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Published On January 15, 2011

CLINICAL RESEARCH

Questioning Statins

Statins' ability to control cholestrerol is undeniable. Less certain, after almost 25 years, is whether benefits outweigh potential harm.

AKIRA ENDO SCANNED THE ROOM, WAITING FOR HIS TURN TO SPEAK. The turnout was impressive—some 200 physicians and scientists. Endo had traveled from Tokyo to the sixth International Symposium on Drugs Affecting Lipid Metabolism in Philadelphia on this day in 1977 to elaborate on his discovery of a molecule called compactin in blue-green mold. In college Endo had been impressed by the biography of Alexander Fleming, the Scottish scientist who discovered penicillin in a moldy culture plate. Endo knew that penicillin and other antibiotics can inhibit many enzymes, and he hoped that studying molds might yield a substance that would block HMG-CoA reductase, an enzyme that raises cholesterol levels. After testing more than 6,000 fungal extracts, he finally found one that safely inhibited the enzyme. He thought compactin might hold the key to treating elevated cholesterol, which had recently been linked to heart attacks and strokes.

As a French scientist finished his talk on cholesterol-lowering drugs called fibrates, Endo took the podium—and the room began to empty. Only 30 or so attendees lingered to hear his presentation, “Effects of ML-236B, a Competitive Inhibitor of HMG-CoA Reductase, on Cholesterol Metabolism,” and there were no questions when he finished.

Endo left the conference dejected, but before heading back to Japan, he accepted an invitation to visit the University of Texas Southwestern Medical Center laboratory of Michael Brown and Joseph Goldstein, who had read several of Endo’s papers on compactin. Brown and Goldstein had met as interns at Massachusetts General Hospital and went on to conduct groundbreaking research on cholesterol metabolism. One major achievement was their 1973 discovery of a receptor for low-density lipoprotein, or LDL, a protein that removes that “bad” form of cholesterol from the blood. Endo signed on to collaborate with the two scientists, and their subsequent research demonstrated that compactin did more than block HMG-CoA reductase; it also turned up the activity of LDL receptors. And while Endo’s audience in Philadelphia was blasé about compactin, drug companies could hardly have been less so: Next year will mark the 25th anniversary of the class of drugs born from Endo’s discovery, the HMG-CoA reductase inhibitors, better known as statins.

The first statin sold in this country—Mevacor (lovastatin), approved by the Food and Drug Administration in 1987 for patients whose cholesterol levels couldn’t be controlled by diet—was followed by a half dozen more, which are now among the most widely prescribed drugs in the United States. Many doctors agree that statins, which have been shown capable of reducing LDL cholesterol by 35% to 55%, represent one of the most important advances in modern medicine. “Statins have had the largest impact of any medicine ever developed, short of penicillin,” says Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital.

Yet the drugs were nearly abandoned during several crucial stages of development, and despite defenders’ assurances that statins are safe, they have been linked to reports of side effects from the beginning. Complaints about muscle pain and fatigue are the most common, though some users have reported cognitive and psychological problems such as poor memory and depression. For statins, the common perception that the drugs may cause unpleasant side effects could help explain why so many people quit refilling their prescriptions. In one trial, three of four elderly patients instructed to take a statin stopped using the pills as directed within five years.

What’s more, statins have always had doubters who insist the drugs are overprescribed, and lately the criticisms have seemed particularly forceful. In March 2010, an article in Time questioned whether statins are safe and effective in women. Three months later, a number of articles and editorials in the Archives of Internal Medicine challenged the use of statins in the primary prevention of heart disease. That’s what three of four statin prescriptions are for—to treat high-risk patients who don’t yet have coronary artery disease. One study in particular—the JUPITER trial, whose findings suggested that statins may be under­prescribed in the United States—received intense criticism in the Archives issue. “I like to practice evidence-based medicine,” says Rita Redberg, the journal’s editor. “The evidence is not strong enough to support statins for primary prevention.”

One physician looks at a pill and sees a potent defense against the leading cause of death in the United States and much of the world. Another sees an expensive illusion that offers most patients false hope and potential harm. How can that be?

DESPITE ITS SINISTER REPUTATION, CHOLESTEROL IS ESSENTIAL FOR HUMAN HEALTH. The membranes around every cell in the body require cholesterol, as do certain hormones, bile acids and vitamin D. But in the 1950s and 1960s, evidence from epidemiological studies showed that people with high blood levels of cholesterol have a heightened risk of heart attacks. Subsequent research identified the cholesterol carried to the body’s cells in LDL particles as the culprit.

