A Heart Drug Far Surpasses Expectations [WPost]
By David Brown
Washington Post Staff Writer
Saturday, May 19, 2001; Page A1
There was a time when medicines claiming to do more than one thing – tame the bowels, stop the headache, regrow the hair – were guaranteed to be snake oil. A person could be confident such medicines did nothing.
Eventually, exceptions appeared. A blood-pressure drug called minoxidil, weirdly, also grows hair on people's heads. Tetracycline antibiotics kill bacteria and relieve rheumatoid arthritis. Aspirin kills pain, cuts inflammation, reduces the risk of heart attack and probably helps prevent some forms of cancer.
Now, a class of drugs called "statins" is laying a claim to be the all-time champion of unanticipated benefits.
Statins originally were approved as treatment for high cholesterol, but it's now clear they help prevent heart attacks and strokes. They probably reduce a person's risk for developing diabetes and Alzheimer's disease. They lower the rate of rejection in people with certain organ transplants. They eventually could have a role in treating some cancers.
New evidence of their effects seems to tumble out of research laboratories every few months. Already, though, they are something genuinely rare – a family of pharmaceuticals whose benefits were seriously underestimated, rather than seriously exaggerated, when they arrived on the market.
"Some of my colleagues feel it should be put in the water supply," said David A. Drachman, a neurologist at the University of Massachusetts Medical School. He was joking, of course – but not entirely. Last year Drachman published a study showing that statins reduced the risk of dementia in British adults.
The drugs are already best-sellers, prescribed to about 12 million Americans. Of the top 10 drugs in sales value in the United States last year, two were statins – atorvastatin (in second place) and simvastatin (fourth).
More people should be taking them, many experts believe, based on the prevalence of heart disease. Just this week, the National Institutes of Health issued new cholesterol guidelines that called for tripling the number of Americans taking cholesterol-lowering drugs.
The number may grow when the oldest statin, Merck's lovastatin, goes off patent later this year and generic versions are made. Their popularity, however, could rise dramatically if research reveals more possible uses.
"I would never have dreamed it, and I am not predicting it at this stage. But it is conceivable . . . you could practically give it to every older person," said Antonio M. Gotto, a cardiologist and dean of the Weill Medical School of Cornell University.
The original statins were extracted from fungi. (Two of the five now on the market are wholly man-made.) They all work by inhibiting, but not completely blocking, the body's synthesis of cholesterol – a substance essential to cell membranes and the starting material for many hormones, including the sex hormones, such as estrogen and testosterone.
When the FDA approved lovastatin, the first in the class, in 1987, it did so because the drug reduced the form of cholesterol responsible for the fatty deposits that narrow arteries. Researchers assumed – but couldn't prove – the drugs would lower a person's risk for heart attack. It had been difficult, in fact, to show that other cholesterol-lowering drugs already on the market reduced heart attacks and saved lives.
Soon enough, there was no doubt.
A series of large drug trials, done in the United States and Europe, proved that statins reduced the rate of heart attack by about one-third. That was true both for people who had already had a heart attack, and for people at high risk for one.
Something, though, was very strange in these studies. Statins worked fast – too fast for cholesterol reduction to be the full reason for their benefit.
After just a year, heart attack survivors taking the drugs had a 25 percent lower risk of death than survivors not taking the drugs. A study published this month showed a slight benefit even as early as four months. Cholesterol-filled plaques blocking arteries don't shrink that quickly, no matter how low a person's cholesterol goes.
Researchers began mining these heart attack studies (and the blood samples saved from the patients). They dug out a lot of unsuspected nuggets of data.
For example, heart attack survivors benefited from statins even when they started with normal cholesterol levels. The same was true for people whose cholesterol levels fell only slightly while taking the drugs. Curiously, the drugs seemed to reduce something called "C-reactive protein," a bloodstream sign of inflammation that was a yardstick for heart attack risk.
Furthermore, statins didn't just help prevent heart attacks. People randomly assigned to take them in the studies had fewer strokes. As with heart attacks, the reduction was about 30 percent. This was remarkable because high cholesterol isn't a big risk factor for stroke. High blood pressure is – but statins don't affect blood pressure.
