The questionable wisdom of a low-fat diet and cholesterol reduction

Sm.

Pergamon

Med. Vol. 39, No. 3. pp. 433-447, 1994 Copyright C 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0277-9536194 $7.00 + 0.00

0277-9536(93)EOO48-J

THE QUESTIONABLE AND

WISDOM

CHOLESTEROL DALE

Department

Sci.

of Psychology,

OF A LOW-FAT

DIET

REDUCTION

M. ATRENS

The University

of Sydney,

Sydney

2006, N.S.W.,

Australia

Abstract-The prevalent wisdom that a low-fat diet and cholesterol reduction are essential to good cardiovascular health is coming under increased scrutiny. An examination of the foundations of this view suggests that in many respects it was ill-conceived from the outset and, with the accumulation of new evidence, it is becoming progressively less tenable. Cross-sectional, longitudinal and cross-cultural investigations have variously suggested that the relationship between dietary fat intake and death from heart disease is positive, negative and random. These data are incompatible with the view that dietary fat intake has any causal role in cardiovascular health. Although hypercholesterolemia is associated with increased liability to death from heart disease, it is as frequently associated with increased overall life expectancy as with decreased life expectancy. These findings are incompatible with labelling hypercholesterolemia an overall health hazard. Moreover, it is questionable if the cardiovascular liability associated with hypercholesterolemia is either causal or reversible. The complex relationships between diet, serum cholesterol, atherosclerosis and mortality and their interactions with genetic and environmental factors suggest that the effects of simple dietary prescriptions are unlikely to be predictable, let alone beneficial. These cautions are borne out by numerous studies which have shown that multifactorial primary intervention to lower cholesterol levels is as likely to increase death from cardiovascular causes as to decrease it. Importantly, the only significant overall effect of cholesterol-lowering intervention that has ever been shown is increased mortality. The stress and helplessness associated with misapprehensions as to the dangers of dietary fat and the asceticism inherent in the war on cholesterol have considerable implications for health practices. Recent research in behavioral immunology suggests that stress and helplessness are likely to compromise immunity and promote ill-health. Kqv wordsdietary

fat, cholesterol,

heart disease,

cardiovascular

notion that high fat intake causes poor overall health and particularly poor cardiovascular health is the central pillar of the current concept of a healthy diet. Medical, heart and nutrition foundations throughout the western world advocate the need to reduce dietary fat intake [l]. It is vividly portrayed as a life and death issue. The desirability of reducing fat intake is reinforced by television commercials in which an eminent heart surgeon standing beside a box of breakfast cereal says sombrely: “If Australians could reduce their cholesterol levels by 5% it would save up to 15 lives a day.” The electrocardiogram tracings on breakfast cereal boxes clearly suggest that the cereals promote cardiovascular health. Cholesterol awareness programs have reached every corner of the western world. Dietary fat intake is said to lead to premature death from cardiovascular causes through its effects on blood lipids and the development of atherosclerosis [I, 21. The image of dietary fat congealing in arteries to form a lethal sludge occupies a prominent place in the public psyche. The view that a high fat diet is atherogenic and that reducing fat intake and serum cholesterol levels is a viable means of combating heart disease persists in spite of the fact that every main tenet of this belief structure has been found to

disease,

lack consistent [3-301.

The

stress, public

and,

THE POLITICS

in some

health

cases,

OF PUBLIC

any

support

HEALTH

What are, in reality, fairly simple questions concerning the effects of diet on health and the usefulness of dietary change in promoting good health have taken on a meta-empirical quality. The big money, power politics of public health and the enormous profits realised from selling ‘healthy’ foods and cholesterol-lowering drugs have obscured the emerging answers to two simple and related questions: “Does a low-fat diet promote good health?” and “Is cholesterol reduction desirable for the general public?” There are striking parallels with the increasingly questionable diet-cancer hypothesis [3 11. The Council on Scientific Affairs of the American Medical Association [31] has recently distanced itself from any such simple associations between diet and cancer. Moreover, among the millions who have made ‘lite’, ‘low-fat’ and ‘cholesterol-free’ central elements of their lifestyle, there is great reluctance even to entertain the possibility that their commitment to asceticism may have been for naught. Increasing evidence that this commitment may actually have been counterproductive is therefore cause for great concern. 433

434

DALE M. ATKENS

There are clear parallels here with the weight loss industry where the public fervently subscribes to a medically-endorsed view that weight reduction is generally attainable and promotes good health. This view persists. not because of the evidence supporting it. but in spite of overwhelming evidence to the contrary. Numerous reviews have shown that every significant clement that sustains the weight loss industry has been subject to major and repeated misinterpretation [32]. The general failure to recognise and act on clear empirical guidelines is the hallmark of a meta-empirical belief. It reflects the intrusion of political, commercial and emotional factors into the scientific evaluation procedure. Such intrusions are not conducive to good science or good health. As with the industry generated by the diet-cancer hypothesis, the weight loss movement is maintained by commercial and professional interests [32234]. Many who have organised their lives around the pursuit of weight loss are distressed by the increasingly unavoidable reality that this goal may not be attainable and their efforts unhealthy [32234]. A desperate struggle with one’s one basic regulatory mechanisms, particularly one that is almost certainly doomed to fail, exacts an enormous toll in physiological and psychological pathology [32. 33. 355381. The application of dietary principles in the sphere of public health has seen the emergence of a new form of meta-truth. committee consensus [39]. The goal of these committees is ostensibly to extract truth from a morass of conflicting claims and evidence. However. there is increasing evidence that the pressures under which the committees operate may inhibit their objectivity [3, 13, 14, 16, 17. l9.40.41]. In the urgency to take affirmative action there is an unfortunate tendency to take premature action. Vast amounts of time and more than U.S.$l.OOO,OOO,OOO has been spent on primary intervention trials in which cholesterol-lowering has been used in attempts to prevent heart disease [4l]. At the same time there is increasing evidence that these interventions have been ill-founded, non-productive and even harmful [4--30. 32. 33. 36- 381. The growing discrepancy between lofty committee aspirations and the dismal record of their achievements. amplified by the great sums of money involved has led to a tendency to sanitise what increasingly appear to be very harsh truths. There is real reason to doubt whether the public perception of truth at the moment is the outcome of informed disputation, as opposed to a matter of dcfizcto legislation by vigorously promoted committee consensus. The facts often appear to be highly negotiable. In an increasing number of cases consensual truths are often arrived at not on the basis of the data, but in spite of them [3, 12. 15, 18, 19,41,42]. These meta-truths have the unique property of being logically and empirically independent of the evidence on which they are said to be based.

