In lieu of “American Heart Month” and the American Heart Association’s (AHA) campaign to “Go Red” – in support of women preventing heart disease and living longer, healthier lives – I thought it would be apropos to (finally) post part two of The Great Cholesterol Consensus. For those who have not read part one, it can be found here.
Indeed, when referring to heart disease and potential modifiable risk factors – like blood cholesterol levels – a question presents itself, and it is this: what is it that we are really talking about? In the very real sense you and I (and anyone for that matter) are talking about preventing disease in order to prolong life. Therefore, if an entity, like the AHA, is to make recommendations concerning blood levels of cholesterol (which they most assuredly do), then those recommendations should be based on a clear body of evidence that shows that reducing one’s cholesterol a) reduces their risk of dying from heart disease, while b) increasing their chances of living a longer and healthier life (red clothing optional). Thus, the importance of not only heart disease mortality (i.e. death) comes into play, but that of overall mortality as well. Put simply, it makes no sense to reduce one’s risk of dying from heart disease just to arbitrarily increase their risk of dying from some other life-threatening disease instead!
Today’s follow-up will delve into such questions by taking a look at some of the commonly cited observational research that is used to support the lipid hypothesis and the notion that everyone should mindlessly work to lower their blood cholesterol levels in order to live a longer and healthier existence. This is usually done through either nutritional means, such as replacing saturated fats with unsaturated fats, and/or the administration of prescription drugs (i.e. cholesterol-lowering medication like statins). What you will soon find out, however, is that the current nutrition and health orthodoxy might actually be increasing your risk of dying at a younger age by promoting such recommendations that ignore contradictory evidence. So without further ado, let’s begin!
Falling cholesterol levels in Framingham
We’ll start with one of the longest running, and perhaps one of the most popular, diet-heart studies in the United States – the Framingham Heart Study (FHS). Conceived in 1948 FHS started out as a public health effort which sought to identify common factors/characteristics that contribute to cardiovascular disease (CVD). It was postulated that as the years pass by, participants in the study will inevitably succumb to disease and theories with regards to various factors and heart disease would be able to be tested. From this framework, FHS has had almost 2,500 publications in a multitude of prestigious scientific journals. So, just how beneficial has cholesterol-lowering been shown to be in one the most famous diet-heart studies ever conducted?
In a 1990 joint statement by the AHA and the National Heart, Lung, and Blood Institute (NHLBI), it was reported that:
“The […] results from the Framingham Study indicate that a 1% reduction in an individual’s total serum cholesterol level translates into an approximate 2% reduction in CHD risk” . This, however, couldn’t be farther from the truth.
The study you were told about – the results you weren’t
From 1951 to 1955, almost 2,000 men and 2,500 women between 31 to 65 years old and free of CVD had their blood levels of cholesterol measured. In a 30-year follow-up paper reporting on the rate of all new cases of both overall and CVD deaths researchers found that, in those under 50 years old, higher cholesterol was indeed associated with increased overall and CVD mortality . However, only a fraction (<10%) of all CVD deaths occur in those under 50 years old . Therefore any association between cholesterol and heart disease death is relevant to only a trivial proportion of cases. In those older than 50, when the vast majority (>90%) of people die of CVD, there was absolutely no association between cholesterol levels and CVD mortality.
Framingham isn’t the only study to show discordant findings between cholesterol levels and mortality in older individuals. There is a multitude of research showing either an inverse [4-7] or a ‘U-shaped’ association (i.e. highest risk at both low and high levels of cholesterol) [8-13] between cholesterol levels and risk of CVD incidence and/or death for those older than 60. Moreover, there is evidence that shows that increased cholesterol levels are associated with increased longevity in the elderly [6, 14-17]. Simply put, for older individuals, moderate to high cholesterol levels may not be such a bad thing and may even be predictive of an increased life-span! Nevertheless, this still doesn’t answer the question of whether or not lowering blood cholesterol by 1% leads to a 2% reduction in heart disease risk as suggested by the 1990 AHA/NHLBI joint statement.
For those in the Framingham cohort over 50 years old and whose cholesterol decreased over the first 14 years of the study actually saw an increase in both all-cause and CVD mortality. I’ll repeat that: those who saw their cholesterol levels drop saw a simultaneous increase in total and CVD death. Indeed, for every 1mg/dL/year drop in cholesterol during the first 14 years of the study there was a 14% and 11% increase in both CVD and all-cause mortality, respectively – not quite the 2% reduction in heart disease risk we are led to believe.
The Japanese non-argument
With almost religious fervor, supporters of the diet-heart theory bring up the Japanese as if they were proof that cholesterol and saturated fat cause heart disease. This, as it is commonly argued, is because the Japanese tend to eat much less total and saturated fat than Americans do, thus allowing them to keep their blood cholesterol levels low as well as their rates or death from heart disease. So, do lower intakes of saturated fat and lower levels of blood cholesterol offer some protective effect against heart disease and death in the Japanese?
