New Horizons for Cholesterol Ester Transfer Protein Inhibitors

New Horizons for Cholesterol Ester Transfer Protein Inhibitors
 

Gregory G. Schwartz

Curr Atheroscler Rep. 2011 Nov 15.

Abstract

High-density lipoprotein (HDL) cholesterol levels bear an inverse relationship to cardiovascular risk. To date, however, no intervention specifically targeting HDL has been demonstrated to reduce cardiovascular risk. Cholesterol ester transfer protein (CETP) mediates transfer of cholesterol ester from HDL to apolipoprotein B-containing particles. Most, but not all observational cohort studies indicate that genetic polymorphisms of CETP associated with reduced activity and higher HDL cholesterol levels are also associated with reduced cardiovascular risk. Some, but not all studies indicate that CETP inhibition in rabbits retards atherosclerosis, whereas transgenic CETP expression in mice promotes atherosclerosis. Torcetrapib, the first CETP inhibitor to reach phase III clinical development, was abandoned due to excess mortality associated with increases in aldosterone and blood pressure. Two other CETP inhibitors have entered phase III clinical development. Anacetrapib is a potent inhibitor of CETP that produces very large increases in HDL cholesterol and large reductions in low-density lipoprotein (LDL) cholesterol, beyond those achieved with statins. Dalcetrapib is a less potent CETP inhibitor that produces smaller increases in HDL cholesterol with minimal effect on LDL cholesterol. Both agents appear to allow efflux of cholesterol from macrophages to HDL in vitro, and neither agent affects blood pressure or aldosterone in vivo. Two large cardiovascular outcomes trials, one with anacetrapib and one with dalcetrapib, should provide a conclusive test of the hypothesis that inhibition of CETP decreases cardiovascular risk.

Rationale

Raising HDL-C is an attractive treatment option to further reduce cardiovascular morbidity and mortality, additional to the clinical benefit of statins.  One of the strategies to modulate HDL metabolism is the inhibition of cholesterol ester transfer protein (CETP). Large outcomes trials are expected to further clarify the relation of CETP to cardiovascular risk.

Conclusion

There is a clinical need for lipid-modulating strategies in addition to statins. The REVEAL and the dal-OUTCOMES are designed to show whether CETP inhibition is a valid treatment target in atherosclerosis.

References

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2. Kastelein JJ, Duivenvoorden R, Deanfield J, et al. Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flowmediated vasodilatation. Curr Med Res Opin 2011, 27:141–150.
3. http://www.escardio.org/congresses/esc-2011/congress-reports/Documents/28-8-HotLine/dal-VESSEL-presenter-Luescher-slides.pdf Accessed 12 Sept 2011. This link provides the presentation of the dal-VESSEL study at the European Society of Cardiology congress in August 2011.
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6. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009, 158:896–901.