But now some prominent cardiologists say the results of two recent clinical trials have raised serious questions about that theory -- and the value of two widely used cholesterol-lowering medicines, Zetia and its sister drug, Vytorin. Other new cholesterol-fighting drugs, including one that Merck hopes to begin selling this year, may also require closer scrutiny, they say.
''The idea that you're just going to lower LDL and people are going to get better, that's too simplistic, much too simplistic,'' said Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif. LDL, or low-density lipoprotein, is the so-called bad cholesterol, in contrast to high-density lipoprotein, or HDL.
For patients and drug companies, the stakes are enormous. Led by best sellers like Lipitor from Pfizer, cholesterol-lowering medicines, taken by tens of millions of patients daily, are the largest drug category worldwide, with annual sales of $40 billion.
Despite widespread use of the drugs, though, heart disease remains the biggest killer in the United States and other industrialized nations, and many people still have cholesterol levels far higher than doctors recommend.
As a result, drug companies are investing billions of dollars in experimental new cholesterol-lowering medicines that may eventually be used alongside the existing drugs. If the new questions result in slower approvals, it would be yet another handicap for the drug industry.
Because the link between excessive LDL cholesterol and cardiovascular disease has been so widely accepted, the Food and Drug Administration generally has not required drug companies to prove that cholesterol medicines actually reduce heart attacks before approval.
They have not had to conduct so-called outcome or events trials beforehand, which are expensive studies that involve thousands of patients and track whether episodes like heart attacks are reduced.
So far, proof that a drug lowers LDL cholesterol has generally been enough to lead to approval. Only then does the drug's maker begin an events trial. And until the results of that trial are available, a process that can take several years, doctors and patients must accept the medicine's benefits largely on faith.
''You've got a huge chasm between F.D.A. licensure and a clinical events trial,'' said Dr. Allen J. Taylor, the chief of cardiology at Walter Reed Army Medical Center.
Nonetheless, the multistep process has worked well for several cholesterol drugs -- including Lipitor and Zocor, which are in a class of drugs known as statins. In those cases, the postapproval trials confirmed that the drugs reduce heart attacks and strokes, adding to confidence about the link between cholesterol and heart disease.
Doctors generally believe that the amount by which cholesterol is lowered, not the method of lowering it, is what matters.
That continues to be the assumption of Dr. Scott M. Grundy, a professor of medicine at the University of Texas Southwestern Medical Center who was the chairman of a panel in 2001 that set national guidelines for cholesterol treatment.
''LDL lowering, however it occurs, delays development of coronary atherosclerosis and reduces risk for heart attack,'' Dr. Grundy said this week. In atherosclerosis, plaque builds up in the arteries, eventually leading to blood clots and other problems that cause heart attacks and strokes.
