The Origins of the Cholesterol Con, Part II

Last week, I wrote about the “cholesterol con,” the widespread belief that “bad Cholesterol” ( LDL cholesterol) is a major factor driving heart disease, and that cholesterol-lowering drugs like Lipitor and Crestor can protect us against fatal heart attacks. These drugs, which are called “statins,” are the most widely-prescribed pills in the history of human medicine. In 2007 world-wide sales totaled $33 billion. They are particularly popular in the U.S., where 18 million Americans take them.

We thought we knew how they worked. But last month, when Merck/Schering Plough finally released the dismal results of a clinical trial of Zetia, a cholesterol-lowering drug prescribed to about 1 million people, the medical world was stunned. Dr. Steven E. Nissen, chairman of cardiology at the Cleveland Clinic called the findings “shocking.”  It turns out that while Zetia does lower cholesterol levels, the study failed to show any measurable medical benefit.

This announcement caused both doctors and the mainstream media to take a second look at the received wisdom that “bad cholesterol” plays a major role in causing cardiac disease. A Business Week cover story asked the forbidden question, “Do Cholesterol Drugs Do Any Good?

The answer, says Dr. Jon Abramson, a clinical instructor at Harvard Medical School, and the author of  Overdosed America, is that “statins show a clear benefit for one group—people under 65 who have already had a heart attack or who have diabetes. But,” says Abramson,  “there are no studies to show that these drugs will protect  older patients  over 65—or younger patients who are not already suffering from diabetes or established heart disease –from  having a fatal heart attack. Nevertheless, 8 or 9 million patients who fall into this category continue to take the drugs, which means that they are exposed to the risks that come with taking statins –which can include severe muscle pain, memory loss, and sexual dysfunction.”

Finally—and here is the stunner—it turns out we don’t have any clear evidence that statins help the first group by lowering cholesterol levels.  It’s true that they do lower cholesterol, but many researchers are no longer convinced that this is what helps patients avoid a second heart attack. It now seems likely that they work by reducing inflammation. In other words, these very expensive drugs seem to do the same thing that aspirin does.  (Are they more effective than the humble aspirin? We’ll need head-to-head studies to find out.)

In the past, some physicians have questioned the connection between
high cholesterol and heart disease. After all, as 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 . . . 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.”

Why then, were we all so certain that LDL cholesterol led to fatal
heart attacks? The truth is that we were not “all” so sure. Within the
medical profession, there have always been skeptics—particularly in the
U.K.  But in the U.S., the Popes of cardiology, the American Heart
Association and the College of Cardiologist  each put their imprimatur
on the cholesterol story, insisting on its truth, until finally, it
became dogma.

As science writer Gary Taubes pointed out in a recent New York Times
Op-ed: “The idea that cholesterol plays a key role in heart disease is
so tightly woven into modern medical thinking that it is no longer
considered open to question.” Taubes, whose work has appeared in The
Best American Science Writing, Science, and the New York Times
Magazine, explains that “because medical authorities have always
approached the cholesterol hypothesis as a public health issue, rather
than as a scientific one, we’re repeatedly reminded that it shouldn’t
be questioned. Heart attacks kill hundreds of thousands of Americans
every year, statin therapy can save lives, and skepticism might be
perceived as a reason to delay action. So let’s just trust our
assumptions, get people to change their diets and put high-risk people
on statins and other cholesterol-lowering drugs.”

Taubes sees things differently. “Science suggests a different approach:
test the hypothesis rigorously and see if it survives.” But when it
comes to the cholesterol theory, this is what never happened. Go back
to 1950, and you will understand why.

As the second half of the twentieth century began, public health
experts were flummoxed by the steep  rise in heart attacks. Turn-of-the
century records suggest that heart disease caused no more than 10
percent of all deaths—many more people died of pneumonia or
tuberculosis. But by 1950 coronary heart disease, or CHD, was the
leading source of mortality in the United States, causing more than 30
percent of all deaths.

One common-sense explanation comes to mind: With improved sanitation,
plus new drugs, fewer people were dying of infectious diseases. So they
were living long enough to die of a heart attack.

But to many, that didn’t seem sufficient.  So in 1949, the National Heart Institute introduced the protocol for the Framingham Study.
The research, which began in 1960, set out to investigate the factors
leading to cardiovascular disease (CVD) and began with these
hypotheses:

1.    CVD increases with age. It occurs earlier and more frequently in males.
2.    Persons with hypertension developed CVD at a greater rate than those who are not hyper-tensive.
3.    Elevated blood cholesterol level is associated with an increased risk of CVD.
4.    Tobacco smoking is associated with an increased occurrence of CVD.
5.    Habitual use of alcohol is associated with increased incidence of CVD.
6.    Increased physical activity is associated with a decrease in the development of CVD.
7.    An increase in thyroid function is associated with a decrease in the development of CVD.
8.    A high blood hemoglobin or hematocrit level are associated with an increased rate of the development of CVD.
9.    An increase in body weight predisposes to CVD.
10.  There is an increased rate of the development of CVD in people with diabetes mellitus.
11.    There is higher incidence of CVD in people with gout.

