American College of Physicians: Internal Medicine — Doctors for Adults ®

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When can statins be too much of a good thing?

From the March ACP-ASIM Observer, copyright 2002 by the American College of Physicians-American Society of Internal Medicine.

By Margie Patlak

A look at how statins work

Talk to Kentucky general internist Joseph Weigel, FACP, about statins, and he describes a dilemma that many physicians face.

In the 15 years since statins hit the market, Dr. Weigel has witnessed a dramatic drop in the number of patients who experience strokes or serious heart attacks. In addition, his patients who have already had heart attacks or bypass surgery are living longer, healthier lives.

"The data showing the benefits of statins for primary prevention of coronary events in high-risk patients and for secondary prevention are so overwhelming that all of these patients should be on a statin now," Dr. Weigel explained. "The next step is deciding whether to treat almost everybody with them."

Given recent evidence pointing out just how powerful statins can be, it's a question that more and more physicians are asking. Recent data from the Heart Protection Study, for example, show that even relatively young people who have no heart disease and scant blood levels of low-density lipoprotein (LDL) cholesterol can dramatically lower their risk of suffering a heart attack or other cardiac event by taking simvastatin.

In addition, scientific journals regularly report new benefits of statins, saying they may prevent everything from heart attacks and strokes to osteoporosis and diabetes. Statins are thought to be so beneficial that some observers have half-jokingly suggested that the drug be added to the drinking water.

But despite their considerable promise, statins come with certain risks, side effects and high cost. Last summer, for example, cerivastatin (Baycol) was recalled after 31 patients died of rhabdomyolysis. The incident was a sobering reminder that cholesterol-busters may not be for everyone.

So who should get statins? For which patients do the benefits of statins outweigh their risks? Many doctors, including the experts, are struggling to answer those questions.

Beyond the guidelines

When it comes to prescribing statins, most doctors start with guidelines from the National Cholesterol Education Program (NCEP), which were created by a panel of experts convened by the National Heart, Lung and Blood Institute.

Last revised in May 2001, the guidelines help doctors calculate the risk of developing coronary heart disease over the next 10 years for patients without heart disease who have multiple risk factors. If the patient has a high risk of developing heart disease—greater than 20%—the guidelines call for keeping the patient's LDL cholesterol below 100 mg/dL. Patients with diabetes and those who already have symptomatic heart disease or atherosclerosis are automatically classified as high-risk and have an LDL cholesterol goal of less than 100 mg/dL.

To meet that goal, the guidelines suggest lifestyle changes such as diet and exercise, or drug therapy. If the patient falls into lower-risk groups, the guidelines suggest higher LDL thresholds and starting drug therapy between 130 mg/dL and 190 mg/dL.

Although few doctors have qualms about prescribing statins to patients with heart disease and elevated LDL levels, there is debate about whether patients with cardiovascular disease but low cholesterol levels should receive the drugs. Critics say that the guidelines are too conservative, and do not recognize benefits of statins that go beyond merely lowering cholesterol levels. Vanderbilt University cardiologist David J. Maron, MD, for example, pointed out that besides lowering LDL cholesterol levels, statins can also help with inflammation, thrombosis and endothelial function.

As a result, he suggested that physicians prescribe statins to patients with any type of heart disease or apparent atherosclerosis, regardless of their baseline LDL cholesterol levels. He said he would prescribe a statin to these patients even if they had LDL cholesterol levels of less than 100. (If patients have very high triglyceride levels, he would consider another class of drugs.)

To support this somewhat aggressive position, Dr. Maron cited data from the Heart Protection Study. He noted that the study showed that simvastatin slashed the risk of heart attack, stroke and other cardiovascular events by nearly a quarter in high-risk patients (that figure rose to one-third when noncompliant subjects were excluded), regardless of their age, gender, baseline LDL cholesterol levels or previous history of heart disease. Even patients who had baseline LDL levels close to 100 mg/dL benefited from statins. (The results of this study have not yet been published in a medical journal.)

Advocates of more aggressive statin use view this result as proof that statins can do much more than simply lower cholesterol levels. "The Heart Protection Study indicates that we need to delete the section of the guidelines that say you should treat patients with cardiovascular disease only if their cholesterol gets to a certain level," noted Donald B. Hunninghake, FACP, of the University of Minnesota. (Dr. Hunninghake was part of the committee that developed the recent NCEP guidelines.)

While the study results are clearly encouraging, not everyone agrees with that interpretation. Cardiologist John C. LaRosa, FACP, for example, said the data do not mean that physicians should disregard patients' cholesterol levels. "This study shows that even patients with low cholesterol levels can benefit from additional cholesterol-lowering, not that cholesterol levels aren't important," said Dr. LaRosa, who is president of the State University of New York Downstate Medical Center in Brooklyn.

He noted that although intriguing lab data have suggested that statins may do more than lower cholesterol, there is no evidence that those benefits are clinically important. He pointed out, for example, that researchers have not shown that statins' ability to prevent cardiovascular events stems from something other than the drugs' ability to lower cholesterol.

