Why did a promising heart drug fail?

news@nature.com ^ | 6 December 2006 | Helen Pearson

[neverdem]

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Published online: 6 December 2006; | doi:10.1038/news061204-8

Why did a promising heart drug fail?

Doomed drug highlights complications of meddling with cholesterol.

Helen Pearson

High-density lipoproteins may be good for you, but at least one drug that acts on them is not.Hybrid Medical Animation / Science Photo Library

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.

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.

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."

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.

The only thing we know is dead in the water is torcetrapib.  Michael Miller, University of Maryland Medical Center.

Under pressure

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.

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.

Going up

Most researchers remain confident that elevating high density lipoproteins levels by one means or another is one of the best routes for helping heart disease patients. But HDLs are complex and not entirely understood.

One approved drug, called niacin, is known to both raise HDL and reduce cardiovascular risk but also causes an unpleasant sensation of heat and tingling. Researchers are exploring whether they can bypass this side effect and whether niacin can lower disease risk more than statins alone.

Scientists are also working on several other means 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 Medical Center, Baltimore.

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[spanalot]

what spiraling heart disease? it is way down since the 60's

[kinoxi]

At least they are heeding the trial's failures and ending it (torcetrapib).

[Brad’s Gramma]

No kidding they should be stopping this! We just found out that the study Gramps was in....involved this very drug.

He has an appointment next week to find out if he has any health problems due to this.

Rains. Pours.

[kinoxi]

Best wishes concerning his appointment.

[operation clinton cleanup]

One approved drug, called niacin, is known to both raise HDL and reduce cardiovascular risk but also causes an unpleasant sensation of heat and tingling. Researchers are exploring whether they can bypass this side effect and whether niacin can lower disease risk more than statins alone.

I thought Niacin was a vitamin, not a drug.

[Brad’s Gramma]

Thanks....we're sorta kinda hoping and praying he was on the placebo ourselves...

[kinoxi]

I've heard sporadic references to companies trying to (and succeeding) patent DNA, so why not vitamins?

[Brad’s Gramma]

http://blogs.nature.com/news/blog/2006/12/why_did_a_promising_heart_drug.html


All you ever needed to know about niacin and then some.

Maybe. :)

It's a link off of the above link provided by the poster of this thread.

[Revolting cat!]

Best wishes.

By the way, you're a Gramma and your Gramps is still kicking? Wow! Are you Filipino? (I've known a Filipino of 36 who was a gramma and her own gramma was still around (she told me: "Eh, no big deal!")

[hosepipe]

[ I thought Niacin was a vitamin, not a drug. ]

Shuuush.. Don't make "them" mad or they will make food a drug and we will need a script to get any..

[Brad’s Gramma]

Me=Grammie.
Husband=Gramps.

Silly goose.

HOWEVER! My father, who is 85...one of HIS AUNTS is still alive and well, thank you very much! ;)

[Balding_Eagle]

How did they rope him in to that?

Didn't they tell him that ANY drug trial, by it's very nature is outside the normal parameters?

[Brad’s Gramma]

I honestly can't answer that because I don't know...

[operation clinton cleanup]

Thanks! I think I will stock up on Vitamin B-3 (Niacin) before it is declared a drug.

[neverdem]

I thought Niacin was a vitamin, not a drug.

When it's used in physiologic doses, it's a vitamin. But when you use it in pharmacologic doses, it's working as a drug.

[Brad’s Gramma]

Could you either type that in English or very slowly for the mentally challenged?

:)

WHAT did you just say??????

[Sloth]

If this is really the problem:

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.

...then hopefully the effects would go away pretty soon after getting off the drug.

[Hildy]

I always wondered why they didn't do this earlier. I have an unusual situation where my cholesteral is REALLY high...like 240. But my good cholesterol is SO HIGH that it negates the bad cholesterol. Doctors are always surprised by how high the good is...it's hereditary. My Mom had it too. One of the few good health things I got from my Mom!

[Hildy]

I always wondered why they didn't do this earlier. I have an unusual situation where my cholesteral is REALLY high...like 240. But my good cholesterol is SO HIGH that it negates the bad cholesterol. Doctors are always surprised by how high the good is...it's hereditary. My Mom had it too. One of the few good health things I got from my Mom!