Studies raise questions about drugs' efficacy against disease

A series of surprising findings about some of the most widely accepted assumptions in medicine has renewed debate about how aggressively doctors use drugs to prevent and treat some of the nation's leading health problems.

In addition to casting doubt on notions such as lowering cholesterol to prevent heart disease and normalizing blood sugar to protect diabetics, the studies involving well-known drugs such as Avandia and Vytorin have also rekindled concern about whether new medications are being tested adequately before being allowed on the market.

"We definitely need to pause and reassess our assumptions about what is best for patients," said Harlan M. Krumholz, a professor of medicine at Yale University. "Clearly we have more to learn."

No one is arguing that common strategies such as lowering cholesterol and blood sugar are unnecessary for many patients. But a number of researchers question whether too many Americans are being prescribed drugs, or combinations of drugs, including medications that have not been clearly shown to extend or improve life.

"There is a wake-up call in all of this," said Steven E. Nissen, a Cleveland Clinic cardiologist who often advises the government about new drugs. "We can't rely on assumptions. We don't always understand the biology of how drugs work as well as we think."

Others, however, warn against overreacting to a handful of studies, including some that are clearly preliminary. They argue that there is ample evidence to support current mainstream medical practice and that, if anything, too few patients are receiving recommended care.

"We have to be careful we don't get swept up by these swings and go too far one way or the other," said Sidney Smith, a professor of medicine at the University of North Carolina.

The first of the unexpected findings came in December 2006, when Pfizer abruptly terminated the development of a promising cholesterol drug. The drug, torcetrapib, was designed to cut the risk for heart disease by boosting "good" HDL cholesterol, a new strategy that was considered one of the most promising for fighting the nation's leading killer. But patients taking the compound in a large international study appeared to be at increased risk of dying.

About six months later, Nissen and his colleagues reported that the drug Avandia, which was widely used to lower diabetics' blood sugar levels, appeared to increase the risk of heart attacks.

Then, last month, Merck-Schering Plough Pharmaceuticals, a joint venture between the two companies, disclosed the results of a long-awaited study that suggested that its popular cholesterol-lowering drug Vytorin did not slow the progression of heart disease. That stirred uncertainty about whether driving cholesterol levels ever downward always helps and whether approving cholesterol-lowering drugs without showing that they reduce the risk for disease is appropriate.

Finally, 11 days ago, the National Institutes of Health announced that it was halting part of a major diabetes study after finding more deaths among patients who tried to push their blood sugar levels as close to normal as possible, raising more questions about whether lower is always better.

"I don't think you can leave these episodes and not shake your head and say, 'Wow, we really don't know as much as we think we do,'" Krumholz said.

Part of the problem, Krumholz, Nissen and others say, is how the government sometimes evaluates drugs, relying on "surrogate endpoints" instead of medications' ability to treat or prevent illnesses. Cholesterol-lowering drugs, for example, can be approved based on their power to cut cholesterol and not on whether they protect against heart attacks or strokes. Diabetes drugs can be approved based on whether they reduce a protein known as hemoglobin A1C &

a measure of blood sugar &

and not on their effect on complications caused by high blood sugar.

"There are a lot of things we do in this country where we treat these surrogate measures with very little evidence that we are actually treating the patient," said Nortin M. Hadler, a professor of medicine at the University of North Carolina.

If one drug prevents heart attacks by lowering cholesterol, that does not guarantee that another will do the same if it works differently, critics argue. And drugs may have unforeseen hazards that outweigh any benefits, or they may not produce secondary effects, such as lowering inflammation, that add to their usefulness.

"It's not necessarily how low you go, but how you get there," Nissen said.

Pharmaceutical industry representatives, however, argue that the use of surrogate endpoints has been shown to be reliable and helps speed valuable drugs to patients. It would take much longer and cost much more to conduct studies that measure the effect on diseases.

"If you took that approach, in all likelihood you'll be denying patients the opportunity to be successfully treated because you'll increase the time it would take to make a drug more widely available," said Alan Goldhammer, deputy vice president of regulatory affairs for the Pharmaceutical Research and Manufacturers of America, an industry trade group.

One solution, some experts say, may be to approve drugs based on surrogate measures but require drug companies to quickly follow up with studies to prove that the medications are helping patients.

"It should be done only with the proviso for following up with a trial to prove that the drug improved the things we really care about &

survival, heart attack, stroke &

major symptoms that make people feel better or live longer," Nissen said.

FDA officials said that is something the agency might consider but added that evaluating surrogate endpoints for drug approvals has been very useful.

"Some people don't respond adequately to available therapy," said Robert Temple of the FDA's center for drug evaluation and research. "You have to make a judgment about whether you want to have a way of treating that now or you want to wait five years, 10 years, who knows? That's a judgment that has to be made."

Some critics go even further than questioning the use of surrogate measures to approve drugs. They argue that the evidence supporting the widespread use of many cholesterol-lowering and blood-sugar-lowering drugs is weak, except for select patients. The popularity of these drugs has been driven by industry-funded studies that overstate their value for preventing disease, they argue, exposing far too many people to the potential risks of the medications themselves.

"What's going on here is our research enterprise is almost completely controlled by the pharmaceutical industry," said John Abramson, a clinical instructor at Harvard Medical School and author of the book "Overdosed America." "It's their job to create a need for their products. Their job is not to maximize public health."

Abramson, Hadler and others argue that more emphasis should be placed on improving cholesterol, blood pressure, blood sugar and other risk factors through lifestyle changes, such as eating better, maintaining a healthy weight and exercising more.

"People are making a ton of money by selling the drugs and the monitoring equipment," said Howard Brody, director of the Institute for the Medical Humanities at the University of Texas Medical Branch at Galveston. "It distracts our patients from what really matters more, which may be getting more exercise or making lifestyle changes that ultimately may be more beneficial than obsessing about their blood sugar or playing with their little monitor device."

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