Blood pressure

The controversy surrounding the lipid hypothesis, in particular the relationship between elevated total and LDL cholesterol and coronary heart disease was considered largely resolved and regarded as scientific fact within the scientific community by 1984 when the expert panel from the National Institutes of Health (NIH) reviewed the relevant literature and agreed that the relationship was causal.1 2 The panel concluded:

Elevated blood cholesterol level is a major cause of coronary artery disease. It has been established beyond a reasonable doubt that lowering definitely elevated blood cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will reduce the risk of heart attacks due to coronary heart disease… Further, we are persuaded that the blood cholesterol level of most Americans is undesirably high, in large part because of our high dietary intake of calories, saturated fat, and cholesterol… There is no doubt that appropriate changes in our diet will reduce blood cholesterol levels.

Since 1984 evidence accumulated from over 100 randomized controlled trials of various medical and dietary based lipid modifying interventions has further established that lowering LDL cholesterol significantly decreases the risk of coronary heart disease and all-cause mortality, independent of changes to HDL cholesterol and triglycerides, and non-lipid effects of specific drugs.3 4

Controversy however has lingered over whether medical and dietary based interventions to lower total and LDL cholesterol, and perhaps triglycerides may increase the risk of certain stroke subtypes, in particular hemorrhagic stroke. Controversy has arisen in part due to the interpretation of certain statin trials, prospective cohort studies, and observational studies in certain populations with unique cardiovascular profiles, in particular the Japanese.5 6 7 This has led some to suggest that physiological levels of LDL cholesterol (less than 70 mg/dl; 1.8 mmol/l), the levels observed in newborn humans, free-ranging mammals, and human populations on low cholesterol diets that do not develop atherosclerosis [reviewed previously] may somehow increase the risk of hemorrhagic stroke.

There are two major categories of stroke, ischemic and hemorrhagic. Ischemic stroke occurs as a result of an obstruction with the blood supply to the brain, while hemorrhagic stroke occurs as a result of a rapture of a weakened blood vessel. In contrast to the observed decline of stroke incident in Japan where there was a significant improvement in a number of major risk factors but an increase in mean serum cholesterol, Finland experienced one of the highest rates of stroke mortality in the world as well as one of the largest declines, which was in part explained by a decrease in serum cholesterol.8 Unlike Japan, Finland also experienced the highest rate of coronary heart disease mortality in the world as well as the largest decline, which was predominantly explained by cholesterol lowering dietary changes [reviewed previously]. Furthermore, evidence suggests that Japanese Zen monks who consume significantly less meat and fish than the general Japanese population experience lower rates of stroke and all-cause mortality, independent of BMI, alcohol intake and other lifestyle factors.9

At the opposite end of the dietary spectrum higher rates of stroke mortality have been observed among the three main Inuit populations, including those in Greenland, Canada and Alaska compared to their non-Inuit Western counterparts, yet experience similar rates of non-stroke cardiovascular mortality.10 Evidence of atherosclerosis and other chronic and degenerative diseases have been observed in numerous preserved Inuit mummies that date back to pre-western contact, suggesting that their high rate of cardiovascular mortality cannot be entirely explained by influences of modern dietary and lifestyle factors [reviewed previously]. Furthermore, the declining rates of cardiovascular mortality, including stroke among the Inuit undergoing a rapid transition towards a western diet and lifestyle has raised questions regarding the health properties of the traditional Inuit diet based on marine animals.10

Coronary atherosclerosis in a pre-contact Inuit mummy dating back 1,600 years*

Recently the largest meta-analysis of statin based randomized controlled trials on the effect of lowering LDL cholesterol and risk of stroke was published, including 31 trials with >182,000 participants and >6,200 cases of stroke. Statins significantly decreased the risk of total and ischemic stroke and all-cause mortality, without evidence of publication bias, consistent with findings from animal studies.5 11 There was however a small statistically insignificant increase in incidence of hemorrhagic stroke in the statin group which was not related to either the degree of reduction of LDL or the achieved LDL. The researchers provided the following possible explanation for these findings:

In addition to their lipid-lowering properties, statins may have antithrombotic properties by inhibiting platelet aggregation and enhancing fibrinolysis. The antithrombotic affects of statins could account for a theoretically increased risk of bleeding complications.

