The world is changing fast and to keep up you need local knowledge with global context.
“If the data doesn’t exist to support your hypothesis, you simply spin the results as if it did” – Prof. Noakes on Keys’ Cholesterol Con
In Part Ten of Professor Tim Noakes’ ‘Ancel Keys’ Cholesterol Con’ series, Noakes looked at events between 1978 and 1995 relating to the identification of dietary trans fats as uniquely damaging to human health and the initiation of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Project. In Part Eleven, Noakes continues with the tale of Keys’ cholesterol con, picking up in 1979, when the first results of the Helsinki Policemen Study were published. However, as the findings of this study, along with those of several others detailed in the article, didn’t fit the chosen narrative, they were largely ignored and insulin resistance remained underrecognised as a precursor for CHD. Noakes further sets out the criticism of, and events that occurred in response to, the publication of the US Department of Agriculture Dietary Goals for Americans, as well as inconvenient findings published by further studies up until 1984. Regardless of the fact that definitive data was “ungettable”, the results were spun to support the Keys’ Diet-Heart Hypothesis. – Nadya Swart
Ancel Keys’ Cholesterol Con. Part 11. 1979-1984
By Professor Tim Noakes
1979. The first results of the Helsinki Policemen Study are published.
The goal of this novel study, which began in 1971, was to determine whether or not insulin resistance can be used to predict those who will develop CHD in the future. Recall that up until 1965 there was real interest in the role of carbohydrate-sensitive hypertriglyceridemia, itself a marker of insulin resistance, as a key driver of CHD (1). But then John Hickson and the Sugar Research Foundation stepped in (2,3) and the role of carbohydrates and insulin resistance were written out of history. And forgotten. Fortunately, the Helsinki Policemen Study continued.
The results published in 1979 (4) found that 5-year incidence of CHD deaths and non-fatal heart attacks were significantly related to elevated 1-hr post-glucose ingestion blood glucose concentrations but, somewhat surprisingly, not to fasting or 2-hr post-glucose ingestion blood glucose concentrations. Ten year mortality as well as CHD deaths and non-fatal heart attacks were also higher in those with the highest fasting, 1-hr and 2-hr post-glucose ingestion blood glucose concentrations.
In addition, plasma insulin concentrations, either fasting, or 1-hr or 2-hr post-glucose ingestion were independent risk factors for subsequent development of CHD. Thus, the authors concluded that these results “support…the view that high post (glucose) load plasma insulin level is associated with an increased CHD risk” (4, p.140).
Subsequently, the 91/2 (5) and 22-year (6) follow-up confirmed and extended these findings (Figures 1 and 2).
Legend to Figure 1: Incidence of major CHD events at 5, 10, 15 and 22 years in the Helsinki Policemen Study by Quintiles of fasting, 1-hr, 2-hr blood insulin concentrations and area under the insulin curve (AUC); the latter three following ingestion of a glucose load. Note that at each examination, there is a rising CHD incidence with rising blood insulin concentrations (Quintile 1 = lowest; Quintile 5 = highest). Reproduced from figure 1 in reference 6.
Figure 1 shows that incidence of CHD rates is lowest in those with the lowest blood insulin concentrations under all conditions. The best discriminator appears to be the 1-hr blood insulin concentration following glucose ingestion.
Legend to Figure 2: Survival curves without major CHD events for 5 Quintiles of subjects based on the blood insulin area under the curve (AUC) following glucose ingestion. Risk for a major CHD event was significantly greater in subjects in Quintile 5 (who had the highest and most sustained insulin responses to glucose ingestion). Reproduced from figure 2 in reference 6.
Figure 2 shows that those with the lowest blood insulin responses during the 2-hr glucose tolerance test (following glucose ingestion) (Quintile 1) had a significantly lower risk for developing major CHD events during 22 years of follow-up than did those with the greatest insulin responses.
The authors concluded that the AUC blood insulin response to glucose ingestion was a significant independent risk factor for CHD so that “the predictive value of AUC insulin was of the same magnitude as that of cholesterol” (6, p.402). However, they warned that the association may “still be explained through other factors clustering with hyperinsulinemia and insulin resistance” (p.403).
In their discussion, the authors drew attention to a number of other studies that have found this same relationship between increasing levels of insulin resistance and probability of developing CHD (7-10).
For example, the Paris Civil Service Study (7-9) also known as the Paris Prospective Study, concluded that hyperinsulinemia together with hypertriglyceridemia, insulin resistance and central obesity may “play a deleterious role with regard to cardiovascular disease risk” (9, p.461).
They found that the mean annual CHD mortality rate increased progressively with increasing degrees of insulin resistance/impaired glucose tolerance (figure 3).
Legend to figure 3: In the 11-year follow-up of the Paris Prospective Study, the mean annual CHD mortality rate rose as an exponential function of the degree of glucose intolerance. Rates were lowest in those with a normal 2-hr post-glucose ingestion blood glucose concentration (Red panel: G2<7.8mmol/L: Normoglycemics) and were highest in those with diagnosed T2DM (Green panel: Known Diabetics). Reproduced from figure 1 in reference 9.
Figure 3 shows that mean annual CHD mortality rates were lowest in those with normal 2-hour post-glucose ingestion blood glucose concentrations but rose progressively in those with impaired glucose tolerance (measured as a 2-hour post-glucose ingestion blood glucose concentration >7.8mmol/L but <11.1mmol/L); in those with recently diagnosed T2DM (2-hour post-glucose ingestion blood glucose concentration >11.1mmol/L); and was highest in those with known T2DM. Accordingly they argued that: “The evidence suggests that the development of arterial damage or conditions for cardiovascular complication, probably start long before diabetes is diagnosed by chronic hyperglycemia, if it ever is” (9, p.466). They also provided a figure (figure 4) to explain how this might happen over decades.
Legend to figure 4: Proposed time sequence for development of coronary heart disease and type 2 diabetes mellitus in those with insulin resistance (subsisting on high carbohydrate diets – my addition). Reproduced from figure 4 in reference 9.
Figure 4 proposes that persons who have varying degrees of insulin resistance before the age of 40 show a progressive increase in insulin resistance as they age (and ingest a high carbohydrate diet – my addition). As a result, by age 40 they show hyperinsulinemia and hyperglycemia, especially following carbohydrate ingestion, as well as rising blood triglyceride concentrations, with the development of arterial hypertension. This combination then causes the progressive development of coronary atherosclerosis and coronary artery disease, which first becomes clinically apparent after age 50.
