New Ally Against Heart Disease

By Christine Gorman

Madelon Fuller's childhood memories of Waxahachie, Texas (pop. 18,560), include chasing fireflies, catching crawdads and eating plenty of fried okra, gravy-soaked chicken-fried steak and eggs. Not surprisingly, Fuller's cholesterol level went into orbit -- 324 mg per 100 ml of blood, in contrast to an optimal level of 200 mg -- and by age 44 she had had triple-bypass surgery. She went on a restrictive diet, and her cholesterol level plunged. But her arteries were still choking. Early this year her doctor suggested adding an experimental drug called lovastatin to her regimen. Within four months the magic number was 156 mg. Says Fuller, now 54, of the drug: "I really believe that it's saving my life."

Last week the Food and Drug Administration gave its approval to lovastatin. The move will give millions of Americans a potent new ally in their battle against heart disease, the nation's No. 1 killer. Developed and manufactured by Merck & Co., the New Jersey-based pharmaceutical giant, the drug will be ) marketed under the trade name Mevacor. It is the first of a new class of compounds specifically designed to control cholesterol production. Says Scott Grundy, director of the Center for Human Nutrition at the University of Texas Health Science Center at Dallas: "This is the first practical treatment for very high cholesterol levels."

The search for a new anticholesterol drug began in Japan. Akiro Endo, a scientist with the pharmaceutical firm Sankyo, wondered whether soil molds that kill cholesterol-containing bacteria might have evolved the ability to block cholesterol synthesis. In 1976, after testing 10,000 compounds, Endo found one that inhibited a key enzyme in the cholesterol-manufacturing process. Researchers at Merck soon discovered similar compounds, including lovastatin, but the finds would have remained research oddities without the Nobel-prizewinning work of UTHSCD's Joseph Goldstein and Michael Brown.

The pair spent much of the 1970s painstakingly deciphering how the body regulates cholesterol levels. Just as oil and water cannot mix without a detergent, cholesterol cannot enter the bloodstream unless it is ferried within a complex of molecules called low-density lipoprotein, or LDL. The Texas researchers found that the LDL ferries travel to docks called LDL receptors. More important, they learned that low cholesterol levels in the liver trigger the production of more receptors, which pull LDL out of the blood. But if the liver does not make enough receptors, the LDL levels in the blood will rise. The trick, Goldstein and Brown theorized, was to stimulate the receptors, thus reducing cholesterol levels.

They thought that a compound like lovastatin might do the job. Working with Grundy and David Bilheimer, another UTHSCD researcher, they tried it in 1982 on six patients. Within a few weeks, blood-cholesterol levels had dropped from an average of 350 to 250. Furthermore, the drug actually boosted the amount of high-density lipoprotein (HDL), a natural substance that seems to scavenge excess cholesterol out of the bloodstream. "That study really opened people's eyes," recalls Grundy.

Merck proceeded to develop lovastatin in earnest. Over the next four years the drug was tested on 750 people. Result: their LDL levels dropped by 19% to 39%. Although other drugs, such as cholestyramine and nicotinic acid, can reduce cholesterol levels significantly, they seem to work best on people whose levels are not very high. Lovastatin's greater effectiveness, Grundy explains, lies in its ability to inhibit cholesterol production in the liver, preventing further arterial blockage.

Drugs, however, are not a substitute for diet and exercise, warns Ira Goldberg, an endocrinologist at Columbia-Presbyterian Medical Center in New York City. He has already uncovered backsliders among his lovastatin patients. "We saw a couple of people whose cholesterol levels had gone down 30% to 40% but then started creeping back up." Doctors are concerned that lifelong use of lovastatin, which could cost $1,000 or more a year, may cause some people to develop cataracts or liver problems. "The real test will be the next few years, when a lot of people are taking the drug," says UTHSCD's Brown. "Will there be unexpected side effects, and will we begin to see a drop in heart attacks?"

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CREDIT: TIME Diagram by Joe Lertola

CAPTION: Cholesterol produced in the liver can collect in the arteries, contributing to blockage.

DESCRIPTION: Color illustration shows how arteries can get clogged up by cholesterol.

CHART: TEXT NOT AVAILABLE

CREDIT: TIME Diagram by Joe Lertola

CAPTION: The new drug inhibits cholesterol production, reducing excess in the bloodstream.

DESCRIPTION: Color illustration shows how new drug lovastatin inhibits cholesterol production.