The status of statins

They reduce harmful cholesterol, but should healthy women be taking them?

Where would we be without cholesterol? It's a vital component of cell membranes and nerve sheaths. It forms the basis of sex hormones. It enables bile acids to process the food we eat. As Martha Stewart might say, "It's a good thing." But since the mid-1960s, we've learned that we can have too much of a good thing. Medical research has demonstrated that excess levels of cholesterol in the blood can lead to atherosclerosis, heart attacks, and strokes.

Healthier living can reduce cholesterol levels, but by only so much. If levels are very high or must be brought down rapidly, more is needed. Billions of dollars and years of research have gone into developing an ideal drug for reducing cholesterol — specifically LDL cholesterol, the bad kind. In 1987, with the introduction of lovastatin (Mevacor), it appeared that the magic pill had arrived.

Lovastatin was the first in a line of compounds known as statins, which now sit at the top of the drug sales charts. Statin use continues to grow as guidelines for cholesterol are revised downward and clinical studies show that these drugs are effective in preventing heart attacks in men with elevated cholesterol and in members of both sexes who already have heart disease. Controlled trials haven't shown that statins can prevent heart attacks in healthy women with elevated cholesterol, but these drugs are increasingly prescribed for that purpose anyway, because there is no evidence of sex-related differences in the metabolism of statins or their side effects and adverse outcomes.

The evidence for statins

Since lovastatin's introduction in 1987, more than 100,000 people have participated in controlled trials of statins. Nearly six out of seven participants have been men, mainly because men develop heart disease earlier and make up a greater share of heart patients. These studies have found a 25% to 40% reduction in male cardiac events and cardiac deaths. Perhaps not surprisingly, they are less informative about the effects of statins on women. Many studies simply combined data for men and women, and others didn't include enough women to permit statistically significant conclusions.

Hoping to get more definitive answers, researchers from the University of California at San Francisco and the University of North Carolina combined and re-analyzed the data for women in several major statin studies. Writing in the Journal of the American Medical Association (May 12, 2004), they offered these conclusions:

Statins reduce the risk of cardiovascular events in women who already have heart disease. Five studies yielded data on women with existing coronary artery disease — the Scandinavian Simvastatin Survival Study (4S), the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II) trial, the Cholesterol and Recurrent Events (CARE) trial, the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, and the Heart Protection Study (HPS). Women who took statins had about a 20% lower risk of coronary events than women taking placebo pills.
Statins reduce the risk of fatal heart attacks in women with cardiovascular disease. Women taking statins were 26% less likely to die of coronary disease than those taking a placebo. However, both groups had a similar risk of death from all causes.
It's not clear whether statins reduce the risk of cardiovascular events or cardiac death in healthy women with high cholesterol.

Statins (HMG-CoA reductase inhibitors)
Generic name	Brand name	Comments
lovastatin	Altoprev, Mevacor	Lowers LDL and triglycerides; raises HDL. Should not be taken by pregnant women, heavy drinkers, or people with active or chronic liver disease. Should be used with caution by those taking gemfibrozil, cyclosporine, clofibrate, erythromycin, or niacin. Can increase the effect of warfarin.
pravastatin	Pravachol, Pravigard
simvastatin	Zocor
atorvastatin	Lipitor
fluvastatin	Lescol
rosuvastatin*	Crestor
*Should be started at low doses in people over age 65, those who have hypothyroidism or kidney disease, and Asian Americans, to reduce the risk for severe muscle damage and kidney failure.

Other effects of statins

Statins should be taken only when cholesterol remains high despite lifestyle changes (reducing dietary fats, losing excess weight, and exercising more). Many people have been on these drugs for many years, and we are beginning to discover that they may do more than lower cholesterol. For example:

They may reduce breast cancer risk. There's some evidence from the Women's Health Initiative (WHI) and other studies that certain statins protect against breast cancer. The WHI data showed an 18% reduced risk for new breast cancers among women taking lovastatin, simvastatin (Zocor), and fluvastatin (Lescol) — but no effect for pravastatin (Pravachol) or atorvastatin (Lipitor).

They may reduce gallstones. A 2007 report from the Nurses' Health Study indicates that statin use might help prevent gallstones from forming, particularly in women who have diabetes. Women in the study who were taking statins had an 18% lower rate of gallbladder surgery, compared with women not taking statins; for diabetic women who had been taking statins for two or more years, the reduction was 75%.

They may slow cognitive decline. More than 3,300 participants in the Cardiovascular Health Study — an NIH-sponsored observational investigation of women and men ages 65 or older — were given cognitive tests annually for seven years. The test scores of those who were taking statins declined less from year to year.

They may reduce C-reactive protein (CRP). In several studies, statin use has been associated with a reduction in CRP, the inflammatory marker that is emerging as a risk factor for heart disease. An ongoing study — Justification for the Use of Statins in Primary Prevention — is testing whether a newer statin, rosuvastatin (Crestor), can reduce heart attack risk in men and women with normal LDL cholesterol but elevated C-reactive protein levels.

