November 19th, 2010

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 Wednesday 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 the last day of AHA 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 its ability to boost HDL.

REVEAL Revealed

At a news conference at the AHA, and in a press release, 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 Defined

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 in the placebo group. 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 “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.

One Response to “Will This Be the HDL Decade? REVEAL Revealed, Mixed Results for Apo-A1”

  1. rafael dajer, physician says:

    I think that we need a little more time making investigation about physiological mechanisms that explain high or low HDL level in order not to fail on new drugs to get higher levels of HDL, including exercise.

    Competing interests pertaining specifically to this post, comment, or both:
    there is not any conflicts of interest in my comment.