The British National Advisory Council on Nutrition Education admitted that in any one country there is no convincing evidence that dietary fat leads to heart disease [6]. This admission is so telling because it is from an agency that is among those most strongly advocating reducing fat intake. They base their recommendations on their intuitive ‘feel’ for the data. This feel comes from their unshakeable belief that fat is a villain. Given the fact that they admit that their belief persists not so much because of the data. but in spite of them. it sounds very much like a prejudice [40]. Reiser [23] analyzed the ten references in the Rationale of the Diet-Heart Statement of the American Heart Association and found that nearly all ol them were irrelevant or actually contradicted the recommendations being made in the statement. His misgivings were expressed as follows: “the Rationale is not a logical explanation of the dietary recommendations but an assemblage of obsolete and misquoted references” [23]. This unfortunate tendency is very much alive today. The reduction in cardiovascular mortality in Norway during World War II is cited as an example of the salutary effects of an austere. low-fat diet [2]. This view neglects the overriding fact that whereas cardiovascular mortality may have dccreased. overall mortality increased [43] as did morbidity from almost all other causes [44]. Morcovcr. Norwegian investigators point out that cvcn the decrease in cardiovascular mortality may have been an artifact of changed classification proccdurcs in addition to beginning before the decline in the load supply and ending before the rccovcry of the food supply [43]. THE FRENCH PARADOX

It has recently been reported that men and women in the critical 35564 age group in southwest France have very high fat intake [45]. yet their cardiovascular mortality is among the very lowest in the world [46]. The popular press has labelled this finding. the French paradox. It has made the front page of countless newspapers and prime time television around the world. Calling the unusually good cardiovascular health of the indulgent people of Southwestern France a paradox has an important strategic advantage. since as long as it remains in this exceptional category it poses minimal embarrassment for the conventional wisdom of the danger of dietary fat. After all. with complex issues such as the relationship between diet and disease, anomalous data are to be expected from time to time. However. it is now time to question whether the French findings are at all paradoxical. The present analysis suggests that rather than being paradoxical. the French findings are entirely typical of a wide range of data bearing on the problem of the relation of dietary fat to health. The data are so riddled with inconsistencies and

The questionable wisdom of a low-fat diet and cholesterol reduction contradictions that it is unreasonable to extract from them any grand courses of action for public health. Instead of being a paradox, the French may be seen as illustrating a general paradigm of chaotic and poorly understood diet-health relationships. A broad based elucidation of this issue should bring the question of the relationship between dietary fat and cardiovascular health back into the empirical arena where it should have remained all along. It is not a matter of optimism vs pessimism [47], or negotiating an acceptable compromise, or yet another consensus view [I]; it is a matter of whether the data support the current ‘demonic’ status of dietary fat and the general desirability of reducing serum cholesterol levels. There are five main lines of evidence that may be brought to bear on this issue. They are:

I. epidemiological 2. 3. 4. 5.

laboratory experiments migration studies prospective studies primary intervention studies.

In light of the great complexity of the underlying physiology and biochemistry, to say nothing of the formidable intricacies of epidemiology, the evidence from these diverse sources is surprisingly consistent. Epidemiological data show that the relationship between fat intake and cardiovascular mortality is rife with major inconsistencies. Various studies have shown positive, negative and random relationships. Laboratory experiments show that fat intake and high cholesterol levels do not explain the occurrence of atherosclerosis [9,48]. These findings are inconsistent with the belief that there is a causal relationship between dietary fat and cardiovascular mortality. Whereas migration studies often show adverse changes in health, these changes bear no consistent relation to any dietary variables [42,49, 501. Further, prospective studies show that in spite of the fact that hypercholesterolemia is usually associated with increased liability to heart disease, it is as commonly associated with increased, as with decreased life expectancy. Lastly, primary intervention studies have shown that lowering cholesterol is as likely to increase cardiovascular mortality as to decrease it. However, the most conclusive indictment of the popular wisdom is that the only significant overall effect of lowering cholesterol to prevent heart disease that has ever been shown is increased mortality [51-53]! The existing data do not implicate dietary fat in the etiology of heart disease, nor do they support the general desirability of reducing fat intake and cholesterol levels.