Other factors were later added to the list, including HDL and LDL lipid fractions

Ultimately, “the Framingham study determined that higher total
cholesterol levels significantly correlate with an increased risk of
death from coronary heart disease only through the age of 60” observes
“Evidence for Caution: Women and Statin Use,” a well-documented 2007 report
from The Canadian Women’s Health Network. Moreover, the research showed
that cholesterol was only one of many factors leading to CVD for
younger patients.

“Tales From the Other Drug Wars," a paper
presented at a 1999 health conference in Vancouver, also stresses that
“The Framingham Study actually found an association between blood
cholesterol and coronary heart disease in young and middle-aged men
only. No corresponding association was found in women or in the
elderly, and it is in the latter group that most of the cases of heart
disease occur.” And while the study linked blood cholesterol to heart
disease in younger men, the study also found no association between
dietary cholesterol (cholesterol. that comes from what we eat)  and the
risk of coronary heart disease, even in young and middle-aged men.

“Dietary saturated fats were not associated with heart disease even
after adjusting for other risk factors. Buried deep in the massive
number of reports produced from the study is a quote from the
investigators saying “…there is, in short, no suggestion of any
relationship between diet and the subsequent development of coronary
heart disease in the study group.”

Many of the other factors that the Framingham Study investigated
—including lack of physical activity, obesity, stress, smoking and
alcoholism would prove very important, yet “for a variety of reasons,”
the focus shifted to cholesterol” the 2007 Canadian report (“Evidence
for Caution”) notes, which now “ has become the most prominent and
feared risk factor for both women and men—perhaps because it is the
most easily modifiable. By contrast there is no pill for the effects of
air pollution, which is a substantial risk factor for heart disease,
especially for women.”

Thus began what the report calls “the “cholesterolization” of
cardiovascular disease – that is, emphasis on a single risk factor. . .
Cholesterol has come to represent a virtual disease state in itself,
rather than one risk factor among many, and has distracted from
grappling with other risk factors that are strong indicators of
cardiovascular disease and cardiovascular risk.”

Yet, as Taubes points out in his NYT Op-ed, the Framingham study did
not support this conclusion:  The researchers concluded that the
molecules that carry LDL cholesterol (low-density lipoproteins) were
only “ a’ marginal risk factor’ for heart disease” while  the
“cholesterol carried by high-density lipoprotein” actually “lowered
the risk of heart disease.”

“These findings led directly to the notion that low-density
lipoproteins carry ‘bad’ cholesterol and high-density lipoproteins
carry ‘good’ cholesterol,” Taubes explains.  “And then the precise
terminology was jettisoned in favor of the common shorthand. The
lipoproteins LDL and HDL became ”good cholesterol’ and ‘bad
cholesterol’ and the molecule carrying the cholesterol was now
conflated with its cholesterol cargo.

“The truth is, we’ve always had reason to question the idea that
cholesterol is an agent of disease,” says Taubes. “Indeed, what the
Framingham researchers meant in 1977 when they described LDL
cholesterol as a ”marginal risk factor” is that a large proportion of
people who suffer heart attacks have relatively low LDL cholesterol.

“So how did we come to believe strongly that LDL cholesterol is so bad
for us?” he asks. “It was partly due to the observation that eating
saturated fat raises LDL cholesterol, and we’ve assumed that saturated
fat is bad for us. This logic is circular, though: saturated fat is bad
because it raises LDL cholesterol, and LDL cholesterol is bad because
it is the thing that saturated fat raises.” Yet, he points out, “in
clinical trials, researchers have been unable to generate compelling
evidence that saturated fat in the diet causes heart disease.

“The other important piece of evidence for the cholesterol hypothesis
is that statin drugs like Lipitor lower LDL cholesterol and also
prevent heart attacks. The higher the potency of statins, the greater
the cholesterol lowering and the fewer the heart attacks. This is
perceived as implying cause and effect: statins reduce LDL cholesterol
and prevent heart disease, so reducing LDL cholesterol prevents heart
disease. This belief is held with such conviction that the Food and
Drug Administration now approves drugs to prevent heart disease, as it
did with Zetia, solely on the evidence that they lower LDL cholesterol.

“But the logic is specious because most drugs have multiple actions,”
Taubes notes. “It’s like insisting that aspirin prevents heart disease
by getting rid of headaches.”

Indeed, as noted above, many researchers now believe that statins help
some cardiac patients the way aspirin help many cardiac patients: not
by lowering cholesterol or by easing headaches, but by reducing
inflammation. 

Nevertheless, in the 1950s, the theory that saturated fat and
cholesterol from animal sources raise cholesterol levels in the blood,
leading to deposits of cholesterol and fatty material in the arteries
that, in turn, leads to fatal heart disease took off.  It was called
the Lipid theory, and before long food manufacturers would recognize
just how much money there was to be made by promoting it.

At the time there was relatively little profit  to be made by trying to
persuade Americans to stop smoking (smoking cessation clinics still
don’t make anyone rich), and expensive gyms that encourage exercise had
not yet become widely popular. But there was a fortune to be made by
persuading Americans that if they ate foods low in saturated fats, they
could live longer.

