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Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 7: The Statins — Gift to Mankind (Part 2)
Wednesday, November 12, 2014 10:13 am Email this article
EXCEL, the Expanded Clinical Evaluation of Lovastatin
This trial was performed by Dr. Reagan H. Bradford and his team from a large number of American clinics and research institutions, including the Merck Sharp & Dohme Research Laboratories at West Point, NY, where the drug was produced where the drug was produced. More than 8,000 healthy individuals (called “patients” in the trial reports) with cholesterol levels between 240 and 300 mg/dl (6.2-7.7 mmol/l) received one of four different doses of lovastatin (Mevacor®) or a placebo.
With a view to reporting on possible adverse effects of the treatment, preliminary study results were published after only one year of the trial. No significant side effects were reported, but in the fine print the authors were obliged to mention that death due to all causes was 0.5 percent in the four lovastatin groups combined (32 or 33 individuals out of a group of about 6,600—no exact figures were given in the report) compared to 0.2 percent in the placebo group (three or four individuals out of a group of 1,650). By taking all the lovastatin groups together, the difference would have been statistically significant if the number of deaths in the treatment groups were 33, but not if it were 32. Even if the difference wasn’t statistically significant after one year, it would certainly have become significant if the tendency to a higher mortality in the treatment groups had continued throughout the trial. In any case, the aim of the treatment was to lower mortality and most certainly no lowering was achieved.
Today at least 20 reports from the EXCEL trial have been published in various medical journals. These reports tell us how well lovastatin is tolerated and how effective it is in lowering blood cholesterol levels in various populations, but not one of them has reported the final outcome of the trial, although more than ten years have passed since it began. Therefore, we do not know whether the increased mortality, seen after just one year of treatment, has continued throughout the trial.
Why have we never heard about this outcome of the first statin trial, which was one of the largest? I asked that question in a letter to Merck, Sharp & Dohme. They answered that, “the trial was not designed to measure the clinical outcome, only to test whether the drug was tolerable and did not produce any serious side effects.”
On May 16, 2001, an expert panel from the National Cholesterol Education Program published new guidelines for “the detection, evaluation and treatment of high blood cholesterol.” The guidelines introduced new risk factors that demand preventive measures (or “risk-reduction therapy,” as they call it) and widened the limits for the old ones.
The main target is LDL-cholesterol, they said, because “research from experimental animals, laboratory investigations, epidemiology and genetic forms of hypercholesterolemia indicate that elevated LDL-cholesterol is a major cause of heart disease.” (If you have read this book from the beginning you will probably agree with me that such research has indicated nothing of the kind.) The optimal values should be 150 mg/dl (3.8 mmol/l) for LDL and 200 mg/dl (6.1 mmol/l) for total cholesterol. But if there were any risk factors present, the optimal cholesterol level should be even lower. The more risk factors, the lower cholesterol should be.
In the highest risk category were patients with heart disease because, according to the statistics from Framingham, they run a more than 20 percent risk of having a new heart attack in ten years. (The report did not tell us where to find these figures, however.) Other atherosclerotic diseases were said to be just as risky, such as is diabetes from the age of twenty. And the presence of two or more other serious risk factors was said to put the patient at a similar risk.
The new guidelines provided an intricate scoring system showing how the different risk factors were graded. Men with an accumulated score of 15 or more belonged to the highest risk category. And it was easy to get a high score. For instance, if you were seventy years old, you were automatically given 12 points. A cholesterol level above 275 mg/dl (7.05 mmol/l) at age 39 gave you 11 points, less with increasing age. An untreated systolic blood pressure reading of 130 mm Hg (which is completely normal) got one point, two if you were on antihypertensive treatment.
Smokers below age 40 got eight points, and you are a smoker if you have smoked at least one cigarette during the previous month. Women needed a higher score to be placed in the highest risk category, but they got more points for their risk factors.
The guidelines recommended that everybody over age 20 had his or her cholesterol level tested every fifth year. If you were in the highest risk category and your LDL-cholesterol was above 100 mg/dl (2.6 mmol/l), you should change your life habits; if your LDL was above 130 mg/dl, (3.3 mmol/l) you should immediately start cholesterol-lowering treatment. But you might as well start with both measures, said the guidelines, because few people succeeded in lowering their cholesterol by life-habit intervention alone—although in another place in the paper the authors claimed that life-habit intervention was an effective way of lowering cholesterol!