hazard to cardiovascular health [2,54-561. Keys [55,56] showed that over a 10 year period death from coronary heart disease in seven countries was positively associated with the amount of saturated fat in the diet. In spite of the extraordinary exposure that these findings have been given, it is questionable whether they support the conclusion that dietary fat is a culprit in heart disease. The most serious shortcoming of the data from the Seven Countries Study is that they are not representative of the broad spectrum of international comparisons. Another study of 37 countries found no association between any dietary variables and death from heart disease [42]. Plotting death from heart disease against dietary fat intake in 15 countries produces an essentially random relationship. These numerous and striking dissociations of fat intake from death due to heart disease argue strongly against a close association, let alone a causal relationship. It should be added that further statistical dredging through the masses of diet-health data by examining selected dietary ingredients and age groups in certain countries at certain times sometimes shows strong correlations. This is a mathematical inevitability. For example, Renaud and De Lorgeril [54] show a strong correlation in 15 countries between cardiovascular mortality and the consumption of dairy fat. This relationship does not apply to overall fat intake and it only holds when the dairy fat intake is calculated excluding cheese! That even the significant correlations do not represent causal associations is indicated by the existence of numerous clear failures of fat intake to correlate with cardiovascular mortality (see below). It is important to note that even if the betweencountries relationships between dietary fat intake and any form of mortality were strong and consistent (which they clearly are not) they would at most suggest the desirability of examining these relationships within countries. The latter relationships are much more critical since they are far less contaminated with the racial, social and environmental confounds that make the drawing of valid inferences from international comparisons so difficult.

900 . U.S.A.

800 700 % z ‘c1

600

-

500

-

2

400

-

u

300

-

200

-

100

RELATIONSHIP OF FAT INTAKE TO MORTALITY-BETWEEN COUNTRIES

Comparisons between different countries play a major role in the thesis that dietary fat is a particular

435

0

-

Australia Finland

.

N.Z.0 .

U.K. Denmark

Netherlands Japan l

W.Germany Italy,

I

I

20

40

Fig. 1. The relationship from coronary

.

l .

.

1France

1 60 Fat

mortality

. l Canada

80

intake

100

.’ \

. Sweden Norway

Switzerland 1 I

120

140

I 160

(g/day)

between dietary fat intake and heart disease in 15 countries [14].

436

DALE

M.

Davey Smith et (11.[57] have pointed out that even clear, dose-response relationships that are independent from other factors must be interpreted with caution. Such relationships may bc used to suggest that smoking causes suicide and poor dental health causes myocardial infarction [57]. Although such claims may be dismissed on the grounds that they lack biological plausibility, in diet-health relations plausibility may be stretched so far as to make it meaningless. They point out that a pseudo-plausible explanation can be offered for the relationship between caffeine consumption and hip fracture. In the diet-heart debate these fundamental conceptual cautions are often ignored and the merest suggestion of a relationship may be transduced into assumed causality [2]. This conceptual inadequacy is compounded by the erroneous assumption that causal relationships are necessarily reversible. Another form of cross-cultural data comes from migration studies. Numerous studies have shown that migrants assume the disease patterns of their adopted country [49]. For example, Japanese migrants to the U.S.A. suffer increased mortality from heart disease and this is said to be due to their abandoning the low-fat, eastern diet in favour of the high-fat, western diet. Whereas the migration studies clearly illustrate powerful environmental influences, it is incorrect to assume that the culprit is increased fat intake. Given the large number of environmental and social differences between cultures such as Japan and the U.S.A., to isolate any one as the cause of changes in health is gratuitous. This is underscored by the findings of large differences in many other dietary and health-related practices in the migrants [42.49]. Moreover, the finding that Swedish migrants to the U.S.A. also show increased cardiovascular mortality with unchanged fat intake [SO]. flatly contraindicates dietary fat as a significant variable. The importance of predisposing racial factors has recently been shown in a comparison of South African black and white males who were maintained on identical diets in a remote site in Namibia. In spite of very similar dietary, smoking and educational factors, the biochemical profiles of the blacks suggested they were at much lower risk for heart disease [58]. Moreover, these biochemical differences are present at birth [5X]. Similarly. relative to white Americans, Hispanic-Americans have high cardiovascular risk profiles, yet they have a significantly lower incidence of myocardial infarction [59]. A major element in this anomaly is the lower lipoprotein A levels in the Hispanic-Americans and it is significant that lipoprotein A levels are mainly determined by genetic factors [59]. Whereas there is a paucity of data reasonably implicating diet as a cause of ill-health in migrants, there is a great deal of data showing the importance of racial factors in addition to social factors and the adverse effects of the stress attendant to social change

ATRENS

[59-651. In light of these numerous and unequivocal health-modulating effects associated with migration, inferring that the adverse health changes in migrants are due to increased fat intake or to changes in any dietary variable, is not justified. Overall, cross-cultural data in all forms are replete with findings which are either inconsistent with or flatly contradict a significant role for dietary fat. The fact that some of the findings do appear to suggest a significant role for dietary fat is overwhelmed by the mass of findings that point to very different conclusions. Any significant failures of dietary fat and death from cardiovascular disease to covary in the expected manner indicate that those cases where such covariation is observed can not represent causal effects. To ignore this fundamental point is to do violcncc to the most basic canons of logic [28. 57.661. RELATIONSHIP OF FAT INTAKE TO MORTALITY-WITHIN COUNTRIES

