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Published On May 20, 2021

CLINICAL RESEARCH

The Cholesterol Deniers

For decades, a tiny encampment of researchers has held that statin treatment is a hoax. In a time when contrarian views roar to life on social media, how can medicine keep minority opinions from doing irreparable harm?

CARDIOLOGIST STEVEN NISSEN, chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic, delights in the reputation he has earned among his critics. One prized possession is a photograph digitally doctored to show him wearing a tinfoil dunce cap, with the headline, “Steven Nissen goes full quack.” The image appeared on the home page of Natural News, a website that promotes fringe theories about vaccines and other practices of conventional medicine. “Those guys call me the statinator,” Nissen says, a testament to his passionate advocacy of statin drugs—a tool to prevent heart attacks and strokes by reducing high levels of low-density lipoprotein cholesterol (LDL-C).

Nissen certainly isn’t alone in advocating statins. They are one of the most prescribed drugs in the United States and the best available tool to fight heart disease, the country’s leading cause of death. But Natural News isn’t the only statin detractor, either. The International Network of Cholesterol Skeptics (THINCS) has, since 2003, been a gathering place for clinicians, researchers and science writers who question the accepted theory on cholesterol—that it contributes to heart disease, and that statins can help prevent heart attacks and strokes. Even some prominent mainstream physicians—including, perhaps most notably, cardiologist and JAMA Internal Medicine editor Rita Redberg—question the science that has established high cholesterol as a medical problem that must be treated. “We are telling people to take a daily drug for 20 to 30 years, and we have no trial that follows people for more than five years,” Redberg says. 

Longstanding debates in medicine are nothing new, and sometimes outsider theories have led to valuable insights. Such camps can trade volleys for decades—many arguments from the “cholesterol deniers” are variations on themes from 10 or 20 years ago. What has changed, perhaps dangerously, is the degree to which these views can catch on in the public media landscape and exist, unchallenged, in the walled-off information silos of the 21st century. 

Indeed, minority viewpoints have always been more likely to be reported than mainstream views, and the same is true for the cholesterol debate. Journal articles from cholesterol contrarians make their way into the press far more often than those that extol statins’ virtues. One study found that news stories about statins in the British press were twice as likely to be negative as positive. “The media publish articles that people will click on, and it’s intriguing to read an article that says you don’t have to take a very common medication or that you can live a less healthy lifestyle,” says Ann Marie Navar, associate professor of cardiology at the University of Texas Southwestern Medical Center, who serves as associate editor of JAMA Cardiology and as a board member of the American Society for Preventive Cardiology. 

That reporting comes to rest in digital media, where the majority of Americans now read their news, and where misinformation can spread unchecked. Nissen, who finds the views of statin deniers radical and dangerous, says their studies frequently reach the public through “cult-like messaging” on social media and websites such as Natural News. He worries that these studies dissuade patients from taking a drug that may save their lives. Indeed, about 40% of those at highest risk for cardiovascular disease who are prescribed statins stop taking them or don’t take them as prescribed after three months.

One response has been to point fingers at online places where inaccurate stories are disseminated. In 2019, the editors of nearly 30 cardiovascular medical journals wrote a letter blaming the media for the “wanton spread of medical misinformation” about statins. “Misinformation travels faster through social networks than truth,” they wrote, and they called on the media and social channels to act responsibly and to refrain from giving “rogue” voices the same weight as the views of mainstream science.

But it is perhaps naïve to think that disagreements among researchers will not be politicized by the general public. The problem of minority viewpoints spreading virally became critically dangerous during the COVID-19 crisis and its concurrent “infodemic”—the spread of fake news and the promotion of unorthodox theories. Former Stanford University radiologist Scott Atlas, who served on the White House coronavirus task force during the Trump administration, challenged the use of masks to prevent the spread of COVID-19. Physician Jane Orient, executive director of the Association of American Physicians and Surgeons, was one of many prominent figures to promote the antimalarial drug hydroxychloroquine to treat COVID-19; clinical trials ultimately showed the medication to be ineffective and sometimes harmful. Both ideas still echo in online communities, hindering efforts to control the pandemic.

For statins, with so many lives on the line, is it time to stop ignoring the dangerous views of a small-but-vocal group of cholesterol deniers? “The whole point of science is to refute accepted theories and hypotheses,” says Donald Lloyd-Jones, chair of the Department of Preventive Medicine at the Northwestern University Feinberg School of Medicine and president-elect of the American Heart Association. “But there comes a point—and I think cholesterol reached that point long ago—where this kind of debate creates harm and does not advance the knowledge of science.”

