DEFINE: CETP inhibition with anacetrapib

DEFINE: Anacetrapib raises HDL, reassuring safety profile

Treatment with the cholesteryl ester transfer protein inhibitor (CETP) anacetrapib substantially increased HDL cholesterol over and beyond the effects of atorvastatin in patients with or at high risk of coronary heart disease. There was also no increase in systolic blood or electrolytes with anacetrapib, in contrast with findings previously reported with torcetrapib. These results of the Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) trial were simultaneously reported at the annual American Heart Association Scientific Sessions, Chicago, USA and published online in the New England Journal of Medicine. Here HDL Forum Editors give their view of the relevance of the DEFINE results.

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; doi:10.1056/NEJMoa1009744.

Background to DEFINE

The methodology of DEFINE has been previously reported on HDL Forum (1). Briefly DEFINE was a randomized, double-blind placebo-controlled study in patients with coronary heart disease (CHD) or CHD risk equivalents. Patients who achieved guideline-recommended LDL cholesterol targets with statin treatment (with or without other lipid-modifying therapy) were randomized to treatment with anacetrapib 100 mg daily or placebo. The duration of treatment was 18 months, with a 3 month post-study follow-up.

The primary endpoint was the percent change in LDL cholesterol levels. Secondary endpoints include the change in HDL cholesterol levels and the safety and adverse event profile of anacetrapib.

DEFINE: Substantial lipid changes

In 1623 randomized patients, HDL cholesterol was increased by 138.1% (from 41 mg/dL [1.06 mmol/L] to 101 mg/dL [2.6 mmol/L]) at 24 weeks in the anacetrapib group, versus statin alone (change from 40 mg/dL [1.03 mmol/L] to 46 [1.19 mmol/L]). In addition, anacetrapib was associated with substantial decreases in LDL cholesterol (by 39.8%), non-HDL cholesterol (by 36.1%) and lipoprotein(a) (by 36.4%) and a small decrease in triglycerides versus statin alone (Figure 1). These lipid changes were sustained throughout the 76-week treatment period.

DEFINE: reassuring safety profile

Importantly, no changes in blood pressure, electrolytes or aldosterone levels were observed with anacetrapib treatment (Table 1). These findings are consistent with results from an earlier study in dyslipidemic patients (2).

Events were reviewed by an independent adjudication committee and monitored by by an independent external safety committee. Major cardiovascular events occurred in 16 (2.0%) patients treated with statin plus anacetrapib and 21 (2.6%) with statin alone (p=0.40). of interest was the difference in patients undergoing revascularisation, predominantly percutaneous coronary intervention: 8 (1.0%) with anacetrapib versus 28 (3.5%) with statin alone A predefine Bayesian analysis provided 94% predictive confidence that anacetrapib was not associated with a 25% increase in cardiovascular events, as previously reported with torcetrapib in ILLUMINATE (3).

According to Dr Christopher Cannon lead author and co-chair of the study with Professor Philip Barter: 'DEFINE, a moderate sized study, has provided encouraging results with anacetrapib in statin-treated high-risk patients, which pave the way for a large outcomes study with this CETP inhibitor. Within the limits of the study, the safety data are reassuring that anacetrapib is not associated with the off-target effects that led to the demise of torcetrapib.'

At the end of his presentation, Dr Cannon announced plans for the REVEAL study, involving about 30,000 high-risk patients, to be initiated in 2011. REVEA, will be sufficiently powered to detect an effect with anacetrapib on major atherosclerotic events, a composite of coronary death, MI, and revascularization but not stroke.

HDL Forum Editors provide their view on the DEFINE findings.

Professor John Chapman President, European Atherosclerosis Society, from INSERM UMR-S939, Hôpital de la Pitié, Paris, France said : 'The results from DEFINE clearly indicate that this is only the beginning for the CETP inhibitors. Although we have as yet no information on the vascular impact of anacetrapib, the magnitude of HDL and LDL changes observed in DEFINE are of particular interest. We await the results of REVEAL.'

Professor Philip Barter, Heart Research Institute and the senior author of the DEFINE paper provides his view on these findings. 'The DEFINE results are crucial for the continuing development of the CETP inhibitors. The substantial lipid changes and reassuring safety profile of anacetrapib shown by DEFINE provide support for larger outcomes studies. The clinical relevance of the substantial changes in lipids, notably the 138% increase in HDL cholesterol, to residual cardiovascular risk clearly warrants further evaluation.'

References

1. Cannon CP, Dansky HM, Davidson M et al. Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with anacEtrapib. Am Heart J 2009;158:513-19.

2. Bloomfield D, Carlson GL, Sapre A et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009;157:352-360.e2.

3. 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.

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