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Satellite Report: In focus, cardiovascular risk, high-density lipoprotein and the role of CETP

The potential of the CETP inhibitors was the focus of this Satellite Symposium on Saturday 27th August, 2011, Paris.

Increasingly experts agree that HDL functionality may be more relevant to atherosclerosis and cardiovascular disease than measurement of plasma levels of HDL cholesterol. As overviewed by Professor Alberto Zambon, Padua University, Italy, HDL are highly heterogeneous in terms of structure, intravascular metabolism and biological activity. The complexity of the HDL particle is underscored by evidence that the surface of the HDL particle comprises more than 50 different proteins involved in cholesterol homeostasis, lipid binding, antioxidant, acute-phase response, immune response, and endopeptidase/protease inhibition. In patients with acute coronary syndromes, studies have shown that the proteome of HDL differs from that of normal healthy individuals, specifically involving reductions in levels of apolipoprotein (apoA)-IV and increases in levels of serum amyloid A (SAA) and complement C3 (C3), reflecting a shift to an inflammatory profile which may influence the protective effects of HDL.(1) This provides further evidence that, unlike LDL, measurement of HDL cholesterol is likely to be a poor marker for the functionality of HDL.

Recent data, previously reviewed by HDL Forum, have highlighted the relevance of HDL functionality to cardiovascular risk. A study by Khera et al (2011) showed that in healthy volunteers, there was a significant inverse association between macrophage cholesterol efflux capacity and carotid intima-media thickness (CIMT), even after adjustment for plasma levels of HDL cholesterol. There was no association between plasma HDL cholesterol concentration and CIMT. Increased efflux capacity was also an independent inverse predictor of risk for coronary artery disease in coronary heart disease (CHD) patients.(2) However, there remains much work to standardize the measurement of HDL functionality.

Professor Kastelein, University of Amsterdam, The Netherlands overviewed the mode of action and status of CETP inhibitor development. After termination of torcetrapib, there are currently three CETP inhibitors in development, dalcetrapib, anacetrapib, and evacetrapib. Dalcetrapib and anacetrapib are more advanced in development. These two agents differ in mode of action and correspondingly the associated lipid effects; dalcetrapib raises HDL cholesterol by ~25-35%,(3) whereas anacetrapib raises HDL cholesterol more substantially (by 138% in the recent DEFINE trial[4]) with concomitant lowering of LDL cholesterol and lipoprotein(a) by about 40%. Results from recent mid-term trials have provided a reassuring safety profile for each agent and robust support for ongoing outcomes trials. Of these, dal-OUTCOMES will be first to report.

Dalcetrapib is covered by an extensive programme of clinical development, including investigation of its effects on the vessel wall and endothelial function. These studies are highly relevant in view of the failure of torcetrapib. Two studies reporting at ESC Congress 2011 provided new insights: dal-VESSEL and dal-PLAQUE (see separate HDL Forum report).

Professor Zahi Fayad, Mount Sinai Medical School, New York, USA USA overviewed dal-PLAQUE. This is a phase IIB, double-blind trial of dalcetrapib 600 mg/day or placebo (i.e. current standard of care) in 130 patients with CHD or CHD risk equivalents, looking at the effects of dalcetrapib on the vessel wall. The study aimed to address the uncertainty whether HDL produced by CETP inhibition was pro-atherogenic or pro-inflammatory. The primary endpoints in the study were structural and inflammatory indices of atherosclerosis assessed using non-invasive multimodality imaging. Results were reported at a poster session and published on-line by The Lancet on September 12, 2011 (5).

In brief, dal-PLAQUE showed that treatment with dalcetrapib was associated with a reduction in plaque burden, as assessed by magnetic resonance imaging (MRI) at 24 months (significant reduction in total vessel area of the most diseased segment, change from baseline -4.01 mm3 [-7.23 to -0.80], p=0.041 and average wall area, -2.2 mm2 [-4.54 to 0.13], p=0.12). There was no evidence of a pro-inflammatory effect after 6 months on dalcetrapib as measured by 18F-fluoro-deoxyglucose uptake by PET/CT. In conclusion, data from dal-PLAQUE provide reassuring evidence that dalcetrapib does not have a pro-inflammatory effect, and on MRI there was evidence of less progression compared with patients treated according to current standards of care.

Dal-VESSEL which assessed the effect of dalcetrapib on endothelial function was reported at a Hotline session at ESC Congress Paris 2011 (see separate report).

References

1. Alwaili K, Bailey D, Awan Z, Bailey SD, Ruel I, Hafiane A, Krimbou L, Laboissiere S, Genest J. The HDL proteome in acute coronary syndromes shifts to an inflammatory profile. Biochim Biophys Acta. 2011 Jul 23. [Epub ahead of print].

2. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.

3. Stein EA, Stroes ES, Steiner G et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91.

4. Cannon CP, Shah S, Hayes MD et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010; 363:2406-15.

5. Fayad ZA, Mani V, Woodward M, et al; for the dal-PLAQUE Investigators. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011 Sep 9. [Epub ahead of print].

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