If dietary fat intake is an nnportant determinant ot cardiovascular health. these two parameters should covary over time. This longitudinal approach avoids some of the difficulties inherent in the cross-cultural approach. A correspondence between changes in fat intake and changes in death from heart disease would make the argument for causality at least plausible. However. any general failure to show the expected correspondence eliminates the possibility of a causal relation. Figure 2 shows two. rather different patterns of changes in death from ischaemic heart disease. In Australia and Canada the death rate rose fairly sharply and peaked sometime in the 1960s after which there was a sharp and progressive fall. In the United States the death rate was quite constant through the 1960s after which them was a sharp and progressive fall much like that in the other countries. As Figure 3 shows. dietary fat intake in all three countries has followed quite similar patterns of increase. Most noteworthy is the steady increases in dietary fat intake after 1970 during which time death from ischaemic heart discasc was declining precipitously. Whereas the data until 1970 arc roughly consistent with a positive association of changes in dietary fat intake and death from heart disease [2. 61. the data after I970 are not. To the contrary. they suggest a negative association. Overall. the changes in death from heart disease over the last 40 years bear no consistent relationship to dietary fat intake [67770]. The data from Japan show how complete this dissociation can be. Death from heart disease has been steadily declining in Japan since 1950. while fat intake has shown one of the greatest and most rapid increases seen anywhere in the world [6]. As with the post-1970 data from Canada. Australia and the U.S.A. these data suggest that fat intake is inversely related to death from heart disease. Pickard [42] has also shown that across ten English counties cardio-

The questionable

15

5

5

5 -9

wisdom

of a low-fat

diet and cholesterol

437

reduction

I

I

I

19:55 .59

1960-64

z ‘G 2 -15 i?? f 0 $

-25

-)-

Australia

e

Canada

b

U.S.A.

-35 -45 1 Fig. 2. Temporal

changes

vascular death rate was inversely intake.

In a recent

long-term

in death from ischaemic heart disease (expressed as a % of the death 1950-54) in three English-speaking countries [67]. related study

to dietary

of 10,059

fat

Israeli

civil servants, high fat intake was associated with the lowest incidence of death from heart disease and longest life expectancy [71]. In addition, there are striking regional differences in cardiovascular mortality within nations which bear no apparent relationship to diet or blood lipid risk factors [72-751. Thus, depending on which aspects of the data are selected, the critical longitudinal and cross-sectional relationships between dietary fat intake and death from heart disease within countries, have been shown to be positive, negative and random. Such striking diversity argues strongly against there being a fundamental association of any sort, let alone a positive causal relationship between dietary fat and death from heart disease. Even if there were a positive, causal relationship between dietary fat intake and death from heart

196:-63---1969-71

-

Canada

v

U.S.A.

---+--

Australia

rate of

disease, rational intervention requires that this relationship be reversible. At the moment the relationship may not be reasonably described as either positive or causal, consequently it is meaningless to speculate as to whether there is any reversibility. These elementary considerations pose serious problems for the advocacy of a reduction in dietary fat. Cholesterol levels and death from coronary heart disease do not covary in numerous significant respects. At almost all ages women have higher cholesterol levels than men, yet women have consistently lower cardiovascular mortality [76-781. Similarly, death from coronary heart disease may not covary with atherosclerosis. The Masai of Africa have extremely high fat intake and substantial atherosclerosis, yet death from cardiovascular causes is almost unknown among the Masai [79]. It has been known for a long time that high cholesterol levels are not necessarily associated with high levels of atherosclerosis

1979-81

1986-88

-25 1

Fig. 3. Temporal

changes

in dietary fat intake (expressed as a % of the fat intake English-speaking countries [68-701.

of 1948-50)

in three

DALE M. ATRENS

438 5 1 /

1955-59

1

‘\

1960-64

\

1965-69

/

1970-74

I I

I

1975-791980-84

.

\

-55 1

Fig. 4. Temporal changes in death from ischaemic heart disease in Japan expressed as a % of the death rate in

1950-54 [67].

I

I

1969.71

1979.81

Fig. 5. Temporal changes a % of the fat intake

[80]. Such failures to covary in the expected manner raise very serious difficulties for the simple hypotheses that are prevalent. RELATIONSHIP OF DIETARY ATHEROSCLEROSIS

19061-63

FAT TO

The furore about coronary artery disease began in earnest during the Korean war when post-mortems on young soldiers revealed arteries with extensive blockage [81]. This should not have been so surprising since it basically illustrated that the ideally smooth, unoccluded artery probably does not exist in adults. Nor should it have been construed as indicating an epidemic since very similar amounts of blockage had been shown in young soldiers early in World War I [82]. The flawed conclusion about an epidemic of atherosclerosis occurred at a time when deaths from heart disease appeared to be increasing rapidly. It was assumed that an assumed epidemic of atherosclerosis was behind an assumed epidemic of heart disease [83]. Doubts have been expressed concerning whether the epidemic of heart disease was genuine [26], but the situation with respect to the putative epidemic of atherosclerosis is much clearer; there never was any evidence to support this contention [28, 831. However, there is little doubt that atherosclerosis is a genuine risk factor for heart disease [2, 10.28, 48, 841. Since lipids and cholesterol are common food elements, it is not unreasonable to expect that improper diet may play a role in the development of atherosclerosis. Conversely, it is at least plausible that changing from an atherogenic diet may have salutary effects. This is the message in the electrocardiograms featured on cereal boxes.

