Healthy Skepticism Library item: 8307

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Publication type: news

Herper M.
The Conundrum Of Good Cholesterol
Forbes.com 2007 Feb 7
http://www.forbes.com/2007/02/07/hdl-good-cholesterol-jama-biz-cz_mh_0207cholesterol.html?partner=yahootix

Full text:

High-density lipoprotein, better known as HDL or “good cholesterol,” has become a medical mainstay. Doctors check it to predict whether patients are at risk for heart attacks and strokes. Low levels can be treated with drugs, particularly versions of the B-vitamin niacin including Niaspan, from Abbott Laboratories.

A study boosting HDL’s role should hardly be noticed. But the question of exactly what makes HDL work is now one of the most closely watched in the drug business. The reason: in December, Pfizer’s Pfizer (nyse: PFE – news – people ) $900 million effort to create a good cholesterol-raising pill failed spectacularly at preventing heart attacks and strokes. In a 10,000-patient trial, more patients died on the Pfizer drug, torcetrapib, than on placebo. That failure means that investors and researchers will zero in on the HDL analysis published in the current issue of the Journal of the American Medical Association.

What could have gone wrong in the Pfizer study? There are four possibilities: (1) HDL might be less important than it seemed; (2) torcetrapib’s known side effect, high blood pressure, might have been worse than expected, causing heart attacks; (3) the high blood pressure, which was unexplained, could have been caused by some other effect of the drug on blood vessel walls that turned out to be deadly; or (4) torcetrapib raised HDL, but that HDL didn’t prevent heart attacks as it should have.

The new JAMA paper argues that HDL is still important. It analyzed data from studies conducted by Steven Nissen, head of cardiology at the Cleveland Clinic, that used tiny ultrasound probes to measure the buildup of plaque in patients who were taking common cholesterol-lowering drugs called statins: Pravachol, Lipitor and Crestor. In some of the studies, they were also taking other medicines.

These statin drugs do a great job cutting LDL, the bad cholesterol that cakes up in arteries and then breaks off, causing heart attacks. But they’re pretty bad at raising HDL, boosting it on average 8%, compared with a 27% drop in bad cholesterol. However, the JAMA researchers found that patients with these little changes in HDL had less plaque in their arteries at the end of the study. The impact of the little HDL increase appears as important as that of the big LDL decrease.

AstraZeneca’s (nyse: AZN – news – people ) Crestor did best at boosting HDL; that could further boost Crestor, which after years of doldrums saw sales increase 60% to $2 billion. But the bigger lesson here is that HDL does seem to be important. That leaves cardiologists wondering what exactly went wrong with torcetrapib. Drug companies are probably fretting too: Merck (nyse: MRK – news – people ) and Roche have to decide what to do with their own torcetrapib-like compounds, which do not raise blood pressure as Pfizer’s did.

A lot will ride on data expected in March at the annual meeting of the American College of Cardiology in New Orleans. This data should give a better idea of torcetrapib’s blood pressure side effects. And Nissen will be presenting imaging data, much like that used in the JAMA analysis, of a study using torcetrapib.

If torcetrapib made “bad” HDL, the amount of plaque in patients’ arteries would increase. That would mean a stop for all other such medicines. If the drug worked, but had some other side effect, the amount of plaque in the arteries might decrease. But the data could be muddied—some of Nissen’s previous work indicates that increases in blood pressure can cause increases in the amount of plaque in arteries.

Waiting for torcetrapib is likely to draw more attention to the idea that good cholesterol can sometimes go bad. The idea that HDL can be dysfunctional has already been gaining ground. Stephen Nicholls, the Cleveland Clinic cardiologist who took the lead in reanalyzing this data, did a study in his last job, in Sydney, Australia, that indicated that a bad diet can actually make HDL less effective at its main job—cleaning cholesterol plaque out of the arteries.

One thing seems clear: the science of HDL, which might have seemed simple before, is looking increasingly complicated.