QJM Advance Access originally published online on November 28, 2008
QJM 2009 102(2):81-86; doi:10.1093/qjmed/hcn158
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History of the cholesterol controversy in Britain*
From the Department of Metabolic Medicine, Division of Investigative Sciences, Imperial College, Hammersmith Hospital, Ducane Road, London W12 0NN, UK
Address correspondence to Professor G. Thompson, Department of Metabolic Medicine, Division of Investigative Sciences, Imperial College, Hammersmith Hospital, Ducane Road, London W12 0NN. email: g.thompson{at}imperial.ac.uk
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Summary |
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Summary
The beginnings of the...The lipid hypothesis, the concept that cholesterol plays a causal role in atherosclerosis and cardiovascular disease, has been the subject of a controversy which started in the 1950s, peaked in the 1970s and 80s and then subsided in the 1990s. It was finally resolved by the positive outcome of the Scandinavian Simvastatin Survival Study, the first of 14 prevention trials using statins which showed that lowering cholesterol reduced both cardiovascular events and total mortality. This commentary focuses primarily on the events and people involved in the cholesterol controversy in Britain. The foremost critics of the lipid hypothesis are now deceased but unfortunately for many of the patients with hypercholesterolaemia and coronary heart disease it took the best part of 50 years to disprove the sceptics. This brief account relates why it took so long.
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The beginnings of the controversy |
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According to Oliver1 the cholesterol controversy in Britain dates back to 1950 when the Hammersmith-trained cardiologist Paul Wood stated that ‘considerations should be given to the possibility that raised cholesterol might result from coronary heart disease’. This comment helps explain his subsequent dismissal as ‘irrelevant to cardiology’ of Oliver and Boyd's finding in 1953 that plasma cholesterol levels in coronary patients in the United Kingdom were higher than controls.2
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Early cholesterol-lowering diet trials |
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The best epidemiological evidence at that time of the relationship linking diet, serum cholesterol and coronary heart disease (CHD) was the Seven Countries Study, which had shown that countries with a high intake of saturated fat had a higher incidence of CHD than those where the intake was low and a raised serum cholesterol infrequent. Hence early coronary prevention trials utilized either low fat- or polyunsaturated fat-enriched diets to lower serum cholesterol. Three such secondary prevention trials were undertaken in Britain in the 1960s, one of which used corn oil,3 another a low-fat diet4 and the third used soya bean oil.5 All had a negative outcome, raising further doubts about the validity of the lipid hypothesis in the minds of cardiologists. Consequently, interest shifted towards lowering serum cholesterol by pharmacological means.
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Lipid-lowering drug trials in the pre-statin era |
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In 1963, Oliver reported the lipid-lowering properties of chlorphenoxyisobutyric acid or clofibrate.6 Although this compound achieved a significant reduction in mortality and in non-fatal myocardial infarcts in two trials conducted in patients with angina there was no evidence that this was due to the 11–12% reduction in serum cholesterol it engendered.7,8 An alternative explanation was that clofibrate had an anti-thrombotic effect.
A major limitation of secondary prevention trials is that the outcome is determined more by the extent of myocardial damage consequent on previous infarction than on the severity of the underlying coronary atherosclerosis. In 1965, Oliver and Morris and others therefore embarked on a World Health Organization (WHO)-sponsored primary prevention trial of clofibrate.9 Serum cholesterol decreased by 9% in those on clofibrate, which was associated with a 25% decrease in non-fatal myocardial infarcts compared with controls after 5 years. However, the incidence of fatal myocardial infarcts was similar and the crude death rate was actually higher in clofibrate-treated subjects. The authors concluded that lowering serum cholesterol reduced the incidence of CHD but that it was unsafe to use clofibrate for this purpose.
The lipid hypothesis remained in doubt for another 6 years until it was resuscitated in 1984 by the US Coronary Primary Prevention Trial, which demonstrated that cholestyramine significantly reduced coronary mortality and showed that the reduction in risk was proportional to the decrease in serum cholesterol achieved.10,11
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A pure and white ‘red herring’ |
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Prior to 1984, the absence of convincing evidence that lowering cholesterol beneficially influenced outcome left room for alternative explanations for the rise in coronary mortality after the second world war. In 1974, The Times published an article by the nutritionist John Yudkin, who suggested that the evidence linking saturated fat, serum cholesterol and coronary disease was circumstantial, lacking proof of causality.12 An alternative explanation, he proposed, was an excess of sugar in the diet.13
Consumption of sugar in Britain had increased 25-fold during the past 200 years and Yudkin cited data that a high intake of sucrose could raise serum cholesterol and triglyceride, especially the latter, and cause other metabolic abnormalities seen in subjects with coronary disease. Yudkin's claims regarding the link between sugar and vascular disease were based on remarkably scanty experimental evidence. In 1964 he estimated the intake of sucrose in 45 men with coronary or peripheral vascular disease to be significantly greater than that of 25 controls.14 On the basis of these results, he suggested that the relationship between sucrose and vascular disease was causal. Three years later, following criticisms of the methodology used to estimate sucrose intake, Yudkin carried out a second study and again found a significantly higher intake of sucrose among patients with CHD.15
In the light of these findings, the Medical Research Council convened a working party to investigate the relationship between sugar and vascular disease. After conducting further studies, the working party concluded that ‘the evidence in favour of a high sugar intake as a major factor in the development of myocardial infarction is extremely slender.’16 The sucrose hypothesis soon faded away and the biochemical abnormalities which Yudkin attributed to excess sugar consumption are now recognized as being part of the metabolic syndrome.