The authors concluded that all these precursors for CHD can be reversed by weight-reduction, exercise and use of medications like metformin. Clearly, their advice has not been adopted to any great extent since insulin resistance remains underrecognised as a precursor for CHD.
The Bogalusa (Children) Heart Study (11) also found that, compared to children with the lowest blood insulin concentrations at the start of the 8-year follow-up period, those with the highest concentrations showed higher body mass indices, blood glucose, triglyceride, LDL and VLDL cholesterol concentrations, lower HDL cholesterol concentrations, higher systolic and diastolic blood pressures, and higher prevalence of parental history of diabetes and hypertension. Those children whose blood insulin concentrations remained high during the observation period had higher prevalence of obesity, hypertension and blood lipid abnormalities.
So the authors concluded that: “Elevated insulin levels persist from childhood through young adulthood, resulting in clinically relevant adverse cardiovascular risk profile in young adults” (11, p.54).
In a 6-year follow-up study of Colombian patients who had suffered an acute heart attack (12), it was found that elevated blood insulin concentrations was a stronger predictor of CHD recurrence than was the blood cholesterol or LDL cholesterol concentrations or current blood pressure. The only more powerful risk predictors were a history of hypertension and an episode of heart failure during hospitalisation.
These findings have led some to conclude that “insulin resistance is the most important single cause of coronary artery disease” (13, p.1449).
Note the emphasis on the word “cause”. If this conclusion is correct, then removal of the cause should absolutely prevent the disease.
Since we cannot “cure” insulin resistance, we cannot remove the “cause”. But what we can hope to achieve is to prevent the worst effects of insulin resistance by eating carbohydrate-restricted diets.
1980. The inconvenient results of the WHO European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease are released.
The WHO European Collaborative Trial, at the time the largest intervention trial of its kind yet undertaken, began to report its first results in the 1980s (14-22).
An initial report in 1983, (18) which had yet to include the complete data from the Polish cohort, reported that whilst the Belgian cohort reported a significant 24% reduction in total incidence of CHD events, similar reductions in the Italian and Polish cohorts failed to achieve statistical significance. The UK cohort showed no benefits whatsoever.
The final report 3 years later (21) began with the now familiar post hoc explanations of why other experiments had failed to prove what everyone knows to be true – modifying CHD risk must (my emphasis) reduce CHD rates.
Thus, the authors claimed that the Oslo Secondary Prevention (Diet Heart) Trial ….. had found that “the incidence of CHD was halved” (21, p.871) without acknowledging that total mortality was unchanged (figure 4 in 23) despite large reductions in blood cholesterol concentrations (figure 1 in 23). The concept that lowering the blood cholesterol concentrations by having subjects eat manufactured foods that had only recently entered the human food chain might produce untoward effects had yet to enter the collective conscience of those driving Keys’ Twin Hypotheses.
Continuing their misinformation, the authors concluded that the reason why neither the MRFIT trial discussed shortly, nor the Goteborg Trial (24) had produced a significant reduction in fatal CHD was simply because the CHD risk factors had not been reduced sufficiently. The possibility that the hypothesis they were testing had been disproven was simply too ghastly to contemplate.
Thus, in a classic circular argument, the authors concluded: “Taken together, these trials are consistent with the theory that benefit is proportional to reduction in risk factors; and where this reduction is large, the fall in CHD in high-risk men can also be large and statistically significant” (21, p.871).
But the alternate (null hypothesis) explanation that the reduction in CHD risk factors, whether large or small, has no impact on future CHD risk is not disproven by these trials. Thus, the authors’ post-hoc conclusion that more would have been achieved if there had been a greater reduction in CHD risk factors is simply that – another unsubstantiated hypothesis. A more rigorous peer review by persons independent of the diet-heart scam should have exposed this error.
Yet that could never happen since the submitted manuscript to The Lancet would have been reviewed by persons naturally inclined to Keys’ Twin Hypotheses, because their own careers depended on Keys being correct. Pointing out to the authors of this Lancet article that they had proved the null hypothesis – that is, that reversal of coronary risk factors did not prevent any measured aspect of coronary heart disease in their study – was unthinkable because of the potential damage it could do to their own future careers.
The final analysis found that a 10% reduction in total CHD, a 7% reduction in fatal CHD, a 15% reduction in non-fatal heart attacks and a 5% reduction in total mortality in the intervention group were all statistically insignificant (21, p.871).
Yet the authors continued to interpret their non-significant findings somewhat differently. Instead, these statistically-non significant findings – which means that they could have resulted purely from chance with nothing to do with the intervention – “are large enough to be of great public health importance, in relation to the small cost of intervention; but they do not achieve the conventional level of significance, and therefore by themselves they constitute only moderate evidence that intervention is effective” (21, p.871).
In fact Sir, No! The intervention failed. Full stop. It provides zero evidence for benefit. The outcome was equally as likely to have been the results purely of chance.
Get over it.
McCormick and Skrabanek (25) have extended this argument. They argue that 5 different multiple risk factor intervention trials involving 828,000 man-years of observation have failed to show any difference in CHD deaths (1015 vs 1049; intervention vs control) or in total deaths (3009 vs 2947; higher in the intervention group).
They also reference the study of Thom et al. (26) who presented a figure showing secular trends in heart disease death rates in men and women in 26 countries between 1950 and 1978 (Figure 5).
Legend to Figure 5: Trends in CHD death rates in men and women in 26 countries over 6 time periods between 1950 to 1978. Reproduced from figure 2 in reference 26.
McCormick and Skrabanek (25) draw the following conclusions: “The most striking feature of these trends is an almost uniform decline of mortality in women (in all countries between 1950-1978), which is accompanied by an increase in mortality in men in many countries. Changes in smoking habits during these years were in the opposite direction to that which would be expected: men smoked less while women smoked the same amount or more. Presumably men and women tend to eat the same food, so that changed diet seems to be an unlikely explanation, and we have no evidence that the prevalence and management of hypertension are different between the sexes” (p.841).
Thus, the conclusion would seem to be that differences in neither smoking habits nor in diet can explain changing heart disease incidences in men and women in this random collection of 26 countries.
