Overdosed America (21 page)

The picture that emerges is so contrary to the faith that we doctors place in the process of how medical science gets translated into clinical practice that it may be hard for most doctors to believe. But it’s true: the majority of participants in the formulation of clinical guidelines have active financial relationships with companies manufacturing the very drugs that are being decided upon.

In 2001
, the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults issued perhaps the most influential document in the history of modern American medicine. Written as part of the National Cholesterol Education Program, the updated guidelines incorporated the findings of the most recent clinical trials into concise recommendations designed to assist doctors in reducing their patients’ risk of developing coronary heart disease (CHD). The recommendations are bold and offer the tantalizing hope that coronary heart disease in all but the very old will become a far less common occurrence. This goal can be reached, according to the guidelines, by increasing the number of Americans taking statin drugs, from 13 million to 36 million.

The new recommendations call for doctors to measure adult patients’ cholesterol and triglyceride levels every five years. A two-step assessment of risk is then suggested: First, “major risk factors” are identified, including cigarette smoking, high blood pressure, low HDL (good) cholesterol (less than 40 mg/dL), a strong family history of coronary heart disease, and older age—i.e., men who have reached the age of 45 and women who have reached the age of 55. For people with two or more major risk factors, the probability of developing coronary heart disease over the next 10 years is then calculated based upon a “risk score” developed from the findings of the
Framingham Heart Study
. If the risk of developing CHD over the next ten years is 10 percent or more, and the LDL cholesterol level remains 130 mg/dL or higher
*
after a trial of diet and exercise, the new guidelines call for treatment with a statin drug to head off coronary heart disease at the pass.

The excitement generated by these new guidelines was unprecedented. Dr. Claude Lenfant, the director of the National Heart, Lung, and Blood Institute, under whose auspices the NCEP does its work, told the
New York Times
that if the new guidelines were followed, coronary heart disease “would no longer be the number one killer [in the United States].” With even greater enthusiasm, the lead author of the guidelines, Dr. Scott M. Grundy, said, “These statins are amazing drugs.. . . When you say you can’t put that many people on drugs, you’ve got to balance that against the tremendous devastation of coronary heart disease.” This certainly seems like due cause for excitement.

The new guidelines were formulated by a panel of 14 experts and approved by representatives from 22 prestigious nonprofit medical societies, including the American College of Cardiology and the American Medical Association. The guidelines make specific recommendations for men, women, and people 65 and older who do not have coronary heart disease (“primary prevention”), and for those who already do (“secondary prevention”). An 11-page executive summary of the full report was published in the May 16, 2001, issue of JAMA. Virtually all cardiologists and primary care doctors who treat adults are familiar with these recommendations. But few have read the uninviting 284-page full-length version of the NCEP expert panel’s report, available on the Internet. Most doctors probably figured it wasn’t necessary. The summary assures its readers that the full document is “an evidence-based and extensively referenced report that provides the scientific rationale for the recommendations contained in the executive summary.”

The updated guidelines rely heavily on the findings of five large clinical trials of CHD prevention with statins that had become available since the previous version of the guidelines were issued in 1993. The executive summary published in JAMA is clear about its primary approach to CHD prevention: after a brief discussion of the changes introduced in the new guidelines and the new method of individual risk assessment, the bulk of the recommendations address LDL cholesterol as “the primary target of therapy.” Largely as a result of these guidelines, cholesterol control has become the main focus of preventive health care in the United States.

Doctors aren’t required to follow these (or any) guidelines to the letter, but most do for several reasons: they want to practice the best medicine possible; they want their medical decisions to be consistent with community standards; and they know that if they do not follow current guidelines, they have a greater risk of getting sued should something go wrong. For these reasons, plus the enormous publicity that continues to surround the issue of cholesterol, the updated guidelines are playing a larger role than any guidelines that have come before in shaping both doctors’ and patients’ health care priorities.