19X6-88

in dietary fat intake (expressed of 195456) in Japan [68-701.

as

The reasonableness of the dietary hypothesis of atherogenesis still largely depends on the classic fat-feeding experiments of Anitschkow and his colleagues which began before World War I [2. 851. However, there are many reasons to question whether these findings support the dietary hypothesis of atherosclerosis [lo, 27, 48. 86, 871. First. since rabbits do not develop atherosclerosis, their arterial pathologies have little import for human atherosclerosis [88, 891. Moreover, the altered lipoprotein patterns observed following fat feeding is related to the high level of protein in the semipurified diets [90]. Additionally, there are great species differences in the effects of diet on blood lipids and lipoproteins [91]. Although rats are widely used in this type of research, they are remarkably resistant to diet-induced atherosclerosis. Nakamura ef al. [92] have shown that 6 months on an ideal ‘atherogenic‘ diet failed to produce aortic lesions in rats. It seems that dietary manipulations produce vascular lesions in rats only when supplemented with the antithyroid drug, thiouracil [93]. However, since thiouracil damages the aortic wall [94], the relevance of these findings to dietary induction of atherosclerosis, particularly in humans, are minimal. If anything, the rat data suggest that dietary factors play only a very minor role in the development of arterial pathologies. Humans appear to be the only primates that are afflicted with occlusive atherosclerosis. Cliff [9] has analyzed a number of the primate feeding experiments and found that the cholesterol composition of the diets effective in producing arterial pathologies was ‘stupendously’ [9] out of proportion to any human or animal dietary intake. The stress of wildly imbalanced diets suggests great caution in interpreting their effects.

The questionable

wisdom

of a low-fat

Given the increasing evidence for an immunological component to atherogenesis [ 10,48,95-971 and the immunological impairment caused by stress [61-631, this is not a trivial confound. The best laboratory models of human coronary artery disease are seen in pigeons and domestic fowl [9]. These birds develop occlusive coronary artery lesions that are quite similar to those seen in humans. However, these lesions have a prominent viral component and dietary factors appear to be of only minor importance in their etiology. Fabricant [98] showed that, without a concurrent viral infection, nutritional manipulations did not produce any signs of atherogenesis. Additionally, when lesions did develop they were independent of serum cholesterol. Thus it is highly questionable whether lipids are atherogenic within the ranges in which they are normally consumed by humans or any other species. The relationship between dietary factors and serum cholesterol levels are far too complex to allow the extraction of simple directives [99-1021 and this is to say nothing of the similarly complex relations between serum cholesterol and atherogenesis as well as that between atherosclerosis and mortality [28,29, 1031. Irrespective of whether atherosclerosis is caused by dietary fat. it remains possible that restricted fat intake may reverse atherosclerosis. These views are partly derived from observations that starvation and various wasting diseases are associated with an apparent reversal of atherosclerosis [48]. Whereas severe dietary restriction, cholesterol-lowering drugs and even hypoxia may reduce the lipid content of atherosclerotic lesions, histological investigations indicate that they do not reverse the atherogenic process or repair the lesion (for review see Ref. [48]). It is noteworthy that the reports of the regression of atherosclerosis by cholesterol lowering (for reviews see Refs [2, 1041) rely heavily on angiographic data which have lower reliability and validity than direct

diet and cholesterol

Dyer ef al. [l+Study Dyer et al. [ 12t_Study Dyer er al. [ l2]-Study Dyer et al. [ 12]-Study Goldbourt CI al. [7l] Kagan PI al. [IO61 Keys [55] Kozarevic cf al. [IO71 Neaton er al. [IO81 Peterson er al. [ 1091 Salmond er al. [I IO] Sherwin et al. [I I I] Shurtleff [I 121 Shurtleff [I 121 Smith PI al. [I 131 TGmberg er al. [I 141 Tiirnberg e, al. [ II41 Westlund er al. II I51

PROSPECTIVE

STUDIES-CHOLESTEROL

AND

MORTALITY

If high cholesterol levels are a health hazard, they should be reflected in increased mortality, particularly

Subjects I 2 3 4

439

histological examination. Similarly, evaluating angiographic data is not a straightforward process and focusing on different parameters may lead to quite different interpretations of the same data [105]. Moreover, apparently improved angiograms do not necessarily lead to reductions in mortality [103]. There is an enormously complex syntax to this argument and time after time crucial links in this syntax continue to be assumed even in the face of grossly conflicting evidence. Thus the crucial experimental evidence for the hypothesis that dietary lipids are atherogenic and that dietary restriction may reverse atherosclerosis is either absent, equivocal, or flatly contradict the hypothesis. These experiments may be relevant to the effects of stress-induced immune dysfunction on lipid handling, but they provide very little support for the widely-assumed atherogenic properties of dietary fat in humans or for the desirability of reducing fat intake to combat atherogenesis. Indeed, given the strong evidence for immunological factors in atherogenesis [IO, 48,955971, the inhibited immunity associated with the stress inherent in the pervasive and irrational fear of fat and cholesterol, is likely to be counterproductive [61-631. The implications of the failure of direct experimental evidence to support the dietary hypothesis of atherogenesis are considerable. The hypothesis that dietary fat promotes poor cardiovascular health and, by inference, that dietary fat reduction is desirable, must rely entirely on lower quality. indirect evidence. This evidence consists of epidemiological data as well as information from prospective and intervention studies.

Table I. The effects of high cholesterol levels on mortahty overall mortality Reference

reduction

11,233 I899 6890 5750 women 10,059 7961 12.770 11,121 23,490 black me” 10,000 630 me” & women 361,662 26,000 36,000 women 17,718 46, I40 46.570 women 6886

from heart disease and

Mortality change Heart disease Overall

t

t

The arrows indicate either statistically significant (minimum P -z 0.05, two-tailed) increases or decreases, whereas the dashes indicate no significant change. The data are from white males unless otherwise specified.

