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The REVEAL trial has shown for the first time that adding a CETP inhibitor to intensive statin therapy reduces the incidence of cardiovascular events in high-risk patients. The effect of anacetrapib on the primary end point, a 9% reduction in risk, was too small to provide a clinically important benefit. In a trial of more than 30,000 patients

The REVEAL study randomized 30,449 patients with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy (baseline mean LDL-C 61 mg/dL; HDL-C 40 mg/dL) to anacetrapib 100 mg once daily or placebo.

During 4.1 years of follow-up, the primary outcome of coronary death, MI, or coronary revascularization occurred in 10.8% of the anacetrapib group vs 11.8% of those on placebo (rate ratio 0.91, 95% CI 0.85–0.97; P=0.004).

"The reductions in LDL, [apolipoprotein B] apo B, and non-HDL cholesterol all line up with what you would expect in terms of the event-rate reductions seen, and we don't seem to be seeing anything over and above this, even though there was a doubling of HDL cholesterol. But how exactly the drug is bringing about the event reduction is impossible to say."

 The REVEAL trial was much larger than the other CETP-inhibitor trials with double the number of patients, events, and treatment time than any of the other studies, and the benefit did not start to be seen until 2 years of treatment. This may help explain why a positive result was achieved," he said

And although the drug appears to have a relatively benign side-effect profile, with a small increase in blood pressure and a small reduction in kidney function, the fact that it accumulates in adipose tissue and stays in the body for up to 5 years is seen as a concern.

Although the major dalcetrapib trial—dal-OUTCOMES—did not show a benefit on cardiovascular events, Tardif genotyped the trial population and found that patients with a certain genetic profile (those homozygous for a variant in the ADCY9 gene, which account for 20% of the population) actually showed a large benefit of the drug. He is now leading a trial (dal-GENE) exclusively in patients with this genotype to try to confirm a benefit of the drug, and he suggests that a similar strategy may be possible for the other CETP inhibitors too.

 "All I can say is that in REVEAL everyone was on intense-dose statins already and they had very low LDL levels (mean 61 mg/dL) at baseline, and still we saw some benefit.  It is not unreasonable to extrapolate that if these people weren't on statins the CETP inhibitor may have had more effect as their baseline LDL would have been higher."


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