Will This Be the HDL Decade? REVEAL Revealed, Mixed Results for Apo-A1

For a long time HDL has been called the “good cholesterol.” Are we now entering the HDL decade? Two HDL-related trials were presented today at the AHA, and an array of additional trials are planned or underway, prompting the  lead investigator of one of those trials, Chris Cannon, to speculate that this decade may be the HDL decade.

Whether or not the 2010s turn out to be the HDL decade, there can be no question that today was HDL day. In addition to the excitement generated by Cannon’s trial, DEFINE, Merck and Oxford announced a major mega-trial to test the drug used in that trial, anacetrapib, in 30,000 patients. Less easy to interpret were the results of a small study, ASSERT, looking at a novel compound and it’s ability to boost HDL.

REVEAL Revealed

At a news conference at the AHA, and in a  press release (see bottom of this story), Oxford’s Rory Collins announced the REVEAL study, which will test anaceptrapib in 30,000 patients with heart disease on a background of statin therapy. Scheduled followup is 4 years, but if the clinical effect is as powerful as the effect on lipids, some experts believe the trial could be stopped earlier for efficacy.

DEFINE was the hot topic of the day at the AHA. One program committee member told me that the trial was scheduled for Wednesday to keep people at the meeting. It also helps to have a charismatic investigator like Chris Cannon. There’s a reason some people in Boston call Chris Cannon TIMI TV. He gives great interviews and delivers perfect sound bites. The DEFINE press release quoted Cannon’s summation of the lipid effects of anaceptrapib in the trial: “Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL.”

At the press conference Cannon preserved his quotability quotient. Asked about the difference in revascularizations in DEFINE (8 in the anaceptrapib group, 28 in the control group), Cannon told reporters: “when I saw those numbers, I actually sent a text message to Dr. Braunwald.” Cannon texted Braunwald (and that in itself is an interesting fact) that he (Cannon) thought this was the first real signal that CETP inhibition might actually have a clinical effect. Cannon told reporters that it was a “hint in reading the tea leaves.” (It should be noted that revascularization is a notoriously soft end point, and that although investigators were blinded to lipid levels during the study, patients and treating physicians may well have been influenced by their knowledge of lipid levels.)

Mixed Results for ASSERT

The ASSERT study tested the efficacy, safety and tolerability at 12 weeks of RVX-208, an oral drug that stimulates apo A-1 synthesis. Theoretically, this should enhance HDL-mediated reverse cholesterol transport, which some believe is the body’s natural mechanism to reverse atherosclerosis. But, as many experts have pointed out, HDL is extremely complex and there remain large areas of uncertainty about the way it works.

ASSERT, which randomized 299 patients to placebo or one of 3 doses of RVX-208, missed its primary endpoint and raised a few safety concerns, but also exhibited some effects with fascinating potential. The primary endpoint, the median change in Apo A-1 from baseline, was not significantly  higher in the combined RVX -208 groups than placebo. In the high dose RVX-208 group, total HDL increased only modestly, by 5%.

The other note of caution is that liver enzymes became elevated in 18 patients taking RVX-208. Study investigator SJ Nicholls reported that the elevations were reversed when the patients went off the drug, but obviously this area will be watched closely in future trials.

But here’s where the news gets better for RVX-208: in the high dose group large HDL increased by 21% and small HDL decreased by 4%. What this might mean is that the drug is in fact enhancing reverse cholesterol transport. In addition, at 12 weeks the investigators observed no plateau in the effect of RVX-208 in raising HDL components, suggesting that changes in these components  might well grow larger over a longer period.

The discussant for the trial, Eliot Brinton, said that a drug like RVX-208 “that has a modest effect on HDL levels might have a large clinical effect.” Brinton talked about the difficulty of measuring the “‘goodness’ of good cholesterol” and pointed out that there is “no consensus in the field of what to measure or how to measure it.” HDL is complex in its composition, metabolism, and function, and we are unable to accurately assess any HDL-related intervention in terms of its actual impact on atherosclerosis and cardiovascular risk, he said. Apo A-1 “probably ‘knows’ how to prevent atherosclerosis,” he continued, and he said it was reasonable to do a larger study.”

Steve Nissen, another highly visible cardiologist with a penchant for good quotes, told reporters that he would be leading the next trial of RVX-208, an IVUS study. Details are not yet decided, but Nissen mentioned a 26 week study as one possibility. Nissen said he was encouraged by both the DEFINE and ASSERT results and that HDL remains an exciting area of research.

Here is the REVEAL press release form the Oxford Clinical Trial Service Unit:

Major international study to test new drug to cut heart disease

A major international study to test whether a new type of cholesterol treatment can prevent coronary deaths and heart attacks will start in early 2011, it was announced today (Wednesday 17 November).

The REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) trial will investigate whether a drug called anacetrapib can drive down the risks of coronary deaths, heart attacks and other vascular complications. The study will involve 30,000 people who have some form of heart or other vascular disease from the UK, North America, China, Germany, Italy, Scandinavia and elsewhere.

The study is being coordinated by the Clinical Trial Service Unit (CTSU) at Oxford University. The CTSU is well known for running huge international studies, including the ground-breaking Heart Protection Study which showed that a third of all heart attacks and strokes can be safely avoided in people at risk of vascular disease by using statins to lower bad ‘LDL‘ cholesterol. The unit also showed that more intensive lowering of LDL cholesterol with statins safely produces extra benefits.