1980. The Food and Nutrition Board of the National Academy of Sciences releases Towards Healthful Diets.
The publication of the US Department of Agriculture Dietary Goals for Americans (USDADGA) (27) was heavily criticised by many members of the National Academy of Sciences (NAS), most especially its President Philip Handler who posed the question: “What right has the federal government to propose that the American people conduct a vast nutritional experiment, with themselves as subjects, on the strength of so very little evidence that it will do them any good?” He added: “… resolution of this dilemma turns on a value judgement. The dilemma posed is not a scientific question; it is a question of ethics, morals, politics. Those who argue either position strongly are expressing their values; they are not making scientific judgments” (28, p.51).
The organisation’s response was to publish a contrary and more conservative opinion entitled Toward Healthful Diets (29). The emphasis of the review was that the USDADGA was basing recommendations in the absence of any scientific evidence that the USDADGA would do good with no risk of harm.
Thus, the Board began by expressing its concern that the dietary recommendations of “various agencies in government, voluntary health groups, consumer advocates, and health-food interests, often lack a sound scientific basis and some are contradictory to one another” (29, p.3). The Board’s statement sought to reduce this confusion.
It began by arguing that it is scientifically unsound to make single all-inclusive recommendations to the public regarding intakes of energy, protein, fat, cholesterol, carbohydrate, fiber, and sodium since these needs vary with age, sex and many other factors. Importantly, “the nutritional needs of the young growing infant are distinctly different from the inactive octogenarian..” (p.3).
It continued by stressing that the US population has never been healthier; the mortality rate for CHD had declined by 20% during the previous 20 years and in 1980 continued to decline at a rate of 2% per year. None of this could have been achieved “unless most people made wise food choices” (p.4).
Whilst the Board felt it desirable to set appropriate guidelines, it was “concerned about the adequacy of the scientific undergirding on which these recommendations are based” (p.4). In a direct counter to the undue influence of Keys’ epidemiological studies, it noted: “The Board recognises that epidemiology establishes coincidence, but not cause and effect… The Board believes that advice should be given to the public when the strength, extent, consistency, coherence, and plausibility of the evidence from (different) lines of investigation…converge to indicate that certain dietary practices…promote health benefits without incurring undue risks” (p.4).
With regard to the prevention and management of obesity, the report presented the conventional Calories In Calories Out model which, 4 decades later, we know has proven to be completely unhelpful.
With regard to cardiovascular disease, the report stated that “the causes of atherosclerosis are unknown” (p.7). On cardiovascular disease risk factors, the report made the point that certain risk factors have been detected on the basis of epidemiological studies (which we now accept cannot prove causation). “Risk factors are those factors found to be statistically associated with an increased incidence of disease. They cannot, without independent evidence, be considered to be causative agents of the disease. Risk factors are “fellow travellers” that may aggravate some event in the overall pathogenesis of the disease or develop in parallel with true causes. At the present time, only 50 percent of the risk of persons in the United States for coronary artery disease can be accounted for statistically by recognised risk factors (30)” (p.7-8).
The report continues by arguing that, in 1980, “the prevention of atherosclerosis is based upon the assumption, not yet adequately tested, that reduction of high serum cholesterol levels, i.e., those greater than 250 mg/dl (6.5mmol/L), will reduce the probability of cardiovascular disease (30,31)”. Whilst acknowledging that studies of dietary interventions performed in metabolic units can lower blood cholesterol concentrations (32,33), the evidence from the US Diet-Heart study (34) was that when adopted by the general population, the reductions were only about 60% as effective as the laboratory studies – “Clearly, other factors in addition to adherence to diet influence serum lipid values of free-living persons in an as yet unpredictable manner” (p.9).
Perhaps more importantly, the report noted that; “Intervention trials in which diet modification was employed to alter the incidence of coronary artery disease and mortality in middle-aged men have been generally negative. Seven large-scale studies…comprising about 20,000 men-years of observation, in which decreases in serum cholesterol concentrations of 7 to 16 percent occurred, there was a marginal decrease in coronary disease incidence but no effect on overall mortality. In addition, …the effects of the drugs on incidence of coronary artery disease were not impressive, and some unpredicted toxicities were observed….It appears, therefore, that although high serum cholesterol and LDL levels are positive risk factors for coronary heart disease, it has not been proven that lowering these levels by dietary intervention will consistently affect the rate of new coronary events (my emphasis added)” (p.9).
So: “Despite these generally unimpressive results, some organisations…have recommended that dietary lipids be reduced from 40 percent to about 30 percent of calories and that the ratio of polyunsaturated to saturated fat (P:S ratio) be changed …order to achieve lower serum cholesterol levels in the population generally. Unfortunately, the benefit of altering the diet to this extent has not been established” (p.9).
On the basis of this absence of any evidence that reducing dietary fat or cholesterol content would influence CHD outcomes, the Board basically advised that only those wishing to lose weight should reduce their dietary fat intake. It made no specific recommendation for cholesterol intake but did suggest that it might be prudent for those in the high-risk categories to increase their intake of polyunsaturated fats. Only those with either a family history of CHD or with risk factors for CHD should receive therapy “under a physician’s guidance” (p.10).
With regard to T2DM, the report reflected the thinking of the time stating that persons with T2DM needed to replace simple dietary carbohydrates with complex carbohydrates. The concept of the low-carbohydrate high-fat diet for the management of T2DM was still an historical mirage (35).
But importantly, they did report that “there is no evidence that fasting serum cholesterol and lipoprotein levels are higher in well-regulated diabetic men than in normal men (36)” (p.14) even though CHD “and other manifestations of atherosclerosis are more common in diabetic persons than others” (p.14).
Which brings up the statement of Keys’ acolyte, Daniel Steinberg, who would chair the 1984 NIH Consensus Conference which, as I describe subsequently (37), was nothing more than his own personal consensus statement, that: “Most diabetic patients die of coronary heart disease, not coma or microvascular complications. For reasons still unclear, atherosclerosis proceeds at a higher rate in these patients, and heart attacks occur about a decade earlier. When the diabetes is under good control, the LDL levels are not necessarily increased but a low HDL is the rule” (38, p.1347).
Perhaps, inconveniently, it’s the insulin resistance, Dr Steinberg!
