Paradox: A Correlate Does Not a Surrogate Make

Cholesterol Paradox: A Correlate Does Not a Surrogate Make – Robert DuBroff – Evid Based Med. 2017

The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world.

Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect.

The public is certainly not aware that lowering cholesterol to prevent heart disease is just a theory because, as is the case with most things medical, it is presented as a fact. 

This is exactly what has happened with opioids, making the public believe that these effective medications are useless for chronic pain and always horrendously addictive for all people under all circumstances.

The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease.

This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point.

In clinical trials, a surrogate endpoint (or marker) is a measure of effect of a specific treatment that may correlate with a realclinical endpointbut does not necessarily have a guaranteed relationship. The National Institutes of Health (USA) defines surrogate endpoint as “a biomarker intended to substitute for a clinical endpoint”.

Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.


The cholesterol hypothesis has been debated for years, but in light of recent clinical trial results, a reappraisal of the evidence is warranted.

Cholesterol is an ostensibly ideal surrogate target: it is present in atherosclerotic plaque; cholesterol is an established risk factor for CHD; Mendelian randomisation studies suggest benefit from lifelong reduced cholesterol levels and cholesterol-lowering drug trials have reduced the risk of cardiovascular (CV) events.

Consequently, it seemed impossible that the gold standard of modern medical research—a large, double-blind, randomized controlled trial (RCT)—could undermine, rather than confirm, this theory.

Yet the ACCELERATE trial reported that evacetrapib, a novel cholesteryl ester transfer protein inhibitor, reduced low-density lipoprotein (LDL) cholesterol by 37%, raised high-density lipoprotein (HDL) cholesterol by 130%, but produced no discernible reduction in CV events or mortality in high-risk patients.

I believe the ACCELERATE trial adds to the chorus that cholesterol is not a valid surrogate end point.

Many experts cite numerous RCTs of statins in support of the cholesterol hypothesis, but we should not ignore the dozens of cholesterol-lowering trials that do not.

Table 1 lists 44 cholesterol-lowering RCTs that reported no mortality benefit. Most reported no reduction in CV events, and several reported substantial harm (CDP, HERS, Minnesota Coronary Experiment, Sydney Diet Heart Study, WHI, WHO).

This lack of benefit was seen even with profound reductions in LDL cholesterol (50% in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial).

A recent analysis concluded that statins would only postpone death by a median of 3.1 and 4.2 days for primary and secondary prevention, respectively

Finally, consider that the cholesterol hypothesis may have inadvertently contributed to the very disease we seek to prevent.

The cholesterol hypothesis risks oversimplifying the complex interaction of cholesterol, diet and coronary disease, leading many statin users to overeat with consequent obesity.

the food industry developed and continues to promote low-cholesterol foods that are nonetheless high in sugar and refined carbohydrates. These dietary changes have likely contributed to the current epidemic of obesity and diabetes that can lead to CV disease.

The empirical record is now clear that lowering cholesterol through diet or with eight different classes of drugs does not significantly prolong life or consistently prevent CHD.

Yet experts continue to proclaim the success of cholesterol-lowering.

Fifty-four years ago, Thomas Kuhn described this reluctance to acknowledge anomalies in a theory

Dr Kuhn wrote that a paradigm shift would only occur when the evidence contradicting a theory is overwhelming. Therefore, we must accept the empirical record even though it contradicts our long-held beliefs.

Other researchers believe this reluctance can be explained by the tendency to “see what you want to see,” and ignore what you do not.

The debate over the cholesterol hypothesis has continued because the results of cholesterol-lowering interventions are inconsistent and contradictory.

Nevertheless, clinical guidelines continue to emphasize the critical importance of cholesterol-lowering to prevent CHD. Unfortunately, I believe this one-dimensional approach may have impeded the advancement of science and our search for other preventive strategies.