440

DALE

M.

from cardiovascular causes, This relationship has been intensively investigated in a number of prospective studies. The results of these studies are quite consistent. Of the 18 prospective studies, 13 showed that high cholesterol levels were associated with increased mortality from cardiovascular disease [55. 106, 108, 109, I I l-1 161, five showed no association [ 12. I IO. II61 and none showed a negative association. Therefore. these data constitute a good case for there being a fundamental association between high cholesterol levels and increased risk of death from cardiovascular disease. In contrast, the effects of high cholesterol levels on overall mortality are very different from those on cardiovascular mortality. Five studies have reported increased overall mortality [l2, 71. I I I, 113, II41 eight have reported unchanged overall mortality [ 12,55, 106. 108, I IO, I 151 and five have reported decreased overall mortality [lO7. 109. I 12. I 141. The four examples of cardiovascular mortality being increased while overall mortality is unchanged 155. 106, I 15. I 171 suggest that the cardiovascular liability associated with hypercholesterolemia was fully compensated for by a reduction in other causes of death. However, the four examples of decreased overall mortality in spite of increased cardiovascular mortality [ 109. I 12, I 141 suggest that the cardiovascular hazard was more than compensated for. Thus I3 of the I8 prospective studies suggest that hypercholesterolemia is tither irrelevant to or a positive indicator for overall health. These data are incompatible with the global labelling of hypercholesterolemia as a health hazard. There is a common tendency to assume that death from heart disease is a sufficient indicator of atherosclerosis However, death from cardiovascular causes may occur with minimal atherosclerosis and even extensive atherosclerosis may not become clinically apparent. let alone result in fatality [28.29]. Similarly. the assumption that hypercholesterolemia is the direct precursor of, and functionally equivalent to. atherosclerosis has little justification. As early as 1936 histological investigations in humans showed no correlation between serum cholesterol and severity of atherosclerosis (801. There is a persistent confusion in this area between statistical significance and scientific significance. Because of the large sample sizes in the prospective studies most relationships are statistically significant. In this case the magnitude of the effects is far more important than their probability value. In a proportional hazards analysis, the Framingham Longevity Study found serum cholesterol levels to be a significant hazard [I 181. However, of the seventeen variables measured, cholesterol was the It~st important. The Beta coefficients for cholesterol were about one tenth those of the next least important variable and several hundred times smaller than those of the most important variables. Such marginal associations

ATKENS

are mere statistical artifacts with little or no real import. Thus the prospective studies suggest that the ongoing war on cholesterol is based upon a fundamental misunderstanding of hypercholesterolemia’s implications for health. It appears that the health assets associated with hypercholesterolemia arc usually either equal to or greater than any liabilities. If the assets were reversible in the same manner that it is hoped the liabilities are [I, 21, the implications are clear; lowering cholesterol levels is more likely to increase overall mortality than decrease it [I 19. 1201. The primary intervention studies discussed below show that this grim assessment is unfortunately accurate.

PREVENTIVE

INTERVENTION

STUDIES-LOWERING

CHOLESTEROL

Since hypercholesterolemia does not appear to be an overall health hazard. it may not be generally desirable to lower cholesterol levels even assuming that any risk associated with hypercholesterolemia is reversible. The wisdom of this C~PCNI has been borne out by a number of preventive intervention studies. In light of the diversity in the cohorts and the variety of intervention techniques used. the results are consistent. Of the I5 preventive studies, only 3 signilicantly reduced deaths from cardiovascular disease [l23, 125. 1301 and none reduced overall mortality. Thus, in these studies which are widely claimed to be ‘successes’. the benefits on cardiovascular health wet-c fully compensated for by adverse cffccts on other causes of mortality. Even the success stories clearly do not support a general health-promoting role for lowering cholesterol. However, they at least suggest some possible benefit of some aspect of the intervcntion for cardiovascular mortality. The remaining data paint u bleaker picture of the cffccts of cholesterol lowering. In 3 of the I4 studies. intervention was associated with substantially and significantly incrcascd deaths from heart disease [5l. 52. 1221. These findings flatly contradict the wisdom of the merits of lowering cholesterol even tn the restricted sphere of preventing heart disease in tncn said to be at particular risk. The effects of these preventive interventions on overall mortality arc as consistent as they are frightening. The only statistically significant effects of intervention have been negative. All three of the studies that found effects on overall mortality found incrud mortality [5l-531. The claimed successes for intervention are not real successes at all. but the failures are real and unequivocal failures. This has been most recently illustrated in the follow-up to the Finnish Businessman’s Study [52]. Further. the strong association between low cholesterol levels and death from violent causes [I321 suggests caution in indiscriminately attempting to lower cholesterol

The questionable

wisdom

of a low-fat

diet and cholesterol

441

reduction

Table 2. Summary of preventive mtervention trials examining the effects of lowermg cholesterol mortality from heart disease and overall mortality Name of trial

Number

Anti-coronary Club [51] Coronary Primary Prevention [I211 Finmsh Busmessmen I [I221 Finmsh Busmessmen 2 [52] Finnish Mental Hospital [I231 Fmnish Mental Hospital [I231 Giiteborg Study [I241 Helsmkl Heart Study [I251 Minnesota study [I261 MRFIT [I271 North Karelia [12X] Oslo study [I291 Veterans Administration [I301 WHO Clotihrate [53] WHO Collaboratwe [I311

of subjects

814 3806 1815 IOlrl 5000 5000 women 30,000 408 I 9000 12,866 I2.000 1232 8X8 10.000 60.8X1

Mortality change Heart disease Overall t

T r T !

r

1

1 f

The arrows mdvcate either statistically significant (minimum P -c 0.05. two-tailed) decreases. whereas the dashes indicate no significant change.

