The Cholesterol Con -- Where Were the Doctors?
After the stock market bubble burst, the New York Times asked: "Where were the analysts? Why didn't they warn us?"
To be perfectly honest, this was a somewhat disingenuous question. As experienced financial journalists understood all too well, the analysts plugging the high-flying issues of the 1990s were employed by Wall Street firms raking in billions as investors bet their nest eggs on one hot stock after another. It really wasn't in their employers' interest for analysts to tell us that their products were wildly overpriced. When a small investor wades into the financial world, there are two words he needs to keep in mind: caveat emptor.
But physicians, I firmly believe, are different from the folks employed by Merrill Lynch. (I don't mean to knock people who work at ML. I am simply saying that they have a very different job description.) When consulting with your doctor, you should not have to be wary. You are not a customer; you are a patient. And your physician is a professional who has pledged to put your interests ahead of his or her own.
This brings me to the question I ask in my headline: During the many years of the Cholesterol Con, where were the doctors? When everyone from the makers of Mazola Corn Oil to the Popes of Cardiology assured us that virtually anyone could ward off heart disease by lowering their cholesterol, why didn't more of our doctors raise an eyebrow and warn us: "Actually, that's not what the research shows"?
No doubt, you've heard about the recent Business Week cover story, "Do Cholesterol Drugs Do Any Good?", which blew the lid off the theory that "statins" -- drugs like Lipitor, Crestor, Mevacor, Zocor and Pravachol -- can cut the odds that you will die of a heart attack by slowing the production of cholesterol in your body and increasing the liver's ability to remove LDL, or "bad cholesterol," from your blood.
It's true that these drugs can help some people -- but not nearly as many as we have been told. Moreover, and this is the kicker, we don't have any clear evidence that they work by lowering cholesterol.
Although medical research suggests that statins can definitely benefit one group -- men under 70 who already have had a heart attack -- researchers are no longer convinced that the drugs stave off a second attack by lowering the patient's cholesterol. The drugs do lower cholesterol, but that is not what helps the patient.
In other words, researchers are questioning the bedrock assumption that high levels of "bad cholesterol" cause heart disease. "Higher LDL levels do help set the stage for heart disease by contributing to the buildup of plaque in arteries. But something else has to happen before people get heart disease," Dr. Ronald M. Krauss, director of atherosclerosis research at the Oakland Research Institute, told Business Week. "When you look at patients with heart disease, their cholesterol levels are not that [much] higher than those without heart disease," he added. "Compare countries, for example. Spaniards have LDL levels similar to Americans', but less than half the rate of heart disease. The Swiss have even higher cholesterol levels, but their rates of heart disease are also lower. Australian aborigines have low cholesterol but high rates of heart disease."
"Current evidence supports ignoring LDL cholesterol altogether," Dr. Rodney A. Hayward, professor of internal medicine at the University of Michigan, told Business Week's reporter.
In recent years, researchers have begun to suspect that statins help patients, not by lowering cholesterol levels, but by reducing inflammation. If this theory is right, "this seems likely to shunt cholesterol reduction into a small corner of the overall picture of heart disease," the Guardian reported four years ago.
And if the key to statins is that they reduce inflammation, it's worth keeping in mind that this is what other effective heart treatments like aspirin and the omega-3 fatty acids found in fish oils, garlic and vitamin E do -- at a much lower cost and with far fewer side effects.
But hold onto your hats, I still haven't gotten to what is most shocking about the cholesterol story. What raises my blood pressure is the knowledge that Business Week's scoop isn't really "new" news." With all due respect to Business Week, which showed real courage in putting the story on its cover, and to its author, John Carey, who did a superb job of explaining the medical research, the truth is that medical researchers have been questioning for many years the theory that widespread use of statins to lower cholesterol will save lives.
You can find the research questioning the benefits of statins in medical journals like Lancet (2001) and BMJ (2006), as well as in reports from medical conferences ("Tales From the Other Drug Wars," 1999).
Occasionally, doubts popped up in the mainstream press and then disappeared.
Five years ago, veteran healthcare blogger Matthew Holt pointed to a BMJ article suggesting that statins might be no better than aspirin. That same year, Holt raised pointed questions regarding the risk of taking statins, including possible memory loss."