Emerging risk factors
The indications for treatment were stronger if there were other risk factors than those mentioned above, for instance if you were overweight, if you exercised too little or if you ate too much animal fat. Even “emerging” risk factors should be taken into consideration, and by emerging risk factors the authors included almost all laboratory tests that, on average, had been found higher in patients with heart disease. According to the authors, “the emerging risk factors do not categorically modify LDL-cholesterol goals; however, they appear to contribute to CHD risk to varying degrees and can have utility in selected persons to guide intensity of risk-reduction therapy.” (In other words, take a bunch of laboratory tests and most of us become candidates for statin treatment.)
One of the emerging risk factors was called “subclinical atherosclerotic disease.” The guidelines gave no explanation for this new concept. The term comes from a new technique called electron beam tomography that is a method for depicting calcifications without putting a catheter up into the coronary arteries. The degree of calcification is said to reflect the degree of atherosclerosis and is therefore a much better predictor of future heart attack than high blood cholesterol or, for that matter, any other risk factor. According to an advertisement for one of those huge health centers that have become popular in the US, “The electron beam tomography scan gives individuals who have risk factors for heart disease a painless, non-invasive way to obtain peace of mind knowing that early indications of heart disease are or are not present.”
Whether you obtain peace of mind is questionable because in the most recent study using electron beam tomography, sixty percent of a group of healthy women over age 55 had “subclinical atherosclerosis,” yet, according to the new guidelines, half of these women belonged to the low-risk category. In other words, with one blow this new technique has landed many further millions of healthy people into the high-risk category.
The most surprising finding, at least for those who have not read this book, was the lack of an association between degree of calcification and total or LDL-cholesterol or any other lipid fraction. The authors of the study had no comments about this finding—which of course is totally devastating to the cholesterol hypothesis—except to say that they considered the new guidelines insufficient and suggested regular electron beam tomography for the whole population. I sent a short letter to William W. Parmley, the editor of the journal (JAMA) where I told about the many other studies with similar results and asked him, why the authors did not question the cholesterol hypothesis. He answered: “Because of space limitations we are able to publish only a few letters addressing controversial issues.”
More new risk factors
The guidelines stated officially for the first time that high triglycerides should be lowered and low HDL-cholesterol should be raised. True enough, admitted the authors, no study has proven that raising HDL-cholesterol provides any benefit. (There is no evidence that lowering triglycerides provides any benefit either.) Nevertheless, they recommend treatment with clofibrate (Atromid-S® Abitrate®) or nicotinic acid (niacin®). Obviously, the many unsuccessful trials with these drugs and their many harmful side effects had been completely forgotten.
As an argument for using cholesterol-lowering drugs, the supporters claim that 20 percent of patients with coronary heart disease have a heart attack within ten years. But that number is obtained by including minor symptoms without any clinical significance. Many people survive even a major heart attack with few or no symptoms after recovery.
Heart attacks may even appear without any symptoms. I have seen many patients myself with indisputable ECG indications of a recent myocardial infarction, but who recall no more than slight discomfort, if any symptoms at all, during the preceding weeks. What matters is how many die and this is much less than 20 percent.
Lower and lower
New guidelines have appeared regularly for at least 40 years. In 2004, new trials inspired the National Heart, Lung, and Blood Institute to publish a set of updated guidelines, according to which, cholesterol should be lowered even more aggressively than before. This advice was based on three trials.
In two of them, REVERSAL and PROVE-IT, half of the patients were treated with 40 mg pravastatin, half with 80 mg atorvastatin. The “best” effect was seen in the high-dose groups, where LDL-cholesterol was lowered by 46 and 51 percent respectively, whereas in the pravastatin groups it was lowered by 25 and 22 percent respectively. Therefore, the authors argued that we should take cholesterol down to much lower levels than previously recommended. They also considered their result as proof of exposure-response.