Source: Photo Euphoria/Getty Images

AT ABOUT THE TIME the famed Framingham Heart Study commenced in 1948, researchers began to pay serious attention to cholesterol and its effect on arteries. Along with other epidemiological studies, Framingham established high cholesterol as a risk factor for cardiovascular disease, adding to a list that also includes hypertension, smoking, obesity, diabetes and lack of exercise. By 1984, the National Institutes of Health had asserted that “it has been established beyond a reasonable doubt that lowering … blood levels of low-density lipoprotein cholesterol will reduce the risk of heart attacks due to coronary heart disease.” People with high cholesterol were advised to modify their diets, and it was recommended that all Americans reduce the amount of fat they consumed. Yet dietary changes usually resulted in only minor improvements, and the few drugs available then to reduce LDL cholesterol weren’t very effective, says cardiologist Christopher Labos, an associate in the Office for Science and Society at McGill University in Montreal. 

The following year, Michael Brown and Joseph Goldstein won a Nobel Prize for their discovery that familial hypercholesterolemia—a condition in which people are born with extremely high levels of LDL-C and have an elevated risk of premature heart attacks—is caused by mutations in the gene that encodes the LDL receptor responsible for clearing LDL-C from the blood. “That discovery confirmed that LDL cholesterol is a key target for reducing future cardiovascular disease,” says Pradeep Natarajan, director of preventive cardiology at Massachusetts General Hospital.

Lloyd-Jones considers it indisputable that LDL-C is the primary culprit in creating atherosclerotic plaques. “That is simply the biology,” he says. “Under the microscope, you can see LDL particles eliciting an inflammatory response from the body and doing direct damage to artery walls.” Humans need only a small amount of 

LDL cholesterol to make hormones and for cellular repair, and any excess creates arterial plaques, Lloyd-Jones says. “LDL cholesterol meets all of the criteria for a causal risk factor, and if the LDL level is high enough, it causes atherosclerosis,” he says.

The vast majority of cardiologists and primary care clinicians agree with that assessment. “Only a few completely deny the role of cholesterol in causing cardiovascular disease,” estimates Salim Virani, chair of the prevention of cardiovascular disease section of the American College of Cardiology and professor of cardiology and cardiovascular research at Baylor College of Medicine.

Statins’ effectiveness in treating LDL-C is also not in dispute, according to most physicians. “Statins reduce the risk of cardiovascular disease by 15% to 30%, and they’ve greatly contributed to the dramatic drop in deaths from atherosclerotic vascular disease,” says Mason Freeman, chief of the Lipid Metabolism Unit at MGH. He estimates that the vast majority of interventional cardiologists over age 40 who work in cardiac catheterization labs take statins themselves. “I don’t think there is a higher endorsement for the benefits of statins than that the doctors who understand most about the ravages of a disease personally take the preventive medicine,” he says. “The science is crystal clear that statins reduce cardiovascular risk, but individuals on statin therapy can still have atherosclerotic vascular events, such as a heart attack or stroke.”

It’s that last fact that opens the door to critics, Freeman says, with many attacks based on a supposedly weak connection between statin use and reduced incidence of heart problems and strokes. Yet those criticisms, according to mainstream researchers who have looked into them, are based on questionable studies or don’t reflect the biology of atherosclerosis. “They use data in a very selective way, focusing on one data point instead of looking at the evidence of the entire study,” Virani says. “Or they use observational data to build a case for their theories and disregard large randomized trials or epidemiological studies. That leads to misinterpretation of the evidence.” 

One tactic, according to UT Southwestern’s Navar, is to cite evidence from short-term trials in which no participants taking statins died and few had heart attacks or strokes. This is misleading, Navar says. While not all statin trials show a reduction in deaths, a five-year trial can’t reflect statins’ true power. “We aren’t trying to prevent cardiovascular events in the next five years with a statin,” she says. “The goal is to provide protection over the next 15 to 30 years. The longer you take a statin, the more benefit you get by preventing plaque from building up in your arteries.” 

Source: Sam Kaplan/Trunk Archive

In addition, not dying after a heart attack isn’t the only outcome that matters to patients, Virani says. Many people today survive heart attacks and strokes but may face significant disability and poor quality of life.

Physicians who doubt the conventional wisdom about cholesterol and statins hold a range of views, but those from THINCS members tend to be the most extreme. In recent medical journal articles, THINCS director Uffe Ravnskov, a nonpracticing Danish physician and independent researcher, and David Diamond, a cognitive neuroscientist at the University of South Florida, dismissed almost all of what the medical mainstream believes about cholesterol and statins. They concluded, from a multi-study review, that elderly people with high LDL-C live just as long as or, in most cases, longer than those with normal or low LDL-C. Ravnskov also argued that infections are a common cause of cardiovascular disease and that LDL-C plays an important role in the body’s immune response against harmful pathogens. In line with these claims, they find fault with European guidelines on managing heart disease and diabetes, which recommend prescribing statins as part of treatment to cut levels of LDL-C. Diamond says he believes statins may have a small benefit in preventing heart attacks and strokes, but he ascribes that result to the drugs’ ability to reduce inflammation and blood clotting. 

