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In a double blind secondary prevention clinical trial (ILLUMINATE Study), lipids were modified similar to those in the preliminary trials, but the trial was terminated after 1 year because of a significant increase in cardiovascular events and death in the torcetrapib and statin group as compared to those on statin alone. Moreover, the patients on torcetrapib showed an increase in percent atheroma volume assessed by ultrasound (ILLUSTRATE Study).
Based on current knowledge of the metabolic pathways, it is not surprising torcetrapib increased plasma HDLC but did not reduce heart disease, because inhibition of the CETP pathway increases plasma HDLC by reducing exchange with VLDL that would theoretically reduce RCT.
But a recently published study suggested loss of function by a mutation in the ABCA1 gene causing a decrease in plasma HDLC was not associated with increased risk of CHD in humans. This would be contrary to current thought suggesting ABCAI is the first step in RCT and transporter facilitation would enhance RCT and reduce CHD. Moreover, a study with mice questioned whether or not SR-BI promoted RCT in vivo.
Although these findings do not necessarily negate the RCT hypothesis, they do require some modifications in it. For example, there is evidence there are other ways besides the ABCAI that cholesterol can be moved to HDL, and these mechanisms may be facilitated when ABCAI is nonfunctional.
But, what does seems clear is that, although persons with natural levels of plasma HDLC (such as pre-menopause women) greater then 60 mg/dL are at reduced risk for CHD, therapeutic modification of RCT to reduce CHD may not necessarily be reflected by increased plasma HDLC levels. Thus, it seems increasing plasma HDLC by CETP inhibition does not lead to less CHD.
On the other hand, one would expect facilitation of ABCAI by therapeutic manipulation to increase RCT, and this would be reflected by an increase in plasma HDLC, but if up-regulation of SR BI is used to facilitate RCT, it would be expected that plasma HDLC would decrease with therapeutic modification. It is also clear we still have a long way to go and a lot to learn about modifying RCT towards reducing CHD and determining how such modifications can be monitored with biomarkers. HDLC may not be the biomarker of choice.
Dr. Levinson is professor of pathology and laboratory medicine, University of Louisville, KY, and chair, CLAS Publications Committee. This column was produced in conjunction with the Clinical Ligand Assay Society (http://www.clas.org/).
References and Additional Reading
- Tall A, et al. George Lyman Duff Memorial Lecture:Lipid transfer proteins, HDL metabolism and atherogenesis. Thromb Vasc Biol 2000;20:1185-88.
- Cuchel M, Rader DJ. Macrophage reverse cholesterol transport. Circulation 2006:113:2548-55.
- Movva R, Rader DJ. Laboratory assessment of HDL heterogeneity and function. Clin Chem 2008;54:788-800.
- Barter. ILLUMINATE Investigators. Effect of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
- Frikke-Schmidt R, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 2008;299:2524-32.
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