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BusinessWeek
January 17, 2008

Do Cholesterol Drugs Do Any Good?
Research suggests that, except among high-risk heart patients, the
benefits of statins such as Lipitor are overstated
By John Carey

Martin Winn's cholesterol level was inching up. Cycling up hills, he
felt chest pain that might have been angina. So he and his doctor
decided he should be on a cholesterol-lowering medication called a
statin. He was in good company. Such drugs are the best-selling
medicines in history, used by more than 13 million Americans and an
additional 12 million patients around the world, producing $27.8
billion in sales in 2006. Half of that went to Pfizer (PFE) for its
leading statin, Lipitor. Statins certainly performed as they should
for Winn, dropping his cholesterol level by 20%. "I assumed I'd get a
longer life," says the retired machinist in Vancouver, B.C., now 71.
But here the story takes a twist. Winn's doctor, James M. Wright, is
no ordinary family physician. A professor at the University of British
Columbia, he is also director of the government-funded Therapeutics
Initiative, whose purpose is to pore over the data on particular drugs
and figure out how well they work. Just as Winn started on his
treatment, Wright's team was analyzing evidence from years of trials
with statins and not liking what it found.

Yes, Wright saw, the drugs can be life-saving in patients who already
have suffered heart attacks, somewhat reducing the chances of a
recurrence that could lead to an early death. But Wright had a
surprise when he looked at the data for the majority of patients, like
Winn, who don't have heart disease. He found no benefit in people over
the age of 65, no matter how much their cholesterol declines, and no
benefit in women of any age. He did see a small reduction in the
number of heart attacks for middle-aged men taking statins in clinical
trials. But even for these men, there was no overall reduction in
total deaths or illnesses requiring hospitalization--despite big
reductions in "bad" cholesterol. "Most people are taking something
with no chance of benefit and a risk of harm," says Wright. Based on
the evidence, and the fact that Winn didn't actually have angina,
Wright changed his mind about treating him with statins--and Winn, too,
was persuaded. "Because there's no apparent benefit," he says, "I
don't take them anymore."

Wait a minute. Americans are bombarded with the message from doctors,
companies, and the media that high levels of bad cholesterol are the
ticket to an early grave and must be brought down. Statins, the
message continues, are the most potent weapons in that struggle. The
drugs are thought to be so essential that, according to the official
government guidelines from the National Cholesterol Education Program
(NCEP), 40 million Americans should be taking them. Some researchers
have even suggested--half-jokingly--that the medications should be put
in the water supply, like fluoride for teeth. Statins are sold by
Merck (MRK) (Mevacor and Zocor), AstraZeneca (AZN) (Crestor), and
Bristol-Myers Squibb (BMY) (Pravachol) in addition to Pfizer. And it's
almost impossible to avoid reminders from the industry that the drugs
are vital. A current TV and newspaper campaign by Pfizer, for
instance, stars artificial heart inventor and Lipitor user Dr. Robert
Jarvik. The printed ad proclaims that "Lipitor reduces the risk of
heart attack by 36%...in patients with multiple risk factors for heart
disease."

So how can anyone question the benefits of such a drug?

For one thing, many researchers harbor doubts about the need to drive
down cholesterol levels in the first place. Those doubts were
strengthened on Jan. 14, when Merck and Schering-Plough (SGP) revealed
results of a trial in which one popular cholesterol-lowering drug, a
statin, was fortified by another, Zetia, which operates by a different
mechanism. The combination did succeed in forcing down patients'
cholesterol further than with just the statin alone. But even with two
years of treatment, the further reductions brought no health benefit.

DOING THE MATH

The second crucial point is hiding in plain sight in Pfizer's own
Lipitor newspaper ad. The dramatic 36% figure has an asterisk. Read
the smaller type. It says: "That means in a large clinical study, 3%
of patients taking a sugar pill or placebo had a heart attack compared
to 2% of patients taking Lipitor."

Now do some simple math. The numbers in that sentence mean that for
every 100 people in the trial, which lasted 3 1/3 years, three people
on placebos and two people on Lipitor had heart attacks. The
difference credited to the drug? One fewer heart attack per 100
people. So to spare one person a heart attack, 100 people had to take
Lipitor for more than three years. The other 99 got no measurable
benefit. Or to put it in terms of a little-known but useful statistic,
the number needed to treat (or NNT) for one person to benefit is 100.

Compare that with, say, today's standard antibiotic therapy to
eradicate ulcer-causing H. pylori stomach bacteria. The NNT is 1.1.
Give the drugs to 11 people, and 10 will be cured.

