HDL developments good news for heart

Therapies: Researchers are creating ways to boost "good cholesterol," which, if successful, could drastically cut heart disease.

Medicine & Science

November 24, 2003|By David Kohn | David Kohn,SUN STAFF

For hearts and blood vessels, HDLs are knights in shining armor.

Better known as "good" cholesterol, these high-density lipoproteins clear the plaque stuck to artery walls by low-density lipoproteins (LDLs), the "bad" cholesterol.

Since the 1970s, doctors have known that the battle between these biomolecular adversaries can determine life or death. But while researchers have come up with powerful medicines to lower LDL, they have had little luck with drugs to increase HDL.

FOR THE RECORD - An article in Monday's editions of The Sun on new cholesterol drugs incorrectly stated that high doses of vitamin B6 can increase the body's levels of high-density lipoproteins (HDL). Large doses of B6 do not increase HDL and can cause nerve damage. High doses of vitamin B3 can boost HDL levels.
The Sun regrets the error.

Now, after more than a decade of work, scientists are unraveling HDL's secrets and developing a variety of HDL-boosting drugs and therapies. If they are successful, these advances could drastically cut heart disease, which kills half a million Americans each year.

Of almost 13 million people in the United States with heart ailments, more than half don't have enough HDL, according to University of Pennsylvania cardiologist Dr. Daniel Rader. He called low HDL a key untreated risk.

"HDL is the next frontier for heart disease," said Dr. P.K. Shah, director of cardiology research at Cedars Sinai Hospital in Los Angeles. Since 1992, Shah has been experimenting with a type of HDL that seems to be particularly good at removing cholesterol from artery walls.

Doctors discovered this HDL variant two decades ago in the blood of an Italian villager. Although the man had very low levels of HDL, he also had no sign of cardiovascular disease. It turned out that his HDL particles were larger than normal, an attribute that seemed to improve their ability to cart off cholesterol.

Eventually, Shah succeeded in creating a synthetic version of this jumbo HDL and began testing it on animals. Known as ETC-216, the compound reduced arterial plaque in mice and rabbits.

Last year, Esperion Therapeutics, a small Michigan biotech company, funded a study of ETC-216. Researchers tried it on a group of 47 people who had recently suffered heart attacks. After five injections over five weeks, the drug reduced their plaque by 4 percent.

"It doesn't sound like a lot, but that's several years worth of plaque," said the study's lead author, Dr. Steven Nissen, a cardiologist at the Cleveland Clinic. "We were pretty astonished at how much plaque had been removed."

Not everyone is so gung-ho about the results. "It's a small study, and it has to be duplicated," said Dr. Roger Blumenthal, director of the Johns Hopkins University Preventative Cardiology Center. He called the 4 percent plaque decrease "modest."

Esperion, is planning a larger, longer trial with ETC-216. If all goes well, Nissen says, the drug could be on the market by 2007.

But that's not Shah's only HDL project. He is also working with the gene that produces the jumbo HDL molecule. He has successfully inserted this variant DNA into mice, whose bodies then produced a continuous flow of powerhouse HDL. In these mice, the extra HDL rapidly reduced plaque, he said.

The advantage of this approach is convenience: A single injection of the gene could increase the body's plaque-fighting capacity for a lifetime. Shah plans to talk with the Food and Drug Administration and other agencies about testing HDL gene therapy on humans, and hopes to begin clinical trials within three years.

If safe and effective, these HDL boosters could offer key advantages over current drugs. Today, doctors generally treat cholesterol problems with statins, a class of drugs that work by decreasing LDL levels. Although they stop plaque buildup, they usually don't get rid of existing deposits. HDL therapies seem more effective at removing plaque.

"Statins have been the best thing that we've ever had in cardiovascular disease. They've reduced mortality by a third. That's fantastic, but it still means that two-thirds of mortality remains," said UCLA cardiologist Dr. Alan Fogelman, who along with several colleagues has developed a synthetic version of HDL.

Unlike natural HDL, their invention, D4F, isn't destroyed by digestive enzymes, which means it can be taken orally.

In tests on mice, D4F lowered plaque by 75 percent in six weeks. Fogelman, who calls the results "dramatic," hopes to begin human trials next summer. "We're a long way from mice to humans," he said. "But if you're a mouse, we can prevent your atherosclerosis."

Major drug companies also are developing HDL boosters. Pfizer, for example, is working on a drug that inhibits production of cholesterol ester transfer protein (CETP), a chemical that breaks down HDL particles. The company has started a large human trial of the compound, known as torcetrapib. It plans to combine the drug with a statin, creating a one-two punch that simultaneously raises HDL and lowers LDL.

Others are also experimenting with CETP blockers. A Massachusetts company, Avant Immunotherapeutics, recently finished a small human trial on a vaccine that triggers an anti-CETP immune reaction.

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