Cholesterol controversy - June 13th 2016

Monday June 13th 2016

The UK national press, including radio and television, reported on Monday June 13th 2016 a “new surprise and controversy” in respect coronary heart disease and survival.

The report concerned a paper published in the British Medical Journal on-line edition. This was a meta-analysis of a number of previous publications  linking survival to blood levels of cholesterol. The conclusion was that above the age of 60 years a high level of cholesterol is not a danger but it gives a survival advantage. Although this was regarded as a controversy, it will come as no surprise to readers of this Blog as I have indicated this finding on previous occasions. 

Framingham

The most important cholesterol–survival study was in Framingham, Massachusetts, which I reported in a  post in December 2015. This was a highly detailed follow-up study lasting for thirty years, and it will never be repeated. The major concern was the large number of deaths from coronary heart disease (CHD) during the epidemic, with large numbers of premature deaths. Now that the epidemic has almost come to an end there is no incentive for further detailed epidemiological study.

Between 1951 and 1955, when the epidemic of CHD had become obvious and a serious public health problem, the study recruited 1959 men and 2415 women who were free of cancer and heart disease. They were between the ages of 31 and 65 years. They were followed in great detail for thirty years, at the end of which the conclusion was clear. For the purpose of data analysis the subjects were grouped into quartiles based on the blood levels of cholesterol.

In Figure 1 we can see that in men aged 31–39 there was a survival advantage in those with the lowest blood levels of cholesterol, 84% after 30 years, compared to those with highest cholesterol levels, only 68% after 30 years.

Figure 1. Survival of men aged 31–39, Framingham

It can be seen in Figure 2 that the overall survival for 30 years was much better in 30 year old women compared to 30 year old men. However in women of this age-group the survival advantage of a low blood cholesterol level was much less, 91% compared to 85%  for the highest cholesterol levels after 30 years.

Figure 2.  Survival of women aged 31–39, Framingham

In Figure 3 we can see that in men aged 56–65 survival was not influenced by the blood level of cholesterol. We can also see that at that time only about 10% of men aged 56–65 lived to the age of 90.

Figure 3.  Survival of men aged 56–65, Framingham

The conclusion in this landmark paper included the comment:

This conclusion was subsequently ignored.

The Framingham study did not not recruit people aged above 65 years, but other studies have done. I have previously reported the Paris study, the Honolulu study, and the New Haven study. 

Paris, Honolulu, New Haven

These studies all demonstrated something different. In the age group above the age of 70 years, those with the highest blood levels of cholesterol had the best survival. This can be seen in the survival curves in the Honolulu study, Figure 4, showing that those with the lowest blood levels of cholesterol had the lowest survival at 6 years.

Figure 4. Survival by cholesterol level. Honolulu

The conclusion of the Honolulu Heart Program was that "These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4·65 mmol/L) in elderly people".  

It would appear that no notice was taken of this study.

Similarly, as shown in Figure 5, in the Paris study, the worst survival was in those with the lowest blood levels of cholesterol. The study carefully and successfully excluded any person who had cancer, which could have contributed to both low cholesterol and death.

Figure 5. Survival by cholesterol level. Paris

There was a further study from New Haven, Connecticut, showing that cholesterol was not an indicator of cardiovascular risk in the elderly. The data is shown differently from the other studies. The end-point of the study was the percentage of those who died from CHD after four years. This was grouped on three blood level groups of cholesterol, for men and for women.

Figure 6 . Deaths from CHD at four years based on cholesterol level. New Haven.

We can see in Figure 6 that in the New Haven study of people over the age of 70 years, the CHD death rate was highest in men and women with the lowest blood cholesterol levels.The authors of the study (highly respected) state that the results do not support the hypothesis that high cholesterol is a risk factor for death or CHD death in older persons.

It is clear and it is not new that in people above the age of 60 years a high blood cholesterol is of no concern and if anything it is a good thing. But these results have been hidden from public view for a long time. Is is good that the information is now being brought to attention by the recent British Medical Journal publication. 

A high cholesterol is a good thing when you are above the age of 60

The conclusion that a high blood level of cholesterol (LDL-cholesterol) "may not cause heart disease in the elderly" and might be a good thing conflicts with “conventional wisdom”, led by pharmaceutical and academic vested interest. The misconception that cholesterol is bad fuels vast profits for the pharmaceutical industry and the academic departments that it supports (the main objective of these departments is the pursuit not of truth but of research funds).

There is no justification in testing the blood cholesterol level in people above the age of 60 years.

But what about statins?

