1. The failure of a high-profile cholesterol drughas thrown a spotlight on the complicatedmachinery that regulates cholesterol levels. Butmany researchers remain confident that drugs toboost levels of ’good’ cholesterol are still one of themost promising means to combat spiralling heartdisease.

2. Drug company Pfizer announced on 2December that it was cancelling all clinical trials oftorcetrapib, a drug designed to raise heart-protective high-density lipoproteins (HDLs). In atrial of 15000 patients, a safety board found that more people died or suffered cardiovascularproblems after taking the drug plus a cholesterol-lowering statin than those in a control groupwho took the statin alone.

3. The news came as a kick in the teeth to many cardiologists because earlier tests inanimals and people suggested it would lower rates of cardiovascular disease. "There have beenno red flags to my knowledge," says John Chapman, a specialist in lipoproteins andatherosclerosis at the National Institute for Health and Medical Research (INSERM) in Paris whohas also studied torcetrapib. "This cancellation came as a complete shock."

4. Torcetrapib is one of the most advanced of a new breed of drugs designed to raiselevels of HDLs, which ferry cholesterol out of artery-clogging plaques to the liver for removalfrom the body. Specifically, torcetrapib blocks a protein called cholesterol ester transferprotein (CETP), which normally transfers the cholesterol from high-density lipoproteins to lowdensity, plaque-promoting ones. Statins, in contrast, mainly work by lowering the ’bad’ low-density lipoproteins.

Under pressure

5. Researchers are now trying to work out why and how the drug backfired, something thatwill not become clear until the clinical details are released by Pfizer. One hint lies in evidencefrom earlier trials that it slightly raises blood pressure in some patients. It was thought thatthis mild problem would be offset by the heart benefits of the drug. But it is possible that itactually proved fatal in some patients who already suffered high blood pressure. If bloodpressure is the explanation, it would actually be good news for drug developers because itsuggests that the problems are specific to this compound. Other prototype drugs that arebeing developed to block CETP work in a slightly different way and might not suffer the samedownfall.

6. But it is also possible that the whole idea of blocking CETP is flawed, says Moti Kashyap,who directs atherosclerosis research at the VA Medical Center in Long Beach, California. WhenHDLs excrete cholesterol in the liver, they actually rely on LDLs for part of this process. Soinhibiting CETP, which prevents the transfer of cholesterol from HDL to LDL, might actuallycause an abnormal and irreversible accumulation of cholesterol in the body. "You’re blocking aphysiologic mechanism to eliminate cholesterol and effectively constipating the pathway,"says Kashyap. Going up

7. Most researchers remain confident that elevating high density lipoproteins levels by onemeans or another is one of the best routes for helping heart disease patients. But HDLs arecomplex and not entirely understood. One approved drug, called niacin, is known to both raiseHDL and reduce cardiovascular risk but also causes an unpleasant sensation of heat andtingling. Researchers are exploring whether they can bypass this side effect and whether niacincan lower disease risk more than statins alone. Scientists are also working on several othermeans to bump up high-density lipoproteins by, for example, introducing synthetic HDLs. "The only thing we know is dead in the water is torcetrapib, not the whole idea of raising HDL,"says Michael Miller, director of preventive cardiology at the University of Maryland MedicalCenter, Baltimore.