Anacetrapib is a new type of cholesterol treatment, belonging to a drug class known as CETP (Cholesteryl Ester Transfer Protein) inhibitors, which is being developed by Merck Sharp & Dohme. It has been found to produce substantial reductions in blood levels of ‘bad’ LDL cholesterol (equivalent to, and additional to, those achieved with statin drugs), and it more than doubles ‘good’ HDL cholesterol levels.

Anacetrapib has been studied in about 2,000 people, of whom about 500 have taken it for 18 months. In that research, which is also being reported today, anacetrapib was not associated with adverse effects on any of the key safety endpoints, including blood pressure or other vascular risk factors.

Large randomized studies have shown that lowering LDL cholesterol by 40 mg/dL (1 mmol/L) for 4-5 years with statin therapy cuts the risks of heart attacks and strokes by about a quarter, and recent studies suggest that more intensive LDL-lowering can produce extra benefits. But, despite the use of statins, the risk of heart attacks, strokes and other vascular complications among people who have vascular disease remains high.

Previous studies have also shown that people with high blood levels of HDL cholesterol tend to have fewer heart attacks or coronary deaths. However, there is limited evidence of any benefits with the drugs that are currently available to raise HDL cholesterol, and widespread use of the most effective of these HDL-raising drugs – which is called niacin – is limited by side-effects and poor tolerability.

Dr Martin Landray of Oxford University, one of the co-principal investigators of REVEAL, said: “This study could mark the start of a new era of cholesterol treatment. Anacetrapib has really dramatic effects on blood levels of cholesterol, even in those already on a statin, and it appears to be well tolerated.

“The key question now is whether these cholesterol changes prevent coronary deaths and heart attacks. It is also critical to determine whether there are any unexpected side-effects over the longer term. The potential is massive, but we need a really large trial to provide a definitive answer – REVEAL is that trial.”

Dr Louise Bowman of Oxford University, the other co-principal investigator, said: “This is a very exciting opportunity to try and improve life for the millions of people who have, or will develop, heart disease in the years to come.

“Large studies like REVEAL are vital if we are to discover new, safe and effective ways to reduce further the suffering caused by heart attacks, strokes and risky heart artery by-pass procedures.

“If the impressive effects of anacetrapib on cholesterol levels are translated into fewer deaths and heart attacks, then this treatment has the potential to produce substantial benefit for patients.”

REVEAL is a huge research undertaking and will take more than 6 years to complete, involving doctors and nurses in about 400 hospitals around the world. It will recruit 30,000 men and women aged at least 50 with a history of heart attack, stroke or peripheral arterial disease.

Oxford’s CTSU has designed the study and will be responsible for coordinating it and analysing its results, independently of the funders. A Steering Committee of international academic experts, chaired by Professor Rory Collins from Oxford University, will be responsible for the overall running of the study.

CTSU will be the central coordinating centre, with 6 regional coordinating centres initially in the UK, North America, China, Germany, Italy and Scandinavia. The TIMI research group in Boston, led by Professor Eugene Braunwald, a renowned expert in heart disease, will coordinate the North American part of the study.

REVEAL is being funded by Merck Sharp & Dohme, which developed anacetrapib. A grant of £96 million towards the cost of this multi-million dollar study has been provided to the University of Oxford.

Professor Andrew Hamilton, Vice Chancellor of Oxford University, said: “I am delighted that Oxford’s Clinical Trial Service Unit will run this major international trial. The new project on such a large scale reinforces Oxford medicine’s position at the forefront of international research. The University has built up the skills and expertise over many years to independently undertake these complex – and very important – clinical trials, the results of which can potentially save millions of lives around the world.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: “This is an important trial, led by BHF-funded researchers. Few drugs raise ‘good’ cholesterol as well as lowering ‘bad’, but CETP inhibitors do both. This research will show whether this drug can improve chances of survival, potentially giving new hope for millions of people whose cholesterol levels put them at serious risk of heart disease.”



REVEAL will involve 30,000 men and women aged at least 50 with a history of heart attack, stroke or peripheral arterial disease. All study participants will be given atorvastatin (a commonly used ‘statin’ drug) to ensure good control of LDL (‘bad’) cholesterol. In addition, they will be randomly allocated to receive anacetrapib or matching placebo (dummy) tablets daily for at least 4 years. Participants will have checks at two and six months, and six monthly thereafter during the study.

The primary objective of the study is to see whether fewer participants given anacetrapib have heart attacks, revascularisation procedures or die from coronary heart disease than do those in the placebo arm. It will start in early 2011 and results are expected within about 6 years

Cholesterol is a type of fat, called a lipid, present in blood and in cell membranes. Low density lipoprotein (LDL) cholesterol is often called ‘bad’ cholesterol because it is taken up by the artery walls, leading to the narrowing of the vessels which causes heart attacks and strokes. On the other hand, high density lipoprotein (HDL) cholesterol is called ‘good’ cholesterol because it removes cholesterol from the circulation, which may then protect against vascular disease.


  1. Will this be the HDL decade?I sure hope so.
    What are the barriers to reach this goal?
    A)The lack of understanding of:Innate Immunology
    B) Failure to distinguish between:Original molecule of the body and Foriegn molecules
    Once the barriers are breached,Medicine will become simple and easy to practice.

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