The Ni-Hon-San Study
In 1975 Dr. Michael Marmot and colleagues showed that the Japanese, after immigrating to the United States (specifically Hawaii and California), increased their risk of coronary death similar to that of Americans. Even more interesting, however, was that there appeared to be a gradient in the occurrence of coronary heart disease (CHD) between the geographical locations – Japan (Nippon) having the lowest rates, Hawaii (Honolulu) intermediate, and California (San Francisco) with the highest. Given that the Japanese tend to eat less total and saturated fat and have lower cholesterol levels than Americans do, increased total and saturated fat consumption was offered as a potential explanation as to why Japanese emigrants increased their risk of dying from heart disease. However, at similar serum cholesterol levels, compared to the native-born Japanese, there was still a greater risk of CHD mortality among Japanese emigrants living in Hawaii and California  – i.e. blood levels of cholesterol could not fully explain the trends in CHD mortality.
To help better explain their earlier findings, Marmot and Syme conducted another study in 1976 and showed that the greatest factor predicting heart disease risk in the Japanese was actually cultural upbringing and not blood cholesterol levels. Indeed, Japanese emigrants who retained more of a traditional upbringing (defined as, among other characteristics; years spent in Japan/Japanese speaking school; religion while growing up; and wife’s cultural background) actually experienced prevalence of CHD similar to those in Japan. Moreover, and quite unexpectedly, those who maintained their Japanese culture the most AND ate a more Westernized (i.e. high-fat) diet actually had lower rates of CHD than those who maintained their culture while eating a traditional lower-fat, Japanese diet . In the end, some of the original studies looking at the Japanese and heart disease did little to help further the lipid hypothesis.
More contradictory evidence provided by the Japanese
In the Honolulu Heart Program (HHP) study, which followed Japanese emigrants living in Hawaii over a 20-year period, researchers found that those, aged 71-93, who maintained low serum cholesterol levels actually increased their risk of death . Moreover, the lowest mortality risks were seen in those who maintained intermediate levels of cholesterol and/or increased (from low to high) their cholesterol levels. Furthermore, in a separate 16-year follow-up of the HHP cohort , the authors observed a significant risk of cancer and all-cause mortality in those, aged 45-68 years whose cholesterol fell from intermediate (180-239mg/dL) to low (<180mg/dL) levels. These findings, again, are all in stark contrast to the perpetuated mantra that, “lower total cholesterol is better.”
Evidence from Japan itself offers similar contradictory evidence to the prevailing medical orthodoxy that lowering you cholesterol will lead to a longer and healthier life. Between 1975 and 1984, researchers began looking at the relationship between cholesterol and mortality in over 12,200 men and women between the ages of 40-69 years old from Osaka, Japan . After almost 9-years follow-up they found that a 34mg/dL drop in cholesterol led to a 21% increased risk of all-cause mortality. Moreover, low cholesterol levels were also accompanied by a 26% increased risk of cancer death! Again, lower has not proved to be better, in any sense of the word.
In the Japanese Lipid Intervention Trial, which studied over 47,000 patients treated with simvastatin (commonly known as Zocor™), researchers saw that those with cholesterol levels between 200-219mg/dL had lower rates of coronary events than those above or below this range . Furthermore, those with total cholesterol between 200-259 mg/dL and LDL cholesterol between 120-159mg/dL (20-59mg/dL above the NCEP recommended levels) had the lowest all-cause mortality rates. The highest death rate was actually seen in those whose total cholesterol was below 160mg/dL – a number I’m sure most doctors would salivate at the sight of.
Lastly, in the Jichi Medical School Cohort Study , conducted in Japan from 1992 to 1995, cholesterol levels were measured in almost 12,300 men and women between 40 to 69 years. Subjects were then followed for a period of 11.9 years and mortality data was assessed. In men, total mortality risk showed a ‘U-shaped’ association. A ‘U-shaped’ association is one where higher mortality can be seen in individuals with both high and low levels of cholesterol compared to those in the middle. Indeed, the highest mortality risk was seen in those in the lowest category of cholesterol levels (<160mg/dL) followed by those with the highest levels (>240mg/dL). Women, however, showed an inverse relationship between cholesterol levels and mortality. With regards to cancer deaths in men, cancer mortality showed an inverse association with cholesterol levels, while women showed the distinct ‘U-shaped’ association. In the end, however, the theme remains the same: lower cholesterol does not necessarily mean a longer, healthier life.