Between 60% and 80% of the cholesterol in blood travels via LDL. (Meanwhile, high-density lipoprotein, or HDL, carries excess cholesterol to the liver for reuse or removal.) LDL particles have an unfortunate habit of burrowing into the walls of arteries, where they are the main component of plaques that, over the course of decades, can become inflamed, rupture and cut off blood flow in the arteries, causing heart attacks and strokes. Under current guidelines, most clinicians will consider prescribing a statin to patients who have an LDL cholesterol level of 130 milligrams per deciliter or higher as well as other risk factors for cardiovascular disease (such as tobacco use, hypertension or a family history of the disease).

After Endo’s discovery of compactin, his employer, Sankyo Research Laboratories, agreed in 1976 to share samples of the compound and experimental data with Merck. At the time, there were a few cholesterol drugs available, but they were only modestly effective, and some had drawbacks. For example, cholestyramine, which is still prescribed occasionally, is a powder that must be mixed in water or another liquid and, to most palates, tastes terrible. Thus, developing a better cholesterol drug was a high priority for pharmaceutical companies, and scientists at Merck identified a chemical similar to compactin that would become known by the generic name lovastatin.

Merck had already started testing lovastatin in men and women in 1980, when Sankyo abruptly canceled its own human trials of compactin and shelved the drug. No explanation was offered, but it was rumored that dogs receiving high doses—100 to 200 times greater than a human dose—had developed tumors. Merck shut down its human trials of lovastatin as a precaution, but the company’s internal safety studies eventually failed to find that the drug caused cancer in animals, and Merck resumed large-scale human trials in 1984.

In the early 1980s, some doctors were still not sold on the idea of cholesterol-lowering drugs, as there was little solid evidence that lowering cholesterol actually prevented heart disease and saved lives. But in 1984, a landmark study found that reducing LDL with cholestyramine cut the risk of coronary artery disease by 19%, and this helped change the attitude of many physicians. Merck’s clinical trials found that lovastatin was even more potent, lowering LDL cholesterol by as much as 39%, and the FDA approved Mevacor on Aug. 31, 1987. The New York Times reported that the new class of drugs was “expected to revolutionize treatment of high cholesterol levels.”

A quarter-century later, many people would say even that lofty prediction was an understatement. The drugs have also provided enormous benefit to the pharmaceutical industry, which followed Mevacor with a list of other statins, including Zocor (simvastatin), Lipitor (atorvastatin), Baycol (cerivastatin), Crestor (rosuvastatin) and, most recently, Livalo (pitavastatin).

STATINS WERE AN IMMEDIATE HIT WITH THE MANY CLINICIANS who had embraced the idea that high LDL levels increase the risk of cardiovascular disease. Other physicians, however, remained skeptical of the benefits—to say nothing of the safety—of lowering cholesterol. Worries about harm stemmed in part from early concerns that the drugs could damage the liver and cause cataracts. (Routine liver and eye testing are no longer required of statin users, though the drugs are not recommended for patients with a history of liver disease.) But new fears were stoked by a 1990 paper in the British Medical Journal linking cholesterol lowering (either through diet or with such pre-statin drugs as cholestyramine, clofibrate and gemfibrozil) to an increased risk of fatal accidents, suicide and homicide. The authors couldn’t explain why such a link might exist but suggested that reducing cholesterol may cause brain changes resulting in aggressive and violent behavior. The BMJ paper also found that although lowering cholesterol levels did prevent deaths by coronary artery disease, it did not seem to prolong life, an observation that would recur in subsequent studies.

Statin use nonetheless began to grow steadily, thanks in part to a major 1994 Scandinavian study showing that a daily dose of Zocor cut the risk of death from heart disease in people with cardiovascular disease by 42%. Then, in 2001, Baycol was taken off the market after reports that some users developed rhabdomyolysis, or muscle wasting. Several dozen cases were fatal.

Rhabdomyolysis is an extremely rare side effect for users of the remaining statins, occurring only about once among 200,000 patients, according to pioneering cholesterol researcher Daniel Steinberg, author of The Cholesterol Wars: The Skeptics vs. the Preponderance of Evidence. However, myopathy, which causes muscle weakness and cramps, may be the most frequent side effect of statins, and it’s one reason people quit taking the drugs. Steinberg estimates that 10% to 15% of statin users develop muscle-related side effects. Yet the pills are “amazingly safe,” he declares. “I’ve never seen a drug with so few serious side effects.”

