Dalcetrapib Boosts HDL Without Benefiting Patients

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.