The above analysis concerns primary intervention where the goal is to prevent heart disease. However, in secondary intervention studies where the goal is to prolong life in those with clinically diagnosed heart disease, there is one study that has shown a significant long-term overall benefit. In the fifteen year follow-up to the Coronary Drug Project, the group originally treated with niacin showed a significant reduction in overall deaths [133]. However, the lack of any cholesterol data in the follow-up means that it is inappropriate to attribute the reduced mortality in the niacin group to cholesterol lowering. Moreover, generalizing from a successful treatment to prevention is not justified. Similarly, it should be added that apart from the niacin success. the picture of the secondary intervention trials is every bit as disappointing as the primary intervention trials [4l]. A number of these studies incorporated antihypertensive therapy and smoking cessation which often, but not always [134]. have salutary effects of their own [84]. The data from the intervention studies show that the beneficial effects of anti-hypertensive therapy and smoking cessation were entirely cancelled out or even reversed by the efforts at lowering cholesterol. These findings indicate that the cholesterol lowering approach is not simply ineffective, but frankly dangerous. There is little question that the results of the intervention studies have been misrepresented [ 12, 16, 411. In one way or another virtually all have been claimed to be ‘successes’ [2], although, as Table 2 indicates, all have been failures; and in at least three cases [5l-531 lethal failures. As only one example of misrepresentation, consider the Oslo study [52]. Although the authors originally specified P < 0.01 as the minimum acceptable level of statistical significance, when the first results were presented this was changed to P < 0.05 [ 1291. Since none of their main effects was significant, they combined non-fatal coronary events with fatal myocardial infarction and sudden death and reported a significant effect. Apart from the NL/ /KK combination of results and the

on

increases

or

changed level of significance, even here significance was only reached using a one-tailed test. In fact, the effect had a one-tailed probability of P < 0.055 which doesn’t even make their own rx post facto revised criterion [129]. Z(illner and Tat6 [2] cite the Anti-Coronary Club as a success even though overall mortality in the intervention group was 154% greater than in the control group! The use of terms such as ‘marginal significance’ and ‘favorable trend’ reflects ignorance of, or disregard for the principles of statistical inference. Data, whether they be two-point comparisons or trends either meet the criteria or they don’t; there is no transitional zone. However egregious, the errors of interpretation that abound in the intervention studies are perpetuated by those who uncritically accept the conclusions presented in the abstracts of these articles. Nearly every study that quotes the Oslo study reports it as an example of successful intervention [2. 1351. The common perception that the

total

deaths

hs

Fig. 6. The effects of multifactorial categories of mortality reported in man’s Study [52]. In each case the a statistically significant (minimum mortality.

intervention on three the Finnish Businessintervention produced P i 0.05) increase in

342

DALE

M.

intervention studies have been successful when the data clearly indicate otherwise reflects the prevalent misinformation in this area. THE POSITIVE SIDE OF CHOLESTEROL

LOWERING

One effect of cholesterol lowering that may be construed as beneficial is the reduction of coronary artery stenosis reported by Blankenhorn clt al. [I 16. 1361. However, the implications of these findings for primary prevention are limited since it is gratuitous to generalise from an assumed treatment effect on arterial grafts to a preventive effect in the general population. At the moment the effect of the treatment on overall mortality may only be assumed since the intervention literature is replete with evidcnce that changing risk factors does not translate into changed risk [41,5ll53, 12lll31]. Moreover, it is not clear whether slowing of restenosis [I 16. 1361 indicates decreased risk since a substantial degree of stenosis is normal in middlcaged men [28]. In fact. the slowing of what could be conceived of as a normal, homeostatic process could be viewed with some concern as a sign of impaired regulation. It is not reasonable to assume that any stenosis will proceed to a pathological endpoint. Whether their observations are cause for joy or alarm will not be decided until mortality data are available from this cohort. Similarly. Ornish er nl. [I371 have reported that lifestyle changes can reduce stenosis in coronary arteries. There are a number of factors that diminish the significance of these findings for the issue of diet. cholesterol and heart disease. First, in terms of a number of serum lipids as well as apolipoprotein A- I, the experimental and control groups were not equivalent to begin with. The control group had much higher levels of apolipoprotein A-l. Since apolipoproteins arc being increasingly implicated in heart disease [5Y. 1381, this is a particularly serious confound. It is significant that apolipoprotein levels are largely under genetic control and are quite unresponsive to dietary variables [l38, 1391. It is also important to note that. since thcrc are no mortality data from the study. the changes are of uncertain significance [ 1371. Lastly, even if their intervention turns out to bc an unqualified success and genuinely lowers mortality, it would be at least as probable to attribute the success to the smoking cessation, stress management and exercise regimen as to the low-fat diet. Whereas anyone wishes for a fdvourable outcome to their study. one’s hopes are diminished by the Pact that to date this type of approach has yielded only false optimism [5l -53. l2l-1311. The consistent failure of low-fat diets and cholesterol-lowering drugs to have genuine therapeutic, as opposed to palliative effects contrasts markedly with the successful effects of platelet inhibition with aspirin. Chronic platelet inhibition reduces the