But careful scrutiny of the full report of the NCEP—and of the key studies supporting its recommendations—reveals a picture strikingly different from what is presented in the executive summary. Rather than presenting a balanced interpretation of the scientific findings, the report seems intent upon building the case for greater use of statins, preferentially presenting data that support greater statin use and
even misrepresenting findings reported
in the original articles. And rather than promoting a balanced approach to coronary heart disease prevention and overall health promotion, the guidelines seem more intent upon getting doctors to focus on lowering LDL cholesterol.

The link between elevated cholesterol and increased risk of heart disease was initially identified by researchers from the Framingham Heart Study. Beginning in 1948, this study enrolled 5000 residents of Framingham, Massachusetts, with the goal of identifying the factors that contribute to coronary heart disease. In 1957 the study first reported that high cholesterol levels increased the risk of heart disease. The different effects of HDL and LDL cholesterol were described in 1977. (Cholesterol is a waxy fat that is attached to a protein for transport in the blood. The difference between “good” cholesterol, HDL, and “bad” cholesterol, LDL, is the protein to which the cholesterol is attached.)

Coronary heart disease develops when one or more of the arteries that supply blood to the heart muscle become blocked, depriving the muscle cells of the oxygen and nutrients needed to function properly. The process starts when LDL cholesterol particles circulating in the blood pass into the walls of the coronary arteries. This sets off an inflammatory reaction that leads to the buildup of white blood cells and other material, collectively called plaque, within the walls of the arteries. HDL cholesterol, on the other hand, seems to pull cholesterol out of the arteries, like a scavenger, and transport it back to the liver.

The buildup of plaque on the inside of artery walls is a slow process, taking many years. Usually there are no symptoms until the internal diameter of a coronary artery becomes narrowed by at least 60 percent. Then, like a garden hose that is being stepped on, the capacity of the partially blocked coronary artery to carry blood to the heart muscle becomes compromised. When the blood supply to an area of the heart is inadequate to meet increased metabolic demand (during exercise or emotional stress, for example), patients often feel crampy, pressure-like pain in the left side of the chest, known as angina. When a coronary artery becomes completely blocked by plaque and there is no other blood supply to the downstream heart tissue, muscle cells die. This is known as a heart attack.

Most heart attacks are not, however, caused by a gradual buildup of plaque. The more frequent scenario is that a smaller area of plaque, for unknown reasons, breaks open (“fractures”) or becomes eroded on its surface. This causes the tiny platelets circulating in the blood to become sticky and form a small blood clot, or thrombus, on top of the plaque. Without any warning, thrombus formation can quickly and completely obstruct the flow of blood through a coronary artery, causing a heart attack. (Aspirin decreases the risk of heart attack by decreasing the stickiness of platelets, thereby making thrombus formation less likely.)

Lowering total and LDL cholesterol with medication, the theory goes, lowers the risk of coronary heart disease by decreasing plaque formation. From the 1960s to the 1980s, drugs of the fibrate class were used to lower cholesterol (though exactly how they worked was not known) and decrease the risk of heart attack. This they did quite well for people who did not yet have heart disease. But after many years of use, as a study done by the World Health Organization found, clofibrate (brand name Atromid-S)
increased
the overall risk of death by 47 percent. (About half the excess deaths were due to cancer.) Similarly, a study done by the National Public Health Institute at the University of Helsinki, Finland, showed that the death rate among people taking the other popular fibrate, gemfibrozil (brand name Lopid), for 8.5 years was 21 percent
higher
than that for the people taking placebos.

The current era of treatment to lower total and LDL cholesterol began in 1987, with the introduction of the first statin drug. Most of the cholesterol in our bodies does not come from our diet but is manufactured in the liver. Statins were developed specifically to mimic one of the intermediate molecules produced in the process of cholesterol synthesis, and thereby trick the liver into slowing down cholesterol production. This decreases the amount of total and LDL cholesterol circulating in the bloodstream. The first statin, Mevacor, is now available as a generic called lovastatin, which costs less than half as much as the brand-name statins. The best-selling statins as of 2003 were Lipitor, Pravachol, and Zocor. The newest entry into the U.S. statin market, Crestor, was approved by the FDA in August 2003.