“The Oiling of America,” a colorful history
of the political campaign against animal fat by Mary Enig, a
biochemist, nutritionist and former researcher at the University of
Maryland, reports that in  1957  the food industry launched a series of
ad campaigns that  touted the health benefits of  products low  in fat
or made with vegetable oils. A typical ad read: “Wheaties may help you
live longer.” Wesson recommended its cooking oil “for your heart’s
sake” and Journal of the American Medical Association ad described
Wesson oil as a “cholesterol depressant.”

Mazola advertisements assured the public that “science finds corn oil
important to your health.” Medical journal ads recommended Fleishmann’s
unsalted margarine for patients with high blood pressure. Dr. Frederick
Stare, head of Harvard University’s Nutrition Department, encouraged
the consumption of corn oil—up to one cup a day—in his syndicated
column.

In a promotional piece specifically for Procter and Gamble’s Puritan
oil, he cited two experiments and one clinical trial as showing that
high blood cholesterol is associated with CHD. Presumably, he was well
paid for his work.

Dr. William Castelli, Director of the Framingham Study was one of
several specialists to endorse Puritan. Dr. Antonio Gotto, Jr., former
AHA president, sent a letter promoting Puritan Oil to practicing
physicians—printed on Baylor College of Medicine, The De Bakey Heart
Center letterhead.

The American Heart Association also pitched in. In 1956, a year before
the food manufacturers’ advertising blitz, an AHA fund-raiser aired on
all three major networks, featuring Irving Page and Jeremiah Stamler of
the AHA. Panelists presented the lipid hypothesis as the cause of the
heart disease epidemic and launched the Prudent Diet, one in which corn
oil, margarine, chicken and cold cereal replaced butter, lard, beef and
eggs.

(“Stamler  would show up again in 1966 as an author of Your Heart Has
Nine Lives
, a little self-help book advocating the substitution of
vegetable oils for butter and other so-called “artery clogging”
saturated fats,” Enig points out in “The Oiling of America.” The book
was sponsored by makers of Mazola Corn Oil and Mazola Margarine.
Stamler did not believe that lack of evidence should deter Americans
from changing   their eating habits. The evidence, he stated, “was
compelling enough to call for altering some habits even before the
final proof is nailed down. . . the definitive proof that middle-aged
men who reduce their blood cholesterol will actually have far fewer
heart attacks waits upon diet studies now in progress.” And, of course,
we still wait for that definite proof that middle-aged men who do not
suffer from established heart disease nevertheless should be on
statins.)

“But the television campaign was not an unqualified success,” Enig
continues, “because one of the panelists, Dr. Dudley White, disputed
his colleagues at the AHA. Dr. White noted that heart disease in the
form of myocardial infarction was nonexistent in 1900, when egg
consumption was three times what it was in 1956 and when corn oil was
unavailable.

“But the lipid hypothesis had already gained enough momentum to keep it
rolling, in spite of Dr. White’s nationally televised plea for common
sense in matters of diet and in spite of the contradictory studies that
were showing up in the scientific literature.”

“The American Medical Association at first opposed the
commercialization of the lipid hypothesis,” Enig reports, “ and warned
that “the anti-fat, anti-cholesterol fad  is not just foolish and
futile. . . it also carries some risk.” The American Heart Association,
however, was committed. In 1961 the AHA published its first dietary
guidelines aimed at the public.”

No doubt many researchers at the AHA were sincere. But it is worth
noting that ultimately the AHA would find a way to turn the War Against
Cholesterol into a profitable cottage industry.

You’ve probably seen the AHA’s “heart check” logo on numerous food
products. No surprise, they don’t give them out for free. Food
manufacturers pay a first-year fee of $7,500 per product, with
subsequent renewals priced at $4,500 according to Steve Millay, a
biostatician, lawyer and  adjunct scholar  at the conservative Cato
Institute, who posted about this on “junk science” in 2001.

“There’s gold in the AHA’s credibility,” Milloy observed. “Several
hundred products now carry the heart-check logo. You do the math.
Adding insult to injury, consumers pay up for the more expensive brands
that can afford to dance with the AHA. Pricey Tropicana grapefruit
juice is ‘heart healthy’ but supermarket bargain brand grapefruit juice
isn’t?”

It wasn’t until 1987, when Merck produced the first statin, that the
pharmaceutical industry began to get in on the action. But when it
joined the party, it began to spread the money around, not only by
advertising, but by paying well-placed cardiologists “consulting fees.”

As I noted in last week’s post, when the National Cholesterol Education
Program (NCEP) published new guidelines in 2004, urging that individual
cholesterol levels be monitored from age 20 and that acceptable levels
be significantly lower than was previously advised for prevention of
cardio vascular disease in both women and men—whether or not they
already suffered from established heart disease—eight of the nine
doctors on the panel making the recommendations had financial ties to
drug makers selling statins. They did not disclose this possible
conflict of interested at the time. Both the American Heart Association
and the American College of Cardiology endorsed the panel’s
recommendation.

At that point, the 2007 Canadian women’s study observes, the “
‘cholesterization’ of heart disease intensified.  Meanwhile, the study
notes:

“a year before the U.S. panel came out with the new guidelines, the
AHRQ, the US agency that reviews the quality of healthcare research,  produced a report
on women and heart disease stating that there was insufficient evidence
to determine whether lowering lipid levels by any method reduced the
risk of heart attack or stroke in women, because women were
under-represented in trials.