The ability to reduce a person's risk of heart attack and stroke – the most common and third most common causes of death in the United States – wasn't bad for a single pill. But it wasn't all.
In a study of 6,000 Scottish men with high cholesterol but no diagnosed heart disease, those assigned to take a drug called pravastatin were 30 percent less likely to develop adult-onset diabetes over a course of about four years than those taking placebo. The risk in both groups, however, was very small.
Another study showed that recipients of heart transplants randomly assigned to take pravastatin suffered fewer serious episodes of organ rejection, and had a smaller chance of dying in the 12 months after surgery compared to patients not taking the drug.
In perhaps the most unusual finding, Drachman and his Massachusetts colleagues last year reported a relationship between statin use and dementia in British adults over age 50 whose health records are part of a national research data base. The people taking a statin had one-third the risk of developing dementia as Britons who had normal cholesterol levels and weren't on the drug.
There has been debate for years about the extent of a connection between atherosclerosis – clogged arteries – and dementia. A study published last month suggests that here, too, statins may be having an effect apart from their ability to decrease cholesterol. A team of German researchers reported that nerve cells exposed to a statin in laboratory dishes produced smaller amounts of a substance called "A-beta protein," which accumulates in the brains of people with Alzheimer's disease.
What could be going on to explain these seemingly unrelated effects? The answer lies in the biochemical chain of events in which statins do their work.
Every statin drug partially inhibits the third step of the 14-step process by which cells construct cholesterol from small, starter molecules. When that early step is blocked by 50 percent or more, a cell produces substantially less cholesterol.
It's now clear, however, that a group of compounds called "isoprenoids," made in the middle of the cholesterol assembly line, have functions of their own. A fraction is siphoned off and used as molecular bolts to attach special signaling proteins to cell membranes.
Statins not only reduce the supply of cholesterol, they also reduce the supply of isoprenoids. That, in turn, has a cascade of effects on the signals a cell sends to other cells, and to itself. The end results include these:
Statins boost the production of nitric oxide (NO) in blood vessel walls. That boosts blood flow and slows the formation of clots – two things that help prevent a heart attack or minimize an attack's damaging effects. They reduce the growth and movement of smooth-muscle cells, which are major constituents of artery-clogging "plaques." They reduce the inflammation in plaques that makes them more likely to burst open and precipitate a heart attack.
Statins also alter the immune system in subtle ways. They reduce the activation of an important class of cells called T-lymphocytes – an action that probably explains the drugs' effects on diabetes and organ rejection. Curiously, the drugs also trigger suicide in some cancer cells, including one type of leukemia, cervical cancer, and several tumors of children.
So far, the anti-cancer effect has been seen only in laboratory studies, and only when cells are exposed to a drug at doses far higher than what people take to lower cholesterol. Studies are underway testing the safety of high-dose statin treatment in cancer patients.
"This research is really at its infancy," said Linda Penn, an immunologist at Toronto's Princess Margaret Hospital and the Ontario Cancer Institute, who reported the cancer cell experiments early this year. "But the excitement is that because statins are on the market, we can fast-track their testing, unlike many of the other novel cancer drugs coming down the line."
Not every once-touted action of the drugs has panned out.
Experiments several years ago showed that statins stimulated bone formation in rats, suggesting the drugs might be useful for osteoporosis. But two large studies, including one published last month, found no reduction in fractures in the heart disease trials, raising serious doubts that the drugs have any meaningful effect on bones.
Overall, however, the scientific world's view of statins has evolved in a direction opposite from what many biologists expected.
That's because many scientists were suspicious of statins when the drugs hit the market, despite their remarkable lack of side effects. Tampering with something as crucial to cellular health as cholesterol production was seen as risky, and some experts expected a downside – and maybe a disaster – would eventually appear.
That still could happen. Many people will be on the drugs for most of their lives – an unusual state of affairs. In general, though, fears have been replaced by hopes – many hopes.
"The history of pharmacology is full of stories of unexpected findings, even late in the life of a drug," said Carl J. Vaughan, a statin researcher at Cornell. "But I think we are reasonably certain there aren't any [bad] surprises in store."
© 2001 The Washington Post Company
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