Cholesterol buzz

For those still craving more perspectives on cholesterol and statins — the cover story of Business Week is devoted to this very issue. The articles offer information that has not been reported anywhere else. Here's a glimpse at this special issue.

The cover article begins by sharing the findings of Dr. James M. Wright, professor at the University of British Columbia and director of the government-funded Therapeutics Initiative. This organization reviews the raw data on drug trials to determine their effectiveness. Dr. Wright had analyzed years of statin trials and learned that for patients who’d already had heart attacks, they reduced the chances somewhat of a recurrence, but:

Do Cholesterol Drugs Do Any Good?

Research suggests that, except among high-risk heart patients, the benefits of statins such as Lipitor are overstated

...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....

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... 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 revealed results of a trial in which one popular cholesterol-lowering drug, a statin, was fortified by another, Zetia... forcing down patients' cholesterol further... But even with two years of treatment... brought no health benefit.

While some cholesterol-lowering drugs seem to help some heart disease patients, it’s not consistently related to changes in their cholesterol levels and even the experts aren’t sure how statins might actually work. Business Week went on to explain:

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."... 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...

[B]ecause 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....

The article discusses at length the debates surrounding major public preventive health efforts that may only benefit a few, while exposing large numbers of people to side effects and paying large amounts for drugs. Putting NNTs into perspective, while also explaining the difference between treating surrogate endpoints and affecting actual clinical outcomes, they wrote:

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."...

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 consumer confusion? The article explains how benefits are advertised and described in the best light by using relative risks, while side effects are downplayed. The problem drug companies face 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,” it said. Many question cholesterol as a cause, and hence a preventative for heart disease, however, as it explained:

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." ... Add it all together, and “current evidence supports ignoring LDL cholesterol altogether," says [Dr. Rodney A. Hayward, professor of internal medicine at the University of Michigan Medical School.]