Next big thing in heart disease: clean-out pills
By DANIEL Q. HANEY, AP Medical Editor February 03, 2004
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Heart researchers may be closing in at last on a long-fantasized goal - treatments that flush out the nasty globs of gunk that clog the heart's plumbing.
This idea goes beyond merely preventing new coronary artery disease. The intention is to actually clear away what's already there, to clean up the source of heart attacks before they happen.
Ideally, the human body already does this on its own, and the new medicines are intended to enhance the natural artery cleansing process. If testing goes as scientists hope, the strategy could prove to be as important for preventing heart disease as the cholesterol-lowering statin drugs introduced in the late 1980s.
"If it works, we are talking about the potential of reducing cardiac events by 50 or 60 percent or more," says Dr. Steven Nissen of the Cleveland Clinic. "We are talking about really controlling the disease."
Nissen is working with about a half dozen of these drugs, and it is too soon to know which of these and others in the pipeline will eventually make it into drug stores. But when they arrive - and many researchers seem confident some will - the medicines are likely to become part of a heart-protecting cocktail of medicines doctors envision to increase good cholesterol, lower the bad variety and reduce bloodstream inflammation.
The new drugs boost high-density lipoproteins - HDL. This is the friendly half of cholesterol's yin and yang, often outgunned by its evil counterpart, LDL.
The interest in HDL is a big shift in attention for the field of heart disease prevention. Ever since the arrival of statins, its main preoccupation has been reducing LDL, which carries in the cholesterol that clogs the arteries.
The statins' benefits have been impressive, even though cardiovascular disease remains the world's biggest killer. They cut LDL in half, which helps stabilizes the disease and reduce heart attacks and deaths by one-quarter to one-third.
"To an optimist, that's terrific," says Dr. Prediman Shah, cardiology chief at Cedars-Sinai Medical Center in Los Angeles. "But the glass is still two-thirds empty. To contain the continuing ravages of this disease, there has to be something else."
He and many other believe that something is HDL. In its garbage truck role, HDL scoops up cholesterol from the arteries and carries it back to the liver for disposal.
Doctors' have suspected its importance since the 1970s. Studies that follow people through life show the higher one's HDL, the lower the risk of heart attacks. Each single point of increase is matched by a two percent to three percent reduction in heart disease.
In the United States, men's average HDL is about 45 and women's is 55. HDL under 40 is an especially bad sign, while anything over 60 is considered good. Those with HDL over 75 may even be blessed with what's called the "longevity syndrome."
"Just like your LDL can't be too low, your HDL can't be too high," says Dr. Lori Mosca, head of preventive cardiology at Columbia University. "I have patients with HDL over 120, and I tell them that's probably how long they will live."
Such off-the-chart amounts result from good genes, not healthy habits. For most people, budging HDL upward is difficult, although exercising, losing weight, drinking modestly, and quitting smoking can all help.
Attacking heart disease with HDL has been slow to take hold, in part because of skimpy evidence this tinkering will make a difference. Even though people with high HDL tend to have healthy hearts, that does not prove raising everyone else's HDL will save lives. Some animal studies and other research suggest it will, but "there has not been an enormous amount of data to support the HDL-raising effect, in large part because there was not enough financial interest in it," says Dr. Harvey Hecht, head of preventive cardiology at New York City's Beth Israel Medical Center.
Until recently, the only pills that raised HDL even modestly were generic or over the counter. The best of them, niacin, is a vitamin. Without exclusive rights, drug companies have no incentive to prove such compounds work.
"We know lowering LDL saves lives. Now we need to know if raising HDL adds to that," Dr. Jennifer Robinson, a University of Iowa epidemiologist.
For many skeptics, though, the doubts began to fade last fall with the publication of a remarkable study. The story began in the early 1980s, when researchers discovered a man in the northern Italy village of Limone sul Garda who had very low HDL but no sign of cardiovascular disease. Blood tests revealed about 40 more villagers with the same peculiarity. All traced their origins to a common ancestor born in 1780.
Eventually it was discovered these people carry a slightly unusual version of the main protein that makes up their HDL. Researchers called this ApoA-I Milano and wondered if it might be a supercharged version of HDL. In the first of many animal studies, Shah injected the protein into rabbits with clogged arteries. It quickly cleared them out.