But you cannot study exposure-response with two different drugs, because there are large differences between the other, the so-called pleiotropic effects of the various statins. Furthermore, the eight times higher dose of atorvastatin (the usual dose is 10 mg) only cut cholesterol marginally more than the usual dose. In a previous atorvastatin trial named ASCOT for instance, 10 mg atorvastatin lowered LDL-cholesterol by 35 percent whereas the eight-times-higher dose in the two trials mentioned above lowered it only by a further 12 percent and 16 percent respectively.
In a third trial, named TNT (Treatment to New Targets), about 10,000 patients with stable heart disease were treated with atorvastatin for five years; half of them with 10 mg and half with 80 mg. Again, the “best” effect was seen after 80 mg and the authors claimed that their study was a further support to the new guidelines. Some curious things emerged from that trial, however.
First, total mortality was almost identical in the two groups; 5.6 percent in the low-dose group, 5.7 percent in the high-dose group. The reason was that the fewer who died from cardiovascular disease was outnumbered by a larger number dying from other causes. These causes were not given, however, and our request for more details was ignored.
Second, heart mortality was significantly lower in the high-dose group, but the report only provided the number of “non-procedure-related myocardial infarctions.” By non-procedure-related infarctions is meant heart attacks that have not occurred during operations or diagnostic investigations at the hospital. The latter infarctions should, of course, have been included as they have been in all other trials. There can only be one explanation why the researchers have omitted them—their number was higher in the high-dose group. Had more occurred in the low-dose group, the authors with all certainty would have reported them.
Benefits and risks
The fact that the number of side effects was larger than the number of patients that benefited from treatment should have given the authors great concern, all of whom have strong financial ties to Pfizer, the sponsor of the trial. If doctors recommend a high statin dose to their patients, they should be able to tell them whether the benefit of such treatment counterbalance possible harmful side effects, but no such useful information emerges from this trial report.
Patients with non-fatal cardiovascular diseases such as a myocardial infarction and stroke often recover completely. It is therefore not self-evident that the many side effects are balanced by the lower incidence of cardiovascular events. A relevant question to a patient with heart disease is whether he prefers memory loss (which with all certainty was not regarded as a side effect, as nothing about that is mentioned anywhere in the official reports or on the drug labels) instead of a non-fatal heart attack, which often heals without serious sequels. Or ask whether he prefers polyneuropathy, which may become permanent as an invalidating and very unpleasant condition, or a minor stroke, which may heal without any sequels.
An alarming report
After the publication of the new guidelines, yet another trial comparing normal and high-dose was published, the IDEAL trial. In this trial, where usual-dose simvastatin was compared with 80 mg atorvastatin, no significant difference was seen either as regards the major endpoints. Even worse, the number of adverse effects was far higher. Almost 90 percent had side effects and almost half of these were recorded as serious. No, this isn’t a printing error: almost half of them!
The authors did not comment on this alarming finding except by mentioning that, “there was no difference between the groups in the frequency of adverse events that were rated as serious.” Nor did they inform the reader about the nature of these events. In their answer to our request the authors responded as follows:
“The numbers do not represent only drug-related adverse effects. In accordance with good clinical trial practice, the study protocol required that all observed or volunteered adverse events, whether or not considered drug-related, should be recorded during the trial. This included worsening or increase in severity or frequency of preexisting conditions as well as minor and serious new signs, symptoms, or laboratory findings. In a population of middle-aged or elderly coronary disease patients aged up to 80 years, it is rare that anyone does not have at least an episode of common cold or a minor musculoskeletal injury over a period of 5 years. The frequency of all adverse events in the IDEAL study was therefore as expected. Adverse events considered definitely or possibly drug-related were few, and significant differences between the two treatment groups were presented in the article. The frequency was not greater than in comparable trials.”
How could the authors know whether the frequency of all adverse events was “as expected?” The number of common colds and minor injuries has never been reported in any previous trial; neither can they be classified as serious. And why didn’t they tell us about which adverse effects they considered drug-related?
The large number of side effects may have another explanation. As mentioned above, almost half of the patients originally selected for the TNT trial were excluded because of various types of weaknesses or diseases or because they didn’t tolerate the drug. In the IDEAL trial, only eight percent were excluded. These patients may therefore have been more similar to patients in real life, and many of the “new signs, symptoms, or laboratory findings” may have been due to the drugs.