“According to US research,” the report adds “high cholesterol in women
is not a statistically significant risk factor for sudden cardiac
death. On the other hand, smoking is one of the most important
predictors of sudden cardiac death in women.” Which makes one wonder:
why doesn’t the American Heart Association start a television campaign
to try to persuade more women and girls to stop smoking?

Finally, despite widespread skepticism about statins and cholesterol,
don’t expect the controversy to end anytime soon. There is just too
much money and too much political muscle supporting the theory that 18
million Americans should be on statins.

Millions have been made not only selling statins, but also testing
patients’ cholesterol levels on an annual basis. As “The Other Drug
Wars” puts it, “the case of cholesterol illustrates well how the
demands for testing and drugs interact: testing leads to increased
utilization of cholesterol lowering drugs, which in turn leads to even
more testing, which in turn leads to more drug utilization.”

In 1999, the authors of “The other Drug Wars” were pessimistic that
reason would ever trump hype. Quoting T.J. Moore’s book, Heart Failure,
they noted that “The National Heart Lung, and Blood Institute’s eager
partners in promoting cholesterol consciousness are the drug companies
which are understandably very excited that the government is creating
their largest new market in decades…A program that may have truly begun
in sincere but somewhat misguided zeal for the public good, became very
quickly intertwined with greed. The world was learning how much money
could actually be made scaring people about cholesterol.”

“Crowds of other agencies and companies have joined in the sustained
reinforcement of the importance of cholesterol through the
advertisement of their respective products,” the authors of “The Other
Drugs Wars” continued.  “One can hardly open a magazine or browse the
internet without seeing offerings of the latest anti-cholesterol
miracle drug, new low-cholesterol wonder diet, new life-saving
cholesterol treating device or health-conscious cholesterol-lowering
food product.

“The voice of evidence questioning the value of directing so many
public resources towards cholesterol control was and is still being
lost amongst the thousands of advertising messages directed at the
public.”

Perhaps the time has come for “the voice of evidence” to make itself
heard.  It’s not just that money is being wasted –or that close to half
of the 18 million Americans taking statins may not benefit. All of them
are being exposed to risks which range from serious muscle pain to
memory loss that can look like Alzheimer’s. And too often, well-meaning
physicians who have been sold on statins ignore their complaints.

28 thoughts on “The Origins of the Cholesterol Con, Part II

  1. Maggie,
    I believe that you are referring to the ENHANCE trial. The only published data I have been able to track down is here: Am Heart J. 2005 Feb;149(2):234-9.
    I think that the results of that particular study were taken out of context. The subjects were people with familial hypercholesteremia. They started with cholesterols in the 300 mg/dl range, which were brought down by ~50%. While this seems like a large reduction, people seem to ignore that the absolute level of cholesterol is what has generally been pointed to as being important.
    It may very well be true that cholesterol has no, or little, effect on arthrosclerosis, but I’m not sure that the Zetia trial applies to the majority of the population or to how doctors treat high cholesterol. We do not aim for a % reduction, but rather for an absolute number (<100 or <70, depending on risk factors). So, reducing someone's cholesterol from 300 to 150 really doesn't address the issue if 150 is still unhealthy.
    I would, however, be interested in a head-to-head statin vs. aspirin =).

  2. Good job on this series (and thanks for mentioning the Center for Science in the Public Interest’s work on this in 2004 in last week’s post).

  3. “Why then, were we all so certain that HDL cholesterol led to fatal heart attacks?”
    I’m confused (or maybe I need to read more slowly), shouldn’t that be LDL?

  4. Ryan, Merrill, Dr. Rick and Tom
    Thanks very much–and Ryan,
    thank you for picking up the typo!
    Tom, I’m on deadline right now and need to give your comment some thought, but I promise I’ll get back to you soon– mm

  5. Perhaps I’m missing something about the idea of comparing aspirin (presumably low-dose) against statins. I’ve not seen anything to suggest low-dose aspirin is working as an anti-inflammatory, significantly blocking prostaglandin synthesis by inhibiting cyclo-oxygenases. My understanding was that the cardiac benefit was specific to aspirin, not other NSAIDs, by irreversibly acetylating the precursor to thromboxane B on platelets.
    On a quick search, I saw some arguments that the basic lipid-lowering effect of statins, HMG-CoA-reductase inhibition, may itself have a cardiac benefit. There were some nonspecific allusions that there might be a different anti-inflammatory effect involved.
    Can anyone point me in the direction of details on the latter? If the inflammatory substances in question are prostaglandins or leukotrienes, would not another NSAID be a better comparison than aspirin?

