★Why did a promising heart drug fail ？

    Doomed drug highlights complications of meddling with cholesterol.

    1.The failure of a high-profile cholesterol drug has thrown a spotlight
on the complicated machinery that regulates cholesterol levels.But many
researchers remain confident that drugs to boost levels of 'good' cholesterol
are still one of the most promising means to combat spiralling heart disease.

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

    3.The news came as a kick in the teeth to many cardiologists because
earlier tests in animals and people suggested it would lower rates of
cardiovascular disease."There have been no red flags to my knowledge，
" says John Chapman ，a specialist in lipoproteins and atherosclerosis
at the National Institute for Health and Medical Research （INSERM） in
Paris who has 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 raise levels of HDLs，which ferry cholesterol out of artery-clogging
plaques to the liver for removal from the body.Specifically ，torcetrapib
blocks a protein called cholesterol ester transfer protein（CETP），which
normally transfers the cholesterol from high-density lipoproteins to low
density ，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 that will not become clear until the clinical details are released
by Pfizer.One hint lies in evidence from earlier trials that it slightly
raises blood pressure in some patients.It was thought that this mild problem
would be offset by the heart benefits of the drug.But it is possible that
it actually proved fatal in some patients who already suffered high blood
pressure.If blood pressure is the explanation ，it would actually be good
news for drug developers because it suggests that the problems are specific
to this compound.Other prototype drugs that are being developed to block
CETP work in a slightly different way and might not suffer the same downfall.

    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.When HDLs excrete cholesterol
in the liver，they actually rely on LDLs for part of this process.So inhibiting
CETP，which prevents the transfer of cholesterol from HDL to LDL，might
actually cause an abnormal and irreversible accumulation of cholesterol
in the body."You're blocking a physiologic mechanism to eliminate cholesterol
and effectively constipating the pathway，" says Kashyap.

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