The Multiple Risk Factor Intervention Trial (MR. FIT)
Another commonly touted study in support of the diet-heart theory is the famous Multiple Risk Factor Intervention Trial (MRFIT) – well, sort of. Rather than citing the actual MRFIT Trial (which was a total bust), diet-heart theorists boast the findings of the 350,000 primary screenees who did not make the cut for the actual randomized controlled trial . These men were excluded based on a number of clinical features that run the gamut; history of heart attack, diabetes requiring medication, high systolic and diastolic blood pressure, serum cholesterol over 350mg/dL, history of chest pain, 150% over desired body weight, and various drug treatments for lipids and blood glucose, just to name a few. Simply put, these men were already very unhealthy and predisposed to disease. However, instead of just ignoring these subjects, they were followed for a period of six years and the results on cholesterol and CHD mortality were published in the prestigious Journal of the American Medical Association. In this observational study, Stamler et al. saw a “continuous, graded (dose-related), and strong” relationship between cholesterol levels and CHD mortality in men aged 35 to 57. Unfortunately, what this study failed to do was also report on overall mortality.
A few years after the 1986 publication, another group of researchers took the MRFIT data and divided the study participants into 10 categories according to serum total cholesterol level and looked at both CHD mortality as well as overall mortality . While CHD mortality risk did show a steady gradual increase with each successive category, overall mortality showed (if graphed) the distinct ‘U-shaped’ relationship. Indeed, those in the lowest category of total cholesterol (<140mg/dL) had higher death rates (308.6 deaths per 10,000) than all but those in the highest category (>300mg/dL with 352.8 deaths per 10,000).
Another note of importance is that if we are going to talk about the MRFIT screenees who did not undergo the clinical trial it would make sense to also talk about the almost 13,000 subjects who were included in the official study and who were randomized to either 1) anti-hypertensive medication plus encouragement of smoking cessation and dietary counseling aimed at reducing fat and cholesterol, or 2) no intervention at all (i.e. usual care) . After about 7-years follow-up, despite slightly greater reductions in blood pressure and cholesterol levels in the treatment group, there was little difference in CVD or all-cause mortality between the two groups. The only noteworthy reduction in mortality was seen in those who stopped smoking, regardless of treatment.
The MONICA Project – The WHO Project?
At the time of the MRFIT Trial the 350,000+ screenees constituted of one of the largest cohorts with standardized cholesterol measurements and long-term mortality follow-up data. To this day I’m sure some people still think it is. However, to their dismay, the largest study ever conducted on the relationship between diet and cardiovascular mortality is not the MRFIT Trial but rather the MONItoring trends in CArdiovascular diseases (MONICA) Project conducted by the World Health Organization (WHO) in the 1980’s . Involving 32 centers in 21 different countries, MONICA consisted of a total of ten million men and women between the ages of 35 to 64 and followed them for a period of 10 years. Quite simply, this is the mother of all diet-heart studies… that you haven’t heard of.
And why haven’t you heard of MONICA? To quote a 1999 British Medical Journal letter-to-the-editor, “MONICA did not deliver on task it set out to accomplish”  – e.g. assessing the impact (of which there was none) of traditional risk factors (like high blood cholesterol levels) on CVD mortality. Indeed, cholesterol explained very little (<25%) of the variance in cardiovascular and heart disease death rates. Moreover, despite mean high blood cholesterol levels and dietary animal/saturated fat intakes lower than those in Western Europe, CVD mortality was highest in the former communist countries of Central and Eastern Europe. The intake of antioxidant-rich fruits and vegetables was also lower in Central/Eastern Europe along with increased alcohol consumption and psycho-social stress undoubtedly caused by fragile economic and political climates. To quote the concluding remarks of another study that analyzed 40 of the European MONICA populations (15 communist, 25 democratic) and similarly found no association between high levels of blood cholesterol and CVD mortality ;
“In communist [i.e. Eastern/Central] Europe there was high consumption of spirits, low consumption of fruits and extremely low intake of citrus fruit. Instead of exaggerated anti-cholesterol propaganda emphasis should be given to the prevention of antioxidant deficiencies by the increase of fruit and vegetable consumption and to the decrease in salt, spirit and cigarette consumption.”
Well if that’s not the understatement of the century! In a subsequent 2004 observational study , 19 countries were divided into 4 distinct groups based on cultural patterns (Central/Eastern Europe; Western Europe/US; Mediterranean Countries; and Asia) and then diet and CHD mortality was assessed. It was shown that CHD mortality was highest in Central/Eastern Europe despite dietary cholesterol and saturated fat intakes on par with the other groups (except for Japan – no shocker there). Instead, the model that explained the majority (86% in men, 90% in women) of the variation in heart disease death was one which included a diet rich in fruits, vegetables, and their accompanying cardio-protective antioxidants.
