Doubts Emerge on the Value of Very Low Cholesterol Levels

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From Nature magazine.

Soon after Joseph Francis learned that his levels of ?bad? LDL cholesterol sat at twice the norm, he discovered the short?comings of cholesterol-lowering drugs ? and of the clinical advice guiding their use. Francis, the director of clinical analysis and reporting at the Veterans Health Administration (VA) in Washington DC, started taking Lipitor (atorvastatin), a cholesterol-lowering statin and the best-selling drug in pharmaceutical history. His LDL plummeted, but still hovered just above a target mandated by clinical guidelines. Adding other medications had no effect, and upping the dose of Lipitor made his muscles hurt ? a rare side effect of statins, which can cause muscle breakdown.

So Francis pulled back to moderate Lipitor doses and decided that he could live with his high cholesterol. Later, he learned that other patients were being aggressively treated by doctors chasing stringent LDL targets. But Francis found the science behind the target guidelines to be surprisingly ambiguous. ?You couldn?t necessarily say lowering LDL further was going to benefit the patient,? he says.

The standard advice may soon change. For the first time in more than a decade, the US National Heart, Lung and Blood Institute is revising the clinical guidelines that shaped Francis?s treatment (see ?How low can you go??). Expected to be released later this year, the fourth set of guidelines, called ATP IV, has been drawn up by an expert panel of 15 cardiologists appointed by the institute. The guidelines will set the tone for clinical practice in the United States and beyond, and will profoundly influence pharmaceutical markets. They will also reflect the growing debate over cholesterol targets, which have never been directly tested in clinical trials.

Since 2002, when ATP III called on doctors to push LDL levels below set targets, the concept of low cholesterol has become synonymous with heart health. Patients brag about their cholesterol scores, physicians joke about adding statins to drinking water, and some hospitals reward doctors when patients hit cholesterol targets.

In 2011, US doctors wrote nearly 250 million prescriptions for cholesterol-lowering drugs, creating a US$18.5-billion market, according to IMS Health, a health-care technology and information company based in Danbury, Connecticut. ?The drug industry in particular is very much in favour of target-based measures,? says Joseph Drozda, a cardiologist and director of outcomes research at Mercy Health in Chesterfield, Missouri. ?It drives the use of products.?

ATP III reflected a growing consensus among physicians that sharply lowering cholesterol would lessen the likelihood of heart attacks and strokes, says Richard Cooper, an epidemiologist at the Loyola University of Chicago Stritch School of Medicine in Illinois, who served on the committee that compiled the guidelines. The committee drew heavily on clinical data, but also took extrapolations from basic research and post hoc analyses of clinical trials. LDL targets were set to be ?less than? specific values to send a message, Cooper says. ?We didn?t want to explicitly say ?the lower the better? because there wasn?t evidence for that,? he says. ?But everybody had the strong feeling that was the correct answer.?

By contrast, the ATP IV committee has pledged to hew strictly to the science and to focus on data from randomized clinical trials, says committee chairman Neil Stone, a cardiologist at Northwestern University School of Medicine in Chicago. If so, Krumholz argues, LDL targets will be cast aside because they have never been explicitly tested. Clinical trials have shown repeatedly that statins reduce the risk of heart attack and stroke, but lowering LDL with other medications does not work as well. The benefits of statins may reflect their other effects on the body, including fighting inflammation, another risk factor for heart disease.

Krumholz?s scepticism is rooted in experience. In 2008 and 2010, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial challenged dogma when it reported that lowering blood pressure or blood sugar to prespecified targets did not reduce the risk of heart attack or stroke. In the case of blood sugar, the risks were worsened. The trial demonstrated the folly of assuming that risk factors must have a causal role in disease, says Robert Vogel, a cardiologist at the University of Colorado, Denver. ?Short people have a higher risk of heart disease,? he says. ?But wearing high heels does not lower your risk.?

Jay Cohn, a cardiologist at the University of Minnesota Medical School in Minneapolis, also worries that the focus on LDL levels offers up the wrong patients for statin therapy. Most of those who have a heart attack do not have high LDL, he notes. Cohn advocates treating patients with statins based on the state of health of their arteries, as revealed by noninvasive tests such as ultrasound. ?If your arteries and heart are healthy, I don?t care what your LDL or blood pressure is,? he says.

?We can?t just assume that modifying the risk factor is modifying risk.?
Not all cardiologists want to abolish LDL targets. Indeed, Seth Martin, a fellow in cardiology at Johns Hopkins University School of Medicine in Baltimore, Maryland, believes that ATP IV should reduce LDL targets further. The simplicity of targets has helped to deliver an important public-health message, he says, and motivated many patients to get the statin therapy that he believes they need. ?Just to throw that out the window doesn?t seem like the ideal scenario.?

Whatever the decision, the pharmaceutical industry will be watching closely, says Donny Wong, an analyst at Decision Resources, a market-research company based in Watertown, Massachusetts. Although most statins are off patent, the big pharmaceutical companies are racing to bring the next LDL-lowering drug to market. In particular, millions of dollars have been poured into drugs that inhibit a protein called PCSK9, an enzyme involved in cholesterol synthesis. This approach lowers LDL but has not yet been shown to reduce heart attacks or strokes.

Francis expects the new guidelines to relax the targets. He and his colleagues decided last autumn to change the VA?s own clinical standards, so that they no longer rely solely on an LDL target but instead encourage doctors to prescribe a moderate dose of statin when otherwise healthy patients have high LDL cholesterol. The ATP IV guidelines will take a similar approach, he speculates, noting that the VA consulted several outside experts who are also serving on the ATP committee.

Despite an increasingly vegetarian diet, Francis?s cholesterol has not budged. ?Sometimes I want to call my physician and say, ?Don?t worry about that target,?? he says. ?It?s going to be changing very soon.?
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This story is reprinted with permission from Nature. It was first published on February 26, 2013.

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