Why are trial directors always so eager to sweep all disadvantageous observations under the rug? Aren’t they concerned about future patients? Shouldn’t they follow the words of Hippocrates: “First, do no harm.”
Is the explanation to be found at the end of their letter, which states as follows:
“Financial Disclosures: Dr. Pedersen has reported receiving consultation fees and speaker’s honoraria from Pfizer, Merck, Merck AG, and AstraZeneca and research grants and steering committee fees from Pfizer and Merck. Dr. Kastelein has reported receiving research grants from Pfizer. Drs. Olsson and Holme have reported receiving honoraria from Pfizer as steering committee members. Dr. Bendiksen was previously employed by Pfizer Norway and has reported receiving honoraria from Pfizer as a steering committee member.”
Can we trust the drug companies?
In his book “The Whistleblower,” Peter Rost, a former top executive in Pfizer, reveals a company riddled with corruption. According to Rost, Pfizer and other drug companies spend huge amounts of money to promote their trials. One way is to pay renowned researchers for putting their name on the final trial report, when, in fact, the reports are written by PR firms. Also, according to Richard Smith, former editor at the British Medical Journal, many medical journals are packed with articles ghostwritten by pharmaceutical companies.
The FDA recently cited Pfizer for publishing the results of a Valdecoxib trial in a manner that obscured the risks and the drug now has a black box warning. Pfizer has also pleaded guilty to numerous charges of false advertisements and agreed to pay billions of dollars to satisfy criminal and civil penalties. Pfizer funded the TNT trial, paid its directors and authors, analyzed the data, and assigned one of their employees as co-author of the trial report. There were thus numerous opportunities to have influenced the results, knowingly or unknowingly.
The new guidelines may possibly prevent cardiovascular death in a small minority of patients with cardiovascular disease. But at the same time they may increase mortality from other diseases, transform healthy individuals into unhappy hypochondriacs obsessed with the chemical composition of their food and their blood, reduce the income of ranchers and dairy farmers, undermine the art of cuisine, destroy the joy of eating, and divert health care money from the sick and the poor to the rich and the healthy. The only winners are the drug companies and imitation food industry—and the researchers that they support.
And there are more problems with the advice we receive from the authorities. Read on!
Many side effects from new drugs do not appear before they are used in greater scale. Doctors are told to report all new, unexpected side effects, but there is a great risk that they are underreported. Most drugs have side effects either because they are toxic or because the patient is hypersensitive to the drug. Therefore, the side effects appear very soon after the start of the treatment and the patient therefore easily recognize the symptoms as a result of the treatment. The statins are not directly toxic and they do not result in hypersensitivity reactions. The statins disturb the normal synthesis of several important substances in our body. It may therefore take a long time before these substances are totally depleted and symptoms of deficiency appear. Both the patient and the doctor may therefore overlook that late symptoms may be caused by the drug. Statins are used mostly in old people. Cancer, loss of memory, weak muscles, impotency and heart failure are common in old people and may therefore be considered as natural effects of old age. Furthermore, old people are often treated with many different drugs. In Sweden, for example, old people discharged from a medical or cardiology department are often prescribed a dozen or more different drugs. So, even if doctors should suspect that the patient’s symptom were caused by the medicine, how can someone determine which of the medicines is to blame?
That side effects are underreported is obvious from a study in Rhode Island, USA. A questionnaire sent to all practicing doctors and answered by 74% showed that the serious side effects reported to the FDA during the previous year corresponded to only one percent of the numbers actually seen.
It is comforting to learn that many patients realize themselves that the statins are toxic. In Ontario, Canada researchers studied how many people had continued their statin treatment. A total of more than 140,000 old people were included in the investigation. Two years after the first statin prescription two thirds of those who already had a heart disease, and three fourth of those whose only “disease” was high cholesterol had discontinued.