  6. Maggie,
    The primary endpoint you are discussing is cardiac related mortality. Also knowing statins have other potent anti inflammatory properties and salutary effects (as you point out), from a public health perspective, might it be better to discuss all cause mortality and QALY’s as they relate to this class of medicine as well.
    While the “selling of statins” for one indication of use might be rooted in flawed science, and I think we all realize that that is egregious, the fact remains that this class of drugs still may favorably impact many patients. The crux is in whom, and at what cost. My sense is while they might be overused–but that is not proven, we should not throw the baby out with the bathwater. I would addend this point with you illuminating piece.
    Brad

  7. I believe the benefits of aspirin for preventing strokes and heart attacks are thought to relate to its anti-platelet effects.
    I just want to clarify that ezetimibe (Zetia, a component of Vytorin) is not a statin. It is a cholesterol absorption inhibitor. The ENHANCE results don’t tell us anything about the benefits of statins, as the two groups of patients were on the same dose of simvastatin. The difference between the two groups was that one was also on ezetimibe.
    The fact that an intervention that lowers LDL may not be beneficial is not a new idea. In my view, if the FDA is going to approve drugs based solely on LDL-lowering, it should require the drug company to conduct a clinical trial with clinical endpoints as soon as possible after approval. By clinical endpoints, I mean heart attacks, strokes and deaths. The problem with ezetimibe is that it has never been shown to prevent heart attacks and strokes. There are three ongoing trials testing this but the results will not be out for a few more years.
    If anyone is interested in reading more about the pleiotropic effects of statins, a good source is the following: Wang et al, Pleiotropic effects of statin therapy: molecular mechanisms and clinical results, Trends in Molecular Medicine, Vol 14, Issue 1, Jan. 2008, 37-44.
    I’m not sure how we could know how much of the benefits of statins are due to cholesterol-lowering and how much are due to other effects. It seems unlikely, however, that none of the benefits of statins are related to cholesterol-lowering.
    There was an interesting study done by Helen Hobbs and colleagues related to people who have mutations that cause them to have lifelong low LDL levels. The researchers found that people with these mutations have much lower rates of heart disease than people without the mutation. The study was published in the New England Journal of Medicine in 2006. http://content.nejm.org/cgi/content/abstract/354/12/1264
    Similarly, people with mutations that cause lifelong elevated LDL (i.e., familial hypercholesterolemia) have much higher rates of heart disease than the general population. For example, my husband has this in his family, and his grandfather died of a heart attack at 35. His uncle died of a heart attack at 40.
    See the article by Brown and Goldstein for a succinct review of the evidence that LDL causes atherosclerosis (Koch’s postulates for cholesterol Cell 1992 71: 187-188).

  8. Marilyn–
    The other component of Vytia IS a statin.
    The point is that by by putting two cholesterol-lowering drugs together (one a statin, one not a statin) Merck/Schering expected to see increased health benefits.
    After sitting on the results for a long time (and being threatened by a Congressional investigation) the companies had to admit that the trial showed no health benefits from the double-barreled cholesterol busters.
    The less expensive Statin half of the combination was just as successful on its own.
    This has led researchers to suspect that perhaps, while statins do help some people, they do it, not by lowering “bad” cholesterol, but in some other way. It appears that statins reduce inflammation–just as aspirin does. (And aspirin has helped many cardiac patients.)
    This would help explain why large populations in some countires with high “bad cholesterol” have low levels of heart disease, while others, in
    areas with low “bad” cholesterol have high levels of fatal heart disease.
    With questions surrounding the mortality benefits of statins and the importance of lowering LDL (“bad”) cholesterol being asked in the media, some high-profile cardiologists have spoken out.
    In the January 29, 2008 issue of Circulation, with Drs H Robert Superko (St Joseph’s Translational Research Institute, Atlanta, GA) and Spencer King III (Emory University School of Medicine, Atlanta, GA) debating the effectiveness of lowering LDL to reduce cardiovascular risk and suggesting that new strategies are necessary. . .
    “According to Superko and King, a danger for the future health of patients lies in assumptions that cholesterol reduction alone can stem the tide of coronary heart disease. They argue that “this is not enough” and state that the “well-meaning focus on LDL-cholesterol reduction has deflected interest in other therapeutic aspects of lipoprotein treatment that provide equal or greater benefit.”
    According to Superko and King, a danger for the future health of patients lies in assumptions that cholesterol reduction alone can stem the tide of coronary heart disease. They argue that “this is not enough” and state that the “well-meaning focus on LDL-cholesterol reduction has deflected interest in other therapeutic aspects of lipoprotein treatment that provide equal or greater benefit.”
    .

  9. Marilyn–
    Thanks for picking up on the typo. I’ll have “Ernrig
    changed to “Enig.”
    She is very good—and deserves to have her name spelled right!

  10. Marilyn–
    Thanks for picking up on the typo. I’ll have “Ernrig
    changed to “Enig.”
    She is very good—and deserves to have her name spelled right!

  11. Brad–
    I completely agree that statins do offer a real benfit for a signifcant group of patients.
    I tried to make that clear when quoting Harvard’s Abramson in my first Cholesterol post (scroll down to part I, a week ago) saying thst statins do indeed offer real benfits (which in most cases, outweigh risks) for
    people, “under the age of 65, who already have had a heart attack or suffer from diabetes.”
    Others question whether women in this group enjoy bnefits that outweigh risks . . . but I decided to go with the broader definition of who benefits — while including the concerns about women.
    Bottom line: Given that statins are the most popular drug in his country, we just don’t know nearly as much as we should about exactly who they help–and the risks.
    Thanks for your comment–Maggie

  12. You mean Vytorin, which is a combination of simvastatin and ezetimibe. Actually, it was already known before the ENHANCE results were announced that ezetimibe did not have the same pleiotropic effects as statins. Landmesser, et al, Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans, Circulation. 2005;111:2356-2363. In this study, simvastatin improved endothelial function and ezetimibe did not. Fichtischerer et al., Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for “pleiotropic” functions of statin therapy, European Heart Journal (2006) 27, 1182-1190. In patients with stable coronary artery disease, neither ezetimibe nor ezetimibe combined with simvastatin improved endothelial function, while atorvastatin did improve endothelial function.
    There is no reason to think that elderly patients with heart disease benefit less from statins than younger patients with heart disease.
    Can you name the researchers who believe *all* of the benefits of statins are unrelated to LDL-lowering? I want to look at their research.