As I have pointed out in previous Posts, the problem is that the small benefit of statins is nothing to do with the ability to lower blood levels of cholesterol. The so-called cholesterol experts always talk and write about “cholesterol-lowering with statins”. The clinical trials that they quote are trials of statin therapy, no more and no less. If we forget the cholesterol-lowering effect of statins then everything starts to make sense.

In response to the press release mentioned above (Daily Telegraph, June 13th 2016) was reported:

Professor Colin Baigent, an epidemiologist at Oxford University, said the new study had “serious weaknesses and, as a consequence, has reached completely the wrong conclusion”.

The study mentioned was not a clinical experiment or trial. It was a review of a number of observational studies of some size. The results were clear: high blood cholesterol in people above the age of 60 years gives a health and survival advantage. The conclusion in this respect is straightforward and to suggest that the study reached “the wrong conclusion” is absurd and a highly prejudiced comment: conclusions should follow a study and not precede it. 

I wonder if Professor Baigent ever read the monumental Framingham study, and if so did that 30 year study also reach “the wrong conclusion”?

And there was the quote of an absurd and automatic denial from the British Heart Foundation:

"There is nothing in the current paper to support the author's suggestions that the studies they reviewed cast doubt on the idea that LDL-Cholesterol is a major cause of heart disease or that guidelines on LDL reduction in the elderly need re-evaluating."

The article continues to quote Professor Baigent:

“[studies] have shown that lowering cholesterol using a drug does reduce the risk of heart disease in the elderly, and I find this more compelling than the data in the current study.”

This quotation from Professor Baigent introduces “a drug”, something that was not the subject of the epidemiological studies. A professor of epidemiology should know better than to mix an epidemiology study with a drug trial. Statin drugs do reduce death rate by a small amount in all age-groups, but as I repeatedly mention, this is nothing to do with cholesterol-lowering. The clinical trials alluded to were of statin therapy: cholesterol-lowering and other metabolic effects were not standardised or controlled.

The West of Scotland trial of statin therapy demonstrated after five years an absolute mortality reduction of 0.9% in men aged 65 years 4.1% in controls, 3.2% in treated group). As part of the analysis the participants taking the statin were divided into five groups based on the amount of reduction of blood cholesterol. For each of these groups the reduction of coronary events (compared to controls) was determined. When these were plotted together in a scattergraph, the result was as in Figure 7.

Figure 7. Statin effects - cholesterol reduction and coronary events

There was no association between cholesterol reduction and reduction coronary event rate. Surprisingly the reduction of events was greatest in those with no cholesterol reduction, but the significance of this is doubtful. The event reduction in the three groups with cholesterol reduction was effectively constant. The trend-line is close to flat.

Don’t forget that cholesterol-lowering with diet and medications other than statins (for example ezetimibe) has no effect on mortality: benefits are restricted to statins only. Let Baigent continue to support statin therapy, but accept that a high cholesterol above the age of 60 years is not a risk factor of CHD but has an advantage, as is demonstrated clearly.

Following the report in the Daily Telegraph, the usual denial from well-known diet-heart-cholesterol enthusiasts appeared in The Times a few days later.

The use of statins

We should simply forget about cholesterol. The use of statins should be regarded as an empirical prevention of CHD death. The prescription should be based on the sum of risk factors that must not include blood level of cholesterol, other than in men below the age of 50.

The article headline indicated that because a high blood level of cholesterol is good rather than bad, statins are a “waste of time”. This logic is not correct as statins are of some benefit, but that benefit is not connected to cholesterol. There is a different beneficial effect, probably an anti-inflammatory action. This is generally not appreciated or understood. 

Statins are of only a small benefit. In the first placebo controlled statin trial conducted in the West of Scotland, the subjects were men of age 65 with about the world’s highest incidence of CHD death. The death rate in the placebo group was 4.1% after five years, and lower in the group treated with pravastatin at 3.2%, an absolute reduction of 0.9%. This meant that 100 men had to treated for five years to prevent (delay) one death. The population mortality rate in Scotland at that time was about 850 per 100,000 per year. It is now only about 15 in the UK, a reduction of 98%. 

If we use the proportionate death reduction rate of 25%, we can expect that if undertaken today (not possible in practice) and given the much reduced death rate, the placebo group would have a mortality rate of .074% and the treated group .056%. This indicates that 7400 men would need to be treated in the same way to prevent 2 deaths. The price of preventing (delaying) one death would then be £675,000, much more in younger age-groups. So statins do help but only a little and the help is very expensive.

It is sad that highly qualified cholesterol experts are unable to separate cholesterol risk from statin benefit. Whenever anyone challenges the diet–cholesterol–heart hypothesis there is an immediate and thoughtless reaction to deny the challenge and to claim that the small success of statin therapy “proves” the highly flawed hypothesis (it proved nothing of the sort). Such an inevitable reaction was published in The Times on June 15th 2016.

