To review the current understanding of LDL lowering and cardiovascular events.
- To discuss the complexities in determining the optimal LDL target for statin therapy.
Main Methods:
- Review of recent clinical trials and epidemiological studies on LDL lowering and cardiovascular outcomes.
- Analysis of conflicting data regarding the relationship between LDL levels and cardiac events.
Main Results:
- The relationship between cardiac events and LDL levels is curvilinear, with diminishing benefits at lower LDL concentrations.
- Conflicting results exist regarding the best LDL target, influenced by pretreatment levels and non-lipid-lowering effects of statins.
Conclusions:
- Very aggressive LDL lowering (<80 mg/dL) may offer modest benefits beyond current guidelines but requires careful consideration of potential adverse events.
- Ongoing trials are expected to clarify the optimal LDL targets and therapeutic strategies.
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.