End of the road for the diet-heart theory?

Abstract

A personal account of the diet-cholesterol-heart hypothesis during the last sixty years, from its start with Jeremiah Stamler and Ancel Keys, its rapid rise and progressive fall during the last years. It is pointed out that the clinical picture of a heart attack is not synonymous with atherosclerotic changes in the coronary arteries. Special emphasis is given to the repeat publication of the results with the MRFIT screenees that have been used to obscure the negative results of the randomized multifactorial trials MRFIT in the US and The Gothenburg preventive trial in Sweden.

A part addresses the treatment or prevention of CHD with medicines, where the mode of action and side-effects of the statin group of medicines have been more or less been neglected in the large amount of clinical trials. A better analysis of these features of the family of statins has to be done in order to limit their use to patients who really need them.

My interest in what later became the diet-heart-cholesterol hypothesis started with the presentation that Haquin Malmros made to the International Congress of Internal Medicine in Stockholm 1954. He thought that the rationing of food in the Scandinavian countries during the war caused a decrease in atherosclerotic heart disease during that time. Both the data on availibility of food and death certificates (the term coronary heart disease had not been invented then, and deaths were registered as due to atherosclerosis) were highly uncertain at that time. This has not hindered his paper from becoming a landmark presentation in the history of fat and cholesterol.

Shortly afterwards I was introduced to Jeremiah Stamler at a visit to Louis Katz's cardiovascular laboratory in Chicago. Stamler and Katz were then studying the effect of a diet of egg yolk on the arteries of chickens and thought the vascular changes could be compared to atherosclerosis. When I somewhat later visited Chicago, Stamler had become the head of a new Public Health Service in Chicago. As part of this assignment he tried to persuade middleaged overweight businessmen in the city to change their diet (but without interfering with their smoking habits). Already at that time Stamler was a strong believer in the danger of fat. He became the missionary that Ancel Keys and Matti Karvonen – then an infuential physician in Finland – listened to and learned from, to mention two future important advocates of the theory.

These early episodes stimulated my critical mind and I began looking in detail at the evolving thesis about cholesterol and heart disease. The rapidly increasing literature has not decreased my critical attitude. On the contrary, many of the papers appearing at the large meetings of American Heart Association, were founded more on belief (and optimistic unscientific studies) than on hard evidence 2. It should be noted that the pharmaceutical industry at that time had no medicine in this commercial segment and did not become involved until later.

The start of the missionary zeal

It was Stamler, Keys and Karvonen, promoting the emerging science of epidemiology that invested their total scientific prestige in the cholesterol theory. Stamler and Keys persuaded the American Heart Association to put its influence behind their efforts to spread their theories and Karvonen persuaded the Finnish Board of Health and the World Health Organization to do the same. The National Institute of Health in Bethesda and the large food and pharmaceutical companies in the US joined the mission.

All leading organizations in the USA were thus committed to this hope for a cure for the most dreaded disease in America (especially affecting middleaged business executives at that time). Committees containing these organizations were created that continuously served the American people (and the world) with advice regarding the danger of saturated fat and cholesterol. The erroneous conviction that they were acting on strong scientific evidence made any other theory seem ludicrous. The cooperative effort of these influential organizations thus made it impossible to modify the message even when new data appeared showing the poor foundations for the official truth 2.

The quality of the papers from the leading believers have improved, but the believers are still flooding the literature with repetition of the same message, usually without mentioning other, more critical papers. Several papers still leave a feeling more of propaganda than science – at least to those who read them with a critical mind.

Definition of coronary heart disease

A problem that was discussed early during the so called epidemic of CHD, but then was dropped, is the definition of the disease 1. A heart attack may be due to many different alterations in the structures of the heart, and atherosclerotic lesions in the coronary arteries are only one of many possibilities. In most epidemiological studies the problem of definition of the clinical endpoint has been neglected in the enthusiasm over the cholesterol hypothesis 3.

The term CHD, coronary heart disease, is a diffuse and non-descriptive name for a clinical picture that is ranging from acute death with no or a varying amount, but strategically located, of changes in the coronary arteries, to an extended history of anginal pain and acute episodes of myocardial infarction, leading to death in congestive heart failure, with almost all coronary arteries showing atherosclerotic lesions with or without thrombosis at autopsy.

In most clinical or epidemiological studies the underlying cardiac pathology is seldom discussed and ordinary, routinely obtained, death certificates are treated as scientific facts. During the last decades the cardiac pathologist has been left out, and when he is engaged in the problem, like William Stehbens, nobody is listening to his comments 3.

