Statins and prostate cancer

As a group, the six statin drugs are the best-selling prescription medications in the United States. It's no surprise, since heart disease remains America's leading cause of death. Statin therapy reduces the risk of heart attacks and other clinical manifestations of coronary artery disease by up to 37%, with most of the benefit going to men at high risk.

All the statins lower LDL ("bad") cholesterol by inhibiting HMG-CoA reductase, the enzyme that liver cells use to manufacture cholesterol. The drugs also trick the liver into removing cholesterol from the bloodstream, adding to the cholesterol-lowering benefit. In addition, the statins produce a modest elevation in HDL ("good") cholesterol, and the two newest and most potent statins, atorvastatin (Lipitor) and rosuvastatin (Crestor), also lower blood triglyceride levels.

While the statins' effects on blood lipid levels get (and deserve) most of the attention, these powerful medications have many other actions. Indeed, some of these activities play an important role in protecting the heart. The statins stabilize cholesterol-rich arterial plaques, reducing the likelihood that they will rupture and trigger heart attacks. The drugs have anti-inflammatory properties that may protect the arterial wall from being damaged by cholesterol. In addition, the statins inhibit platelet aggregation, helping to prevent artery-blocking blood clots.

Although the statins are quite safe, their many biological activities explain their potential side effects, including liver inflammation, muscle injury, and interactions with other medications. Statin use has also been associated with a reduced risk of various disorders, ranging from dementia and chronic lung disease to osteoporosis and gallstones. None of these possible noncardiovascular benefits has been proven, but they raise the question of how statins might affect America's No. 2 killer, cancer.

Statins and cancer

When the statins were first introduced in the 1980s, some scientists worried that they might protect the heart at the cost of an increased risk of cancer. Their worry was based on a small number of experiments that showed lipid-lowering drugs appeared to increase the risk of cancer in rodents. But men are not mice, and those fears have proven groundless. In fact, a large series of trials agreed that statins do not increase the risk of cancer.

With these concerns aside, the pendulum began to swing in the opposite direction, as scientists began to ask if statins might actually reduce the risk of cancer. At first, the optimism was based on a series of laboratory experiments. The basic idea is to grow cancer cells in test tubes with or without a statin in the culture medium. Many labs from around the world have been involved, and their results vary. In general, though, scientists agree that statins are able to slow the growth of cells from human cases of prostate cancer, bladder cancer, breast cancer, and other malignancies. Several mechanisms have been identified; they involve altering the expression of cancer genes, affecting the growth of blood vessels or the ability of cancer cells to adhere and spread, and promoting apoptosis, cell death by suicide. In addition, some results suggest that statins may strengthen the effects of standard cancer drugs or radiation.

These lab experiments are interesting, even hopeful. Still, it's a long way from the lab to the clinic. What have we learned about the effects of statin drugs on human cancer?

One way to answer the question is to see if people taking statins have a lower (or higher) risk of developing cancer than otherwise similar people who are not taking these drugs. The major clinical trials of statins all focused on heart disease, but they reported no overall effects on the incidence of malignancy. When researchers have re-evaluated these data to concentrate on cancer, they have reported mixed results. Studies from Canada, Denmark, and the U.S. have found that statin users enjoy a 14% to 28% lower risk of cancer than nonusers, but other studies find no overall reduction in the risk of cancer.

Cancer is not one disease, but many. When scientists have honed in on how statins affect the risk of individual malignancies, they have also produced mixed results for colon cancer, lung cancer, and breast cancer.

Based on these results, most experts agree that there is no conclusive evidence that statins protect against cancer in humans. Still, the hints of benefit are strong enough to warrant additional research. And when the research has turned to prostate cancer, the hints of protection are quite strong.

Statins and prostate cancer

Studies of statins and prostate cancer got off to a disappointing start with a 2002 study that found no benefit for statin use in a case-control study comparing 1,009 men who had prostate cancer with 1,387 men who were healthy. A 2007 study was even more discouraging, reporting that 3,302 men who took a statin had a slightly higher risk of prostate cancer over 15 years than 3,293 men who took a placebo. And a 2008 study of 1,943 men from Washington state found no link between statin use and prostate cancer.

In contrast to these discouraging reports, other studies are much more optimistic. Here are some results:

• A 2005 Oregon study of 302 veterans with an average age of 65 reported a reduction in the overall incidence of prostate cancer and a 76% reduction in aggressive prostate cancer.

• A 2006 Harvard study of 34,989 men linked statin use with a 49% lower risk of prostate cancer and a 61% lower risk of metastatic or fatal disease. The greatest protection was observed in the men who had been taking a statin drug the longest.

• A 2007 analysis from the 55,454-man Cancer Prevention Study II Nutrition Cohort reported that taking a statin for five or more years was associated with a 40% reduction in the risk of advanced (but not total) prostate cancer.

• A 2007 study of 69,047 California men found no benefit from short-term statin use, but a 28% lower risk of prostate cancer among men who took a statin for five years or longer.

• A 2007 Finnish study of 49,446 men reported that statin users enjoyed a 25% lower risk of advanced prostate cancer when compared with men who took other cholesterol-lowering drugs or no cholesterol medication. The benefit grew with increasing duration of statin use.

• A 2008 American study of 62,842 male veterans linked statin use with a 10% reduction in the risk of prostate cancer.

Limitations and possibilities

The most optimistic information about statins and prostate cancer comes from observational studies, which are less persuasive than randomized clinical trials. And the studies also differ in the doses and duration of statin therapy, the particular statin drugs used, and the characteristics of the population being studied. Still, though the results are far from conclusive, they raise hope that statins may reduce the risk of prostate cancer. And there are biologic mechanisms that could explain this effect.

As noted earlier, statins can inhibit the growth of prostate cancer cells grown in the laboratory. But while this effect also applies to other types of cancer cells, there are special reasons to think that statins may have particular effects on the prostate. High cholesterol levels, the true target of statins, appear to drive the growth of prostate cancer in mice and men. Statins appear to reduce prostate-specific antigen (PSA) levels, suggesting a direct effect on prostate biology. Since statins don't lower levels of testosterone or other androgens, a nonhormonal mechanism must be involved. One possibility involves vitamin D; statins appear to boost vitamin D levels, and vitamin D has been linked to protection against prostate cancer.

Statins for the prostate?

No — or, at least, not yet. At the present time, doctors should prescribe a statin only to reduce the risk for cardiovascular events in people at risk. Most often, the decisive risk factor is an elevated LDL cholesterol level, but men with heart disease or other forms of atherosclerosis, diabetes, or hypertension are likely to benefit from statin therapy even if they start out with normal LDL levels. If present trends continue, statin therapy may soon be recommended for vulnerable individuals who start out with low LDL levels. But all men should try to reduce their need for statins by pursuing the best form of prevention, a healthy lifestyle. And instead of feeling "statin envy," men who succeed should remember that a good lifestyle can protect the prostate as well as the heart.

Much more research is needed before statin therapy can be recommended to reduce the risk of prostate cancer or any other noncardiovascular disease. Still, men who need a statin for their hearts may be pleased to learn that prostate protection is a possible "side effect" of statin therapy.