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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 shortcomings 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.”
This story is reprinted with permission from Nature. It was first published on February 26, 2013.
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9 Comments
Add CommentA profound theoretical distinction exists between setting a threshold and considering how the threshold is reached. Discussion of cholesterol seems almost always to confuse the two. Science may not yet understand exactly how cholesterol functions in the body, but it is only common sense that lowering cholesterol with a drug is unlikely to have the same impact as lowering cholesterol with behavioral changes. This common sense conclusion may of course be wrong, but it should be assumed to be true until proven wrong, rather than the common assumption that doing it with a drug is just as good as doing it any other way.
Reply | Report Abuse | Link to thisThere needs to be more attention paid to negative effects of the routine prescribing of statins without regard for cholesterol levels. It happens. There can be negative effects of having one's cholesterol lowered too much.
Reply | Report Abuse | Link to thisWell, we do have to hand it to someone. Well done. Mortality rates from Myocardial Infarction according to the Centers for Disease Control have dropped from 98.3 per 100,000 US Census in 1999, to 60.9 per 100,000 in 2006. That is a dramatic decrease in mortality. Now this may not be due to statin drugs, rather due to an increase in consumer activism inside the production chain of our food, or a completely unheralded and quietly eliminated element of our environmental exposure.
Reply | Report Abuse | Link to thisBut it was discrete and pronounced, whatever it was. As you can see from the CDC site (http://apps.nccd.cdc.gov/NCVDSS_DTM/DetailedData.aspx?state=United%20States&category=1&indicator=84&stratification=Total) the mortality decline is a tight linear and aggressive negative trend, which if anything has slightly accelerated. Which leads me to believe that one primary factor is influencing this risk drop. The drop is prejudiced, like we either knew something, or figured this out.
Well done, but since the rate of obesity is still rising, statin prescriptions are falling, LDL levels are as they have always been, and diabetes is still skyrocketing, I would suggest plurality in that another factor is involved.
Still I love to hear good news for us all.
- TES
There are very clear and routinely ignored downsides to pushing LDL cholesterol too low, including suicidal tendencies. All-cause mortality rises when cholesterol drops too low. Cholesterol is a basic building material used throughout the body, in every cell wall and nerve sheath, every steroid hormone, in the making of vitamin D, and so on. Decreasing it will disrupt these functions. If there is "too much" of it, we should be looking at which of its functions is not being fulfilled.
Reply | Report Abuse | Link to thisSure the pharmaceutical companies "are racing to bring the next LDL-lowering drug to market" ... and, if this one doesn't work, they'll just create another one. As long as they can keep getting doctors to prescribe whatever they make, the endless flow of money will continue to line their pockets - regardless if the medicines they make are warranted or beneficial to their "target" market of choice that week.
Reply | Report Abuse | Link to thisThe article clearly states the professionals said that when it comes to cholesterol levels, "there is no evidence for the lower the better." To quote the article: "..everybody had the strong feeling that was the correct answer."
Let me get this right - these people are prescribing drugs to lower cholesterol - all the time knowing that there is no evidence for "lower being better" - but throwing it out there anyway, because "everybody" had a strong feeling it was the correct thing to do??! Do the words "guinea pig" mean anything to you?
You bet the drug industry is very much in favor of "target-based measures" ... the $18.5 Billion dollars they pulled in for these cholesterol drugs in 2011 is nothing to sneeze at.
Eighteen and one-half billion smackeroos, folks! I'd say that's pretty creative marketing, wouldn't you? These people were able to reap billions of dollars in just one year - by selling a drug, while knowing that the condition their drug treated would not necessarily
benefit the patient. EIGHTEEN BILLION DOLLARS! This whole concept gives rise to the word "ethics" in my mind.
The thing that I find most startling is the consumers who blindly continue to pay out the nose for drugs that aren't even helping them! Conversely, they could be being put in harm's way - because after all, if the drug companies are pushing drugs for conditions they say need
to be altered - all the while, not knowing for certain if the drugs they are pushing are beneficial to the patient! It doesn't take a Rocket Scientist to determine what Big Pharma's imperative is; and it's
not the health of strangers. It's the Almighty Buck.
Why isn't Scientific American showcasing that?
The biggest problem is that they assume that a drug is needed at all to lower cholesterol levels. My LDL was almost at 200 and within 1 year of healthy eating and exercising I had cut it to around 90. During that period my HDL did not change at all.
Reply | Report Abuse | Link to thisUsing a drug to fix something that is easily fixed by behavioral changes is just fueling the laziness of our society.
Medical doctors and health science writers really ought to choose their words more carefully; using the proper terms aids understanding, theirs and ours.
Reply | Report Abuse | Link to thisTake the term 'risk factor'. When a statistically significant correlation is found between a biochemical quantity (like LDL levels) and disease risk (like CVD), that biochemical quantity should initially only be called a 'biomarker' or 'indicator'. That biomarker becomes a risk factor if, and only if, a causal connection can be established between the magnitude of that biomarker and disease risk.
Therefore, the statement “We can’t just assume that modifying the risk factor is modifying risk.” is nonsense. If a high LDL level really is a risk factor for CVD, this means that lowering LDL levels does indeed lower CVD risk. If, on the other hand, lowering LDL levels does not lower CVD risk, then LDL isn't a risk factor - it's only a biomarker or indicator. Modifying a biomarker makes about as much sense as shutting off a smoke detector.
TES - I'm wondering if the lower mortality rate could be due to more and better trained paramedics, with the proper equipment and drugs, allowing fast emergency treatment? Even twenty years ago, the emphasis was on getting the patient to a facility, now the emergency personnel start treatment at the scene, to stabilize first and then assess the situation. If needed, a medical helicopter can whisk you to a major hospital emergency room in a matter of minutes, a trip that takes two hours by car.
Reply | Report Abuse | Link to thisDo you think this might be a major factor in mortality rates?
Ethical Skeptic. Is my maths faulty? A drop of "98.3 per 100,000 US Census in 1999, to 60.9 per 100,000" is a change of 0.0374%. By what stretch of the imagination is that 'dramatic'?
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