Even Dr. Hunninghake, an advocate of expanding statin use, noted you can't ignore cholesterol levels entirely because "all studies suggest that for every 1% you lower LDL, you get a little more than a 1% reduction in the risk of a cardiac event."

Dosages

What dose of statins do you prescribe if you want to do more than reduce cholesterol levels in patients with cardiovascular disease? In the absence of guidelines, Dr. Maron said he tends to use the smallest dose of statin needed to lower a patient's LDL cholesterol to levels prescribed by the NCEP guidelines.

He quickly added, however, that it may make sense to use the same dose used in clinical trials, such as the Heart Protection Study (in which 40 mg of simvastatin was prescribed), to achieve the spectacular risk reduction in cardiac events researchers reported. In the future, he added, other measures, such as levels of C-reactive protein, a marker for inflammation, may help clinicians pinpoint a more appropriate statin dose for these patients.

Prevention polemics

While physicians may disagree about how to prescribe statins to patients who have cardiovascular disease, the issue becomes even more complicated when treating patients who have no symptoms of atheroscelerosis or cardiac disease but have risk factors.

"Once you have coronary disease, you should be taking statins to get your cholesterol levels as low as you can," said Dr. LaRosa. But when it comes to preventing heart disease, "it's hard to know where to draw the line," he said.

Suppose a patient has a moderately elevated cholesterol level but no overt signs of atherosclerosis. The NCEP guidelines say that to start drug treatment, you should find two or more significant risk factors such as cigarette smoking, age or a family history of premature coronary heart disease. If the patient has no risk factors, then the guidelines suggest he or she use diet, exercise and weight loss to lower cholesterol level. But as many doctors know all too well, such efforts frequently fail. A daily dose of statins is literally easier for patients to swallow than maintaining lifestyle changes.

That's why physicians like Dr. Weigel tend to give statins to patients with just one risk factor. "If the family history is strong," he said, "I'll aggressively treat almost anybody—even a 25-year-old with no clinical evidence of vascular disease, an LDL cholesterol level of 145 and a father who had a myocardial infarction when he was 50."

Dr. Weigel said he supports his aggressive use of statins with a simple philosophy: "If you want to improve your patients' longevity, preserving vascular biology with aggressive treatment of lipid abnormalities is very important, even early in life when people don't have any evidence of clinical disease."

Dr. Hunninghake said he largely agrees with that approach. He too goes beyond the guidelines and prescribes statins to patients who have a strong family history of heart disease or unusually low high-density lipoprotein (HDL).

But other physicians, such as North Carolina internist W. James Stackhouse, FACP, take a more conservative approach. In part, they feel they must factor in the high cost of statins.

"It's very hard to look patients in the eye and tell them that they need to be on a drug to reduce their risk of a heart attack over the next five years from eight in 100 to seven in 100, particularly when it's going to cost them $2,000 a year," said Dr. Stackhouse, who will become a College Regent next month. "If it cost 10 cents a pill, we'd all be taking it."

Even advocates of aggressive statin therapy like Dr. Maron say they are wary of starting a lifetime of statin therapy in someone who has only an intermediate risk of heart disease unless there is some evidence of atherosclerosis. To get that evidence, Dr. Maron often uses noninvasive measures to spy on the coronary arteries of such patients.

If the patient is a 45-year-old man with low HDL, normal LDL and a strong family history of coronary artery disease, Dr. Maron said he recommends coronary calcium scanning, a technique that is itself controversial. (For more information, see "CT scans: new screening tool or risky fad?") If he finds calcium in the patient, he assumes that atherosclerosis is also present and starts the patient on drug therapy.

"For a patient with intermediate risk, finding the presence of atherosclerosis is very useful because it can help you decide whether to go down the path of drug therapy," Dr. Maron explained. "Although I might make that decision without it, the patient might not. Demonstrating to the patient that he or she has atherosclerosis can help motivate behavior change."

Compliance issues

Physicians also point out that there are practical considerations to aggressive statin use. How, for example, do you convince patients who feel fine to commit to a lifetime of statin therapy? One study found that of all patients who start statin therapy, half quit within a year.

A significant number of patients stop taking statins because of side effects. On rare occasions, doctors must discontinue prescribing statins because they raise patients' blood levels of liver transaminases. But as Dr. Maron pointed out, there's no convincing evidence that patients have experienced any clinically relevant liver damage from taking the drugs.

A much more common side effect that triggers some patients to stop taking their statins, many doctors reported, is musculo-skeletal aching not linked to elevations in creatinine phosphokinase (CPK). Because blood tests show that there is no apparent muscle damage in these patients, there actually is no need to stop using statins. You can try switching these patients to a different statin, since experts say that drug swapping sometimes relieves muscle aches.

Some doctors even voice skepticism that statins cause such muscle aches. As Dr. Stackhouse noted, "I hear just as many complaints about muscle aches from patients of the same age who are not on the drugs as those who are."

