Questioning HDL
March 15, 2004
Scientists Begin to Question Benefit of 'Good' Cholesterol
By GINA KOLATA
For years, doctors have been saying that to prevent heart disease, patients should pay attention to both the so-called bad cholesterol, or L.D.L., and the good cholesterol, or H.D.L. The good, they said, can counteract the bad.
But now, some scientists say, new and continuing studies have called into question whether high levels of the good cholesterol are always good and, when they are beneficial, how much.
While some heart experts are not ready to change their treatment advice, others have concluded that H.D.L. should play at most a minor role in deciding whether to prescribe cholesterol-lowering drugs. In the meantime, doctors are calling researchers and asking what to do about patients with high H.D.L. levels, or what to do when their own H.D.L. levels are high, and patients are left with conflicting advice.
"There is so much confusion about this that it is unbelievable," said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic.
The good cholesterol hypothesis comes from studies like the Framingham Heart Study, which has followed thousands of people in Framingham, Mass., for decades to see who developed heart disease. The studies showed that if two people had the same levels of the bad cholesterol, L.D.L., but different levels of the good cholesterol, H.D.L., the one with more H.D.L. was less likely to have heart disease.
Researchers examining the biochemistry of the two molecules learned that they have opposite roles. Both transport cholesterol, the fatty substance used to make cell membranes and some hormones, but they carry it in opposite directions.
L.D.L. ferries cholesterol to coronary arteries, where it imbeds and participates in the growth of plaque. H.D.L. takes cholesterol away from arteries to the liver, where it is disposed of.
So with epidemiological studies showing reduced heart disease risk and science showing why, it would seem the picture was clear: the more H.D.L. the better. One H.D.L. molecule might even cancel one of L.D.L.
Too simplistic, says Dr. Daniel Rader, a cholesterol researcher at the University of Pennsylvania School of Medicine. "Yes, high H.D.L. is generally a good thing, but it doesn't mean it is so powerful that it creates a total immunity to heart disease," he said.
Dr. Rader and others say, for example, that there are people who have high levels of H.D.L., but the H.D.L. does not function properly. Instead of being protected from heart disease, these patients may be particularly vulnerable. A simple H.D.L. measurement does not reveal whether a person's high level is good or bad.
Cholesterol researchers say that every clinic has patients with high levels of H.D.L. who ended up with heart disease. The average H.D.L. level for men is 40 to 50 milligrams per deciliter of blood and for women 50 to 60. But, even when H.D.L. levels are much higher, "the L.D.L. can overpower the H.D.L.," said Dr. Christie Ballantyne of Baylor College of Medicine.
Many are like 60-year-old Thomas E. Siko of Chagrin Falls, Ohio, who thought he had nothing to worry about. Heart disease runs in his family on both sides, but no doctor had ever suggested cholesterol-lowering medication. His H.D.L. level was high, at 72, and his L.D.L. only mildly elevated, at 121. (National guidelines say that an L.D.L. level of less than 100 is optimal; 100 to 129 is near or above optimal, depending on other factors; and above 130 is high.)
But last year, after being tested for what he thought was indigestion, Mr. Siko ended up having bypass surgery. Now, with a cholesterol-lowering statin, his L.D.L. level is down to 72 while his H.D.L. is 70. He feels fine. "I run four miles a day," Mr. Siko said.
Part of the confusion arises from an evolving view of the immense importance of reducing L.D.L. levels. Two recent studies, one announced last week, the other published the week before, found that ultra-low levels of L.D.L., down to the 60's or 70's, can protect heart patients from plaque growth in their arteries and from heart attacks and deaths. That raised questions among many doctors and patients of whether their own L.D.L. levels really were optimal and whether their good cholesterol really was canceling out the bad.
Dr. Rader is leading a large study on genetic variations causing high H.D.L. that is trying to sort the question out. But for now he says, "I really don't feel that treatment for high L.D.L. should be withheld just because the H.D.L. level is high."
Instead, Dr. Rader puts high H.D.L. levels to the side and looks at L.D.L. and other risk factors, like a family history of heart disease. If L.D.L. levels and other risk factors tell him to treat, he prescribes L.D.L.-lowering medication. If he is undecided, he brings the high H.D.L. levels back into the picture, allowing them to push him toward or away from treatment.
Dr. Bryan Brewer, chief of the molecular disease branch of the National Heart, Lung and Blood Institute, said no one should ignore high levels of L.D.L. "If you have a high L.D.L. level you should be concerned about it, independently of your H.D.L. You are still at risk," he said.
Dr. Nissen says he focuses on L.D.L. so much that he mostly discounts H.D.L. in deciding whether to give cholesterol-lowering drugs to patients with heart disease or to those with high L.D.L. levels and other risk factors like high blood pressure or a family history of heart disease. He notes that statins are safe drugs that reduce L.D.L. levels and that study after study has shown that lowering L.D.L. prevents heart attacks and deaths.
He says that recent research bears him out. His study, published this month in the Journal of the American Medical Association, looked directly at the accumulation of plaque in coronary arteries when heart patients took cholesterol-lowering drugs. Their H.D.L. levels, he said, played no role in plaque growth; the only thing that mattered was what happened to L.D.L. When L.D.L. levels dropped, plaque growth slowed. That means, Dr. Nissen concludes, that the benefit of lowering L.D.L. is the same whether H.D.L. levels are high or low.
Others have different views on how to weigh H.D.L. in treatment decisions. Many, like Dr. Alan Garber, a professor of internal medicine at Stanford, look at overall risk. The starting place, he says, is assessing how likely it is that people will have heart attacks, given everything known about their L.D.L. and H.D.L. levels, their blood pressure, their family history and whether they smoke or have diabetes.
Dr. Garber said that with data from recent studies, it looked increasingly safe to treat high L.D.L. levels and ignore other factors. But, he said, "that's not the way I would do it." One concern is that people who are otherwise at low risk for heart disease would gain little by taking drugs to reduce their L.D.L. levels but would spend years paying for the drugs, which can cost $100 a month.
Dr. David Waters, of the University of California at San Francisco, also looks at overall risk, but lets a high H.D.L. level counteract one of the other predisposing factors to heart disease in deciding who needs to take drugs to lower L.D.L. levels.
With different doctors using such different reasoning, doctors and patients say they can be frustrated and confused about what to do.
Dr. Christopher Cannon of Brigham and Women's Hospital in Boston needed advice for his mother. Her H.D.L. was above 100, which is very high, but her L.D.L. was 160, also high. Last year, he called Dr. Rader, who said that because Dr. Cannon's mother's only risk factor for heart disease was her L.D.L., he did not advise treatment.
But now, new studies, including one reported last week by Dr. Cannon and his colleagues, are indicating that people might do much better with much lower levels of L.D.L. He looked over his own data and said it showed people with high H.D.L. levels got the same benefit from driving their L.D.L. very low as people whose H.D.L. was low or normal. So, he says, he will be calling Dr. Rader again. "It's time for a reassessment," he said.
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