Evid Based Med. 2017;22(1):15-19. © 2017 BMJ Publishing Group

2 thoughts on “Paradox: A Correlate Does Not a Surrogate Make

  1. Kathy C

    Thanks Zyo,
    This debacle shows how flawed some of this “Research” is. It also shows the power of Marketing. The food Industry has the best Market Psychologists, they do a lot of Research into manipulating people in every way possible to buy their products. It is really tragic that so many people were put on these drugs, while being told by the food Industry that those processed, high in sugar, profitable foods are “Healthy.” We have painted ourselves into a corner, with these Industries, Pharma made sure there was no way for Physicians, Statisticians, or Health Researchers to observe this. The Medical Industry too, in an effort to avoid all “Liability,” Physicians did not want to keep track either. There was no way for a Physician to observe any of this over time.
    The profitability of this drug scheme only perpetuated the Cholesterol Theory, as the Marketers found it was an excellent way to get people away from real food, and into their highly profitable processed alternatives. People were essentially brainwashed by the Food and Pharma Ads. They tied the Cholesterol Theory to “Health” marketing both good health, and sensibility in Advertising. They got the public to repeat the marketing, while endorsing “Seeing your Doctor.” Over the years, i noticed that the more people were concerned about “Cholesterol” the heavier and more unhealthy they were. The brainwashing was so good, that even contrarians believed eggs were bad for them, Even though they are a good source of protein and nutrients. People ate them for millennia, and now High Sugar Cereal was somehow better.
    The Opiate debacle is another Pharma, Insurance and Medical Industry Marketing scheme. Politicians can appear to be “Fighting Big Pharma” while promoting their much more expensive Alternatives. The Industries Lobbyists fought for lose Reporting requirements, except for the opiates. This lack of Data was contorted to make it appear that Opiates were the only problem. The American Public believes whatever the Marketers tell them. It was not hard for this unholy trio of Industries to weave a narrative around those awful opiates.
    The Medical Industry had a problem with all of those people who either survived surgeries, but were left with intractable pain or the people they could not fix. The Insurance Industry did not want to pay for those injured blue Collar Workers, and surgical mistakes either. The Corporate Media which has the same owners, misled the public about Healthcare, Drugs and did not cover the negatives about Healthcare. The Media easily gave the appearance of information about “Health,” most of it had nothing to do with actual health, it was Marketing for Pharma or the Medical Industry. If we rank the most expensive Health issues for the US, or even the costs of any of this, we find the Media has left this out of their coverage. At the same time Pro Publica , the only Independent Group of Researchers claims that Medical Error is the third leading cause of death in the US. They are even urging the C.D.C to change their data collection to reflect this. These Industries decided which data the government or even Medicare could collect.
    They had plenty of time to obscure the data, an important issue for these Industries. Most Researchers are limited to Billing Data, which is the only real Reporting Requirement. The Industries were very influential in the ICD 10 Billing Codes, making sure that Providers could avoid liability. They did the same with the DSMV V, they expanded the categories for Pharma, and at the same time made it easier to Bill for their Services. They changed the description of Chronic Pain, and created a new Disorder to describe people with health issues, it was now a billable disorder. People that the Medical Industry can’t fix, or are navigating the system because of a health condition now have a billable disorder. They even made any frustration, anger or despair over any Medical mishap a “Psychological Disorder.” This helped these industries obscure the Facts. It was easy to get the “Physiological Industries” to expand their Billing., Since they already “believe” so many of the Biased “Studies” that were promoted by the Industry, it was easy to get them to ignore facts and seek a Psychological motivation for gettign sick. They believe their own hype. The Medical Industry found a way to avoid Liability, Insurers could avoid Pay Outs for any deniable injury, and Pharma had a whole new segment of the population to sell Products to.
    All of this has led to an Epidemic of Despair, with no future for so many, and a disconnect from reality, a lot of people turned to drugs. There were people who were prescribed drugs to make up for the failure of their Healthcare too. Injuries from years of work, that were either misdiagnosed or the medical Industry had no cure for, often the cure was worse than the initial Injury. They did not do any “Research” on this expensive part of healthcare. Only the Occasional limited Study here or there. In the late nineties they tried to get physicians to stop recommending back surgery,, because the outcomes were not good. It is difficult to get a figure for the Percentage of “Failed Back Surgeries,” Approximately one in three of these surgeries “Fail.” That is never mentioned in Corporate Media, as people are told they can rate physicians.
    The Internet made it appear that we had Information at our fingertips, yet most of the information that come up in a Google Search is advertising or misleading. These Industries were able to bury factual information is slurry of Mis-Information. For a price inconvenient Internet Articles can be buried, or removed. Our Healthcare System is a Corporate proftit Generator, and it got that way by keeping the facts away from the public. The Public has been told by the Industries what the problems are. People who have an :”Adverse Event” are described by Psychologists as having a Disorder. They don’t track any of this, they only tracked the “Opiate Deaths,” because it is an “Epidemic. It was easy to get the public to believe that people that people with Chronic Pain were “Addicts”. This was the way they discredited people harmed by the Medical Industry, or the ones who had worked hard all of their lives to live in pain in their “Golden Years.”
    The unfortunates who worked repetitive jobs through the pain, if they had sought Medical Attention, they would have been told to exercise or Think Positive, if their insurance did not pay enough. This should have been a Public Health Crisis, but Corporate Media did not cover it. It was inconvenient for all of the industries that made money at the expense of these workers, companies that did not want to pay for Health Insurance either. They just took pain out of the discussion, while they promoted products and a mentality of “Walking it off.” Other Marketers found ways to sell everything from sport equipment to knee braces, and supplements to “Cure” pain, Marketing the Ideology of Alternative Medicine helped obscure the facts, and give people the idea there was a choice. Corporate Media told us that the FDA was Protecting us, at the same time these industries were claiming their regulations were cutting into their profits. These Industries had plenty of money to buy our Politicians, and get their Insiders on any regulatory Boards. They could cherry pick the data that was used to make policy decisions, almost every one in favor of the Industry.
    The Corporate Media railed about “Government Regulations” as these Industries dismantled them over the years. They knew that the only way to affect the data was to undermine collecting it. This led to a skewed alternate reality. They just did not track the mistakes, the side effects or the dead. There is no Reporting Requirement for other Pharmaceuticals. Polypharmacy is contributing to a lot of deaths, yet only if opiates are involved are they reported as an Opiate Death, the rest are mostly reported as “Underlying Causes.” This was a clever way to obscure the deaths, that should have been attributed to Pharma. Even the death reporting us subject to interpretation by underfunded Health Departments. Congress at the behest of industry, took funding away strategically from any Agency they did not like, or interfered with their Profitability.


    1. Zyp Czyk Post author

      You are right – money is now the measure of all value: material, social, and even psychological.

      It’s money, in the end, that creates and motivates all metrics. Metrics are a way to assign value (not really measurement as it should be) to all activity and translate every thing or entity into a cost/benefit ratio.

      Metrics are a monetary value assigned to invaluables, like loyalty, effort, and even love.



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