With regard to public health policy, the report’s warning was crystal clear: “Any public official considering a new public health program for disease prevention must evaluate the potential effectiveness of the proposed action before recommending its adoption. If there is uncertainty about its effectiveness, there must be clear evidence that the proposed intervention will not be harmful or detrimental in other ways. In the case of diseases with multiple and poorly understood etiology, such as cancer and cardiovascular disease, the assumption that dietary change will be effective as a preventive measure is controversial (my added emphasis). These diseases are not primarily nutritional, although they have nutritional determinants that vary in importance from individual to individual. Authorities who resist recommendations for diet modification express a legitimate concern about promising tangible benefits from controversial recommendations that alter people’s lives and habits…Those experts who advocate a more aggressive approach and seek to change the national diet in the hope of preventing these degenerative diseases assume that the risk of change is minimal and rely heavily on epidemiologic evidence for support of their belief in the probability of benefit. Neither the degree of risk nor the extent of benefit can be assumed in the absence of suitable evidence” (p.15). To which one must add that epidemiological studies do not measure degree of risk nor extent of benefit.
Finally, the Board included six dietary recommendations, none of which promoted the low-fat high-carbohydrate diet for disease prevention. Instead, the key advice was:
- Select a nutritionally adequate diet from the foods available, by consuming each day appropriate servings of dairy products, meats or legumes, vegetables and fruits, and cereal and breads (p.16).
Looking back four decades later, the wisdom of these guidelines is now clear. The USDADGA were not based on credible scientific evidence; they were introduced at a time when US citizens were healthier than they had ever been and when heart disease rates were already falling rapidly.
Today, the picture is much bleaker. US life expectancy is falling (39) despite a massive increase in spending on US medical care (40). And obesity (41) and diabetes rates (42) are increasing astronomically.
All because the legitimate concerns raised by the Towards Healthful Diets were brushed aside as if they had no possible relevance.
For they had been written by scientists who had chosen to be on the “wrong” team; the team favouring the truth.
1982. The inconvenient findings of MRFIT are published.
The design of Jeremiah Stamler’s MRFIT launched in 1971, required the screening of 361,662 men in order to identify the 12,866 considered to be at the very highest risk for a future CHD event. As Moore describes: “Plainly the MR.FIT trial had met its first goal: There was plenty of risk to modify” (43, p.41). High blood pressure and smoking were rife and the typical dietary cholesterol intake was twice the recommended amount – “the resultant group was not exactly ready to run the Boston Marathon” (43, p.41).
The group was then divided in two: a Usual Care (UC) group whose members were referred to their physicians for subsequent management; and a Special Investigation Group (SIG) that received the most intensive intervention, the aim of which was to change their health behaviours for the better. Or, at least, to behaviours that the researchers believed would substantially reduce their risks for developing CHD.
The SIG were placed under the added care of “interventionists” who conducted a series of 10 weekly group sessions during which participants were “showered with information about specific foods, taught to shop for groceries, told how to order restaurant meals, even shown how to revise their favourite recipes” (43, p.43). Their food intakes were carefully monitored and they were praised “lavishly for each goal they attained” (43, p.43).
The results of the dietary intervention were extraordinary. Subjects reduced their cholesterol intakes by 42%; saturated fat intakes by 28% and total calorie consumption by 21%. These outcomes have not been matched by any subsequent intervention.
Despite these large dietary changes, blood cholesterol concentrations dropped by only 5-7%. These findings are in line with findings especially from the Framingham (44-46) and Seven Countries Study (23,47) and a host of smaller studies (46) all showing that individual blood cholesterol concentrations in any population cannot be predicted on the basis of what the individuals are eating. This contrasts to metabolic ward studies which, as the Towards Healthful Diets document reported, show more predictable effects of diet on blood cholesterol concentrations (32,33).
Success in the MRFIT was not limited to the dietary intervention. Using every technique then available including monetary rewards, marathon group sessions lasting 2-3 days during which subjects attempt to avoid smoking; hypnosis and aversion therapy, supported by continual monitoring by the interventionists, the number of smokers fell by 50%.
Similarly remarkable changes in abnormal blood pressures were achieved: 87% of hypertensive subjects reduced their blood pressures to below the threshold defining moderate hypertension; with 67% reducing their blood pressures to the normal range.
These changes were sustained for 7 years; enough for most to believe that significantly beneficial outcomes could be expected. Indeed, on the basis of prediction generated by the Framingham study, the authors calculated that there would be 187 fewer deaths in the SIG group; with a 25% reduction in CHD deaths.
On February 28th 1982, nine years after the study had begun, the researchers began to tally the results.
Alas “the trial failed completely” (43, p.45). The was no difference in the total number of deaths from all causes (all-cause mortality) between groups. Instead, of the expected 187 fewer deaths from CHD in the SIG group, there were only 9 fewer deaths; a finding likely due to chance alone.
Remarkably the UC group did extraordinarily well. Left to their and their personal physicians’ devices, the UC group had 40% fewer deaths than expected. Even without any specific advice to change their diets, their blood cholesterol concentrations declined almost as much as did those in the SIG. Without any smoking intervention, 29% of smokers quit. Blood pressures also fell and were only slightly higher than those measured in the SIG at the end of the trial. In contrast, the use of more hypertensive medications in the SIG raised their blood cholesterol concentrations and may have been associated with a not significant “but disquieting” (43, p.46) increase in total deaths in that group.
So after spending $115 million in a trial that lasted 10 years, the researchers had conclusively proved that multiple interventions that substantially modify what are considered to be the most important CHD risk factors (smoking, high blood pressure and elevated blood cholesterol concentrations) had absolutely no effect on the measured health outcomes.
The only reasonable conclusions would have to be that (i) either the accepted “risk factors” for CHD supposedly identified by the Framingham study are not real risk factors. Or (ii) a possibility which, to my knowledge, has never previously been suggested: The dietary change – eating less saturated fat and more polyunsaturated fat – nullified the reasonably expected benefits from the reduced rates of smoking and hypertension.
For example, it is generally accepted that stopping smoking substantially reduces the risk of future CHD events (48). It is also well established that treating more severe hypertension is associated with improved outcomes (49). Thus, by the simple logic of adding 1 plus 1, the MRFIT intervention had to produce better outcomes in the SIG group.
But what if the modification of a third risk factor – for example removing saturated fat from the diet and lowering the blood cholesterol concentrations – produced harm that negated the benefits of reduced rates of smoking and hypertension?
But this question was never asked by those who were looking solely for evidence that dietary and other changes had to be introduced as immediate emergency measures to prevent the oncoming CHD epidemic in the US.
The results of the MRFIT study, like the inconvenient findings from the Framingham study and the Seven Countries Study were simply buried, never to see the light again. And the finding that lower blood cholesterol concentrations were as dangerous for future risk of heart attack and ill health as were very high concentrations were also conveniently hidden until they were re-discovered (see Figure 3 reference 44).