  13. With respect to the proposed clinical trial of aspirin versus a statin, are you suggesting a trial in people without coronary heart disease? Would this be a trial with clinical endpoints?

  14. Maggie,
    I hate to be so picky, but Dr. Abramson’s first name is John, not Jon.
    One thing to keep in mind is that there were no randomized placebo-controlled clinical endpoints trials of statins in people with heterozygous familial hypercholesterolemia (heFH). People with heFH usually have LDL levels in the mid-200s or above. When statins became available, it was considered unethical to put someone with LDL that high on a placebo. (There were some surrogate endpoints trials comparing low-dose statins with high-dose statins in heFH patients.)
    However, it is my impression that Dr. Abramson would support treating a least some people with heFH with a statin even if that person did not have heart disease or diabetes. I base this on the question & answer part of his website, which I looked at last year. Someone with heFH who was on a statin asked Dr. Abramson if he should stay on it. Dr. Abramson said that although there were no studies to answer the question, he guessed that the drug was helping prevent the person from developing heart disease (or words to that effect; I’m paraphrasing). I do not know Dr. Abramson, but since you do, you could ask him about this if you want.
    Also, I may be getting myself in trouble with Merrill, Bonnie, Mike and the other good people at CSPI, but I want to comment on an article in the latest issue of Nutrition Action Healthletter. (At the risk of embarrassing my teenage daughter, I just want to disclose that she goes to school with Bonnie’s daughter and Mike’s daughter.) The article is entitled “Cardio Quiz: Use Your Head to Protect Your Heart” (March 2008). The first sentence of the article states: “By the age of 40, your odds of having coronary heart disease are one out of three if you’re a woman and one out of two if you’re a man.” I think what they meant to say is the following, which I got off the AHA website: “The lifetime risk of developing CHD after age 40 is 49% for men and 32% for women.” I note that I have not tried to confirm whether the latter statement is accurate or not.
    The second thing I want to comment on relates to the discussion on page 11 on foods fortified with plant sterols. The article talks about how you can lower your LDL through consuming these foods, which include Minute Maid HeartWise Orange Juice, Benecol margarine, and so forth. As you can tell by the use of the word “HeartWise” in the name of the Minute Maid orange juice, foods with added plant sterols or stanols are allowed to advertise themselves as “heart healthy” or whatever. The problem with this from my point of view is that this claim was approved solely based on the fact that plant sterols and stanols lower LDL. No studies have been done that show that plant sterols and plant stanols lower the risk of heart attacks and strokes. (It seems unlikely that any such studies will ever be done.) For all we know, consuming these fortified foods may *cause* heart disease (or other bad effects). One reason for caution is that it is known that very high levels of plant sterols are harmful. We know this because there is a rare genetic disease called sitosterolemia in which plant sterols accumulate in the blood. This disease causes tendon xanthomas, arthritis and heart disease. It could be that the stuff is perfectly safe at the levels you would get from eating these fortified foods, but we just don’t know one way or the other.
    I realize Nutrition Action did not actually say that lowering your LDL by eating foods fortified with plant sterols is going to help prevent you from having a heart attack, but that’s the message that people are going to take away. Given that the CSPI crowd tends to be highly skeptical of unsupported advertising claims, the article (or that part of it) just surprised me a little.

  15. I fall into the male, under 65, who has had a heart attack. I take a low dose daily statin so in theory the advatages outweigh the risks.
    However if I was outside that group and and taking statins I think I would be frightened to stop taking them, as the subliminal message is that if I stop, it will only be a short time until I have another heart attack!

  16. Heart Attack Story–
    I know. I completely udnerstand why people would be afraid to stop taking statins–even if they are not in the smaller group that we now think can be helped. (People under 65 who have had a heart attack or suffer from diabetes)
    Note– this is what we Now think. This isn’t carved in stone. Medicine is an evolving science. This could change, in either direction, in the future..
    If I were one of those people, I woudl try to do a little online reserach to find out if there are doctors in my area who are
    a little more sketpical about statins (i.e. realize they are not for everyone), and then seek a second opinion.

  17. LT3Y–
    I hear you, and I appreciate the warning.
    But I spent eleven years writing investigative pieces for a financial magazine (Barron’s) that actually moved the stock market.
    This meant that I had to have a pretty good sense of when someone is trying to lie to me –or trying to “play” me.
    This site doesn’t attract many trolls. And when someone does come on who isn’t helpful, I find that other commenters just don’t respond.

