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Why did a promising heart drug fail?
news@nature.com ^ | 6 December 2006 | Helen Pearson

Posted on 12/07/2006 7:01:34 PM PST by neverdem

news@nature.com - the best science journalism on the web Close window



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.

Visit our newsblog to read and post comments about this story.

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Story from news@nature.com:
http://news.nature.com//news/2006/061204/061204-8.html

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TOPICS: Business/Economy; Culture/Society; News/Current Events
KEYWORDS: cholesterol; health; healthcare; medicine

1 posted on 12/07/2006 7:01:38 PM PST by neverdem
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To: neverdem

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


2 posted on 12/07/2006 7:04:50 PM PST by spanalot
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To: neverdem

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


3 posted on 12/07/2006 7:04:53 PM PST by kinoxi
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To: StarCMC

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.


4 posted on 12/07/2006 7:07:03 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: Brad's Gramma

Best wishes concerning his appointment.


5 posted on 12/07/2006 7:11:50 PM PST by kinoxi
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To: neverdem
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.

6 posted on 12/07/2006 7:13:05 PM PST by operation clinton cleanup (Remember and pray for SSgt. Matt Maupin - MIA/POW- Iraq since 04/09/04)
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To: kinoxi

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


7 posted on 12/07/2006 7:15:29 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: operation clinton cleanup

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


8 posted on 12/07/2006 7:20:04 PM PST by kinoxi
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To: operation clinton cleanup

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.


9 posted on 12/07/2006 7:20:31 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: Brad's Gramma
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!")

10 posted on 12/07/2006 7:22:29 PM PST by Revolting cat! (Who invented rock and roll hiccups?)
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To: operation clinton cleanup
[ 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..

11 posted on 12/07/2006 7:24:49 PM PST by hosepipe (CAUTION: This propaganda is laced with hyperbole)
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To: Revolting cat!

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! ;)


12 posted on 12/07/2006 7:26:40 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: Brad's Gramma

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?


13 posted on 12/07/2006 7:31:32 PM PST by Balding_Eagle (God has blessed Republicans with political enemies who are going senile.)
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To: Balding_Eagle

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


14 posted on 12/07/2006 7:33:30 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: Brad's Gramma
Thanks! I think I will stock up on Vitamin B-3 (Niacin) before it is declared a drug.
15 posted on 12/07/2006 7:34:45 PM PST by operation clinton cleanup (Remember and pray for SSgt. Matt Maupin - MIA/POW- Iraq since 04/09/04)
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To: operation clinton cleanup
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.

16 posted on 12/07/2006 7:34:54 PM PST by neverdem (May you be in heaven a half hour before the devil knows that you're dead.)
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To: neverdem

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

:)

WHAT did you just say??????


17 posted on 12/07/2006 7:36:56 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: Brad's Gramma
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.

18 posted on 12/07/2006 7:38:51 PM PST by Sloth (The GOP is to DemonRats in politics as Michael Jackson is to Jeffrey Dahmer in babysitting.)
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To: spanalot

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!


19 posted on 12/07/2006 7:41:26 PM PST by Hildy ("Death plucks my ear and says - LIVE - I am coming.....")
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To: spanalot

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!


20 posted on 12/07/2006 7:41:29 PM PST by Hildy ("Death plucks my ear and says - LIVE - I am coming.....")
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To: Sloth

If that IS the case....he's been off of it for, dang, I don't know. A week? Two?

Thanks though, that IS helpful!!!


21 posted on 12/07/2006 7:50:04 PM PST by Bradís Gramma (Get right with God....eternity is a long time.....)
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To: El Gato; Ernest_at_the_Beach; Robert A. Cook, PE; lepton; LadyDoc; jb6; tiamat; PGalt; Dianna; ...
Some of you may need this definition to get a handle on the following linked article on alternative splicing and how cells decide to make proteins.

intron(in¡¤tron) (in¢¥tron) a noncoding intervening sequence in a gene; almost all eukaryotic genes contain several introns separating the coding sequences (exons). After the 5¡Ç cap and polyA tail are added to a primary mRNA transcript, the introns are removed and the exons spliced together by enzymes that recognize short sequences that identify exon-intron junctions, resulting in a mature mRNA that is ready for translation (protein synthesis). Called also intervening sequence.

Living view in animals shows how cells decide to make proteins

A Vote for Stem Cell Research

Study says malaria helps spread HIV abstract linked in comment# 40

22 posted on 12/07/2006 7:59:25 PM PST by neverdem (May you be in heaven a half hour before the devil knows that you're dead.)
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To: neverdem

Thx


23 posted on 12/07/2006 8:01:41 PM PST by Quix (LET GOD ARISE AND HIS ENEMIES BE SCATTERED. LET ISRAEL CALL ON GOD AS THEIRS! & ISLAM FLUSH ITSELF)
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To: kinoxi

You can increaseyou HDL and decrease the LDL through dietary changes

I used to have 195-200 total with 48-50 HDL

For the last 4 years I have been at 185 total 75 HDL


24 posted on 12/07/2006 8:09:46 PM PST by uncbob (m first)
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To: uncbob

Dietary changes should be tried first, always IMO.