A low NNT is the sort of effective response many patients expect from
the drugs they take. When Wright and others explain to patients
without prior heart disease that only 1 in 100 is likely to benefit
from taking statins for years, most are astonished. Many, like Winn,
choose to opt out.

Plus, there are reasons to believe the overall benefit for many
patients is even less than what the NNT score of 100 suggests. That
NNT was determined in an industry-sponsored trial using carefully
selected patients with multiple risk factors, which include high blood
pressure or smoking. In contrast, the only large clinical trial funded
by the government, rather than companies, found no statistically
significant benefit at all. And because clinical trials themselves
suffer from potential biases, results claiming small benefits are
always uncertain, says Dr. Nortin M. Hadler, professor of medicine at
the University of North Carolina at Chapel Hill and a longtime drug
industry critic. "Anything over an NNT of 50 is worse than a lottery
ticket; there may be no winners," he argues. Several recent scientific
papers peg the NNT for statins at 250 and up for lower-risk patients,
even if they take it for five years or more. "What if you put 250
people in a room and told them they would each pay $1,000 a year for a
drug they would have to take every day, that many would get diarrhea
and muscle pain, and that 249 would have no benefit? And that they
could do just as well by exercising? How many would take that?" asks
drug industry critic Dr. Jerome R. Hoffman, professor of clinical
medicine at the University of California at Los Angeles.

Drug companies and other statin proponents readily concede that the
number needed to treat is high. "As you calculated, the NNT does come
out to about 100 for this study," said Pfizer representatives in a
written response to questions. But statin promoters have several
counterarguments. First, they insist that a high NNT doesn't always
mean a drug shouldn't be widely used. After all, if millions of people
are taking statins, even the small benefit represented by an NNT over
100 would mean thousands of heart attacks are prevented.

That's a legitimate point, and it raises a tough question about health
policy. How much should we spend on preventative steps, such as the
use of statins or screening for prostate cancer, that end up
benefiting only a small percentage of people? "It's all about whether
we think the population is what matters, in which case we should all
be on statins, or the individual, in which case we should not be,"
says Dr. Peter Trewby, consultant physician at Darlington Memorial
Hospital in Britain. "What is of great value to the population can be
of little benefit to the individual." Think about buying a raffle
ticket for a community charity. It's for a good cause, but you are
unlikely to win the prize.

Statin proponents also argue that when NNTs are calculated after the
drugs have been taken for just three or five years, they're
misleadingly high. Pfizer says that even though only one heart attack
was prevented per 100 people in its trial, "it may be a possibility
that several or even all [100] benefit" by reducing their risk of a
future heart attack. And the benefit grows when the drugs are taken
for more years, backers believe. "It does not make sense to take a
statin for five years," says Dr. Scott M. Grundy, chair of the NCEP
committee that called for more aggressive statin treatment and
director of the Center for Human Nutrition at the University of Texas
Southwestern Medical Center at Dallas. "When you take a cholesterol-
lowering drug, it is a huge commitment," he says. "You take it for
life." Grundy figures the chances of having a heart attack over the
course of a lifetime are about 30% to 50% (higher for men than women).
Statins, he argues, reduce that risk by about 30%. As a result, taking
the drugs for 30 years or more would bring 9 to 15 fewer heart attacks
for every 100 people. So only 7 to 11 people would have to take the
drugs for life for one to benefit.

Critics reply that this rosier picture requires several leaps of
faith. A 30% reduction in heart attacks "is the best-case scenario and
not found in many of the studies," says Wright. What's more, statins
have been in use now for 20 years, and there's little evidence yet
that the NNT decreases the longer people take the drug. Most
important, the statin trials of people without existing heart disease
showed no reduction in deaths or serious health events, despite the
small drop in heart attacks. "We should tell patients that the reduced
cardiovascular risk will be replaced by other serious illnesses," says
Dr. John Abramson, clinical instructor at Harvard Medical School and
author of Overdosed America.

LIFESTYLE CHANGES

In its written response, Pfizer did not challenge this key assertion:
that the drugs do not reduce deaths or serious illness in those
without heart disease. Instead, the company repeated that statins
reduce the "risk of death from coronary events" and added that
Wright's analysis was not published in a peer-reviewed scientific
journal.