The alleged omnipotence of statin drugs
You may probably have read in the newspapers about the many other allegedly positive effects of the wonder drugs, the cholesterol-lowering statins. Carefully placed articles now claim that statins can prevent cancer, ankylosing spondylitis, chronic obstructive pulmonary disease, severe sepsis, heart failure, hip fractures, and much more. The way the researchers have studied these allegedly beneficial effects is confounded with a serious bias, however. As an example I shall analyse one of these claims, the idea that statin treatment prevents Alzheimer’s disease.
First, studies claiming that statin treatment is good for almost any disease do not come from trials where the control individuals have cholesterol levels just as high as those in the treatment group. Instead, comparisons are made between people treated with statins and control people selected from the same community, but who are not treated with statins.
Obviously these people’s cholesterol is lower than those treated with statins, at least lower than their cholesterol before treatment, which means that the researchers have compared the outcome of low-cholesterol people with high-cholesterol people, and there are many studies showing that people with high cholesterol are healthier in many aspects compared to people with low cholesterol.
For starters, most studies have found that old people with high cholesterol live longer than old people with low cholesterol. But we have also some specific data about brain function and cholesterol. For instance, Bianca Schalk and her team at the University Medical Center in Amsterdam, Holland followed more than 1,000 people age 55-85 for three years and found that those whose cholesterol was lower than 200 mg/dl (5.1 mmol/l) were more likely to decline in functional performance tests such as walking, turning around, dressing themselves and standing up and down from a kitchen chair with folded arms.
Another Dutch study showed that among more than 6,000 people above age 55 and followed for nine years, women with high cholesterol developed Parkinson’s disease less often than women with low cholesterol; the higher the cholesterol, the lower was the risk.
Researchers at the Johns Hopkins University, Baltimore and Göteborgs University, Sweden followed 382 old people for ten years. Among those with the highest cholesterol values much fewer had dementia at follow-up than the others. In accordance with these findings is a study from the Framingham Heart study. Here Penelope Elias and her team followed about 2,000 individuals for 16-18 years. A detailed record of their ability to learn, to reason, to concentrate and to organize showed that there was a direct association with these mental performances and cholesterol; the higher cholesterol, the smarter they were.
Let us have a look at Alzheimer’s disease itself. The allegation that low cholesterol prevents Alzheimer comes from comparisons between people on statin treatment and people who are not, and obviously there are unavoidable errors associated with such a comparison. A better way to get an answer is to compare initial cholesterol in people who develop Alzheimer and in those who do not. This was done by Dr. G. Li and others at the University of Washington, Seattle. After five to six years, about 13% of more than 2000 old people had developed Alzheimer’s disease or all-cause dementia and on average, their cholesterol did not differ from the others.
People who take lipid-lowering agents might also be wealthier than those who do not, because statin treatment is expensive and wealthy people are healthier than poor people. The only way to decide whether statin treatment prevents Alzheimer’s or any other disease is a controlled clinical trial. Let us see what they have to tell us about this subject.
The protocol for PROSPER, the trial where old people were treated with pravastatin (Pravachol), included psychometric tests and a mental examination every year. At the end of the study, the directors concluded that their mental functions declined at the same rate in the treatment as in the control group. Similar findings were reported in the WOSCOPS trial. Thus, no evidence either that the statins other effects are able to prevent Alzheimer.
To study the effect of cholesterol lowering on memory, Professor Matthew F. Muldoon assigned 192 healthy adults to a six-month double-blind trial. Half of the participants were treated with Lovastatin and half of them with placebo. At the start and at the end of the trial a large number of tests were performed to assess neuropsychological performance, depression, hostility and quality of life.
Normally, when such tests are performed repeatedly, the test subjects improve because of learning or practice, and this was indeed seen in the control group. But tests of attention and psychomotor speed, which are not subject to this type of error, gave significantly lower scores in the Lovastatin group. The change in performance was unrelated to the percent change in LDL-cholesterol but was significantly related to the level achieved after treatment with Lovastatin; the lower the cholesterol, the worse was the memory.
Thus, the claim that statin treatment or low cholesterol levels protect against Alzheimer’s disease has no scientific basis; if anything these results rather suggest the opposite.