Retired cardiologist Robert DuBroff, who taught at the University of New Mexico, says some patients with high LDL-C may benefit from statins. But he thinks it’s time for physicians to acknowledge that randomized controlled trials have at times produced inconsistent and contradictory evidence about the benefits of cholesterol reduction. His analysis of 35 cholesterol-lowering drug trials, published in BMJ Evidence-Based Medicine in 2020, found that there was no mortality benefit in roughly three-fourths of the trials, and nearly half reported no significant reduction in cardiovascular events. According to his analysis, some of the trials that reported the greatest drop in LDL-C among participants demonstrated no accompanying cardiovascular benefit. But in other trials where LDL-C levels dropped only modestly, there was a robust reduction in cardiovascular risk. “The cause of atherosclerosis is far more complex than we originally thought,” DuBroff says. “But our LDL-centric approach to preventing cardiovascular disease may have distracted us from investigating other mechanisms and treatments.” 

Cardiologists have ready rebuttals for cholesterol deniers’ claims. In some people, low LDL-C is a marker of significant systemic disease, such as severe infection or sepsis—and it’s that underlying systemic disease, rather than low LDL-C by itself, that causes people in some clinical studies to die. 

Another false argument—that people with high cholesterol tend to outlive those with normal cholesterol levels—illustrates the problem of selection bias, Labos says. “If your study includes only people who died from a heart attack, for example, you can make dangerous things such as smoking and high cholesterol seem protective if you don’t properly adjust for them statistically,” he says. The likely reason that some people with no apparent risk factors may die of a heart attack is that their genetic makeup led to the development of heart disease. 

A 2016 meta-analysis examining 25 statin trials showed that the more you reduce cholesterol, the greater the cardiovascular benefit. And Labos’s own study that analyzed data from recent randomized trials of statins found conclusively that statins’ cardiovascular benefit is directly related to their LDL-C-lowering properties rather than to any other effects.   

Redberg has long disputed the majority view of cholesterol and statins. “I believe there is an association between LDL cholesterol and heart disease, but it’s very weak and it’s certainly not causal,” says Redberg, professor of medicine at University of California, San Francisco. She declines to treat patients with statins to prevent a first heart attack or stroke regardless of LDL-C levels. Although current clinical guidelines call for giving statins to anyone who has LDL-C of at least 190 milligrams per deciliter, Redberg advised her mother, who had high total cholesterol, not to take any statins. Redberg attributes the longevity of her mother, who lived to age 94, to a good diet and exercise. “Mine is a minority opinion among physicians, but it should be mainstream,” says Redberg, who launched a “Less is More” series of articles in JAMA Internal Medicine that focuses on what she considers the overmedicalization of Americans.

Redberg says she believes there are minimal benefits in taking a statin to prevent a heart attack or stroke for someone who hasn’t already had one. “If 100 people take statins for primary prevention, only two will avoid a heart attack, which means that 98 won’t get any benefit from the statins, but up to 20% will have adverse effects and none will live longer,” she says.  

But Redberg’s advice about statins is different for those who have already had a heart attack or stroke. For so-called secondary prevention, taking a statin may be worthwhile because the cardiovascular risk is so much higher, she says. “Everyone who has had a heart attack gets a statin, regardless of their cholesterol level, because you are much more likely to have a second heart attack after your first one,” Redberg says. “If your risk of having a second heart attack is 20%, a statin may cut that risk by 2%.” In contrast, a healthy person with high cholesterol may have a 1% chance of having a heart attack, and taking a statin reduces that risk by a mere 0.1%, she says. This is accurate, according to Labos. “The higher your risk, the more you benefit from treatment, which is pretty standard in all fields of medicine,” he says.

Source: Sam Kaplan/Trunk Archive

SOME OF THOSE WHO question the evidence of statins’ benefits point to the lack of transparency in the way much of statin research is conducted and analyzed. For instance, the Cholesterol Treatment Trialists’ (CTT) Collaboration, a division at the University of Oxford in the United Kingdom that has received significant financial support from the pharmaceutical industry, keeps patient-level trial data secret. “Virtually everything we and the experts who write clinical guidelines know about statins comes from the CTT Collaboration,” says John Abramson, a lecturer on health care policy at Harvard Medical School and author of Overdosed America. “Individual patient-level data from the trials remains sealed, which means we have no confidence that the published data are a fair and complete representation of the trials’ results.”  

The CTT Collaboration was formed to bring together participant data from big, long-term randomized controlled trials of statin therapy. Having information about a larger, more diverse population of study participants enables the companies that voluntarily participate in the CTT to report on the effectiveness of statins versus placebo in women, for example, or in people over age 75 or those with a low risk of developing heart disease. Those finer distinctions may enable drugmakers to show that statins as a class are safe and effective for more diverse groups of people. But in return for participating in the CTT, companies were assured that their raw patient data would be kept under wraps. 

