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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 Carey

This Issue

January 28, 2008

Lipitor

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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, M.

, 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, 's team was analyzing

evidence from years of trials with statins and not liking what it

found.

Yes, 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 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 . Based on the evidence, and the fact that Winn

didn't actually have angina, 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. 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 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. 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.