Statins: Miracles for Some, Menace for a Few

By JANE E. BRODY

NY Times, December 10, 2002

Some doctors go so far as to say the statins have had a greater effect on heart disease than anything else introduced in the last 50 years.

Last year, a national group of experts issued guidelines saying statins should be prescribed to some 36 million Americans, three times as many as were taking them then, to reduce their risk of heart disease.

In addition to protecting people at high risk, statins protect people who have already suffered one heart attack. Three large studies have shown that statins reduce the risk of second heart attacks by 30 percent and the risk of death from second heart attacks by 40 percent.

There are also strong hints that statins may protect against strokes, Alzheimer's disease and osteoporosis and may perhaps one day be useful in treating multiple sclerosis and other autoimmune diseases.

Given their apparent wide range of actions, statins have been called the modern-day equivalent of aspirin. Some experts have even suggested that they be sold over the counter.

But like aspirin and all other drugs, statins sometimes cause serious side effects. The most serious involves the muscles, a disorder called rhabdomyolysis, rare but debilitating and deadly if not detected in its early stages.

In August 2001, Bayer voluntarily recalled cerivastatin, marketed as Baycol, after 31 people died from rhabdomyolysis caused by the drug.

This complication occurs far less often with the five statins still on the market, but any and all of them can occasionally cause muscle disorders, even years after the drugs have been used with no apparent ill effects.

And, it appears, many patients are unaware of the signs of trouble associated with statins, and many prescribing doctors fail to warn patients about dangerous drug interactions or to perform the periodic tests needed to assure continued safe use of a prescribed statin.

For example, last summer an 82-year-old Kansas woman died as a result of longstanding but undetected muscle disease caused by the statin she had been taking for years to control her cholesterol.

For the entire time she was taking it, the woman experienced muscle pains that were never properly attributed to the drug. She even had a shoulder operation, which did nothing, of course, to cure the drug-induced pain that might have been correctly diagnosed through a simple blood test.

Then she was mistreated with an antifungal agent for skin lesions that actually resulted, not from a fungus, but from the muscle breakdown caused by the drug.

When combined with statins, the antifungals can greatly increase the risk and severity of muscle disorders. Within three months, the woman's condition worsened and she became so weak she could not stand or breathe on her own. Two weeks later, she was dead.

Statins may also cause a liver disorder in about 1 percent of patients. Because of that, everyone taking them should have a periodic blood test to spot early signs of trouble.

How Statins Help
The five statins now on the market are Lipitor (atorvastatin), Mevacor (lovastatin), Zocor (simvastatin), Pravachol (pravastatin) and Lescol (fluvastatin).

They all work to lower blood levels of cholesterol by the same mechanism: they inhibit a liver enzyme called HMG CoA reductase that enables the liver to make cholesterol.

The liver is the body's main source of cholesterol, a fatty alcohol needed to form important hormones and perform other critical cell functions.

When the liver cannot make its own, it removes cholesterol from the blood to fulfill these bodily needs. Thus, blood levels of cholesterol fall and the tendency for arteries to become clogged with fatty deposits is reduced.

Furthermore, statins reduce only the levels of the so-called bad cholesterol, L.D.L., or low-density lipoprotein, which promotes arterial clogging. Statins can also lower another damaging blood fat, triglyceride, somewhat.

But the "good" cholesterol — protective H.D.L., or high-density lipoprotein, which acts like an arterial drain cleaner — actually rises in most people who take a statin drug.

But while cholesterol reduction may be the main effect of statins, the drugs are thought to perform in several other ways to reduce cardiovascular risk.

They appear to stabilize the deposits on artery walls, reducing the chance that clumps will break loose and block major vessels.

They also relax blood vessels, inhibit clotting and may promote the growth of new vessels, all actions that would make heart attacks and strokes less likely.

Perhaps statins' most exciting and potentially most beneficial action seems to be their ability to reduce inflammation, which may play a major role in arterial disease, heart attacks and strokes and is a critical factor in flare-ups of autoimmune diseases.

Detecting a Statin Hazard
In a clinical advisory issued recently, the American College of Cardiology, the American Heart Association and the National Heart, Lung and Blood Institute noted that statins had proved "to be extremely safe in the vast majority of patients receiving them."

But the advisory warned doctors about possible serious adverse effects and factors that could increase the risk of statin-caused muscle disorders.

"A common complaint," the advisory stated, "is nonspecific muscle aches or joint pains." But far more rare is severe myositis characterized by muscle aches, soreness or weakness and associated with greatly elevated levels of an enzyme, creatine kinase, indicative of muscle breakdown.

If this occurs and the drug is not immediately discontinued, myositis can progress to complete muscle breakdown, or rhabdomyolysis, kidney failure and death. These conditions can occur at any time in statin therapy. The advisory noted that adverse muscle reactions were less likely when lower doses of statins were prescribed, rather than the maximum dosage approved by the Food and Drug Administration.

Severe muscle damage is more likely to occur when statins are combined with certain other medicines, including fibrates (like gemfibrozil) and niacin (used to treat blood lipids); the immunosuppressant cyclosporine; certain antifungal drugs (including ketoconazole); macrolide antibiotics, erythromycin and clarithromycin; H.I.V. protease inhibitors; the antidepressant nefazodone; verapamil, used to treat certain heart abnormalities; and more than a quart a day of grapefruit juice.

Other factors that raise the risk of adverse muscle reactions include advanced age, especially over 80; a small body frame and frailty; chronic kidney disease, especially related to diabetes; and concurrent surgery.

Statins should be stopped in anyone soon to have major surgery. Anyone experiencing muscle pain of unknown origin while taking statins should contact the doctor without delay. If a blood test shows a very high level of creatine kinase, the drug should be stopped immediately.

All patients taking statins should have periodic blood tests for the liver enzyme transaminase, which is elevated when the liver is being damaged.

In addition, the advisory stated, statins should not be prescribed for patients with acute or chronic liver disease, although there is as yet no clear evidence that statins worsen existing liver disease.