Conclusion

It is clear from the observational studies that a high blood level of cholesterol in people above the age of 60 years does not constitute a cardiovascular risk, but on the contrary a survival advantage. This is not new and the suppression of this information must stop. Observational studies such as the Framingham , Honolulu, Paris, and New Haven studies are very  important. 

It is irresponsible of the authors of the Times letter, using impressive titles at the University of Oxford, to rubbish good quality observational studies, and completely ignore the findings of the highly-respected Framingham study and other studies. 

What has happened to scientific objectivity and analysis? 

Perhaps the answer is the pursuit of money. The diet–cholesterol–heart hypothesis is the goose that lays golden eggs, for the diet industry, the pharmaceutical industry, for academic departments, and for a large number of  national and international conferences.

Is the truth important? I think it is.

References:

Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham study. JAMA 1987; 257: 2176-2180.

Schatz IJ et al. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001; 358: 351-355.

http://www.thelancet.com/journals/lancet/article/PIIS0140673601055532/abstract

Forette B, Tortrat D, Wolmark Y. Cholesterol as risk factor for mortality in elderly women. Lancet 1989; 333: 868-870

http://www.ncbi.nlm.nih.gov/pubmed/2564950

Krumholtz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA 1994; 272; 1335-1340.

http://jama.jamanetwork.com/article.aspx?articleid=381733

The cause of disease and the discovery of ignorance

The discovery of ignorance – the cause of disease in the age of enlightenment.

Hooke's microscope

The presence of disease can be determined by examining individuals; this is the process of clinical medicine.

The cause of disease can be established by examining groups or populations; this is the process of epidemiology.

But all this is new.

Understanding the cause of disease

When I was five years of age I was ill with pneumonia. It was very serious and nearly fatal, but fortunately penicillin had just become available. The diagnosis was established by the doctors. My mother, like most people, was anxious to establish “the cause”, by which she really meant the reason. Like most people, she tried to explain "pneumonia" on the basis of one individual - me. 

Shortly before pneumonia

My mother was convinced that the cause of pneumonia (in my case) was that shortly before the illness, when I came home from playing outside on a winters day (remember that this was in the late 1940s, no television, no iPads etc) I had snow in my Wellington boots. Here lay the obvious cause.

My mother had no training in pathology and had no understanding of the concept of disease. But there might have been some truth in her understanding of my “illness”, as opposed to my “disease”. Without this mid-winter chilling event perhaps I would not have developed pneumonia. Perhaps this event made me susceptible to pneumonia, as I understand it with a training in pathology (disease process).

A disease is universal: it can happen anywhere. It is the same pathological process in all countries, even though its distribution and frequency can vary greatly. In respect of pneumonia we recognise a clinical syndrome of fever, shortness of breath, cough productive of sputum, perhaps chest pain related to breathing (pleurisy), occasionally abnormal findings on listening to the chest (auscultation), and abnormalities on chest x-ray. If it turns out to be fatal, then the autopsy will reveal further details of the actual pathology.

Susceptibility

But not everyone develops a disease. I was the only one of my friends who developed pneumonia, perhaps because the cold effect of snow in my boots increased my susceptibility to what is generally regarded as an infection of the lungs.

The illness of an individual is the result of the disease and its cause, but also one or more susceptibility factors. Another way of looking at this in more general terms is that the presence of disease is the result of cause together with susceptibility.

disease  =  cause  x  susceptibility

and

illness  =  disease  x  individual factors

There are many examples of this:

• death in a road traffic accident is the result of impact, but susceptibility includes one or more drivers being under the influence of alcohol or drugs; 

• AIDS is the result of exposure to HIV, but multiple sexual partners increases susceptibility;

• hepatitis C virus (HCV) infection is the result of the virus with intravenous drug use increasing susceptibility.

Individual factors

There is a tendency to put too much emphasis on individual factors when considering why an individual becomes ill or dies, even if such a factor might be completely irrelevant, as judged by the experience of many other victims and an understanding of pathology. 

The world becomes full of amateur doctors with ideas of early death or long life based on extremely limited experience. When someone reaches the age of 100 or more years, there is often a news-reporter posing the question: “To what do you attribute your long life?” The answer will be something that the individual enjoys and especially a food, possibly cabbage. It is most unlikely that the answer will be “Good luck”, as we all think that we understand more than we do. There must always be "an explanation".

The role of God

Everything changed in the Age on Enlightenment, known in French as the Siècle des Lumières  (the Century of Enlightenment), and in German as the Aufklärung).

Although it started in the early 18th century, scientific foundations, the scientific revolution, occurred a century earlier. But it was in the Age of Enlightenment that the greatest discovery in human history came about, the discovery of ignorance.