If we knew for sure that a medicine was completely safe and
inexpensive, then its widespread use would be a no-brainer, even with
a high NNT of 100. But an estimated 10% to 15% of statin users suffer
side effects, including muscle pain, cognitive impairments, and sexual
dysfunction. And the widespread use of statins comes at the cost of
billions of dollars a year, not just for the drugs but also for
doctors' visits, cholesterol screening, and other tests. Since health-
care dollars are finite, "resources are not going to interventions
that might be of benefit," says Dr. Beatrice A. Golomb, associate
professor of medicine at the University of California at San Diego
School of Medicine.

What would work better? Perhaps urging people to switch to a
Mediterranean diet or simply to eat more fish. In several studies,
both lifestyle changes brought greater declines in heart attacks than
statins, though the trials were too small to be completely persuasive.
Being physically fit is also important. "The things that really work
are lifestyle, exercise, diet, and weight reduction," says UCLA's
Hoffman. "They still have a big NNT, but the cost is much less than
drugs and they have benefits for quality of life."

Difficult risk-benefit questions surround most drugs, not just
statins. One dirty little secret of modern medicine is that many drugs
work only in a minority of people. "There's a tendency to assume drugs
work really well, but people would be surprised by the actual
magnitude of the benefits," says Dr. Steven Woloshin, associate
professor of medicine at Dartmouth Medical School.

A good example: Beta-blockers are seen as essential in treating
congestive heart failure. Yet studies show that an average of 24
people must take the drugs for seven months to prevent one
hospitalization from heart failure (thus, an NNT of 24). And 40 people
must take it to prevent one death (NNT of 40). "Even for medications
we consider effective, we see NNTs in the 20s or higher," says Dr.
Henry C. Barry, associate professor of family medicine at Michigan
State University College of Human Medicine.

For many other drugs, the NNTs are large. Take Avandia,
GlaxoSmithKline's (GSK) drug for preventing the deadly progression of
diabetes. The blockbuster, with $2.6 billion in U.S. sales in 2006,
made headlines in 2007 when an analysis of clinical trial data showed
it increased the risk of heart attacks. The largely untold story:
There's little evidence the drug actually helps patients. Yes, Avandia
is very good at lowering blood sugar, just as statins lower
cholesterol levels. But that doesn't translate into preventing the
dire consequences of diabetes, including heart disease, strokes, and
kidney failure. Clinical trials "failed to find a significant
reduction in cardiovascular events even with excellent glucose
control," wrote Dr. Clifford J. Rosen, chair of the Food & Drug
Administration committee that evaluated Avandia, in a recent
commentary in The New England Journal of Medicine. "Avandia is almost
the poster child for everything wrong with our system," says UCLA's
Hoffman. "Its NNT is close to infinite."

Regarding Avandia, Dr. Murray Stewart, Glaxo's vice-president for
clinical development, says that the evidence of its benefits against
heart disease and other major complications of diabetes "is still
inconclusive." But the drug has other benefits, he argues, such as
delaying the need to take insulin.

When other medications widely believed to be effective were put to the
test of a clinical trial, they flunked. Hormone replacement therapy
didn't protect against heart disease. Anti-psychotic drugs were
actually less effective than a placebo in reducing aggression in
patients with intellectual disability.

The truth about drugs' effectiveness wouldn't be as worrisome if
consumers and doctors had an accurate picture of the state of
knowledge and could make rational decisions about treatments. Studies
by Darlington Hospital's Trewby, UBC's Wright, and others, however,
show that patients expect far more than what the drugs actually
deliver.

Why the mismatch? Some of the blame goes to the way results are
presented. A 36% decline in heart attacks sounds more dramatic and
important than an NNT of 100. "It comes as a shock to see the NNT,"
says Dr. Barnett S. Kramer, director of the office of medical
applications of research at the National Institutes of Health. Drug
companies take full advantage of this; they advertise the big
percentage drops in, say, heart attacks, while obscuring the NNT. But
when it comes to side effects, they flip-flop the message, dismissing
concerns by saying only 1 in 100 people suffers a side effect, even if
that represents a 50% increase. "Many physicians don't know the NNT,"
says Dr. Darshak Sanghavi, a pediatric cardiologist and assistant
professor of pediatrics at the University of Massachusetts Medical
School and a fan of using NNTs.