Others, including Beatrice Golomb, a colleague of Steinberg’s at the University of California, San Diego, are less sanguine. Golomb has published several papers linking statins to permanent muscle damage and such cognitive problems as memory loss. Golomb’s data comes from a Website, statineffects.com, that invites statin patients to describe side effects. Critics question this methodology—“she doesn’t have a control group,” Steinberg notes—but Golomb counters that randomized controlled trials often exclude people most likely to suffer adverse events from taking a drug, including those who are sick or who take other medications. And she challenges the conventional wisdom that statin-induced muscle aches and fatigue always go away when a patient stops taking the drugs, citing a “reasonably high fraction” of patients who are left with residual discomfort and weakness. Statin defenders dispute Golomb’s assertion that the drugs cause cognitive problems, noting that memory complaints are widespread among the predominantly middle-aged and older population who take the pills. “Then why would memory loss reverse itself when the patients go off statins?” Golomb asks.

Golomb argues that statins have been proved to prolong life only in middle-aged men with existing heart disease, so she rarely prescribes the drugs for women or people in other groups, including elderly patients. She and others also point out that many trials testing statins’ effectiveness in people without obvious heart disease have come to the same conclusion: Although statin users have fewer heart attacks, they’re just as likely as people given placebos to die during a particular period.

Considering that statins don’t seem to confer the ultimate health benefit—longer life—some clinicians question whether lowering cholesterol is as important as everyone has been led to believe. “If you decrease your chance of having heart attacks, you’d think you would live longer,” Redberg says. “But that doesn’t turn out to be true. So what is the benefit of taking this pill for the rest of your life?”

DEFENDERS OF STATINS SAY THAT PAST STUDIES SUGGESTING the drugs don’t prolong life were inadequate and misleading. “Redberg’s interpretation of the incomplete data and mine are completely different,” says Roger Blumenthal, director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. Blumenthal notes that most primary prevention trials of statins have lasted no longer than four or five years. Relatively few people will die—of heart attacks or any other cause—during such a brief period, he says, making it difficult to generate meaningful data on whether statin users live longer.

However, Blumenthal and many others feel that the main target of the Archives assault—the JUPITER trial—offers powerful evidence that primary prevention with statins does save lives. One important goal of JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) was to address a conundrum in cardiology: Half of all heart attacks and strokes occur in people whose LDL cholesterol is below 130 mg/dL, meaning that under current guidelines, most aren’t candidates for a statin. Statins, however, are known to have additional biological effects—beyond lowering cholesterol—that some scientists think could benefit the heart. One is reducing inflammation in the arteries, which earlier studies have linked to a high risk for heart attacks and strokes. JUPITER was designed to test whether statins would prevent heart attacks and strokes in people with LDL levels currently considered normal, but who have high levels of inflammation.

Investigators recruited nearly 18,000 men and women who were apparently healthy and had normal LDL. But everyone in the trial had elevated C-reactive protein, a measure of systemic inflammation. Half were given the drug Cres­tor, while the remainder took placebos. The results were stunning: Crestor slashed the risk of heart attacks and strokes in this population by roughly half. Moreover, during the study, the overall death rate among statin users was cut by 20%. According to an analysis by Blumenthal and his colleagues, JUPITER’s results suggested that an additional 6.5 million American adults should be considered candidates for the drugs because their CRP is high. This analysis of the JUPITER results predicted that if all of those people received the drugs, 260,000 heart attacks and other cardiovascular problems could be prevented in the United States during just five years.

JUPITER has become a lightning rod for criticism by skeptics who feel that the drugs are already overused. One paper in Archives stated that the “trial was flawed” on several grounds and accused its authors of bias. A major objection was that JUPITER, which ran from 2003 to 2008, was terminated ahead of schedule by an independent monitoring board, which determined that the study had demonstrated the benefits of Crestor; critics charge that stopping a trial early tends to exaggerate the benefits of an experimental therapy. They also note that Paul Ridker, the lead author of JUPITER and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, invented the hs-CRP test, which measures systemic inflammation. One co-signer of the Archives paper was John Abramson, a health policy lecturer at Harvard Medical School and author of Overdosed America: The Broken Promise of American Medicine. He thinks physicians and patients have been taught to focus too much on cholesterol instead of far more effective ways to prevent heart disease: a healthier diet, routine exercise, smoking cessation and other lifestyle interventions.