  18. LT3Y–
    I hear you, and I appreciate the warning.
    But I spent eleven years writing investigative pieces for a financial magazine (Barron’s) that actually moved the stock market.
    This meant that I had to have a pretty good sense of when someone is trying to lie to me –or trying to “play” me.
    This site doesn’t attract many trolls. And when someone does come on who isn’t helpful, I find that other commenters just don’t respond.

  19. I’ve been suffering from memory loss for quite some time and after visiting http://www.photographic-memory.org, I have learnt so much more about memory loss, how to identify symptoms and exercises to improve my condition. I can see imporvement in my condition. You should try too if you are having the same problem as me.

  20. In case anyone is interested, Schering-Plough has filed an application with the FDA for a new indication for Zetia: pediatric primary hypercholesterolemia. I personally would be opposed to that at the current time.

  21. Maggie,
    I’m interested in your thoughts regarding the generalizability of the ENHANCE trial given my previous comment.

  22. Tom (and Marilyn you too may be intersted):
    This is the best account I have found–in plain English- of the degree to which you can or can’t generalize from Enhance. About 2/3 of the way down he gets into the issue that this was an unusual group which could help explain both lack of benefits and lack of adverse events. (These people were already on statins and were able to tolerate statins.)
    How much can we generalize from this study: Bottom line, we don’t know. But it doesn’t look like good news for makers of cholesterol-lowering drugs.
    Friday, January 18, 2008
    Uptake blockers do not improve on statins
    It has not been a very good couple of weeks for big pharma in the public eye. They’ve been taking a pounding in the political arena since the primary season finally got into full swing. Last week, we learned that today’s medicines, rather than funding tomorrow’s miracles, mostly finance power lunches with your cardiologist. And this week, Merck and Schering-Plough, after much delay, finally announced the results of a major study, called ENHANCE, that did not demonstrate any benefit to using the highly-touted drugs Vytorin and Zetia rather than a generic statin.
    Because almost everyone who owns a TV knows that Vytorin blocks both sources of cholesterol, and that “Zetia works differently”, the results seem particularly damning. The companies involved did not help this appearance by holding back the results so long, and indeed doing so may have exposed them to lawsuits from shareholders and customers. The study was primarily performed by imaging the carotid artery, and in this regard no statistically significant difference was observed between patients treated with Vytorin (statin + Zetia) and statin alone. Also, there was no statistically significant difference in the number of patients who died from cardiac events or strokes, or suffered non-fatal infarctions in the study. While vytorin lowered cholesterol levels by 56% after 24 months vs. the 41% lowering seen in the statin group, this did not translate into improved outcomes by any measure.
    So, is this a case of evil pharmaceutical companies trying to gouge consumers over worthless medications? Not exactly. Like every campaign promoting prescription drugs, commercials for Zetia and Vytorin oversold the benefits and did not sufficiently emphasize the risks of these medications. Their failure to improve outcomes in this study is troubling, but because adverse outcomes were so rare overall, it would be difficult to establish an effect one way or another. Also, this study was not geared towards measuring plaques and clots directly; rather it (indirectly) measured the effect of these drugs on atherosclerosis. The effect of uptake blockers on infarction rates was an incidental measurement.
    One important consideration when interpreting these results is that the study group was not constructed to resemble the general population. Rather, the study was performed on individuals who had familial hypercholesteremia, a genetic condition that causes greatly elevated levels of LDL in the bloodstream. Without the data in hand I of course cannot make a solid judgment, but one possibility that immediately suggests itself is that in this population even a significant diminution of LDL levels is not sufficient to improve outcomes. There’s just too much cholesterol for these uptake blockers to affect the outcome. In a normal individual with significantly lower levels of LDL Zetia and Vytorin might have a much greater effect.
    Moreover, all the individuals in this study were already taking statins—which contributed to the low rate of adverse outcomes. It may be that the marginal improvement from adding an LDL blocker on top of a statin simply isn’t that great. However, for individuals who cannot take a statin due to side effects, taking an uptake blocker might be a significant improvement over doing nothing. The study does not, as far as I can tell, speak to this possibility.
    There is always the possibility that this study points to completely unsuspected aspects of arterial disease. For instance, these results might indicate that once lesions form they attract cholesterol very strongly, and therefore only extreme reductions in circulating LDL can affect their growth. Alternately, this outcome may indicate that mechanisms unrelated to circulating lipids play a more significant role in determining plaque thickness than previously suspected. In light of the highly unusual population used as study subjects, any grand pronouncements in this regard are premature. If these findings are replicated in upcoming studies of greater duration on more representative samples, however, a substantial re-examination may be in order.
    The findings of the ENHANCE study don’t really indicate that you should burn your Vytorin prescription and go back to just a generic statin, but it does create doubt as to whether this approach will prove efficacious in the general population. Further study, promptly published, is called for, and it would be wise for Merck and Schering-Plough to pull their advertising campaigns for the time being. Doctors should also be less eager to prescribe Vytorin for patients who are responding well to statins alone, but for patients who are not improving greatly with statins (or cannot take them at all), then a prescription for Vytorin (or Zetia) would still seem to be justified. As always, the best approach is to exercise and eat healthy foods, though that’s much easier said than done.
    0

