Cholesterol as hero

LIKE a kind of pharmaceutical Drano, drugs that increase levels of the so-called good, or HDL, cholesterol may soon be able to clear our blood vessels of artery-clogging gunk. About half a dozen HDL-raising treatments are at various stages of development, and if any of them prove effective, they could revolutionize heart disease treatment the same way that cholesterol-lowering statins did nearly two decades ago.

“Boosting HDL ... is the next frontier in heart disease prevention,” says Dr. Prediman K. Shah, director of cardiology at Cedars-Sinai Medical Center in Los Angeles. “If these drugs work, we potentially could reduce the number of heart attacks and strokes by 80% to 90%, and save millions of lives.”

HDL (high-density lipoprotein) is the form in which cholesterol is shuttled from the arteries and dumped in the liver for disposal. Doctors have long known that people with higher HDL levels suffered fewer heart attacks, but they weren’t sure if raising HDL could reduce the ravages of heart disease and actually prolong life.

That all changed in 2003 with the publication of a study in the Journal of the American Medical Assn. that electrified scientists. In it, 47 patients were given injections of a substance called ApoA-1 Milano. The drug is a synthesized version of a supercharged form of HDL found naturally in residents of a tiny village in Northern Italy. (These villagers are unusual because they have low levels of HDL cholesterol, normally a cardiovascular risk factor, yet have low rates of heart disease.)

After one infusion a week with ApoA-1 Milano for five weeks, the buildup of plaque in the participants’ arteries shrank by about 4%.

“People were shocked by the results because it was the first time a therapy had actually reversed heart disease,” says Dr. Steven Nissen, a cardiologist at the Cleveland Clinic in Ohio who conducted this research. Larger human tests of ApoA-1 Milano are being planned.

Cedars-Sinai Medical Center researchers have taken this approach one step further and injected the ApoA-1 Milano gene into the bone marrow of mice. After 20 weeks, the animals experienced up to a 65% reduction in plaque buildup. The treatment appears to be long-lasting: Once the gene is inside the stem cells of the bone marrow, it seems to perpetually make copies of itself, leading to a steady supply of the ApoA-1 Milano HDL. “A one-time treatment might be enough to have a lifelong supply of the gene,” says Shah, who did this research.

Another drug of interest -- torcetrapib, an oral medication made by Pfizer Inc. -- works by blocking the transformation of HDL cholesterol to LDL. “Essentially, it prevents good cholesterol from becoming bad cholesterol,” says Charles Shear, who is in charge of torcetrapib’s clinical development for Pfizer Global Research and Development in New London, Conn.

In a 2005 study involving 80 patients with low HDL, those who received the drug had their HDL levels increase by an average of 50.3% compared with the placebo group over a period of eight weeks. In a second 2005 study of 493 volunteers, those who took torcetrapib along with the statin drug Lipitor raised their HDL by 52% to 65%, and lowered their bad, or LDL, cholesterol by 41% to 60%.

Torcetrapib is in the final phase of clinical trials of more than 25,000 patients. Pfizer declined to predict how soon it could be available to consumers.

“These drugs are extraordinarily promising, and potentially could actually reverse heart disease,” Nissen says. “But it will take several more years of hard work to move this forward.”

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Giving the good numbers a nudge

There are other ways of boosting HDL, which should be more than 40 milligrams per deciliter for men, and more than 50 for women.

Regular aerobic exercise for at least 30 minutes most days of the week can raise HDL by 3% to 9%. Quitting smoking nudges HDL numbers by up to 4 milligrams per deciliter. Eating a Mediterranean-style diet (one rich in fruits, vegetables, fish and poultry, and low in red meat and saturated fats) helps too. And so does curbing one’s intake of carbs that increase blood sugar, such as those found in cereals, white bread, potatoes and snack food.

Prescription niacin (nicotinic acid or vitamin B3) can also increase HDL by 20% to 35%, although it can cause side effects such as hot flashes, itching and stomach upset. Finally, the cholesterol- lowering drugs known as fibrates (such as Lopid) can raise HDL by 10% to 25%, while statins boost levels only 2% to 15%.