Conference Coverage

Dalcetrapib Boosts HDL Without Benefiting Patients

Publish date: November 28, 2012
By
Mitchel L. Zoler, PhD

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HDL's Clinical Relevance Remains in Doubt

What we’ve learned about HDL cholesterol is that what’s important is not the level of this material but the amount of reverse cholesterol transport that goes on in a patient, driven by apoprotein A-1.

I have studied a family with several members who have HDL cholesterol levels that are 2 or 3 mg/dL, but they have no coronary disease. That’s because they have a hyperaffinity form of apoprotein A-1, the protein that picks up cholesterol from artery walls, forms HDL, and takes the cholesterol to the liver for excretion through the cholesteryl-ester transport mechanism and reverse cholesterol transport.

If you block reverse cholesterol transport, then HDL cholesterol levels rise because they plug up, but that’s not good for patients. It’s never been clear that "cetrapib" drugs boost reverse cholesterol transport. It’s possible that what they really do is raise HDL cholesterol levels by blocking reverse cholesterol transport.

No study results have ever proven that high HDL levels correlate with improved clinical outcomes at the individual-patient level. In large groups, high HDL cholesterol levels correlate with reduced atherosclerosis, but for individual patients, especially in a setting of low levels of LDL cholesterol (either occurring naturally or induced therapeutically), high HDL levels can be worrisome. HDL cholesterol is actually a terrible biomarker of a good atherosclerotic state in individual patients.

For example, results from the AIM-HIGH study showed that treating patients with low LDL cholesterol levels (less than 70 mg/dL) with niacin raised their HDL cholesterol levels but failed to produce clinical benefit (N. Engl. J. Med. 2011;365:2255-67). That result showed it’s very possible that HDL cholesterol is not a relevant marker of reverse cholesterol transport in people whose LDL cholesterol level is below 70 mg/dL.

I like to use a garbage-truck analogy for HDL cholesterol. When the level of cholesterol in the garbage truck is low, is it because there are not enough trucks or because there is not much garbage? When patients’ LDL cholesterol is already below 70 mg/dL, do they lack enough garbage to fill their HDL garbage trucks? In patients with modest levels of LDL cholesterol, even if their HDL cholesterol level is low there may be no reason to raise it higher. On the other hand, in patients with LDL cholesterol levels above the atherogenic threshold, the higher their HDL cholesterol the better.

Dr. Thomas A. Pearson is a professor of community and preventive medicine at the University of Rochester (N.Y.). He said that he has no relevant disclosures. He made these comments in an interview.


 

AT THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION

LOS ANGELES – The idea that raising blood levels of high-density lipoprotein cholesterol will cut cardiovascular events in patients with coronary disease took another hit with the flat clinical impact of dalcetrapib in a pivotal phase III trial with more than 15,000 patients.

Dalcetrapib did what it was supposed to do, at least physiologically: It raised patients’ HDL cholesterol levels by an average of about 30% compared with placebo. Despite that, patients who received the drug showed absolutely no drop in cardiovascular event rates during a median 31 months’ follow-up, Dr. Gregory G. Schwartz reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Dr. Gregory G. Schwartz

Because of the lack of any suggestion of benefit from treatment, the trial’s Data and Safety Monitoring Board recommended stopping the dal-OUTCOMES trial because of futility at one of the study’s prespecified review points.

The disappointing result made dalcetrapib, a cholesterol ester transfer protein (CETP) inhibitor, the second agent from this class to strike out in phase III testing. Five years ago, torcetrapib, the first CETP inhibitor drug to enter advanced clinical testing, crashed and burned in a phase III trial when it significantly boosted patient morbidity and mortality despite raising HDL cholesterol by 72% and cutting LDL levels by 25%, possibly because torcetrapib also boosted systolic blood pressure by an average of about 5 mm Hg (N. Engl. J. Med. 2007;357:2109-22).

Dalcetrapib was not nearly as dangerous as torcetrapib. In the new study, treatment with dalcetrapib was linked to a modest, average 0.6-mm rise in systolic blood pressure, and an equally slight 0.2-mg average increase in blood levels of C-reactive protein. Whether these effects had an impact on the clinical bottom line remains unknown, but the study results showed that the primary efficacy event curve for patients on dalcetrapib was completely superimposed with the curve for patients on placebo, reported Dr. Schwartz, chief of cardiology at the Denver VA Medical Center.

Both Dr. Schwartz and Dr. Alan Tall, the designated discussant for the study at the meeting, agreed that the disappointing performances of dalcetrapib and torcetrapib in phase III trials did not automatically mean that the CETP drug class has totally washed out. They both cited the importance of waiting for results from two other phase III studies now in progress that are testing two more CETP agents that are molecularly distinct from the two that did not pan out. Those agents are anacetrapib, currently being tested in a 30,000-patient study, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification) trial, with results expected in 2017; and evacetrapib, now being tested in an 11,000-patient study, the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes) trial, with results expected in 2015.

"All four drugs have different chemical structures and biological effects," and so the outcomes seen so far with dalcetrapib and torcetrapib "are not necessarily harbingers" of what might lie ahead with the anacetrapib and evacetrapib trials, said Dr. Tall, professor and director of the Center of Research in Molecular Medicine and Atherosclerosis at Columbia University in New York.

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