  23. Tom (and Marilyn you too may be intersted):
    This is the best account I have found–in plain English- of the degree to which you can or can’t generalize from Enhance. About 2/3 of the way down he gets into the issue that this was an unusual group which could help explain both lack of benefits and lack of adverse events. (These people were already on statins and were able to tolerate statins.)
    How much can we generalize from this study: Bottom line, we don’t know. But it doesn’t look like good news for makers of cholesterol-lowering drugs.
    Friday, January 18, 2008
    Uptake blockers do not improve on statins
    It has not been a very good couple of weeks for big pharma in the public eye. They’ve been taking a pounding in the political arena since the primary season finally got into full swing. Last week, we learned that today’s medicines, rather than funding tomorrow’s miracles, mostly finance power lunches with your cardiologist. And this week, Merck and Schering-Plough, after much delay, finally announced the results of a major study, called ENHANCE, that did not demonstrate any benefit to using the highly-touted drugs Vytorin and Zetia rather than a generic statin.
    Because almost everyone who owns a TV knows that Vytorin blocks both sources of cholesterol, and that “Zetia works differently”, the results seem particularly damning. The companies involved did not help this appearance by holding back the results so long, and indeed doing so may have exposed them to lawsuits from shareholders and customers. The study was primarily performed by imaging the carotid artery, and in this regard no statistically significant difference was observed between patients treated with Vytorin (statin + Zetia) and statin alone. Also, there was no statistically significant difference in the number of patients who died from cardiac events or strokes, or suffered non-fatal infarctions in the study. While vytorin lowered cholesterol levels by 56% after 24 months vs. the 41% lowering seen in the statin group, this did not translate into improved outcomes by any measure.
    So, is this a case of evil pharmaceutical companies trying to gouge consumers over worthless medications? Not exactly. Like every campaign promoting prescription drugs, commercials for Zetia and Vytorin oversold the benefits and did not sufficiently emphasize the risks of these medications. Their failure to improve outcomes in this study is troubling, but because adverse outcomes were so rare overall, it would be difficult to establish an effect one way or another. Also, this study was not geared towards measuring plaques and clots directly; rather it (indirectly) measured the effect of these drugs on atherosclerosis. The effect of uptake blockers on infarction rates was an incidental measurement.
    One important consideration when interpreting these results is that the study group was not constructed to resemble the general population. Rather, the study was performed on individuals who had familial hypercholesteremia, a genetic condition that causes greatly elevated levels of LDL in the bloodstream. Without the data in hand I of course cannot make a solid judgment, but one possibility that immediately suggests itself is that in this population even a significant diminution of LDL levels is not sufficient to improve outcomes. There’s just too much cholesterol for these uptake blockers to affect the outcome. In a normal individual with significantly lower levels of LDL Zetia and Vytorin might have a much greater effect.
    Moreover, all the individuals in this study were already taking statins—which contributed to the low rate of adverse outcomes. It may be that the marginal improvement from adding an LDL blocker on top of a statin simply isn’t that great. However, for individuals who cannot take a statin due to side effects, taking an uptake blocker might be a significant improvement over doing nothing. The study does not, as far as I can tell, speak to this possibility.
    There is always the possibility that this study points to completely unsuspected aspects of arterial disease. For instance, these results might indicate that once lesions form they attract cholesterol very strongly, and therefore only extreme reductions in circulating LDL can affect their growth. Alternately, this outcome may indicate that mechanisms unrelated to circulating lipids play a more significant role in determining plaque thickness than previously suspected. In light of the highly unusual population used as study subjects, any grand pronouncements in this regard are premature. If these findings are replicated in upcoming studies of greater duration on more representative samples, however, a substantial re-examination may be in order.
    The findings of the ENHANCE study don’t really indicate that you should burn your Vytorin prescription and go back to just a generic statin, but it does create doubt as to whether this approach will prove efficacious in the general population. Further study, promptly published, is called for, and it would be wise for Merck and Schering-Plough to pull their advertising campaigns for the time being. Doctors should also be less eager to prescribe Vytorin for patients who are responding well to statins alone, but for patients who are not improving greatly with statins (or cannot take them at all), then a prescription for Vytorin (or Zetia) would still seem to be justified. As always, the best approach is to exercise and eat healthy foods, though that’s much easier said than done.
    0

  24. Well, after having both read the article you provided and given some thought to the study population, I stand by my opinion that the study is useless in terms of the general population.
    As I wrote previously, in treating high cholesterol we aim for an absolute number, not a percent decrease. So, the fact that most people in the ENHANCE study ended up with cholesterols in the mid to upper 100s makes me seriously question the conclusion that the combination of a statin and a cholesterol uptake blocker (not an “LDL blocker”, btw) is of no use.

  25. Published on http://www.brainblogger.com:
    A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial
    While it seems that sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor
    Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor as monotherapy. The trial was named the ENHANCE trial, possibly because Zocor is generic now, and not a priority from a profit paradigm of its creator.
    After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.
    The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
    Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.
    The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.
    With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.
    This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.
    Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
    Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.
    This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others. For the sake of everyone.
    Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.
    “Waste no more time arguing what a good man should be. Be one.” — Marcus Aurelius
    Dan Abshear