Of course the trial should have ended the debate – a low-fat “prudent” diet was never going to prove beneficial if even when combined with marked reductions in rates of both smoking rates and hypertension, it failed to produce improved health outcomes.
But the NHI was not about to admit defeat. It simply chose to repeat exactly the same experiment but this time in women. As if repeating the same failed experiment would somehow magically produce a different result – the one that their egos and careers and their places in medical history desperately needed. So would be born the Women’s Health Initiative Randomised Controlled Dietary Modification Trial (WHIRCDMT) discussed subsequently (50).
But there were some findings that Jeremiah Stamler would have been less than keen to share more widely.
First, there was an inverse relationship between blood cholesterol levels and risk of hemorrhagic stroke in these middle-aged men (51). The authors downplayed the significance of this finding by suggesting it would have limited public health impact since “its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from non-hemorrhagic stroke and total cardiovascular disease”.
Second, lung cancer mortality was higher in the intervention group than in the group who continued to eat their usual diets (52). Whilst the authors concluded that this was a chance event, the possibility remains that it might have been the result of converting to a diet with increased polyunsaturated fats. In other words the result of removing saturated fats from the diet.
Third and probably the most significant, it turned out that T2DM was clearly the more important risk factor for death from CHD in the MRFIT population than was the blood cholesterol concentration (53) (Figure 6).
Legend to Figure 6: Total CHD death rates at different blood cholesterol concentrations in persons with and without T2DM in the MRFIT study. Reproduced from data in table 3 of reference 53
Figure 6 shows that total annual CHD deaths increase with increasing blood cholesterol concentrations in those with (blue line) and without (red line) T2DM. However the risk of dying from CHD at any blood cholesterol concentration is about 4-times greater for those with T2DM than it is in those without.
So that a healthy person without T2DM but with a very high blood cholesterol concentration (>280mg/dL; 7.2mmol/L) is still at substantially lower risk – about two-thirds the risk – than is a person with T2DM who has the lowest blood cholesterol concentration (<180mg/dL; 4.7mmol/L).
Accordingly Stamler et al. concluded that: “The findings of MRFIT confirm that diabetes is a strong risk factor for CVD mortality over and above the effects of serum cholesterol, BP, and cigarette use” (53, p.441).
The results of more recently reported analyses from the MRFIT population (54,55) and which strengthen this conclusion are shown in figures 7 and 8.
Legend to figure 7: Percent survival in 4 groups of the MRFIT population followed for 18 years after the end of the trial. The best survival was in those (blue line) who had neither T2DM nor cardiovascular disease (CVD); the worst was in those (red line) who had both conditions. Note that average blood cholesterol concentrations in these 4 groups were essentially identical. Reproduced from figure 1 in reference 54.
Figure 7 shows that long-term percent survival was best in those in the original MRFIT population who had neither T2DM nor cardiovascular disease (CVD); the worst was in those with both conditions. T2DM alone worsened long term prognosis but CVD by itself produced a slightly more unfavourable outcome than T2DM alone.
Note, however, that many persons with CVD likely had undiagnosed T2DM as the diagnostic criteria for T2DM were not rigorous. Many with T2DM would have been missed as the diagnosis of T2DM was made solely on a history of using diabetic medications or having an elevated fasting blood glucose concentration. Such testing will miss a large number of persons with marked hyperinsulinemia and who are at very high risk of developing T2DM relatively soon (56).
But what is really important is that blood LDL cholesterol concentrations were not meaningfully different between groups ranging from 145-162mg/dL (3.7-4.2mmol/L); blood triglyceride concentrations on the other hand were elevated in all three groups with poorer outcomes and, most especially in those with T2DM. Blood triglyceride concentrations were ~100mg/dL (~1.13mmol/L) higher in those with T2DM than in the healthy group, in line with Albrink and Man’s original observations in the 1950s (57).
Table 1 compares the relative risk (Odds ratios) for total mortality, CVD mortality and CHD mortality in the same four groups of MRFIT participants. These are prepared from data in Table 2 in reference 54, p.851.
|Condition||Total Mortality||CVD Mortality||CHD Mortality|
|With CHD vs with T2DM||1.31||1.77||1.96|
|With T2DM vs with neither T2DM nor CHD||1.62||1.77||1.85|
|With CHD vs neither T2DM nor CHD||2.12||3.13||3.63|
|With both T2DM and CHD vs neither T2DM nor CHD||3.34||4.50||5.81|
Table 1 shows that the hazard ratio for all three outcomes is worse in those with CHD than with T2DM (first row; third row vs second row); but is far worse in those with the combination of T2DM and CHD. Hazard ratios approaching 2.0 generally indicate the potential for a causal relationship.
Importantly, these relationships occur even though blood cholesterol concentrations were not greatly different between any of these groups.
It is surprising that this conclusion seems not to have received the attention it deserves from Keys and his acolytes. The evidence in Figures 3, 6 and 7 seems very clear – T2DM is a far more significant risk factor for CHD than is an elevated blood cholesterol concentration. And perhaps the majority of the other “risk” factors.
Dr Tavia Gordon, a key player in the Framingham Heart Study, also queried why Dr Stamler was so reluctant to report that total mortality was highest in subjects with the lowest blood cholesterol concentrations in MRFIT (see figure 3 in 44). Thus: “The excess non-CHD mortality in the lowest quintile (of blood cholesterol concentrations) is, in fact, sufficient to make total mortality in quintile one greater than that in quintile 2. Indeed, in the age groups of 45 years or more, non-CHD mortality in the lowest quintile is higher than in any other quintile” (58, p.1600). Gordon continued: “..it is a bit surprising that the MRFIT investigators use their data to argue the case for lowering serum cholesterol levels when their own trial could demonstrate no benefit from reducing risk factors” (p.1600).
Ah, but you don’t understand Dr Gordon. When Keys and his acolytes hijacked this NHLBI/AHA research program in the 1950s, their ultimate goal was not to discover an ultimate truth.
Perhaps this is why they could not acknowledge the fact that a low blood cholesterol concentration – the ultimate goal of their scientific quest – may carry significant health risks.
