New Horizons for Cholesterol Ester Transfer Protein Inhibitors

Literature - Schwartz G, Curr Atheroscler Rep. 2011 Nov 15

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.

Anacetrapib and dalcetrapib

After the failure of torcetrapib because of off-target effects, two other candidates, anacetrapib and dalcetrapib, are continuing in clinical development. Some of their characteristics are depicted in the figure.

Anacetrapib

From the DEFINE trial, it became clear that anacetrapib is well tolerated and produces market and favorable changes in LDL, HDL, and lipoprotein (a) concentrations [1]. Effects of anacetrapib on reverse cholesterol transport and atherosclerosis progression in vivo are still unknown. The REVEAL trial will evaluate the long-term effect of anacetrapib on cardiovascular morbidity and mortality (expected in 2017).

Dalcetrapib

From the dal-VESSEL trial [2,3] it became clear that dalcetrapib does not have adverse effects on vascular function. In the dal-PLAQUE trial [4,5] dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months. Long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed in the dal-OUTCOMES trial [6] (expected in 2013).

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.

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References

1. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010, 363:2406–2415.
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.
4. Fayad ZA, Mani V,WoodwardM, et al. Rationale and design of dal-PLAQUE: A study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Am Heart J. 2011;162:214–21.
5. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378:1547–59.
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.