Latest trial confirms efficacy/safety profile of CETP inhibition with dalcetrapib
The first mid-term follow-up data on dalcetrapib show a favourable efficacy/safety profile, supporting ongoing clinical development for this potential HDL cholesterol raising strategy. The data were reported and reviewed in the European Heart Journal, and are discussed by HDL Forum Editor Professor Philip Barter, Heart Research Institute, Sydney, Australia.
Stein EA, Roth EM, Rhyne JM et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J Published on-line 22 January 2010.
von Eckardstein A. Mulling over the odds of CETP inhibition. Eur Heart J. Published online 22 January 2010.
Expert opinion remains divided about the potential therapeutic role of cholesteryl ester transfer protein (CETP) inhibition. The scientific rationale for this approach is supported by a) animal studies showing that CETP inhibition is associated with elevation of HDL cholesterol and attenuation of atherosclerosis (1,2), and b) population studies showing that genetic deficiency in CETP activity is associated with reduced coronary heart disease (CHD) mortality (3,4). However, the premature termination of clinical development of the first of these agents, torcetrapib, due to an excess number of deaths in the ILLUMINATE trial (5), has tempered the view of other experts. This is despite post-hoc analyses from ILLUMINATE suggesting that this excess mortality was likely to be due to off-target effects of torcetrapib such as elevation in blood pressure and adreno-cortical activation (5). Recent analysis of data from torcetrapib trials, combined with genetic studies and mechanistic studies in animal models makes it unlikely that the hypertensive effects observed with torcetrapib were related to CETP inhibition (6), (7).
Dalcetrapib is a CETP inhibitor undergoing clinical evaluation. Previous clinical studies have shown that dalcetrapib either as monotherapy or in combination with statins raises HDL cholesterol with no evidence of any effect on blood pressure (8).
In the current double-blind trial, 135 patients with CHD or CHD risk equivalents were randomised (2:1) to dalcetrapib (900 mg/day) or placebo, in addition to atorvastatin for 24 weeks. Seventy-seven patients continued treatment for a further 24 weeks in an extension study.
Treatment with dalcetrapib led to significant increases in plasma HDL cholesterol levels (by ∼33%) and apolipoprotein A-I (by 11-16%) at weeks 24 and 48, together with about 50% reduction in CETP activity (53.5% at 24 weeks and 56.5% at 48 weeks, p<0.0001 at each time point(). There was negligible effect on LDL cholesterol levels (Fig. 1).
Importantly, the study showed no significant increase in the rate of adverse effects, no clinically relevant changes in laboratory parameters such as aldosterone, and no change in vital signs including blood pressure (Fig 2). The authors concluded that the study findings provide additional support for dalcetrapib as a safe and effective treatment for raising HDL cholesterol. The data are especially reassuring given that the dosage used in the study was higher than that selected for phase III trials (600 mg/d).
In the accompanying editorial, Professor Arnold von Eckardstein, Institute of Clinical Chemistry, University Hospital Zurich, Switzerland highlighted the importance of these findings for the continuation of ongoing phase III trials with dalcetrapib (in combination with a statin) assessing treatment effects on atherosclerotic plaque load and hard clinical endpoints.
‘Clearly, the hypothesis that inhibition of CETP activity raises plasma levels of HDL cholesterol is still viable. We await the reporting of results from outcomes trials such as DALOUTCOMES to fully evaluate the role of CETP inhibition in cardiovascular risk reduction’, commented Professor Barter.
References
1. Okamoto H, Yonemori F, Wakitani K et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000;406:203-7.
2. Morehouse LA, Sugarman ED, Bourassa PA et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res 2007;48:1263-72.
3. Boekholdt SM, Kuivenhoven JA, Wareham NJ et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the Prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk Population Study. Circulation 2004;110:1418-23
4. Curb JD, Abbott RD, Rodriguez BL et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 2004;45:948-53.
5. Barter P, Caulfield M, Eriksson M et al. Effects of torcetrapib on morbidity and mortality in patients at high risk for coronary events. New Eng J Med 2007;357:2109-22.
6. Sofat R, Hingorani AD, Smeeth L et al. Separating the mechanism-based on off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation published on-line 21 December 2009. DOI: 10.1161/CIRCULATIONAHA.109.865444
7. Hu X, Dietz JD, Xia C et al. Torcetrapib induces aldosterone and cortisol production by an intra-cellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 2009;150:2211-9.
8. Stein EA, Stroes ESG, Steiner G et al. Safety and tolerability of dalcetrapib (RO4607381/JJT-705): results from five phase II clinical trials. Am J Cardiol 2009;104:82-91.
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