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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[Brad’s Gramma]

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!!!

[neverdem]

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

[Quix]

Thx

[uncbob]

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

[kinoxi]

Dietary changes should be tried first, always IMO.

[Arizona Carolyn]

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.

[neverdem]

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

[uncbob]

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

[William Tell]

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.

[Arizona Carolyn]

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...

[uncbob]

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

[Arizona Carolyn]

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

[uncbob]

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