The whole statin story is a classic case of good drugs pushed too far,
argues Dr. Howard Brody, professor of family medicine at the
University of Texas Medical Branch at Galveston. The drug business is,
after all, a business. Companies are supposed to boost sales and
returns to shareholders. The problem they face, though, is that many
drugs are most effective in relatively small subgroups of sufferers.
With statins, these are the patients who already have heart disease.
But that's not a blockbuster market. So companies have every incentive
to market their drugs as being essential for wider groups of people,
for whom the benefits are, by definition, smaller. "What the shrewd
marketing people at Pfizer and the other companies did was spin it to
make everyone with high cholesterol think they really need to reduce
it," says Dr. Bryan A. Liang, director of the Institute of Health Law
Studies at the California Western School of Law and co-director of the
San Diego Center for Patient Safety. "It was pseudo-science, never
telling you the bottom-line truth, [which is] that the drugs don't
help unless you have pre-existing cardiovascular disease." The
marketing worked, Liang says, "even in the face of studies and people
screaming and yelling, myself included, that it is not based on
evidence."

Pfizer replies that the industry is "highly regulated" and that every
message in ads and marketing "accurately reflects Lipitor's labeling
and the data from the clinical trials."

Drugmakers, however, do make sure that the researchers and doctors who
extol the benefits of medications are well compensated. "It's almost
impossible to find someone who believes strongly in statins who does
not get a lot of money from industry," says Dr. Rodney A. Hayward,
professor of internal medicine at the University of Michigan Medical
School. The NCEP's 2004 guideline update garnered headlines by
recommending lower targets for bad cholesterol, which would put more
Americans on the drugs. But there was also a heated controversy in the
medical community over the fact that 8 of the 9 experts on the panel
had financial ties to industry. "The guideline process went awry,"
says Michigan State's Barry. He and 34 other experts sent a petition
of protest to the National Institutes of Health, saying the evidence
was weak and the panel members were biased by their ties to
companies.

EASY METRICS

The appearance of conflict of interest is "very important to
organizations like ours, and we are all taking it seriously," responds
NIH official and NCEP coordinator Dr. James I. Cleeman. "But the facts
of the science were entirely correct."

Yet Cleeman's confidence is not universally shared. To statin critics,
Americans have come to rely too much on easy-to-grasp health markers.
People like to have a metric, such as cholesterol levels, that can be
monitored and altered. "Once you tell people a number, they will be
fixated on the number and try to get it better," says University of
Texas' Brody. Moreover, "the American cultural norm is that doing
something makes us feel better than just watching and waiting," says
Barry. That applies to doctors as well. They are being pushed by the
national guidelines, by patients' own requests, and by pay-for-
performance rules that reward physicians for checking and reducing
cholesterol. "I bought into it," Brody says. Not to do so is almost
impossible, he adds. "If a physician suggested not checking a
cholesterol level, many patients would stomp out of the office
claiming the guy was a quack."

Yet Brody changed his mind. "I now see it as myth that everyone should
have their cholesterol checked," he says. "In hindsight it was
obvious. Duh! Why didn't I see it before?"

Cholesterol is just one of the risk factors for coronary disease. Dr.
Ronald M. Krauss, director of atherosclerosis research at the Oakland
Research Institute, explains that 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. "When you look at patients with heart disease, their
cholesterol levels are not that [much] higher than those without heart
disease," he says. 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.

Moreover, says MSU's Barry, cholesterol-lowering medications other
than statins "do not prevent heart attacks or strokes." Take Zetia,
which blocks absorption of cholesterol from the intestines. Marketed
by Merck and Schering-Plough, the drug brought in $1.5 billion in
2006, with sales climbing 25% in the first half of 2007, says IMS
Health (RX). The companies combined it with a statin to create a drug
called Vytorin, with over $2 billion in sales in 2007.

In an eagerly awaited trial completed in 2006, the companies compared
Zetia plus a statin with a statin alone in patients with genetically
high cholesterol. But the drugmakers delayed announcing the results,
prompting scientific outrage and the threat of a congressional
investigation. The results, finally revealed on Jan. 14, showed the
combination of Zetia and a statin reduced LDL levels more than the
statin alone. But that didn't bring added benefits. In fact, the
patients' arteries thickened more when taking the combination than
with the statin alone. Skip Irvine, a spokesman for the joint venture,
says the study was small and insists there's a "strong relationship
between lowering LDL cholesterol and reducing cardiovascular death."

IRRELEVANT LDL?

If cholesterol lowering itself isn't a panacea, why is it that statins
do work for people with existing heart disease? In his laboratory at
the Vascular Medicine unit of Brigham & Women's Hospital in Cambridge,
Mass., Dr. James K. Liao began pondering this question more than a
decade ago. The answer, he suspected, was that statins have other
biological effects.