It is important to keep in mind that cholesterol is not a health risk in and of itself. In fact, cholesterol is vital to many of the body’s essential functions. For example, cholesterol is the most common organic molecule in the brain (this could explain why statins have a small but statistically significant negative effect on cognitive function). It is also an essential building block of many of the body’s most important hormones, such as stress hormones, blood sugar–regulating hormones, and sex hormones. (One study that specifically looked for sexual problems associated with cholesterol-lowering therapy found that
statins increase the frequency of sexual dysfunction
by about 50 percent in men.) Cholesterol is also necessary for the transmission of signals from one nerve cell to the next, and is an integral component of the membrane that surrounds each cell.

The essential role that cholesterol plays in many of the body’s biological functions is easily forgotten when one is reading and following the updated guidelines for cholesterol management, and getting caught up in the growing cholesterol-lowering frenzy. The real goal of medical care is, after all, to improve overall health—in this case to decrease the risk of coronary heart disease, serious illness of all kinds, and premature death from all causes—and not simply to lower blood levels of LDL cholesterol.

Even though much of what we know about the relationship between cholesterol and coronary heart disease comes from the Framingham Heart Study, the mother of all cholesterol studies, some of its most important findings will come as a surprise—especially to doctors. An article published in the
Archives of Internal Medicine
in 1993 analyzing data from the Framingham study showed that higher total cholesterol levels significantly correlate with an increased risk of death from coronary heart disease only through the age of 60. This correlation does
not
extend to age 70 or beyond. More important, the article showed that elevated total cholesterol levels correlate with an increased overall risk of death only through the age of 40, and not once the age of 50 is reached. An even more alarming finding from this study, given the current cholesterol-lowering craze, is that the risk of death from causes other than coronary heart disease
increases
significantly with
lower
total cholesterol levels for men and women after they reach the age of 50. (The authors specifically considered but rejected the hypothesis that people with lower cholesterol levels had higher noncardiac death rates because of undiagnosed underlying illness.) Other data from the Framingham Heart Study published in 1999 show that physical activity, unlike total cholesterol levels, is highly correlated with overall mortality rate: The most active third of the original 5000 men and women in the study had a 40 percent lower death rate than the least active third.

So why has our collective national attention become so narrowly focused on lowering LDL cholesterol as the single most important preventive health strategy when the evidence shows that it plays a relatively limited role in our overall health? Part of the answer has to do with the experts’ intellectual commitment to the role of cholesterol in heart disease, having dedicated their careers to furthering the scientific understanding of this relationship. Another part of the answer may have to do with some of the authors’ potential conflicts of interest:
Five of the 14 experts
who participated in writing the guidelines, including the chair of the panel, disclosed financial relationships with manufacturers of statin drugs. Four of these five, including the chair of the panel, had relationships with all three manufacturers of the best-selling statins.

And curiously, although the guidelines recommend reduced intake of saturated fat and cholesterol, the words “egg,” “beef,” and “dairy” do not appear anywhere in the executive summary. (Animal products such as egg yolks, red meat, and dairy fat are the primary dietary sources of saturated fat and cholesterol, and therefore reducing intake of these foods is an integral part of the “therapeutic lifestyle interventions” suggested in the guidelines.) Perhaps the omission has something to do with the fact that, according to the Center for Science in the Public Interest, several of the authors and expert reviewers of the guidelines have, or have had, financial ties to one of the following organizations: the American Egg Board, the National Cattlemen’s Association, and the National Dairy Promotion and Research Board. In contrast, increasing fiber intake is mentioned five times in the executive summary. (One of the authors and two of the reviewers have done research on fiber funded by Procter and Gamble, the manufacturer of Metamucil.)