But many cardiologists have come to JUPITER’s defense, and Blumenthal calls the Archives articles “a real hatchet job.” In several articles, Ridker has dismissed doubts about the integrity of his data. He maintains that the early termination of JUPITER didn’t exaggerate Crestor’s benefits; on the contrary, he says, the data shows that patients who were followed the longest (up to five years) had a greater reduction in cardiovascular risk. Also, an analysis by the FDA found no evidence that the drug’s effects had been exaggerated. Ridker adds that he recognizes the importance of getting patients to adopt heart-healthy habits. “I’m actually very aggressive about lifestyle changes,” Ridker says. “But to deny patients a therapy that has been proven in a randomized, double-blinded, placebo-controlled trial is negligent care.”

BECAUSE WOMEN MADE UP MORE THAN ONE-THIRD OF JUPITER PARTICIPANTS, the results have fueled the debate over whether women benefit from taking statins. Skeptics point to JUPITER data showing that women taking Crestor didn’t die in significantly fewer numbers than those who got a placebo. However, Ridker’s collaborator, cardiologist Samia Mora, says the trend data in JUPITER suggests that if the study had lasted longer, a survival advantage for women would have become apparent. Moreover, the study showed clearly that women taking statins had fewer overall cardiovascular problems. “We know from prior studies that once people get cardiovascular disease, they have a higher rate of mortality,” Mora says. It’s logical to conclude, she argues, that preventing these cardiovascular problems will ultimately save lives.

But a question remains: Why did statins appear to protect the hearts of people who didn’t have high cholesterol? “These drugs are twofers,” says Ridker, who thinks that statins protect the heart through dual mechanisms: by lowering cholesterol and by reducing inflammation. He plans to test the second leg of that hypothesis by giving patients with high CRP the anti-inflammatory drug methotrexate—which doesn’t affect cholesterol levels—to see whether it prevents heart attacks and other cardiovascular problems. (Although theories abound, no one is certain how statins reduce inflammation.)

The FDA now permits AstraZeneca, maker of Crestor, to list elevated CRP as one indication for prescribing the drug. But not all observers are convinced that the anti-inflammatory effect of statins—which is not in dispute—is responsible for the drugs’ heart-protective effects. Steinberg notes that JUPITER didn’t include a third group of people with low cholesterol and low CRP; they could have served as a control group for the people who had low cholesterol and high CRP. Lacking such a comparison, there’s no way to be sure that treating high CRP with a statin prevented heart attacks. “The drug might have gotten the same result in people with normal or low C-reactive protein,” Steinberg says. Nevertheless, he thinks the study makes a strong case for earlier and more aggressive use of statins and other cholesterol interventions. The median baseline LDL level in the study’s participants was 108 mg/dL—normal by current standards—but Steinberg has argued for several decades that 50 mg/dL to 70 mg/dL is probably optimal. He thinks that patients at very high risk for heart attacks—with a 35% lifetime risk—should begin statin therapy as young as age 30.

Whether statins have dual benefits, and despite the voices of skeptics, the drugs are likely to become even more widely used; by 2012 all but Livalo will be available in generic form, which will reduce prices and could make statins more accessible. Most cardiologists would nonetheless welcome additional therapies for driving down LDL even more, but remain grateful that they have statins to prescribe for patients at risk of heart disease.

In a twist worthy of O. Henry, the man who discovered the first statin learned during a medical checkup in 2000 that his own LDL was rising. “Don’t worry,” the doctor told Endo, “I know some very good drugs to lower your cholesterol.” But here’s the real twist: Endo refused the statin prescription. His LDL was only modestly elevated, so Endo decided to try bringing his cholesterol under control by exercising more. Eventually, though, Endo chose to take his own medicine. “The exercise did not work well,” he wrote in an e-mail. “I am now taking a statin. However, I shouldn’t specify which one.”

 

DOSSIER

1. “A Historical Perspective on the Discovery of Statins,” by Akira Endo,Proceedings of the Japan Academy, Series B, Physical and Biological Sciences, Volume 86, 2010. The man some scientists insist should receive the Nobel Prize tells the story of how he discovered the first statin, compactin.

2. “Rosuvastatin to Prevent Vascular Events in Men and Women With Elevated C-Reactive Protein,” by Paul M. Ridker et al., New England Journal of Medicine, Nov. 20, 2008. The controversial JUPITER trial showed that statins prevented heart attacks in apparently healthy people. Skeptics doubted the study’s integrity, while true believers debated how to interpret its results.

3. “Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy,” by Michel de Lorgeril et al., Archives of Internal Medicine, June 28, 2010. De Lorgeril and eight colleagues sharply criticized the JUPITER study, which has been interpreted as evidence that statins are underused.

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