Nevertheless, the very next year, the National Cholesterol Education Program at the U.S. National Heart, Lung and Blood Institute issued new recommendations that drastically lowered the threshold for statin therapy. According to its 2004 report, people at a moderately high risk of developing heart disease (with LDL cholesterol levels between 100 and 129 mg/dL) should be offered statins -- even if they have no previous history of heart disease. Statin therapy also should be recommended to very high-risk patients, the panel said, even if their LDL levels are as low as 70. NCEP declared that the recommendations applied to both men and women, regardless of age.
The bottom line: NCEP was urging millions of Americans to go on statins.
Not everyone agreed, recalls Merrill Goozner, editor of "GoozNews," a top-drawer investigative healthcare blog. In 2004, a few months after the new guidelines came out, a coalition of more than 30 academic physicians and researchers, inspired by Dr. John Abramson (author of Overdosed America: The Broken Promises of American Medicine), decided to write a letter to the National Heart Lung and Blood Institute (NHLBI).
Goozner, who does research at the Center for Science in the Public Interest, organized the group. The letter "outlined all the evidence, which was there in published clinical trials for anyone who cared to look," Goozner recalls, and concluded that while statins "may lower cholesterol in people at low risk and even many subgroups at moderate risk of a heart attack ... there was no evidence that the drugs actually saved lives."
How could this be, if statins lower the risk of heart attack, at least for some people? Preventing a heart attack does not necessarily mean that a life is saved. In many statin studies that show lower heart attack risk, the same number of patients end up dying, whether they are taking statins or not. "You may have helped the heart, but you haven't helped the patient," says Dr. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, and co-author of a 2004 editorial in the Journal of the American College of Cardiology questioning the data on statins. "You still have to look at the impact on the patient overall."
"The letter we sent to the NHLBI also called for an independent panel to review the evidence," Goozner notes, "since the NLHBI panel that made the recommendations had been dominated by physicians with ties to statin manufacturers." Indeed, the National Institutes of Health later admitted that eight of the nine experts on the panel had received financing from one or more of the companies that make statins. (None of the panelists had publicly disclosed their ties to manufacturers when they made their recommendations.)
Just how much "financing" were the panelists receiving? According to the Los Angeles Times, from 2001 to 2003 Dr. Bryan Brewer, a leader at the National Institutes of Health, and "part of the team that gave the nation new cholesterol guidelines in 2004," had accepted "about $114,000 in consulting fees from four companies making or developing the cholesterol-lowering drugs."
But "this is relative peanuts compared to Dr P. Trey Sunderland III, a senior psychiatric researcher at the NIH, who took $508,500 in fees from Pfizer, Inc. whilst collaborating with them and endorsing their drug [Lipitor]," says Dr. Malcolm Kendrick, who is a member of The International Network of Cholesterol Skeptics (THINCS) -- a growing group of scientists, physicians, other academicians and science writers from various countries.
Dr. Abramson, who is a clinical instructor at Harvard Medical School, charges that the study that accompanied the updated 2004 guidelines "knowingly misrepresented the results of the clinical trials that they supposedly relied upon to formulate their recommendations. The problem is that the experts claimed to rely on scientific evidence, but they act as if empowered to ignore the evidence when it is not consistent with their beliefs."
This is a serious allegation. Keep in mind that statins are the most popular drugs in the history of human medicine. Worldwide sales totaled $33 billion in 2007. More than 18 million American now take them.
Nevertheless, "medical research suggests that only about 40 percent to 50 percent of that number are likely to benefit," says Abramson. "The other 8 or 9 million are exposed to the risks that come with taking statins -- which can include severe muscle pain, memory loss, sexual dysfunction -- and one study shows increased risk of cancer in the elderly -- but there are no studies to show that the drugs will protect these patients against fatal heart attacks."
Abramson can cite many studies to support his claims. But first, he stresses that statins can help some people.
"Statins show a clear benefit for one group," he says: "People under 65 who have already had a heart attack or have diabetes. But even in these very high risk people, about 22 have to be treated for five years for one to benefit."
What about middle-aged people who are not diabetic and have not had a heart attack? A 2006 study published in the Annals of Internal Medicine that focused on seven trials involving nearly 43,000 middle-aged adults concluded that statin use did not cut their chances of dying from heart disease.
Is there any benefit for this group? "If they are high risk, statins can be beneficial to people under 65 who haven't had a heart attack, but 50 such men have to be treated for five years for one to benefit." says Abramson. "The other 49 will not be helped. The problem is that we can't know who is going to be the 50th man," he adds. And all 50 will be exposed to the side effects.