Since then, Liao and his team have proved this theory. First, a bit of
biochemistry. Statin drugs work by bollixing up the production of a
substance that gets turned into cholesterol in the liver, thus
reducing levels in the blood. But the same substance turns out to be a
building block for other key chemicals as well. Think of a toy factory
in which the same plastic is fashioned into toy cars, trucks, and
trains. Reducing production of the plastic cuts not only the output of
toy cars (cholesterol) but also trucks and trains. In the body, these
additional products are signaling molecules that tell genes to turn on
or off, causing both side effects and benefits.

Liao has charted some of these biochemical pathways. His recent work
shows that one of the trucks, as it were--a molecule called Rho-kinase--
is key. By reducing the amount of this enzyme, statins dial back
damaging inflammation in arteries. When Liao knocks down the level of
Rho-kinase in rats, they don't get heart disease. "Cholesterol
lowering is not the reason for the benefit of statins," he concludes.

The work also offers a possible explanation of why that benefit is
mainly seen in people with existing heart disease and not in those who
only have elevated cholesterol. Being relatively healthy, their Rho-
kinase levels are normal, so there is little inflammation. But when
people smoke or get high blood pressure, their Rho-kinase levels rise.
Statins would return those levels closer to normal, counteracting the
bad stuff.

Add it all together, and "current evidence supports ignoring LDL
cholesterol altogether," says the University of Michigan's Hayward. In
a country where cholesterol lowering is usually seen as a matter of
life and death, these are fighting words. A prominent heart disease
physician and statin booster fumed at a recent meeting that "Hayward
should be held accountable in a court of law for doing things to kill
people," Hayward recounts. NECP's Cleeman adds that, in his view, the
evidence against Hayward is overwhelming.

But while the new analyses may rile those who have built careers
around the need to reduce LDL, they also point the way to using
statins more effectively. Surprisingly, both sides in the debate agree
on the general approach. For anyone worried about heart disease, the
first step should always be a better diet and increased physical
activity. Do that, and "we would cut the number of people at risk so
dramatically" that far fewer drugs would be needed, says Krauss. For
those people who still might benefit from treatment, a recent analysis
by Hayward shows that statins might better be prescribed based on
patients' risk of heart disease, not on their LDL cholesterol levels.
The higher the risk, the better the drugs seem to work. "If two
patients have the same risk, the evidence says they get the same
benefit from statins, whatever their LDL levels," Hayward says.

Ways to fine-tune this approach may be coming soon. The company that
first sequenced the human genome, Celera Group (CRA), has found a
genetic variation that predicts who benefits from the drugs. Perhaps
60% of the population has it, says Dr. John Sninsky, vice-president of
discovery research, and for everyone else, the NNT is sky-high. "It
does not relate at all to your cholesterol level," Sninsky adds.

If the drugs were used more rationally, drugmakers would take a hit.
But the nation's health and pocketbook might be better off. Could it
happen? Will data on NNTs, the weak link to cholesterol, and knowledge
of genetic variations change what doctors do and what patients
believe? Not until the country changes the incentives in health care,
says UCLA's Hoffman. "The way our health-care system runs, it is not
based on data, it is based on what makes money."

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BusinessWeek
January 17, 2008

In the Real World, a Slew of Side Effects from Statins
By John Carey

A tennis-playing 68-year-old, Dr. H. Denman Scott was talked into
taking Lipitor in 2006 by his doctor because his "bad" cholesterol
(LDL) was a borderline 130. "I had no symptoms," he says, but he
followed the doctor's advice, and the drug dropped his LDL to 60. Then
Scott, a retired professor of medicine, began to have muscle pain.
After 10 months on the drug, he woke one morning with paralyzing
soreness. "I thought it was Lipitor-related," he says. "I'd seen it in
a lot of people I had taken care of over the years." Scott stopped
taking the drug, and two months later the aches went away.

In clinical trials of statins, side effects were relatively rare. But
many doctors believe they are more common in the real world,
afflicting perhaps as many as 15% of patients. After muscle aches,
prominently mentioned on Lipitor's label, common complaints include
cognitive problems ranging from mild confusion to loss of memory.
Former astronaut and retired family doctor Duane Graveline says that
he "descended into the black pit of amnesia" both times he was put on
Lipitor, prompting him to write a book and set up a Web site on
statins' side effects.

One trial also showed an association between statin use and cancer.
Proponents argue that was an anomaly. "You need to look at the big
picture rather than worrying yourself to death over individual
trials," says Dr. Scott Grundy, the lead author of national guidelines
for statin use and who has received honoraria from Pfizer (PFE). But
the big picture is still fuzzy. The safety of statins in long-term use
"is an incredibly important question for which we have very little
data," says Dr. Beatrice Golomb of the University of California at San
Diego.

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