Adverse effects

All drugs have side effects, and statins are no exception. But their side effects are widely known, and, for the most part, mild. They include the following:

Muscle problems. Statins commonly cause muscle pain (myalgia). Rarely, statin use can lead to rhabdomyolysis — severe muscle deterioration, with the release of muscle proteins into the blood. If that happens, the kidneys can fail, overwhelmed by the task of removing those proteins from the body. Fatal rhabdomyolysis occurs in only about one person per million using the currently approved statins.

Statin users who experience muscle pain should be given blood tests to check their levels of creatine kinase (CK), an enzyme released in muscle breakdown. For simple myalgia without elevated CK levels, it may help to switch to a different statin.

Liver toxicity. Long-term statin use has been associated with elevated blood levels of liver enzymes. Statin users should have their blood checked regularly, and if liver enzyme levels reach three times normal, the statin should be replaced with a different type of cholesterol-lowering drug.

When not to take statins

If you're pregnant or plan to become pregnant. Studies in animals and pregnant women have found evidence of a relationship between statin use and fetal abnormalities or risks.
If you're a heavy drinker or have active liver disease. Statins put an additional burden on the liver and may trigger liver failure.

Do you need a statin?

In its latest guidelines, the National Cholesterol Education Program (NCEP) has set goals for LDL cholesterol levels based on individual risk of a heart attack during the next 10 years. You can assess your own risk by using the Framingham risk calculator at http://hp2010.nhlbihin.net/atpiii/calculator.asp. Here are the NCEP's recommendations:

High risk (those who have had a cardiac event or been diagnosed with heart disease or diabetes). The goal is an LDL level of less than 100 milligrams per deciliter (mg/dL) — or, in some cases, less than 70 mg/dL. This can be hard to achieve with lifestyle changes alone, and treatment is urgent, so women in this category routinely receive statins.

Moderately high risk (10-year heart attack risk at 10% to 20%, plus the presence of two or more risk factors, such as smoking, hypertension, or low HDL cholesterol). The goal is an LDL level of less than 130 mg/dL. If LDL cholesterol is 130 mg/dL or higher, begin lifestyle changes and consider statins.

Moderate risk (10-year heart attack risk at less than 10%, plus two or more risk factors). The goal is an LDL level below 130 mg/dL. If LDL cholesterol is 130 mg/dL or higher, begin lifestyle changes; if it's 160 mg/dL or higher, consider statins.

Low risk (zero to one risk factor). The goal is an LDL level below 160 mg/dL. Consider statins if LDL cholesterol exceeds 190 mg/dL.

At age 70, heart disease overtakes cancer as the leading cause of death in women. At the same time, elevated cholesterol in the absence of actual heart disease becomes less important as a risk factor. Studies have yet to show that statins benefit older women who have elevated cholesterol but no symptoms of heart disease. Unfortunately, the Prospective Study of Pravastatin in the Elderly at Risk (the only statin study focused on people over age 70) didn't separate the data by sex. In this study, the placebo group had more cardiac events than the group taking pravastatin, but the death rate in the two groups was the same.

The story behind statins

Statins work by altering the metabolism of cholesterol, a complex fat that the body needs for many purposes. Most of the body's cholesterol is produced by liver cells, and most of the rest comes from the food we eat.

Cholesterol is insoluble in water, so it can't circulate in blood plasma without a protective shroud of lipoproteins, which are part fat and part protein. Cholesterol's ultimate destination depends on whether the shroud consists of low-density lipoprotein (LDL) or high-density lipoprotein (HDL). LDL particles deliver cholesterol to cells throughout the body; HDL particles mop up excess cholesterol and carry it back to the liver for disposal. If the body produces more LDL cholesterol than the cells can absorb, it settles in artery walls and contributes to atherosclerotic plaque. That's why LDL is often called "bad" cholesterol and HDL "good" cholesterol — even though the body needs both kinds.

As researchers came to suspect that high LDL cholesterol levels raised the risk for heart attack and stroke, they began to explore drug treatments. By the 1980s, three classes of drugs were available: fibrates, which reduce the liver's production of triglycerides (noncholesterol fat that's also carried by lipoproteins); bile-acid sequestrants, which reduce cholesterol by binding with bile acids; and niacin, which raises HDL levels and lowers triglycerides. All these agents have unpleasant side effects: fibrates cause nausea and upset stomach; bile acid sequestrants cause flatulence and constipation; and niacin triggers flushing.

Lovastatin was introduced in 1987. This new drug was designed to block the liver enzyme HMG-CoA reductase, which promotes cholesterol production. Lovastatin dramatically reduced circulating cholesterol with negligible side effects. Other similar drugs followed, with names like simvastatin and pravastatin, and the group became known collectively as statins.

How statins work

how-statins-work

Most of the cholesterol circulating in the blood is made by the liver. Statins inhibit the enzyme HMG-CoA reductase, a key player in determining the amount of cholesterol the liver makes.

The bottom line

We still have much to learn, but the benefits of statins seem to outweigh the risks for women with heart disease. They are probably a good bet if you have high cholesterol and have been diagnosed with cardiovascular disease. If you're at increased risk for heart disease and can't get your LDL cholesterol down to acceptable levels, discuss the matter with your doctor. If you're on the fence, stay tuned. New data are emerging all the time.