When Mevacor, the first of a new class of cholesterol-lowering drugs known as statins, hit the market in 1987, doctors and patients were elated. Unlike other drugs available at the time, Mevacor was effective, had only minor but unpleasant side effects, and best of all, could be taken orally once a day.
Today, statins are some of the most widely prescribed drugs in the world: Estimates are that 5 million to 6 million people in the U.S. are taking them. And they've been blockbusters for drugmakers like Merck, whose Zocor logged $2.6 billion in sales in 1999, and Pfizer, whose Lipitor clocked $3 billion the same year.
But the promise of statins may be greater than first realized. Studies over the past two years suggest that these drugs may do more than just lower cholesterol. Although much of the research is still in the early stages, statins also seem to help the body prevent fractures, stroke, inflammation, osteoporosis, and dementia. They may even help in the treatment of immune diseases and avert the rejection of organ transplants.
The potential new uses are "a wonderful additional side effect," says cardiologist Michael Simons of Beth Israel Deaconess Medical Center. "Usually side effects turn out to be toxic, which is what limits the use of the drug. There are not a lot of examples where the side effects turn out to be beneficial," Simons explains.
A major question is whether these effects are a secondary result of lowered cholesterol, as opposed to a direct effect of the drugs themselves. Early indications suggest that statins work directly against these other maladies, at least in some cases. For example, Harvard Medical School neurologist Michael Moskowitz showed that statins protect against strokes in mice -- independent of any effect they might have on cholesterol.
The reason: Statins seem to boost the production of nitric oxide in the mice, and that dilates blood vessels and increases blood flow. Moskowitz suggests that this could explain their protective effect in dementia since researchers think some dementia is caused by nerve cells dying because of decreased blood flow. These independent effects of statins might also point the way to more direct drug targets. For example, the increased nitric-oxide production might also be used to prevent cell death.
In the November issue of the British medical journal The Lancet, researchers from the University of Massachusetts Medical School found that patients who took statins to lower cholesterol also reduced their risk of dementia by 71%, compared with people who had untreated high cholesterol or were treated with other lipid-lowering drugs.
It was in the early 1990s that researchers first started to suspect that statins might be doing more than lowering cholesterol. They found that patients taking statins lived longer and had fewer heart attacks and strokes, which couldn't be explained by just lowered cholesterol. "Clearly they have other effects," says Simons.
Then, in a study published in the journal Science in December, 1999, a team at OsteoScreen in San Antonio, Tex., found that the complex statin molecules promote bone formation by turning on a gene in bone-forming cells called osteoblasts. Researchers determined that a combination of two statins, Zocor and Mevacor, increased new bone formation in mice by about 50% after five days of treatment.
Those results buttressed findings in two studies published in The Journal of the American Medical Association and The Lancet last June, which found that the risk of fractures for elderly patients was cut by half when they took statins.
Current osteoporosis drugs only prevent further bone loss instead of building new bone. So "if it can be proven in randomized trials that statins have a beneficial effect on osteoporosis, that would be a major step forward," says Gregory Mundy, the leader of the OsteoScreen study.
Osteoporosis affects 30 million people in the U.S. and 100 million worldwide. "If you've got these statins that will protect against heart disease and also against osteoporosis, you've got a potentially huge market," says Antonio Gotto, dean of Cornell University Medical School. Both Merck, maker of Mevacor and Zocor, and Pfizer, maker of Lipitor, are now conducting early studies of statins' effect on bone formation.
Merck is also taking advantage of its already vast prescription base of statins to mount studies of other newly recognized side effects. One will look at the effect Zocor has on bone density as part of a trial at Oxford University. But the main goal of the trial is to examine how well statins prevent coronary heart disease and stroke in high-risk patients.
It doesn't end there. In a paper published in the December, 2000, issue of the journal Nature Medicine, statins were shown to suppress some harmful immune-system responses. That might make them useful in treating immune-system diseases or in preventing the body from rejecting transplanted organs, says statin expert Wulf Palinksi of the University of California at Los Angeles Medical School.
Despite these tantalizing findings, analysts don't see statin manufacturers cashing in on new uses of the drugs for at least a few more years. "The extra indications would be an added benefit," says Leonard Yaffe, an analyst at Banc of America Securities. "But we think that the growth is going to be driven from the regulations that will encourage tighter control of cholesterol, as well as the fact that people will likely be treated at higher doses."
Sales of statin as an over-the-counter drug could provide a big revenue boost, he says. The drugmakers are now pushing for the Food & Drug Administration to approve these types of sales. That could be good news for aging Americans who suffer from such conditions as osteoporosis, stroke, or dementia in their later years.
By Alka Agrawal in Stamford, Conn.
Edited by Alex Salkever