Denying science, inventing paradoxes
But MONICA doesn’t stop there! Intra-country comparisons within the MONICA project are also in stark contrast to the diet-heart theory . In Italy, residents from the city of Friuli decreased their mean levels of serum cholesterol by about 0.5mmol/L while those in Brianza increased their cholesterol levels to a similar degree. Despite the divergent trends, both groups saw an almost identical decline in CHD mortality over the 10-year study period!
In Switzerland, residents of the Vaud/Fribourg region saw a slight decrease in their mean serum cholesterol levels while those from Ticino saw the greatest rise in mean serum cholesterol in the entire study. CHD mortality, however, ignored the lipid hypothesis and decreased to a similar degree in both populations.
In Sweden, mean blood cholesterol levels remained stable in Northern Sweden while dropping by about 0.5mmol/L in Gothenburg. CHD death rates, however, declined to a greater extent in Northern Sweden despite the lack of decreasing mean blood cholesterol levels.
Finally, in France, the residents of Strasbourg saw the fourth largest increase in mean serum cholesterol concentrations in the entire study while those of Lille saw the greatest reduction in mean serum cholesterol levels in the entire study. According to the prevailing nutritional dogma, Strasbourg should have increased their rate of CHD death while Lille reduced theirs. While Lille did reduce their rate of CHD death over the study period (by about 1-2%), Strasbourg actually reduced their CHD mortality to a greater degree (~5%).
In the end, the largest study ever conducted on the relationship between cholesterol levels and heart disease is nothing more than a giant flop. Instead of supporting the lipid hypothesis it is rife with contradictions to the prevailing nutrition and health dogma. In the words of Galileo Galilei; “By denying scientific principles, one may maintain any paradox.” Indeed, if I were a lipid-theorist, I may be inclined to assign the title of ‘paradox’ to the above scenarios (‘French Paradox’ anyone?). However, once the contradictory evidence is put into perspective, it becomes evident that any ‘paradoxes’ that may exist are nothing more than scientists trying to ignore conflicting evidence and hold on to their preconceived notions about diet and CVD.
Comments and conclusions on cholesterol
As you can see, upon closer examination, the very studies that are commonly cited as proof that people should lower their blood levels of cholesterol actually show that low and/or falling levels of cholesterol increase one’s risk of overall death and/or death from cancer! Moreover, even if cholesterol reduction were an effective strategy to curb the risk of heart disease it makes no sense to do so only to concomitantly increase the risk of dying from some other life-threatening disease instead! The available evidence suggests such an unfair trade-off, making cholesterol lowering a less-than-appealing undertaking.
One must also realize and keep in mind that the above studies are observational in design. They are NOT meant to establish cause and effect. Even in the studies that do show increased risk of heart disease with increased levels of cholesterol – and conversely, increased risk of cancer with low levels of cholesterol – it still does not mean that high (or low) levels of cholesterol cause disease. Causation can only be established via a randomized controlled trial (RCT) which eliminates the multitude of confounding factors that are rife within observational research. This will be our undertaking in the next installment of this series – i.e. addressing whether or not the RCT data supports or refutes that which is seen in and promoted by the observational research. However, before we do that, we must still examine where the epidemiological research stands with regards to total fat, fat type, and heart disease. Should people be adhering to a lower-fat diet? Does saturated fat lead to the clogging of arteries through the elevation of blood cholesterol levels? Let’s take a look.
Saturated fat and heart disease
Cutting right to the chase, a 2009 meta-analysis of 26 prospective studies examining the association between total fat, fat type, and heart disease showed that total fat intake was not significantly associated with CHD mortality or events . Moreover, saturated fat was also not significantly associated with CHD mortality or events. What may come to surprise many of you is that polyunsaturated fatty-acids (PUFAs) – the allegedly heart-healthy fats that are recommended to reduce the risk of heart disease – were shown to be “strongly [and] significantly” associated with increased CHD mortality. This, however, was only relevant with regards to omega-6 PUFAs – e.g. those PUFAs found in sources such as sunflower, safflower, corn, cottonseed, and soybean oils. Indeed, omega-6 PUFAs were shown to also be significantly associated with increased CHD mortality while omega-3 PUFAs (like those found in fish and flaxseed) were significantly associated with decreased CHD mortality. So far it’s not looking too good for the diet-heart proponents.
Slightly more recently, in similar a 2010 meta-analysis, researchers analyzed 21 prospective studies looking at the association between saturated fat intake and CHD, CVD, and stroke risk . In the end, no association was found between dietary saturated fat intake and disease risk. Therefore, the totality observational research overwhelmingly does not support the notion that saturated fat causes heart disease. However, to quote the concluding remarks of the authors of the aforementioned 2010 meta-analysis,
“[N]utritional epidemiologic studies provide only one category of evidence for evaluating the relation of saturated fat intake to risk for CHD, stroke, and CVD. An overall assessment requires [the] consideration of results [from] clinical trials as well” – which is exactly where we will pick up next time.
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