Older adults have little to gain. The drugs don't help people over 70 even if they have elevated cholesterol levels, according to a report in the Journal of American Cardiology.
Finally, "there is no evidence of any benefit for women who don't already have heart disease or diabetes," says Abramson. According to a 2004 article published in the Journal of the American Medical Association which reviewed all trials in which women with high cholesterol had been randomly assigned to take a cholesterol-lowering drug or a placebo, there was no evidence that statins prolonged women's lives or cut their chances of dying from heart disease.
An editorial published in the Journal of the American College of Cardiology came to the same conclusion -- though there does seem to be a risk that women on statins develop memory loss so severe that their relatives may begin shopping for a nursing home.
Memory loss that can mimic alzheimers is the second most common side affect for people taking statins, right after muscle pain, according to researchers at the University of California, San Diego. For a number of years, they have been running a randomized controlled trial examining the effects of statins on thinking, mood, behavior, and quality of life. Separately, the UCSD researchers have been collecting anecdotal experiences of patients, good and bad, on statins.
"We have some compelling cases," Dr. Beatrice Golomb, the study's lead researcher, told the Wall Street Journal. "In one of them, a San Diego woman, Jane Brunzie, was so forgetful that her daughter was investigating alzheimers care for her and refused to let her baby-sit for her 9-year-old granddaughter. Then the mother stopped taking a statin. 'Literally, within eight days, I was back to normal -- it was that dramatic,' said Mrs. Brunzie, 69 years old."
According to the Journal, "doctors put her on different statins three more times. 'They'd say, "Here, try these samples." Doctors don't want to give up on it,' she said.' Within a few days of starting another one, I'd start losing my words again,' added Mrs. Brunzie, who has gone back to volunteering at the local elementary school she loves and is trying to bring her cholesterol down with dietary changes instead."
Returning to Goozner's story, did the letter his group wrote to the NHLBI in 2004, spark public discussion about the new cholesterol guidelines? No. "We released the letter to the press, but the mainstream of the national press ignored us," Goozner recalls.
In 2008, Goozner is happy to see the statin controversy hit Business Week's cover -- though he can't help but wonder, "Where were these guys three years ago? Now, call me a cynic, but why does my perverted mind think to itself as I watch this coverage: Yeah, now we hear, just when the world's best-selling drug [Lipitor] is about to go off patent."
I suspect Goozer is right. It would have been much harder to publish this story a few years ago.
But there also was a trigger that probably helped spur the Business Week investigation. Last month, Merck-Schering/Plough released a long-awaited study revealing that Vytorin, an expensive combination of two drugs designed to lower cholesterol, brought no added benefits for patients suffering from heart disease.
The two cholesterol-lowering drugs were Zocor, which is a statin, and, Zetia, which is not. When combined, the two drugs did drive cholesterol levels much lower. But the clinical trial offered no evidence that the two cholesterol-busters were more effective in reducing heart attacks than Zocor alone. This raises an obvious question: is cutting cholesterol levels really the key to avoiding heart attacks?
The results of the study helped buttress the strong suspicion that insofar as statins like Zocor do help anyone with heart disease, the beneficial effect has little to do with lowering cholesterol levels.
Meanwhile, Zocor is now available in a generic form that can be purchased for less than $6 for a 30-day supply. By contrast, the new combination, selling under the brand name Vytorin, was fetching more than $100 for a three-day supply. In 2006, the drug brought in $1.5 billion with sales climbing 25 percent in the first half of 2007 to over $2 billion, according to IMS Health.
Naturally, Merck and Schering/Plough, who were marketing Vytorin in a joint venture, were shy about reporting the results of the clinical trials. It was only when they were threatened with a congressional investigation that they made the results public on Jan. 15 -- more than a year and a half after the clinical trials were completed.
The day after the drug makers released the news, the American Heart Association rushed to their defense, declaring that the study was too limited to draw conclusions about Vytorin's ability to reduce heart attacks or deaths compared to Zocor alone. The AHA advised patients not to abruptly stop taking Vytorin without consulting with the doctors who had prescribed it.
The New York Times, to its credit, was quick to respond, noting that "what the [American Heart Association] did not note in its statement ... was that the group receives nearly $2 million a year from Merck/Schering-Plough Pharmaceuticals, the joint venture that markets Vytorin.
This article is part one in a two-part series.