25 posted on 12/07/2006 8:13:12 PM PST by kinoxi
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To: uncbob

How did you raise your HDL? My husband has great Cholesterol, LDL and Trigliceride levels, but we can't get his HDL out of the low to mid 30's. I will say he hates green anything so I do give him greens in the form of pills, and they help, but not enough.


26 posted on 12/07/2006 8:15:46 PM PST by Arizona Carolyn
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To: Brad's Gramma
Could you either type that in English or very slowly for the mentally challenged?

A balanced diet or multivitamin supplements provide a physiologic dose to maintain normal physiology. A pharmacologic dose to increase the HDL is much greater. That's why many patients complain of flushing. It's analogous to gunpowder. There's a little in a firecracker and a lot in a bomb. In a multivitamin you get 20 milligrams(mg) of niacin. For increasing HDL, they use 500 mg, 750 mg and 1000 mg pills

27 posted on 12/07/2006 8:23:42 PM PST by neverdem (May you be in heaven a half hour before the devil knows that you're dead.)
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To: Arizona Carolyn

First of all I jog and exerise regularly so that gave me a baseline of 48-50
Used to be on a low fat diet --non fat dressing on my salads etc

Stayed Low fat BUT Started using olive oil on my salads and bagel half That I dip as part of dinner

Did away with sugary cereals and switched to oat type with a scoop of high protein and non fat milk

Did away with white breads and use whole grain products
Used to use margaraine instead of butter until I learned about the Trans Fatty acids --Switched to Take Control/Benecol Light

Added at least a handful of nuts --Almonds cashews etc to my evening salads

Only eat meat about 4 times a week at dinner--pork trimmed--Ham steaks--90% lean hamburger on a George Foreman grill--Veal--White meat Turkey or Chicken

Other nights it is Shrimp--Salmon--Talapia

Rarely have cakes or pies or chips-nachos etc ( Exception is holidays etc)

Snack on Rice cakes --Sour Dough Pretzels -and very low fat ( no trans ) popcorn that I sprinkle Olive oil on

Couldn't believe the difference it made My tris range from 50-70

I guess I am one of the lucky ones that diet really works for

Others take Statins etc


28 posted on 12/07/2006 8:46:08 PM PST by uncbob (m first)
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To: Hildy
Hildy said: "But my good cholesterol is SO HIGH that it negates the bad cholesterol. "

I've heard of some Italians who were found to have very high cholesterol levels but no heart disease. They were being studied to find out if they might be a source of breakthrough treatments. I wonder how that's coming.

29 posted on 12/07/2006 8:48:01 PM PST by William Tell (RKBA for California (rkba.members.sonic.net) - Volunteer by contacting Dave at rkba@sonic.net)
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To: uncbob
George doesn't eat Statins.. we eat a healty diet, no trans-fats, we even make out own Healthy Butter with 1/2 almond oil and 1/2 butter. Cook with Olive Oil, very little of any breads, but if we do it's whole grain bread. His Cholesterol is only 156 and he does eat eggs every morning because he has a tendency to hypoglycemia bordering on diabetes(has a family history of diabetes)....

I cooked whole grain oats for his breakfast every day for a while and it didn't do anything and his blood sugar fluctuated too much and raised his trigliceride level. With eggs in the a.m. the appetite is holding better and the triglicerides came down.

The only thing that is whacky is the HDL and it may be heriditary (according to the doctor) due to family history of diabetes and heart disease...

30 posted on 12/08/2006 8:46:32 AM PST by Arizona Carolyn
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To: Arizona Carolyn

Sounds like he is doing every thing correct in his diet

I eat eggs 3 days a week at lunch with a big 5 egg omelet but I use the egg beater type product

I know jogging increases HDLs some

I guess it is just genetics in your husbands case

My brother --smoker ( since stopped ) fatty diet--no exercise had HDLs around 35 and had a heart attck with a double bypass at 60 --He is now on statins--watches his diet etc and his total is now 160-170 with good HDL readings in the 60s

I am 70 and have been jogging since I was 40 --quit smoking at 34


31 posted on 12/08/2006 10:46:49 AM PST by uncbob (m first)
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To: uncbob

My husband doesn't drink or smoke. Hasn't for 30 years.


32 posted on 12/08/2006 10:52:28 AM PST by Arizona Carolyn
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To: Arizona Carolyn

When brothers HDL was in the 30s his total was 260 so his LDLs were also very bad

Oh I forgot I don't drink either


33 posted on 12/08/2006 1:08:32 PM PST by uncbob (m first)
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