1984. The inconvenient findings of the LRC CPPT are finally published.
A central problem with the LRC CPPT trial was that the intervention drug, cholestyramine – comprising millions of tiny chemically-activated resin beads in a bulk filler – had to be ingested six times a day. The active drug produced such serious side-effects that in the first year of the study 68% of those in the intervention group reported side effects. The placebo was little better; it contained scoops of finely ground sand mixed with sugar and food colouring.
Worse, cholestyramine reduced the average blood cholesterol concentrations by only 7%.
Finally, after 7.4 years and at a cost of $142 million, the results finally came in. They were not encouraging.
Critically, deaths from all causes were the same in both groups: Of the 1,906 men in the treatment group, 68 had died at the end of the 7.4 year trial compared to 71 in the 1,900 men in the control group. This is the key finding. It matters not if a drug changes the incidence of, say, fatal heart attacks if it simply increases the risk of dying from cancer. In this study there were more deaths from violent and accidental deaths in the cholestyramine group (59, p.351).
Fatal heart attacks were also very similar in both groups – 30 in the intervention vs 38 in the placebo group. But non-fatal heart attacks were rather less common in the intervention group – 130 vs 158. Thus 7.4 years of treatment reduced the risk of having a heart attack from 8.6% to 7% – an 0.2% annual difference in risk. This compared to the 50% reduction that Keys’ cronies had expected (if their hypothesis was correct).
Importantly, this difference failed to satisfy the original 99% chance of the finding being other than due purely to chance. This demanded urgent remedial action. “Instead of admitting the failure, the heart institute researchers went shopping for a statistical test their results might pass”. (43, p.54) In the end they found just such a test. Yet even with that test, their results still barely reached statistical significance. As Steinberg would later write: “It was a narrow squeak. The CPPT came frighteningly close to joining the early dietary trials as ‘case not proved’. In fact, some criticised the investigators for the use of a one-tailed t test” (60, p.5).
But this action represents scientific fraud on a grand scale. Particularly as the authors added the subtitle – 1. Reduction in Incidence of Coronary Heart Disease – to their published manuscript (59). But there had not been any such reduction according to the statistical test that all the participants agreed would be used when they originally planned the trial. So once again when the data failed to match their expectations, the authors simply moved the statistical goalposts (61).
In the scientific papers describing their findings, the authors made the following claims:
“The findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk of CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD” (59, p.351).
For three reasons this is a remarkable statement. First, CHD mortality was NOT reduced by the drug. Second, the authors disclose their bias by stating that the men in the trial were at high risk of developing CHD “because of raised LDL-C levels”. But the reason for undertaking the trial was to determine whether elevated blood cholesterol concentrations cause CHD. So in the absence of definitive evidence the authors simply claim that their data proved their original bias.
And third, on the basis of their hypothesis, the authors predicted a 50% reduction in CHD events during the seven years of the trial. Yet the best they could come up with was an 0.2% difference in annual rates of heart attack. How could that possibly provide “strong evidence for a causal role for these lipids in the pathogenesis of CHD”? The reality is that this difference was very likely due to chance.
The truth is that the paper should never have passed peer review. The fact that it did indicates that the peer review process was broken. Presumably, the paper was reviewed by friends of the directors of one or more of the 12 collaborating laboratories. Those peer reviewers would know that if they wished to remain close to the team looting the NHI coffers performing all this false science, they needed to remain tight with Keys and his cronies.
A second paper subjected the original data to subgroup analysis. This is another deceitful technique often used when the outcome that the researchers desired, is not realised. Subgroup analysis apparently showed that those subjects whose blood cholesterol concentrations fell the most, had 50% lower CHD rates than those whose cholesterol concentrations remained unchanged during the trial (63, p. 365). As a result, “the reduction of CHD incidence in the cholestyramine group seems to be (my emphasis) mediated chiefly by reduction of TOTAL-C and LDL-C levels” (62, p.365).
A more likely interpretation is that those prepared faithfully to ingest a vile concoction six times a day to lower their blood cholesterol concentrations are probably very different from those who simply give up and choose not to take their medications. Any outcome differences could be due to other behaviour differences in those who are differently motivated in other health behaviours.
The authors’ presentation of their results was vigorously critiqued by Kronmal (61): “But, unfortunately, the presentation of the results of the trial did not adequately reflect the weakness of the evidence for a positive effect of cholestyramine in reducing CHD end-point rates. Furthermore, these results (from a highly selected group of males with markedly elevated blood cholesterol concentrations – my addition) were used to make unwarranted extensions to a large portion of the US population. Given the difficulty of getting clear-cut answers to such complex issues as those addressed by the CPPT and the controversy surrounding the lipid hypothesis, one can certainly understand the temptation to present the results in the most favourable possible light. However, it is my opinion that the scientific presentations that are the product of a clinical trial such as the CPPT should be free of such advocacy. A more appropriate forum for such views should be a commentary such as this one” (61, p. 2093).
Which, unfortunately, was not ever going to happen if Keys was involved in any way.
An editorial that accompanied the article began forthrightly: “The trial showed that…one would have to treat 200 people for seven years with cholestyramine to reduce coronary heart disease deaths in three people. There was no significant difference in the total deaths between the two groups because the suicide rate was higher than in the placebo group. For both of these reasons, it is difficult to accept on purely scientific grounds (my added emphasis) that there is conclusive proof of efficacy of reduction of mild to moderate hypercholesterolemia” (63, p. 2094).
Yet, the same editorial concluded with the usual dietary advice – daily fat intake “no more than 30% (or even 20%) of the total caloric intake. The saturated fat intake must be less than 10% (or even 6% to 8%) of total calories and the polyunsaturated fat intake 10% of total calories. Limit the daily intake of cholesterol to 250 to 300mg (in some instances only to 150 to 200 mg per day). Eat a healthy heart diet, and demand it from the food industry” (63, p. 2095).
An identical message was conveyed to the general public. The cover of the March 1984 issue of Time magazine (Figure 8) carried the title – Cholesterol. And Now the Bad News – and featured a dinner plate with two eggs and a rasher of bacon in the form of a rather unhappy facial expression.
Legend to Figure 8. The cover of the March 1984 Time magazine that reported the findings of the LRC CPPT trial. Importantly, the LRC CPPT study was a drug, not a dietary intervention so the cover photo is entirely inappropriate. Furthermore the LRC CPPT study failed to show that lowering blood cholesterol concentrations made any meaningful impact on health outcomes.
The cover design is clearly false since the LRC CPPT was not a diet trial and had nothing to do with eating eggs and bacon.