The coronary arteries as main culprit

The emphasis on the coronary arteries as the dominant cause of the clinical picture of a heart attack began with the animal studies of the influence of a diet rich in cholesterol on the arteries in herbivores, rabbits and chicken. The idea was accepted by biochemists and experimental physiologists and stimulated also the interest of epidemiologists and statisticians. They saw, like the biochemists, a rich field for their specialty. The diffuse clinical picture of a heart attack thus became synonymous with atherosclerosis of the coronary arteries as the most important disease in the western world.

The focus on the arteries became further manifest when it became possible to describe changes of the coronary arteries using angiographic techniques 4–6. This also opened the possibility to treat the syndrome surgically, or through dilating the vessel using a catheter borne balloon. When coronary angiography demonstrated that some patients with heart symptoms did not have occluding changes in the arteries, this had no impact on the preferred diet-heart theory. That surgical intervention did not help all patients with CHD was also disregarded in the overwhelming enthusiasm for the lipid theory.

Only two features to discuss

The literature on coronary heart disease and the diet – cholesterol theory is enormous and impossible to review. There are, however, two features illustrating the way the diet heart theory is promoted, that I want to address here.

One is the adaptation of the MRFIT screenees as a planned epidemiological study, 7 the other is the belief that statins exert their influence on coronary heart disease only through its lipid-lowering effect 8.

Both these features of the literature have augmented the idea that saturated fat in the diet is the cause of coronary heart disease through its influence on the cholesterol value in blood. A continuous wave of articles promoting this idea appears in the main scientific journals on both sides of the Atlantic Ocean.

Efforts to confirm the theory in clinical trials

In USA MRFIT trial was started to demonstrate that a multifactorial approach with interference on serum cholesterol, blood pressure and smoking would lead to prevention of CHD in middle-aged males. To the chagrin of the project leaders the results were negative, an outcome they had not thought possible 9. The negative results of this type of approach was further confirmed in the Göteborg preventive trial, that contained 10 000 middle-aged men invited to change their risk factors, with 20 000 men acting as controls, studied over a period of eleven years 10.

During the planning phase of the MRFIT the authors stated: “It is extremely doubtful whether any other current experimental or analytical studies, except MRFIT, will be able to determine the actual efficacy of multiple risk factor reduction. …. However, if this type of risk factor reduction in middle-aged men really does not result in any decrease in incidence and mortality, then it would be folly to pursue the current health programs.” 11.

Changing the approach

When the expensive and thoroughly planned MRFIT study did not demonstrate what NIH and the planner had hoped, 9 a new idea was born. That was to use the total population of men primarily invited to be screened for MRFIT as a base for follow-up studies. This was done although the first collection of data was not very well controlled because it was conducted just to find 12 000 healthy males deemed to be at high risk for heart disease and willing to take part in a five year controlled experiment involving changes of life style 12.

It is important to note that this first fishing expedition was not planned as a population study following the total of 360 000 males. Thus 336 117 men (in another paper 341 644 men) took part only in the first superficial screening episode, when no physician was present. They were thus never the object of a proper clinical appraisal 12–14.

It was not until the main study had not given the result that the organizers had hoped for 9 that this population was promoted to a base for long time follow-up. This was done although the first screening was not very well organized. The blood pressure was not measured in some patients; one of the centres falsified the values for some patients, but was included anyway. This retrospective accepting of earlier obtained overview data has not stopped the organizers (and the journal editors) to accept the study as a well planned prospective follow-up with results deemed to be of high scientific value.

The scrutiny of all the papers from the MRFIT group shows that the number of men in the group consisting the underlying material for analysis, changes from paper to paper, partly due to the use of some diagnosis obtained at the first screening 7. More disturbing is, however, that the number of death certificates used for defining the end-point of the study, varies considerably in different papers. Some reports mentioned that it was never possible to obtain all death certificates. The number of obtained certificates varies, 94% being the highest number in any paper where this problem was mentioned. In many papers it was not even mentioned, This lack of proper follow-up of deaths is probably due to the absence of planning at the first screening, which was conducted just to find high risk healthy men.

In one paper the authors give a diagnosis for each death – altogether 21 499 men had died when this paper was written. The paper does not mention that some death certificates were missing 15. At least 6% of the death certificates had to be missing as other papers from the group regarding the MRFIT screenees appearing more or less simultaneously, state that only 94% of death certificates was obtained.