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McMichael's anti-cholesterol campaign |
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Sir John McMichael, once described as the greatest clinical scientist of his generation,17 directed the Department of Medicine at the Hammersmith Hospital from 1946–66. His ability to create an atmosphere of enthusiasm and constructive criticism earned worldwide recognition of the Hammersmith as the best place in Britain for postgraduate medical training during the post-war era.18
In 1973, several years after retiring, McMichael took up arms against those who believed that diet played a role in the aetiology of CHD. In the first of several letters to the Lancet, he criticized the International Society of Cardiology for stating that an increased intake of cholesterol and fat was a prerequisite for the development of atherosclerosis.19 He also criticized the recommendations of a joint working party of the Royal College of Physicians and the British Cardiac Society on the Prevention of Coronary Disease, which endorsed the policy of reducing saturated fat intake to lower serum cholesterol,20 and reiterated his conviction that this measure would have little effect on the incidence of coronary disease.
McMichael next turned his attention to the results of the Whitehall Study and questioned whether the correlation of raised cholesterol with coronary risk in patients with angina or an abnormal electrocardiogram might be a consequence of myocardial ischaemia rather than a cause, as Paul Wood had suggested many years before.21 Geoffrey Rose and his colleagues tactfully pointed out that McMichael's conclusions were based on a misinterpretation of their findings.22 Although many of McMichael's criticisms were scientifically naïve his past achievements and reputation ensured that they were well publicized.
After seeing the results of the WHO trial showing an increase in non-cardiovascular causes of death in those on clofibrate, McMichael published a paper entitled ‘Fats and atheroma: an inquest’.23 In this, he alluded to the negative results of the early diet trials as casting doubt on the role of cholesterol in atherogenesis and pointed out the potential dangers of lowering blood levels by polyunsaturated fats and clofibrate. He concluded that official endorsement of these cholesterol-reducing measures should be withdrawn.24
After he died in 1993, a service of thanksgiving was held for him in London. The church was packed with Hammersmith staff, past and present, united in paying tribute to a great man. Although the errors that men publish may live after them, so too does the good that McMichael did.
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Should every cow carry a government health warning? |
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One of the harshest critics of the lipid hypothesis was J.R.A. (Tony) Mitchell, Professor of Medicine at Nottingham and a member of the first Committee On the Medical Aspects (COMA) of Diet and Coronary Heart Disease in 1974.25 The majority of members accepted the evidence that the death rate from ischaemic heart disease correlated with the saturated fat content of the diet and recommended that it should be reduced. A minority including Mitchell felt that this recommendation went too far but agreed to support it except Yudkin, who dissented.26
In 1984, a second COMA report was published on diet in relation to cardiovascular disease.27 On this occasion recommendations to reduce the saturated fat content of the diet and increase its ratio of polyunsaturated to saturated fat were far more specific than those made previously. Nine members of the panel concluded that the incidence of CHD would be reduced by such measures. The 10th, who was not named but was undoubtedly Mitchell,28 believed that the evidence was insufficient to support that conclusion.
Mitchell amplified his doubts in an editorial29 in which he listed beliefs about diet and coronary disease then current:
- CHD is caused by atherosclerosis.
- Atherosclerotic plaques are cholesterol deposits in artery walls.
- A high serum cholesterol is a risk marker for coronary disease.
- Dietary lipids determine serum cholesterol.
Mitchell then put his head on the block by stating that most of them were untrue or irrelevant and would be discarded by the year 2000. In retrospect it is apparent that he was wrong on every count.
Mitchell's approach to prevention was to advise his patients to stop smoking but to say nothing about diet. He attributed to Oliver a similarly cautious approach which, he said, led them to be labelled ‘the abominable no-men’ by ‘cholesterol evangelists’. His own attitude was exemplified by the title of one of his lectures: ‘Should every cow carry a government health warning?’.30 He ended his editorial by quoting H.L. Mencken: ‘The most costly of all follies is to believe passionately in the palpably-not-true.’ Or was it even more costly to passionately deny what later turned out to be true?
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The discovery and development of statins |
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The beginning of the end of the cholesterol controversy came in 1971, the year when Akira Endo, a Japanese microbiologist working for the pharmaceutical company Sankyo, started searching for compounds which would inhibit hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, the key enzyme of cholesterol biosynthesis. After testing more than 6000 fungal strains, he and his colleagues isolated a potent inhibitor of HMG CoA reductase from Penicillium citrinum, which lowered serum cholesterol in experimental animals.31 Initially known as compactin, this compound became the first HMG CoA reductase inhibitor or statin to be used in humans.