In the Time article, Basil Rifkin, the lead researcher of the LRC CPPT, was quoted as saying: “It is now indisputable that lowering cholesterol with diet and drugs can actually cut the risk of developing heart disease and having a heart attack” so that “the more you lower cholesterol and fat in the diet, the more you reduce your risk of heart disease” (28, p.57). Another trial participant, Dr Anthony Gotto who by then had risen to president of the AHA, predicted that “if everyone went along with the cholesterol-lowering program, ‘we will have [atherosclerosis] conquered by the year 2000” (28, p.58).
In an editorial published subsequently in the American Journal of Cardiology, Rifkind concluded that: “The LRC-CPPT findings show that reducing the total cholesterol level by lowering the LDL cholesterol level can diminish the incidence of CHD morbidity and mortality (both false, my addition) in men at high risk for CHD because of increased LDL cholesterol levels (presumed but unproven causal association – my addition). These results have considerable importance for the prevention of CHD through cholesterol lowering at both the clinical and public health levels” (64, p. 30C).
A statement with which I fully agree. If a drug must be taken six times a day for 7 long years by 200 persons considered at the very highest risk for developing heart attack for just 3 to benefit, then I would say we don’t really have any clue about the relationship between blood cholesterol and CHD. And perhaps we should start to act on that realisation.
What is absolutely clear from this study is that elevated blood cholesterol concentrations do not cause CHD.
In another response, Pete Ahrens said that this extrapolation from a drug study to a diet was “unwarranted, unscientific and wishful thinking” (28, p.57).
Gary Taubes subsequently challenged Rifkin to explain his false statements. His defence was that hundreds of millions of dollars had been spent trying to prove Keys’ Diet-Heart Hypothesis before it had become apparent that it was too costly, and therefore impossible, to prove that cholesterol-lowering by diet could prevent CHD. MRFIT had failed dismally. But now the LRC CPPT had “established a fundamental link in the causal chain from lower cholesterol to cardiovascular health. With that, they could take the leap of faith from cholesterol-lowering drugs to cholesterol-lowering diets. ‘It’s an imperfect world,’ Rifkin said. ‘The data that would be definitive is ungettable, so you do your best with what is available’” (28, p.58).
In other words, if the data don’t exist to support your hypothesis, you simply spin the results as if they did.
And that, according to Rifkin and the LRC CPPT gang, is how “good” science should work.
- Kuo PT. Hyperglyceridemia in coronary artery disease and its management. JAMA 1967;201:101-108.
- Noakes TD. Ancel Keys’ Cholesterol Con: Part 6. The Noakes Foundation. https://thenoakesfoundation.org/news/ancel-keys-cholesterol-con-part-6-1960-1967
- Kearns CE, Schmidt LA, Glantz SA. Sugar industry and coronary heart disease research. A historical analysis of internal industry documents. JAMA Intern Med 2016;176:1680-1685.
- Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: Results from two population studies in Finland. Diab Care 1979;2:131-141.
- Pyorala K, Savolainen E, Kaukola S, et al. Plasma insulin as coronary heart disease risk factor: Relationship to other risk factors and predictive value during 91/2-year follow-up of the Helsinki Policeman Study population. Acta Med Scand 1985;218:38-52.
- Pyorala M, Miettinen H, Laakso M, et al. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men. The 22-year follow-up results in the Helsinki Policeman Study. Circulation 1998;98:398-404.
- Ducimetiere P, Eschwege E, Papoz JL, et al. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980;19:205-210.
- Eschwege E, Richard JL, Thibult N, et al. Coronary heart disease mortality in relation with diabetes, blood glucose and plasma insulin levels. The Paris Prospective Study, ten years later. Hormone Metab Res Suppl 1985;15:41-46.
- Fontbonne AM, Eschwege E. Insulin and cardiovascular disease. Paris Population Study. Diab Care 1991;14:461-469.
- Welborne TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diab Care 1979;2:154-160.
- Bao W, Srinivasan SR, Berenson GS. Persistent elevation of plasma insulin levels is associated with increased cardiovascular risk in children and young adults. The Bogalusa Heart Study. Circulation 1996;93:54-59.
- Garcia RG, Rincon MY, Arenas WD, et al. Hyperinsulinemia is a predictor of new cardiovascular events in Colombian patients with a first myocardial infarction. Int J Cardiol 2011;148:85-90.
- Adeva-Andany MM, Martinez-Rodriquez J, Gonzalez-Lucan M, et al. Insulin resistance is a cardiovascular risk factor in humans. Diab Metab Syndr 2019;13:1449-1455.
- World Health Organization European Collaborative Group. Multifactorial trial in the prevention of coronary heart disease: 1. Recruitment and initial findings. Europ Heart J 1980;1:73-80.
- Kornitzer M, De Backer G, Dramaix M, et al. The Belgian Heart Disease Prevention Project. Modification of the Coronary Risk Profile in an industrial population. Circulation 1980;61:18-25.
- Rose G, Tunstall-Pedoe HD, Heller RF. UK Heart Disease Prevention Project: Incidence and Mortality Results. Lancet 1983;1:1062-1065.
- Kornitzer M, De Backer G, Dramaix M, et al. The Belgian Heart Disease Prevention Project: Incidence and mortality results. Lancet 1983;1:1066-1070.
- World Health Organization European Collaborative Group. Multifactorial trial in the prevention of coronary heart disease: 3. Incidence and mortality results. Europ Heart J 1983;4:141-147.
- Kornitzer M. Why those differences between the U.K. and the Belgian Heart Disease Prevention Project results? Prev Med 1984;13:136-139.
- Kornitzer M, Rose G. WHO European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease. Prev Med 1985;14:272-278.
- World Health Organization European Collaborative Group. European Collaborative Trial of Multifactorial prevention of Coronary Heart Disease: Final report on the 6-year results. Lancet 1986;1:869-872.
- De Backer G, Kornitzer M, Dramaix M, et al. The Belgian Heart Disease Prevention Project: 10-year mortality follow-up. Europ Hear J 1988;9:238-242.
- Noakes TD. Ancel Keys’ Cholesterol Con: Part 7. The Noakes Foundation. https://thenoakesfoundation.org/news/blog/ancel-keys-cholesterol-con-part-7-1968-1970
- Wilhelmsen L, Berglund G, Elmfeldt D, et al. The multifactorial primary prevention trial in Goteborg, Sweden. Europ Heart J 1986;7:279-288.