It is remarkable that the editor and peer reviewers of Archives of Internal Medicine did not observe this falsification of data. It seems probable that they, like other editors or reviewers, did not scrutinize the manuscripts from the MRFIT group, backed by the NIH, as thoroughly as they should have done.

Repeat publication

It should also be noted that almost the same material has been published simultaneously in two journals with differing authors and different results 12, 13. Any other group that had behaved this way would have been accused of fraud, or at least plagiarism, but with the powerful NIH behind the papers (and the prospect of selling many reprints) the editors seem to have accepted this double publication without comment.

The important finding from the real MRFIT has thus been obscured through the enormous use of the poor data from the first screening. This is the more remarkable as the concomitant Göteborg trial of a population based series of 10 000 men followed for eleven years with a similar design as the MRFIT also demonstrated no difference in the incidence of heart disease in the experimental compared to the control group of 20 000 men 10.

A more detailed discussion of the MRFIT screenees appears in 7.

The well conducted MRFIT and the Göteborg Preventive Trial thus demonstrated the futility of trying to influence the risk factors in free living middle-aged men using conventional methods. The considerable extra effort that was used did not give the expected decrease in heart attacks. Geoffrey Rose in a commentary to the Göteborg trial stated that this way of prevention is meaningless 10.

Drug treatment aiming at lowering serum cholesterol

In the sixties the WHO organized several studies investigating the prevention or treatment of CHD in Europe using then available medicines. The results were negative which made the cholesterol hypothesis questionable. These studies have been forgotten and to those believing the cholesterol hypothesis these early studies have become nonexistent. One was the clofibrate trial, which showed higher mortality in the treated group, due to severe side effects of the drug. The other was a large, Europe-wide trial of prevention of CHD in factories in several countries through interfering with the usual risk factors, especially cholesterol. It was difficult to get the participating centres of the study to use the same methods. The result of this very large study demonstrated that this approach did not give the results that were anticipated.

The arrival of new medicines

The negative results with the prevalent drugs led the pharmaceutical companies to look for new medicines. After many disheartening results, the introduction of simvastatin by Merck became the start of a new era for drug treatment of CHD. The many shortcomings of the use of statins are discussed in some papers in this issue of the journal. Here, I only want to emphasize a few aspects of the treatment or prevention of CHD using statins. There is no question that statins may decrease the incidence of CHD in some, but not in all, people, but the mode of action is uncertain. The vast clinical literature usually refers to statins as 'cholesterol lowering drugs’.

Nobody questions that statins decrease the level of serum cholesterol. Whether this is the main mode of action has, however, never been shown. On the contrary, the finding that they exert their effect regardless of the cholesterol value indicates that the mode of action is different from their action on cholesterol synthesis. Already 1996 Vaughan, Murphy and Buckley pointed out the many mechanisms that might be of therapeutic value 16.

”There is experimental evidence that statins have effects on immune function, macrophage metabolism, and cell proliferation independent of changes in plasma LDL concentrations and that their modulation of the pathophysiological determinations of acute coronary syndromes accounts for the early benefit observed.”

The statins are thus extremely interesting medicines with many actions on metabolism, vasculature, and muscles. Their effect on the development of CHD may very well be due to some other mode of action than the decrease in cholesterol. The extensive literature on the clinical effects of statins is dominated by cardiologists or epidemiologists, referring to them as cholesterol lowering drugs. Most of these papers are sponsored by the companies that sell statins.

A thorough review of the pharmacology and side effects of statins written by unbiased theoretical pharmacologists is needed to balance the biased view in almost all clinical papers. To describe statins as only lowering cholesterol is dishonest, which has not hindered all official bodies, including regulatory agencies, to use this categorization of the drug family.

The latest studies of new methods decreasing the cholesterol synthesis with further decrease of serum cholesterol in the patients have been poorly reported. The lack of presentation of side effects in these later studies has even made Wall Street uneasy 17–20. When the business journalists have been interested in the poor reports from several companies, some cardiologists have been quoted questioning the whole idea of interfering with cholesterol metabolism. The poor reporting of side effects in all statin studies is now becoming an embarrassment for the industry and regulatory agencies.

A large drawback of the large literature on statin use is the lack of reporting of side effects. Most remarkable is the downplaying of the findings of increase in breast cancer in women in the PROSPER study. Both scientists and laymen have asked regulatory agencies and other governmental bodies to request a thorough reporting of side effects in all studies; so far without any results 21.