ATRENS

probability of a first myocardial infarction by about 50% [140]. Since there is no evidence of significant adverse effects associated with these therapeutic effects, this seems to be a most promising line of investigation. Thrombosis and perhaps artcriospasm appear to be at least as important in maintaining coronary circulation as is the chronic size of the arterial lumen. Moreover. the former factors. particularly thrombosis, offer vastly greater prospects for effective control. Still further evidence that there are genume therapies for cardiovascular disease is provided by the SAVE group [l41]. In a double-blind. placebo controlled design they showed that captopril, an inhibitor of the angiotensin-converting enLyme. had striking therapeutic effects. In patients who had left ventricular dysfunction after a myocardial infarction. captopril produced a large ( - 25%) and statistically significant (P < 0.02) reduction in coronary and all causes mortality. This unequivocal ellect stands in stark contrast to the long lint of ineffective and dangerous cholesterol-lowering interventions. It has become unfortunately common to present morbidity changes which are often favorable. as being cquivalent to mortality changes which clearly are not favorable [2]. It is obvious that the latter arc vastly more important than the former. When both types of data are available, stressing favorable effects on morbidity in the face of adverse effects on mortality may only be considered obfuscation. THE POTENTI.41. FOR HARhl It is indicative of the prev,alent hysteria about cholesterol that so little attention has been directed to the potential for harm through what often amounts to an indiscriminate assault on cholesterol Icvcls. Given the ubiquitous distribution and diverse functions of cholesterol [142]. a prolonged challenge to cholesterol homcostasis has substantial potential for inducing structural and functional pathology. The idea that cholesterol lowering will spccitically target atherosclerosis is entirely without foundation. Cholesterol-lowering treatments arc widely portrayed as ‘silver bullets’ for atherosclerosis when so much cvidencc suggests that they are not at all specific, probably do not alter atherosclerosis, and they are clearly unsafe. Sustained challenge to any aspect of physiological homcostasis is likely to mobilise the hypothalamo-hypophyseal stress axis [6l] and there is littlc doubt of the ability of stress to induce or exacerbate many pathologies [62. 631. It is largely forgotten that a low-fat diet is. for the vast majority. substantially less pleasant than the diet that they would choose in a non-coercive atmosphere [l43]. At one time or another some committee has declared war on virtually every food ingredient the public holds dear. This has created an irrational belief in the powers of food to harm and to help [I I]. A strong sense of urgency coupled with an ineffective

The questionable wisdom of a low-fat diet and cholesterol reduction course of action is a classic recipe for creating learned helplessness and all of its negative sequelae [144]. There is great interest in why those with low or lowered cholesterol levels appear to be at increased risk for cancer, in particular. Although there is no simple answer for this, some of the increased cancer mortality associated with low cholesterol levels may reflect premorbid effects of the disease [113, 1451. In this context, low cholesterol levels may be a ‘marker’ for cancer just as high cholesterol levels may be a ‘marker’ for cardiovascular disease. In either case, changing the value of such a marker would be expected to have little effect on the target disease. The image of addressing the sinking of the Titanic by rearranging the deck chairs is apposite. On the other hand, it is also clear that much of the increased mortality associated with low cholesterol levels is not simply due to a cholesterol-lowering effect of pre-morbid cancer [113, 1201. However, whether the increased mortality represents a causal relationship is not yet certain. Like so many diethealth correlations, it might simply be a specious relationship or reflect the actions of hidden variables. It is also plausible that it represents an indirect effect mediated by the stress associated with homeostatic challenge and/or leading a fear-riddled and self-punitive lifestyle. In either case, these considerations suggest great caution in intervening in the basic regulatory machinery of the organism-“If it ain’t broke, don’t fix it.” CONCLUSIONS

The widespread concern about dietary fat as a cause of poor overall health and particularly poor cardiovascular health is based upon a misapprehension of a number of fundamental relationships. High dietary fat intake is not reliably associated with death from cardiovascular disease either between or within cultures. Experimental investigations provide little support for the notion that high fat diets cause atherosclerosis or that low fat diets reverse atherosclerosis. Whereas hypercholesterolemia is reliably associated with increased risk of death from cardiovascular disease, it is as commonly associated with increased as with decreased life expectancy. Most importantly, the only significant overall effect of lowering cholesterol to prevent coronary heart disease that has ever been shown is increased mortality. The most basic precept of medicine, dating back to the works of Hippocrates, is primum non nocere [foremost cause no harm]. This precept appears to have been forgotten in the illogic that generated and sustains the demonisation of dietary fat and cholesterol. Elementary logical considerations are repeatedly violated and damaging data dismissed or ignored by those who advocate dietary austerity and press on with the war against cholesterol [2]. It is significant that this sort of nutritional hysteria and fear of one’s

443

appetites figure prominently in eating disorders [36,38]. It is difficult to escape the conclusion that anorexia and bulimia have a significant iatrogenic component and that the culprit is the enormous nutritional and cholesterol awareness campaigns to which we have all been subject. In countries that have not been subject to these mass-education campaigns, such as France, Italy and Japan eating disorders are rare [14&149]. It remains possible that select target groups may benefit from dietary and other cholesterol-lowering interventions [ 150, 1511. However, as yet no such group has been identified and the prevalent hysteria about cholesterol is unlikely to facilitate the elucidation of any such rationally-targeted groups. However, it is clear that the general public has nothing to gain and a great deal to lose from subscribing to a fear-riddled and ineffective lifestyle [62,63, 152-l 541. Until there are sound reasons for dietary change and a genera1 cholesterol lowering, urgent messages to adopt these courses of action must be considered as irrational and mischievous. As yet, no such reasons have been offered, nor do there appear to be any on the horizon. It is unacceptable that the zeal and pronouncements of consensus committees and national panels continue to substitute for logic and data. In their advocacy of unpleasant, ineffective and likely dangerous medicine, public health authorities and the medical profession promote ill health, undermine their own credibility and inhibit the discovery of genuine therapies for pressing health problems. Acknowledgement-The

author’s research was supported by grants from the Australian Research Council.

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