REVEAL Revealed: A Slightly Positive CETP Inhibitor Trial

—After 3 strikes a CETP inhibitor finally scores.

BARCELONA — Finally there is a CETP inhibitor that actually confers more benefit than risk: anacetrapib.

The benefit emerged from the Randomized EValuation of the Effects of Anacetrapib through Lipid-modification (HPS3/TIMI55-REVEAL) trial which was presented here at the European Society of Cardiology meeting and published simultaneously in the New England Journal of Medicine.

The study randomized 30,449 patients with atherosclerosis to placebo or the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib. After 4.1 years of followup a major coronary event occurred in 10.8% of patients in the anacetrapib group versus 11.8% of patients in the placebo group, a 9% reduction in risk (P=0.004).

On treatment level of HDL cholesterol was 43 mg/dl higher and non-HDL cholesterol was 17 mg/dl lower in the anacetrapib group than in the placebo group. Anacetrapib treatment was associated with a slightly higher systolic blood pressure level (0.7 mm/Hg) and an elevated risk for a diminished estimated GFR.

REVEAL is by far the largest and longest trial to study a CETP, a drug class that originally raised hopes because they raise HDL levels, the so-called good cholesterol, while also lowering LDL cholesterol. CETP inhibitors can also have other off-target effects.

And here is the real news from REVEAL, it turns out that the benefit seen here is most likely due to the drug’s effect on non-HDL cholesterol.

Three previous large trials with different drugs in the same class came to woe and grief, sparking broad skepticism about all drugs in the class. First, and most spectacular, was the failure of Pfizer’s torcetrapib in the ILLUMINATE trial. It is now widely believed that the failure was due to the off-target effects of the drug. Subsequently, the trial with Roche’s dalcetrapib was stopped for futility, likely a result of the drug’s relatively weak LDL-lowering effect. The third drug, evacetrapib, may have suffered because Lilly rushed the trial and didn’t allow enough time to demonstrate benefit.

Despite the success of the trial many experts question whether the drug has a role in clinical practice. Merck, which manufactures the drug, has not publicly stated whether it intends to go forward with the drug and pursue approval. When contacted yesterday, a company spokesperson said it was still evaluating its options.

Sanjay Kaul, MD, of Cedars-Sinai pointed to the “modest treatment effect (1% absolute and 9% relative risk difference) driven to statistical significance by a large sample size” and the lack of a mortality benefit. Perhaps speaking as a committed Bayesian, he said the “treatment effect is not robust enough to overcome the prior skepticism fueled by three null or negative results.”

This theme was echoed by James Stein, MD, of the University of Wisconsin who said said he was “not sure what to make of this study. There is a very small non fatal CV benefit over 4 years with several concerning side effects. The three other agents did not show cardiovascular benefits. Though the studies were smaller, shorter and used different agents, they still were CETP inhibitors. This study is the outlier. I am worried that what we are seeing here is a mixture of counterbalancing risks and harms that in a huge study over four years can demonstrate mild benefit. I am worried that most of the observed benefit is noise. I’d like to know if the benefits have anything to do with HDL raising or if that is just a distraction. I doubt it does and think it is a distraction. This study needs replication.”


  1. When are people going to be intellectually honest and abandon the lipid hypothesis?

    • They won’t. For the $ame reasons that Ancel Keys et al took the path they did…

      Pride, Power, arrogance, personal investment in a Belief system / Reputation, conflict(s) of Interest etc, will always trump ‘Honesty’ of any variety.

  2. Denise Durak, Psy.D. says

    I think the outcome of this study has been known for a few months. The latest reports from NLA conference, 2017, would suggests raising HDL is unlikely to have significant effects, as Dr. Stein indicates. The inhibition of cholesterol ester into the arterial intima by reduction of ApoB particles or LDL-P could account for the positive, even if small positive effects by inhibiting or reversing cholesterol transport. Certainly it is in the right direction, and increases rational and enthusiasm for further research to validate the potential of the CEPT inhibitor Anacetrapib. I am only a student and not an MD, but inhibition of cholesterol ester from what I have read would promise prevention for some of the patients with the most stubborn lipid metabolism/ elimination problems. I would like to hear what health professionals in lipidology or endocrinology have to say about this study.

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