The importance of sponsors

The early trials with cholesterol lowering medicines was sponsored by the WHO or in some cases the NIH, although NIH has been accused of conflicts of interest 22. The results were by and large negative and the side effects of the treatment were well described.

The following trials using different new medicines interfering with cholesterol synthesis, and especially the many statin trials, have all been conducted under the sponsorship of the companies promoting the compound studied. In contrast to earlier trials the positive results have been emphasized, demonstrating a preventive effect of the statin investigated. In contrast the reporting of side effects, have been poor or, as the occurrence of cancer of the breast in the PROSPER trial, manipulated in a way to make them seem unimportant.

It is well known that clinical trials supported by the industry are characterized by more positive results of the treatment and less side effects than in trial supported by an official agency like the WHO. Almost all literature on the effects of statins is depending on the companies selling the drugs. It is high time that the use of statins is scrutinized as thoroughly as other treatment modalities 23, 24. American, European and Swedish drug regulatory agencies have been content with the substandard reporting of side effects from the companies sponsoring the statin trials. Scientists and laymen 21 have asked the agencies to request a better reporting of side effects without any response.

The information is available

There is probably enough knowledge about the effects and side-effects of the statins. What is needed is an unbiased and complete overview of current knowledge. It is essential to know which of the many effects of these drugs that is of importance for the decrease in CHD incidence, as the belief that the cholesterol lowering is the only important mode of action is no longer tenable. Even some supporters of the cholesterol theory have become uncertain 24. It is also essential with a complete evaluation of all side effects of this group of drugs. Not only have their carcinogenic effects to be better defined; the anti-inflammatory and effects on the muscle cells should also receive more attention.

The heart attack is not a well defined entity

Two fundamental problems are never addressed in the propaganda for cholesterol as the cause of heart disease:

The clinical picture of a heart attack, or what is called acute coronary heart disease, does not represent a well defined pathological entity. 1 It comprises changes of the arteries that may be of varying degree, changes of the myocardium, usually but not only of ischemic origin, and varying forms of alterations of the conduction system of the heart. Added to this is the presence or absence of blood clots in the arteries.

The clinical heart attack is thus depending on a combination of different mechanisms. The belief that it only is a process in the coronary arteries is too simple to be the only base for therapy.

In comparison to the overwhelming literature on biochemistry and epidemiology of the heart attack, scientists working on the pathology of the atherosclerotic lesion and the relation between vascular disease and myocardial failure are few and sparsely referred to. The most knowledgeable vascular pathologist in the world, William Stehbens in New Zealand, is never quoted by clinical epidemiologists or those treating patients, probably because he is one of the researcher that has shown the futility of the present approach to the 'epidemic’ of CHD.

Cholesterol is a normal constituent of the human body

The other feature that is never mentioned is that cholesterol is a normal constituent of the human body, which cannot function without this substance. The serum level furthermore fluctuates 25, 26. The most important origin of serum cholesterol is the liver, where its synthesis is controlled by many safeguards. The brain contains a large amount of cholesterol and the substance is furthermore an important part of the synthesis of hormones and regulation of vitamins in the human body. To interfere with the supply of cholesterol cannot be innocuous, which has been demonstrated with the recently introduced drugs that block the synthesis of cholesterol, depriving the body of this important constituent. Recent results of clinical studies indicate that these drugs may increase the risk for vascular disease!

Regarding diet

Whether the daily diet plays any role in the development of heart attacks has never been satisfactorily resolved. The amount of pseudoscientific articles covering this field is overwhelming. It is therefore rather meaningless trying to review to literature. Most reviewers so far have presented a selection of only the papers that present the view that they believe. However, one good summation of this problem appears in a paper dedicated to Hugh Sinclair, written by two nutrition scientists 26. They concluded:

”One clear conclusion that emerges from this analysis is that the incidence of CHD cannot be related to any single attribute of the diet.”

They further stated that:

”The translation of conclusions from such multidimensional analysis (should it ever become possible) into advice for the consumer on reducing chronic disease risk will always require simplification. Such simplification, however, must be compatible with the evidence that exists and must be presented in a way that the consumer can understand. Research is therefore needed on how the advice should be presented.” 27.

This was written in 1991. Biochemical and metabolic knowledge has increased substantially since then, but any analysis of the kind Ulbricht and Southgate asked for has never been done, nor has the way of presenting advice to the public been thoroughly researched. The situation regarding diet and heart attack is thus as unclear today as it was twenty years ago, when this advice was given.