Those who pay
Financial disclosures for the authors of the NCEP guidelines 2004 were not given in the original publication. After a critical letter from Merrill Goozner of Center for Science in the Public Interest (CSPI) who questioned the scientific basis and objectivity of the guidelines, the financial disclosures were published on the web:
Dr. Grundy has received honoraria from Merck, Pfizer, Sankyo, Bayer, and Bristol-Myers Squibb.
Dr. Hunninghake has current grants from Merck, Pfizer, Kos Pharmaceuticals, Schering Plough, Wyeth Ayerst, Sankyo, Bayer, AstraZeneca, Bristol-Myers Squibb, and G. D. Searle; he has also received consulting honoraria from Merck, Pfizer, Kos Pharmaceuticals, Sankyo, AstraZeneca, and Bayer.
Dr. McBride has received grants and/or research support from Pfizer, Merck, Parke-Davis, and AstraZeneca; has served as a consultant for Kos Pharmaceuticals, Abbott, and Merck; and has received honoraria from Abbott, Bristol-Myers Squibb, Novartis, Merck, Kos Pharmaceuticals, Parke-Davis, Pfizer, and DuPont.
Dr. Pasternak has served as a consultant for and received honoraria from Merck, Pfizer, and Kos Pharmaceuticals, and has received grants from Merck and Pfizer.
Dr. Stone has served as a consultant and/or received honoraria for lectures from Abbott, Bayer, Bristol-Myers Squibb, Kos Pharmaceuticals, Merck, Novartis, Parke-Davis/Pfizer, and Sankyo.
Dr. Schwartz has served as a consultant for and/or conducted research funded by Bristol-Myers Squibb, AstraZeneca, Merck, Johnson & Johnson-Merck, and Pfizer.
Here are links to the other chapters in the book.
- Cholesterol Myths by Uffe Ravnskov, MD, PhD: Forward to Book by Michael Gurr, PhD
- Cholesterol Myths by Uffe Ravnskov, MD, PhD: Author’s Foreword
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Introduction: The Diet-Heart Idea: A Die-Hard Hypothesis
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Myth 1: High-Fat Foods Cause Heart Disease
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Triglycerides
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Myth 2: High Cholesterol Causes Heart Disease
- Cholesterol Myths by Uffe Ravnskov MD: Familial hypercholesterolemia—not as risky as you may think
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Myth 3: High-Fat Foods Raise Blood Cholesterol
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Myth 4: High Cholesterol Blocks Arteries
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Myth 5: Animal Studies Prove the Diet-Heart Idea
- Cholesterol Myths by Uffe Ravnskov MD, PhD: Cholesterol lowering in children
- Cholesterol Myths by Uffe Ravnskov MD: Myth 6: Lowering Cholesterol Will Lengthen Your Life (Part 1)
- Cholesterol Myths by Uffe Ravnskov MD: Myth 6: Lowering Cholesterol Will Lengthen Your Life (Part 2)
- Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 7: The Statins — Gift to Mankind (Part 1)
- Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 7: The Statins — Gift to Mankind (Part 2)
- Cholesterol Myths by Uffe Ravnskov MD PhD: “The most exact data base”—the screenee
- Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 8: Polyunsaturated Oils are Good for You
- Cholesterol Myths by Uffe Ravnskov MD PhD: Dr. Ornish and The Lifestyle Heart trial
- Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 9: The Cholesterol Campaign is Based on Good Science
- Cholesterol Myths by Uffe Ravnskov MD PhD: Insider Insight
- Cholesterol Myths by Uffe Ravnskov MD PhD: Myth 10: All Scientists Support the Diet-Heart Idea
- Cholesterol Myths by Uffe Ravnskov MD PhD: Epilogue
- Cholesterol Myths by Uffe Ravnskov MD PhD: References
This chapter is from the book
The Cholesterol Myths: Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease
by Uffe Ravnskov, MD, PhD.
Dr. Ravnskov has given me the permission to share this version of his book to help educate the world about the cholesterol campaign.
Information about Uffe Ravnskov, MD, PhD is posted here.
More information about Cholesterol Myths is posted on his website here.
Dr. Ravnskov posted his book for free here.
Uffe Ravnskov, MD, PhD is the founder of The International Network of Cholesterol Skeptics (THINCS.org) which can be found here.
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