The CTT Collaboration confirms that it doesn’t routinely share data about individual participants in statin trials. But responding to Abramson’s claims in a letter to The Lancet, the group said that it employs an independent panel to provide “external oversight, and the collaboration responds to external requests for analysis.”   

Editorials in JAMA and The BMJ have criticized the CTT Collaboration for refusing to make all trial data available to other researchers. The editors of The BMJ say they have made multiple requests over several years to the CTT to release the data, but only a handful of collaboration members who conduct statin trials have complied. Secrecy about statin trial results underscores the “deep flaws in our current system for evaluating medicines and guiding clinical decisions,” The BMJ editors wrote

But Baylor’s Salim Virani thinks the focus on the CTT Collaboration is just one more conspiracy theory promoted by anti-statin clinicians. He notes that most of the thousands of researchers who have worked on statin trials over the years are not members of the CTT, and those researchers do make their data available to other scientists. In addition, Virani says, the U.S. Food and Drug Administration reviews all relevant trial data before approving a statin, and if statin makers were attempting to cover up dangerous side effects, it would be discovered during those regulatory reviews. “These conspiracy theories have definitely cost lives by convincing patients not to take statins,” he says.

Statin use doesn’t begin when it’s prescribed but rather when a patient decides to take it. The lopsided coverage of the cholesterol debate outside of medical journals can play into that patient decision in a potentially deadly way, Labos says. “There is a real danger that misinformation causes people to stop taking their medications”—or not to start in the first place. In Australia, for example, statin prescriptions dropped by 14,000 per week following a 2013 television special about the dangers of that class of drugs. The collateral damage, according to a group of researchers, was that more than 60,000 people were affected, and that 1,500 to 3,000 potentially avoidable heart attacks and strokes would occur if those patients remained off statin therapy for the next five years. In Denmark, researchers attributed a 2% rise in heart attacks and a 1% increase in cardiovascular deaths to people abandoning their statins after watching negative news reports about the drug. 

How to keep the public informed about the actual state of the debate among physicians is tricky. On one hand, physicians have an obligation to protect patients by keeping scientifically unsound articles about cholesterol out of medical journals, says Nissen of the Cleveland Clinic. “If medical misinformation is out there and we just shrug, we have shirked our responsibility,” he says. “Journals need reviewers who are scientifically strong and can take apart a meta-analysis and say, ‘This isn’t right.’ What disturbs me is that some pretty good journals seem to allow these contrarian views about cholesterol and statins into their pages,” he says, referring in particular to Redberg’s JAMA Internal Medicine and The BMJ.

But until there are changes in the process through which journals select and review the articles they decide to publish, clinicians will have to make their case person by person, engaging in detailed discussions with their patients about the existing evidence around statins. Some patients, looking at the evidence, may decide their risk doesn’t merit taking a daily statin for years. “It’s a fair argument for a healthy person with high cholesterol to decline a statin, which isn’t going to prevent that many heart attacks or strokes if the patient’s only risk factor is high LDL-C,” Labos says. “But if you have high cholesterol, have a family history of heart disease and have hypertension or other risk factors, then taking a statin will have a much larger preventive benefit. And as you age, your risk of heart disease increases, which also makes taking a statin beneficial.”  

“The way to deal with misinformation is to provide the right information, one patient at a time,” Virani says. “When patients express concerns about taking a statin, the worst thing clinicians can do is be dismissive. Hear them out, provide the evidence and direct them to resources such as clinical guidelines and reputable sites. Then let patients be the judge of whether they want to take a statin.” 

Although statins have been a treatment mainstay for several decades, it could take even longer to extinguish dangerous misinformation about cholesterol and statins. “Eventually there will be a new generation of doctors who can’t believe there ever was an argument about whether reducing cholesterol was a good thing,” Labos says. “No one remembers the time when prominent cardiologists believed that lowering blood pressure was dangerous.” Labos quotes John Hay, writing in The British Medical Journal in 1931: “There is some truth in the saying that the greatest danger to a man with a high blood pressure lies in its discovery, because ‘then some fool is certain to try and reduce it.’” 

DOSSIER

Popular Media and Cardiovascular Medicine: ‘With Great Power There Must Also Come Great Responsibility,’” by Anandita Agarwala et al., Current Atherosclerosis Reports, October 2019. The authors analyze how social media perpetuates medical falsehoods and discuss how clinicians can address their patients’ misconceptions.

Interpretation of the Evidence for the Efficacy and Safety of Statin Therapy,” by Rory Collins et al., The Lancet, September 2016. This exhaustive review examines evidence from clinical trials of statins, outlining their proven benefits, adverse effects—proven and claimed—and the public health consequences of the spread of misinformation about the safety of statins.