Researchers still argue over whether ApoA-I Milano is a better artery cleaner than the normal version, but it hardly matters. The ordinary kind cannot be patented, so it will never be developed as a drug, but the newly discovered mutant could be. The biotech firm that owns the rights, Esperion Therapeutics, sponsored a pilot study in people.
When the results were released in November, heart specialists were simply astonished. Artery clogging in people takes decades, so many assumed reversing it would be a slow business, too. But after just five weekly infusions, the volunteers' artery buildups had actually regressed about 4 percent. Nothing like this had ever been seen before.
"Many of us didn't believe it would do anything," says Dr. Michael Miller, head of preventive cardiology at the University of Maryland. "The big surprise is that it happened within such a short time. It's unbelievable."
Still, the study was small, involving just 47 patients. Years more testing will be needed to prove the treatment truly safe and effective. Even then, it will have to be given by intravenous infusion, probably making it unrealistic for lifelong use. Instead, doctors envision giving it for a month or two to quickly clean up patients' arteries, a treatment that Esperion head Roger Newton estimates will cost between $2,000 and $4,000.
The results set off a frenzy among drug companies, said Nissen, who directed the study, all searching for a more practical pill version of the drug. However,the next HDL pill is likely to be an entirely different variety of medicine.
These drugs, being developed by several companies, work by blocking a protein that allows HDL to give away its cholesterol. HDL ordinarily hauls much of its load back to the liver, but it also hands off some of it to LDL, which in turn may cart it back to the artery walls, among other places. Shutting down this transfer can make HDL levels go up substantially.
The version furthest along is Pfizer's torcetrapib, which Nissen is testing in a two-year study on 886 volunteers. It increases HDL by 60 percent, but will it clean arteries and save lives?
Scientists are unsure. People who are naturally low in the cholesterol-transferring protein do not seem to be protected from heart disease, despite their high HDL. Notwithstanding its nasty reputation, LDL can actually be helpful at times by hauling some of its cholesterol load back to the liver. Some worry that blocking the transfer from HDL to LDL will thwart that housekeeping.
"That would be bad," says Dr. Daniel Rader, head of preventive cardiology at Presbyterian Medical Center in Philadelphia. "There is a lot of disagreement and uncertainty" over what will happen in people, even though the strategy works in rabbits.
Rader says the Holy Grail of HDL research is a drug that will stimulate the liver to make more HDL on its own, but progress is slow. Among other approaches:
- An experimental vaccine against the cholesterol-transferring protein raises HDL about 8 percent, but only in those not already on statins. Una Ryan, president of Avant Immunotherapeutics, said the twice yearly shots could be targeted at the estimated 21 million Americans with low HDL but normal LDL.
- Several companies are testing new versions of drugs called PPARs - for peroxisome proliferator-activated receptor - that also help direct cholesterol flow in the arteries. They raise HDL about 25 percent, lower triglycerides and improve the body's use of insulin. The medicines may prove especially useful for those at risk of diabetes.
- Shah hopes within the next year or two to try gene therapy to prompt the body to manufacture more HDL. His strategy: Insert large quantities of the gene that makes ApoA-I Milano, the HDL protein found in the Italian village, into volunteers' bone marrow. "The idea is to have a permanent supply from one single treatment."
Meanwhile, many specialists recommend more use of the HDL booster already on the market, the vitamin niacin. No one has convincingly proven niacin saves lives, but doctors say evidence from a smattering of studies suggests it may. High doses - typically two to three grams a day - can raise HDL about 25 percent and should only be taken under a doctor's supervision.
Niacin's main drawback is that it can cause unbearable flushing and itching, and about one-third of patients simply cannot stay on it. "If we had a niacin with no side effects, it probably would be much more widely used," says Dr. H. Bryan Brewer, chief of the molecular disease branch at the National Heart, Lung and Blood Institute.
Many experts say they are optimistic that at least some of the new HDL-raising strategies will work out, because it is a logical target with a potentially huge payoff.
"I liken it to Mark McGuire taking a big cut," says Dr. Christie Ballantyne, head of cardiovascular disease prevention at Methodist Hospital in Houston. "This could be a grand slam or it could be a strike out. But it's a bold approach."