Interestingly, compactin had been isolated from a different mould by scientists at Beecham Laboratories in Britain at the same time as Endo's discovery in Japan.32 However, they lost interest when the compound failed to lower serum cholesterol in rodents,33 despite evidence that it inhibited cholesterol synthesis in human tissue.34 Without doubt this was a missed opportunity.
The first clinical studies with compactin35 showed that it reduced serum cholesterol by 27% in patients with familial hypercholesterolaemia, most of the decrease being in LDL cholesterol. However, at that stage Sankyo abruptly suspended their clinical trial programme for undisclosed reasons and it was never licensed for use in man.
Endo had collaborated with the US drug company Merck several years previously by providing them with samples of compactin and in 1980 Alberts et al. isolated an HMG CoA reductase inhibitor from Aspergillus terreus.36 This was initially called mevinolin but later renamed lovastatin and 4 years later it became the first HMG CoA reductase inhibitor to be licensed in the United States.37 Prior to that Merck arranged for the compound to be made available to treat patients with refractory familial hypercholesterolaemia on a named patient basis and my colleagues and I at Hammersmith gratefully took advantage of this facility, as we reported in the QJM.38
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Safety concerns: low cholesterol, murder and suicide |
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Ever since the WHO trial of clofibrate, Oliver had been concerned about the safety of lowering serum cholesterol, pointing out that although this reduced coronary mortality it failed to decrease total mortality, perhaps by increasing non-cardiovascular causes of death.39
In 1990, Muldoon et al. published a meta-analysis of six primary prevention trials of cholesterol reduction.40 Coronary mortality was significantly reduced by drug treatment but total mortality was unchanged, reflecting a significant increase in deaths from accidents, suicide and violence in those on treatment. These findings reawakened Michael Oliver's concerns and he sounded the alarm in editorials with titles, such as ‘Might treatment of hypercholesterolaemia increase non-cardiac mortality?’ and ‘Is cholesterol reduction always safe?’
Anxieties over this issue were brought to public attention in 1992 with the publication of an article by Davey Smith and Pekkanen asking ‘Should there be a moratorium on the use of cholesterol lowering drugs?’41 Their meta-analysis showed a highly significant increase in non-coronary mortality, reflecting an amalgam of cancer, injury and other non-cardiovascular causes of death in the intervention groups of the drug trials. They therefore proposed that prescription of cholesterol-lowering drugs should be restricted until the results of the statin trials became known, still some years hence.
The publication of this article resulted in a plethora of hyperbolical headlines in the newspapers ranging from ‘Heart pills may kill you’ to ‘Murders linked to low-fat drugs’, causing panic among patients taking cholesterol-lowering medication and disquiet to their doctors. Public and professional anxiety regarding the safety of these compounds persisted until Malcolm Law and his colleagues conducted an exhaustively thorough systematic review of 40 published studies42 and attributed the association between low serum cholesterol, cancer and suicide to confounding, a low serum cholesterol often being a consequence of cancer or dietary neglect. Law's analysis helped to reassure clinicians at a time when lipid-lowering drugs were under intense scrutiny.
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The statins trials resolve the controversy |
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In 1994, the Lancet published the results of the Scandinavian Simvastatin Survival Study (4S), which provided unequivocal evidence that treatment of hypercholesterolaemia in patients with existing CHD reduced total mortality.43 This was entirely due to a 42% reduction in coronary mortality by simvastatin and there was no increase in non-cardiovascular causes of death, including cancer and trauma.
The publication of the 4S results had an immediate impact on medical opinion. Even Michael Oliver was impressed and he was co-author of an article entitled ‘Lower patients’ cholesterol now’,44 although this included a caveat about the increase in non-cardiovascular mortality seen in primary prevention trials. However, he relented during a meeting the following year to celebrate the 10th anniversary of Goldstein and Brown's Nobel Prize. It was there that he completed his U-turn, which he justified by quoting Maynard Keynes: ‘When the facts change, I change my mind. What do you do?’.
The final proof of the lipid hypothesis came when data from over 90 000 individuals who participated in 14 statin trials between 1994–2004 were meta-analysed.45 These included two major British trials, the West of Scotland coronary prevention study (WOSCOPS)46 and the Heart Protection Study.47 Overall the results augmented those of 4S and showed decreases of 12% and 19% in total and coronary mortality, respectively, for each 1 mmol/l reduction in LDL cholesterol. No significant changes in non-cardiovascular mortality occurred and the excess risk of rhabdomyolysis, the most serious side effect of statins, was only 0.01%.
In 1953, the year when Oliver and Boyd first showed an association between raised cholesterol and coronary disease in Britain, Pollak published a paper describing the cholesterol-lowering properties of plant sterols, which he concluded by forecasting: ‘Some day, the question as to the value of prophylactic or therapeutic reduction of blood cholesterol will be answered.’48 He was right—more than 50 years later, it has been.
Conflict of interest: None declared.
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Notes |
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*This article is based on the author's book ‘The Cholesterol Controversy’ (ISBN 978-1-85315-802-5), published by the RSM Press.
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References |
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  D. S. Grimes History of the cholesterol hypothesis in Britain QJM, June 1, 2009; 102(6): 436 - 438. [Full Text] [PDF]
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