Jean-Jacques Rousseau

Previously there was always an answer: divine control over all humans and their destinies. This was challenged by, in particular, Jean-Jacques Rousseau (1712–1778), the French-based philosopher who was born in Geneva. 

There are still many people today who believe with great conviction that the Lord watches over us and protects us all. The great challenge to belief comes when a good close friend or relation dies young, or when many innocent deaths result from famine or warfare. A further challenge occurs when it is found that beseeching God through prayer might not work. 

The Age of Enlightenment

But the traditional concept of a universe with the Earth at the centre and God in overall control became challenged by the 17th century observations of Copernicus, Galileo and Kepler. Newton’s studies of light indicated that our view of the world was over-simplified. Studies of human anatomy and physiology provided the foundations for the future understanding of disease.

The 18th century that followed was a time in which the standard answer to all questions, that it is “God’s will”, was questioned. The occurrence of disease was no longer the will of God, and divine retribution for misdeeds obvious or far from obvious. Blaming victims for their sins was no longer automatic. But sadly three centuries after the new age of enlightenment, victim-blaming is something that I hear far too often. The sins are now against man rather than against God.

The Discovery of Ignorance

I first learned of this concept when listening to Yuval Noah Harari being interviewed at the Hay-on-Wye Literary Festival in May 2015. Following this I read his remarkable book “Sapiens”.

Yuval Noah Harari

The discovery and acknowledgement of ignorance was such an important step in human evolution, and especially in the 17th and 18th centuries, but now it is almost forgotten. The astounding scientific developments of the 20th have created new gods in the form of scientists. We expect them to know everything, and this is the impression given by news broadcasts on so many days.

It is the same with doctors. They give the impression of knowing everything, and that is what patients and their families expect. They do not expect is their doctor to say “I do not know”. This is taken to be a shortcoming of the individual doctor and so the family will go on an often futile journey until they find a doctor who claims that she (most doctors are now female or shortly will be) does know.

But there is a difference in answering the question “What is the cause of my family member’s illness?” and “What is the cause of my family member’s disease?” The answer to the first question is the name of a disease or a syndrome. The doctor should be able to answer this question as it applies to an individual patient. But stating the cause of a disease is very different; it is answering the question on behalf of medical science as a whole. It is here that she (he) can say “Medical science does not know” rather than “I don’t know”. 

Studies of populations

It is difficult for people to accept that “the doctor does not know”, but it is often the case that “doctors do not know”, and this is acceptable if explained. But this leaves the vacuum of understanding that is filled by guesses based on little experience, often filled by alternative practitioners who do not base their “explanations” on the basis of objective and well-researched pathology.

With the Age of Enlightenment came attempts at understanding disease without invoking God. There were several epidemics of cholera in London in the 19th century, and they were generally assumed to be the result of “poisoned air”, not an unreasonable conjecture. However the physician John Snow (1813–1858) made observations (new investigative epidemiology) that led him to conclude (correctly) that it was the result of “poisoned water”.

The causes of disease

Girolamo Fracastoro

The germ theory of disease was first proposed by Girolamo Fracastoro (1475–1553), and it is fortunate he was not executed for such heresy. His idea was well ahead of its time and it was in the 1670's that the Dutch microscopist Antonie van Leeuwenhoek (1632–1723) discovered vast numbers of "little animals", previously unknown. 

This was soon confirmed by Robert Hooke (1635–1703), who recognised and was the first to use the term "cell" to describe the basic building block of life. Microbiology then developed into the exciting science that we know today. It has been epidemiology, microscopy and microbiology that have done more than anything else to develop our understanding of disease.

Robert Hooke

Antonie van Leeuwenhoek

Robert Koch

Robert Koch (1843–1910) recognised the microbial cause of tuberculosis (TB). During the previous century it was considered to be “constitutional”. This means inherited, part of the make-up of the individual. Inheritance is another major pillar of the understanding of the cause of the disease, also recognising that there is more to inheritance than genetics. Now in the 21st century we are starting to understand the importance of our inherited microbiome.

Coronary heart disease

The key to understanding is humility, and the start of knowledge is the recognition of ignorance. The application of these factors might enable us to understand the nature of coronary heart disease (CHD).

My recent Blog Posts have concentrated on CHD, identifying its epidemic nature, its sudden onset and its rapid decline. I have not discussed its cause. Despite the fact that it has been one of the most serious epidemics of all time and certainly by far the most serious epidemic of the 20th century, its cause is not known. 

This is not generally admitted, but it needs to be acknowledged. Ignorance is generally not admitted by experts.

Thoughts on the cause of CHD will follow shortly.