Dr. Hunninghake added, "In the first clinical trial we did with Mevacor [lovastatin], that complaint occurred in about 20% of the placebo group as well as the treated group. All you can tell these people is that if their CPKs are normal, it's not going to progress to anything bad."

Dr. Weigel, however, said he started taking complaints of muscle aches more seriously after a patient developed rhabdomyolysis from taking cerivastatin with gemfibrozil and spent three weeks in the hospital. "I'm now very emphatic that patients report side effects," he said. "I monitor patients for CPK and liver enzymes at least every three to four months. They can't get the drugs without that."

There is no easy solution, however. As Dr. Hunninghake noted, a patient could have a normal CPK one day and develop myopathy a few weeks later-an outcome that vigilant monitoring won't necessarily prevent. "That's why patient education is so important," he said. Doctors should tell patients to contact them if they develop severe muscle aches or pass dark urine.

Dr. Maron suggested a number of measures to improve patient adherence to statins, such as using physician assistants and nurse practitioners to bolster patient education efforts. He also noted that regular blood cholesterol-level monitoring can convince patients to stay the course. "It gives them feedback about the impact of their compliance and keeps them interacting with the health care provider," he explained.

Safety concerns

Myopathy or rhabdomyolysis was an extremely rare side effect that occurred much more frequently with Baycol (cerivastatin) than other statins. Since the drug was recalled, however, many doctors have become more wary of prescribing statins with fibrates because about half the patients who got rhabdomyolysis from taking cerivastatin also got it when they took gemfibrozil. "We were moving much more aggressively toward a paradigm of combining statins with fibrates to manage lipids than I think we will in the future," noted Dr. Maron.

When given to patients alone, statins, fibrates and niacin can each cause myopathy. As a result, there is concern that patients might be more likely to develop myopathy or rhabdomyolysis if these drugs are taken in combination. You should also be wary of other drugs that increase the risk of side effects when taken with statins, including cyclosporine, certain antifungal drugs or antidepressants, erythromycin-type antibiotics and HIV protease inhibitors.

But the Baycol recall hasn't dampened most doctors' enthusiasm for statins. "They are a remarkably safe class of drugs," said Dr. Maron. "Given the huge market experience and the careful clinical trial experience, all the statins on the market have a very clean record."

If half of all patients stop taking statins, Dr. Weigel said, "it's our responsibility as physicians to try to find out why." While you may need to harangue your patients to make sure they're taking their statins regularly, physicians say there is a definite payoff.

Even Dr. Stackhouse, who views statins more conservatively than some, noted, "These drugs are as great as everybody makes them out to be."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.

A look at how statins work

Statins are probably the most multi-talented drugs on the market. Not only do they slash patients' risk of developing heart disease and stroke, but they also appear to stave off diabetes, osteoporosis, dementia and possibly even tumor progression.

How can one type of drug do so much? The answer is beginning to unfold in laboratories around the world.

Researchers have long known that statins lower cholesterol in blood circulation by tampering with the enzyme (HMG Co-A reductase) that triggers cholesterol production in the liver. Statins may also hamper the liver's synthesis of certain kinds of cholesterol- or triglyceride-ferrying lipoproteins known for fostering atherosclerosis. The end result is that statins frequently cut blood LDL cholesterol levels nearly in half, as well as modestly lower triglyceride levels and raise HDL levels.

Most, if not all, statins also perform several additional feats in the laboratory that may help counter atherosclerosis and/or myocardial or cerebral infarctions. The drugs, for example, relax the endothelial cells that line blood vessels, counter inflammation, stabilize plaque, hamper blood clotting and prompt new blood vessels to sprout. Some of these effects may be downstream results of LDL-cholesterol lowering, but there is evidence that they might also occur independent of a drop in cholesterol level, for reasons that are not yet fully apparent.

Concordant with the rising suspicion that cholesterol and various lipids play a major role in the development of several types of dementia, including Alzheimer's disease, one clinical study found that using statins lowered the risk of developing dementia by nearly one third.

Statins have other effects that go far beyond the cardiovascular arena, due to the drugs' ability to interfere with the actions of the enzyme HMG Co-A reductase. Laboratory and animal studies show statins can boost bone formation in two ways: by stemming the number of bone-eating osteoclasts and by triggering the differentiation of more bone-building osteoblasts. These findings may explain why some large clinical studies found that using statins slashed women's fracture risk by more than half.

In vitro studies also found that statins can hamper the growth of tumor cells, such as breast cancer and leukemia cells. By disrupting the activity of HMG Co-A reductase, statins apparently prevent the production of the molecular anchors in cell membranes that are needed to nab the compounds that signal tumor cells to proliferate.

Finally, a clinical study found that for unknown reasons, pravastatin cut the risk of developing diabetes by as much as 30%.

While these findings are still too preliminary to change the standard of care, they do offer a look at how you may be using statins in the not-so-distant future. Besides, as Kentucky internist Joseph Weigel, FACP noted, "I don't prescribe statins to prevent osteoporosis. But if I get it as a bonus package, that's great, and I let patients know that's a possibility."

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