- McCormick J, Skrabanek P. Coronary heart disease is not preventable by population interventions. Lancet 1988;2:839-841.
- Thom TJ, Epstein F, Feldman JJ, et al. Trends in total mortality and mortality from heart disease in 26 countries from 1950-1978. Int J Epidemiol 1985;14:510-520.
- Select Committee on Nutrition and Human Needs United States Senate. Dietary goals for the United States. US Government Printing Office, Washington, DC, 1977 1-79.
- Taubes G. Good calories bad calories. Fats, carbs, and the controversial science of diet and health. Anchor Books, New York, NY. 2008.
- National Research Council Food and Nutrition Board. Towards Healthful Diets. National Academy of Sciences, Washington DC, 1980.
- Ahrens EH. Dietary fats and coronary heart disease: Unfinished business. Lancet 1979;2:1345-1348.
- Ahrens EH. The management of hyperlipidemia: Whether, rather than how. Ann Intern Med 1976;85:87-93.
- Keys A, Anderson JT, Grande F. Serum cholesterol response to changes of diet. The effect of cholesterol in the diet. Metabolism 1965;14:759-765.
- Ahrens EH, Connor WE, Bierman EL, et al. The evidence relating six dietary factors to the Nation’s health. Am J Clin Nutr 1979;32:2621-2646.
- American Heart Association. National Diet-Heart Study Research Group: Final report. Circulation 1968;Suppl 1(1):1-425.
- Henderson G. Court of Last Appeal: The early history of the high-fat diet for diabetes. J Diab Metab 2016;7:8; Newburgh LH, Marsh PL. The use of a high fat diet in the treatment of diabetes mellitus. Arch Intern Med 1920;26:647-662.
- Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med 1977;296:1365-1371.
- Noakes TD. Ancel Keys’ Cholesterol Con: Part 12. The Noakes Foundation.
- Steinberg D. An interpretive history of the cholesterol controversy, part V: The discovery of the statins and the end of the controversy. J Lipid Res 2006;47:1339-1351.
- Woolf SH, Schoomaker H. Life expectancy and mortality rates in the United States, 1959-2017. JAMA 2019;332:1996-2016.
- Papanicoas I, Woskie LR, Jha AK. Health care spending in the United States and other higher-income countries. JAMA 2018;319:1024-1039
- Stokes A, Ni Y, Preston SH. Prevalence and trends in lifetime obesity in the U.S., 1988-2014. Am J Prev Med 2017;53:567-575.
- Menke A, Casagrande S, Geiss L, et al. Prevalence of and Trends in Diabetes Among Adults in the United States,1988 – 2012. JAMA 2015;314:1021–1029.
- Moore TJ. Heart Failure: A Critical Inquiry into American Medicine and the Revolution in Heart Care. New York, NY: Simon and Schuster, 1989.
- Noakes TD. It’s the insulin resistance, stupid. Part 9. CrossFit Essentials (Please complete this reference)
- Jacobs DR, Anderson JT, Blackburn H. Diet and serum cholesterol. Do zero correlations negate the relationship. Am J Epidemiol 1079;110:77-87.
- Noakes TD. Ancel Keys’ Cholesterol Con: Part 5. The Noakes Foundation. https://thenoakesfoundation.org/news/ancel-keys-cholesterol-con-part-5
- Noakes TD. It’s the insulin resistance, stupid. Part 8. CrossFit Essentials. https://www.crossfit.com/essentials/its-the-insulin-resistance-stupid-part-8
- Duncan MS, Freiberg MS, Greevy RA, et al. Association of smoking cessation with subsequent risk of cardiovascular disease. JAMA 2019;322:642–650.
- Staessen JA, Thijs L, Wang J-G. Blood pressure reduction and cardiovascular prevention: An update including the 2003–2004 Secondary Prevention Trials. Hypertens Res 2005;28:385-407.
- Noakes TD. Ancel Keys’ Cholesterol Con: Part 13. The Noakes Foundation.
- Iso H, Jacobs DR, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intevention Trial. N Engl J Med 1989;320:904-910.
- Shaten BJ, Kuller LH, Kjelsberg MO, et al. Lung cancer mortality after 16 years in MRFIT participants in intervention and usual care groups. Ann Epidemiol 1997;7:125-136.
- Stamler J, Wentworth D, Vaccaro O, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diab Care 1993;16:434-444.
- Eberly LE, Yang L, Cohen JD, et al. Impact of incident diabetes and incident nonfatal cardiovascular disease on 18-year morality. Diab Care 2003;26:848-854.
- Vaccaro O, Eberly LE, Neaton JD, et al. Impact of diabetes and previous myocardial infarction on long-term survival. Arch Intern Med 2004;164:1438-1443.
- Crofts C, Schofield G, Zinn C, Wheldon M, Kraft J. Identifying hyperinsulinaemia in the absence of impaired glucose tolerance: An examination of the Kraft database. Diab Res Clin Pract 2016;118:50-57; DiNicolantonio JJ, Bhutani J, O’Keefe JH, Crofts C. Postprandial insulin assay as the earliest biomarker for diagnosing pre-diabetes, type 2 diabetes and increased cardiovascular risk. Open Heart 2017 2017 Nov 27;4(2):e000656.
- Noakes TD. It’s the insulin resistance, stupid. Part 1. CrossFit Essentials. https://www.crossfit.com/essentials/its-the-insulin-resistance-stupid-part-1
- Gordon T. Serum cholesterol and death from coronary heart disease. JAMA 1987;257:1600.
- Lipid Clinics Research Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364.
- Steinberg D. An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it – almost. J Lipid Res 2006;47:1-14.
- Kronmal RA. Commentary on the published results of the Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1985;253:2091-2093.
- Lipid Clinics Research Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-374.
- Rahimtooola SH. Cholesterol and coronary heart disease: a perspective. JAMA 1985;253:2094-2095.
- Rifkind BM. Lipid Research Clinics Coronary Primary Prevention Trial: Results and implications. Am J Cardiol 1984;54:30C-34C.
- The trans fat debacle and its impact on human health – Prof Noakes on Keys’ Cholesterol Con
- Pfizer bleeds unsuspecting public, laughs all the way to the bank with over $100bn revenue in 2022
- Anthony “I am the Science” Fauci conveniently develops amnesia in his seven hour deposition
Cyril Ramaphosa: The Audio Biography
Listen to the story of Cyril Ramaphosa's rise to presidential power, narrated by our very own Alec Hogg.