All of the very large prospective cohort studies that included >300,000 participants have either found no association between total and LDL cholesterol and risk of hemorrhagic stroke, or an inverse association confined to participants with hypertension, or a positive association confined to participants with low blood pressure.6 12 13 14 15 A prospective study with >787,000 Korean participants and >9,900 cases of stroke found that while serum cholesterol was associated with a higher risk of ischemic stroke, the researchers found suggestive evidence that the inverse association between serum cholesterol and hemorrhagic stroke confined to hypertensive participants was not causal, but acted as a marker of binge drinking.14 The researchers explained:

In our study, increased risk of hemorrhagic stroke in people with low concentrations of blood cholesterol (less than 4.14 mmol/l) was restricted to those with high GGT values [a measure of alcohol intake]; this relation was less evident when alcohol consumption was measured by self report. The measures of blood pressure might not have been a true reflection of risk, as transient high blood pressure associated with binge drinking may have an important role in hemorrhagic stroke. At low concentrations of GGT, low serum cholesterol was not associated with a higher risk of hemorrhagic stroke. In effect, low blood cholesterol may act as a marker of the health damaging effects of alcohol, rather than be a cause of hemorrhagic stroke.

There maybe limitations with the studies which only address whether blood pressure considered by hypertension status modifies the association between serum cholesterol and risk of stroke. As with hypercholesterolemia, the definition of hypertension, blood pressure of >140/90 mmHg, far exceeds levels that have been clearly scientifically documented as being optimal. For example, a meta-analysis of 61 prospective studies including >958,000 participants and >11,900 cases of stroke deaths found that lower usual blood pressure was associated with a reduced risk of mortality from stroke and coronary heart disease, without any evidence of a threshold down to at least 115/75 mmHg.16 These findings are consistent with a meta-analysis of 147 randomized controlled trials that administered blood pressure lowering medication.17 This justifies investigating whether optimal blood pressure compared to high-normal blood pressure further modifies the association between serum lipids and the risk of stroke subtypes.

A meta-analysis of 61 prospective studies with >892,000 participants and >11,600 cases of stroke deaths found not only that serum cholesterol was inversely associated with total and hemorrhagic stroke mortality in participants with very high baseline systolic blood pressure (>145 mmHg), but that lower serum cholesterol was actually associated with a significantly lower risk of hemorrhagic, ischemic and total stroke mortality in participants with near optimal or ‘physiological’ baseline systolic blood pressure (less than 125 mmHg)(Fig. 1).6 As most participants in the age range most susceptible to stroke had either high-normal blood pressure or hypertension, the combined results were biased towards finding an inverse association between serum cholesterol and hemorrhagic stroke mortality.

Figure 1. Systolic blood pressure specific hazard ratios for 1 mmol/L lower usual total cholesterol and risk of stroke mortality

If this association is causal and not obscured by other factors such as binge drinking, this may explain why populations with low cholesterol and high blood pressure such as the Japanese have high rates of stroke, in particular hemorrhagic stroke, and populations that maintain physiological levels of both cholesterol and blood pressure throughout life have an observed absence of stroke.18

There is limited suggestive evidence that the atherosclerosis build-up process in the carotid and major cerebral arteries caused by excess LDL cholesterol in-turn reduces arterial blood supply to the brain that would otherwise cause the blood vessels in the brain to rupture in the presence of high blood pressure, thus explaining why elevated cholesterol may lower the risk of cerebral hemorrhage in people with high blood pressure.19 Indeed, a Japanese study found there was an inverse association between cholesterol and hemorrhagic stroke in an earlier cohort when the mean blood pressure was high and atherosclerosis was relatively low, but no association in the later cohort of the same population when mean blood pressure was reduced from hypertensive to high-normal blood pressure.20

Evidence from several but not all observational studies also found that low triglycerides were associated with a statistically significant or non-significant increased risk of hemorrhagic stroke.12 21 22 23 24 25 26 There is limited data regarding whether the association between low triglycerides and hemorrhagic stroke is modified by blood pressure or alcohol intake, but at least one large study found that the association was stronger among participants with high blood pressure.22

As there is convincing evidence that blood pressure increases the risk of stroke at any given cholesterol concentration, it would be advisable that everyone should aim to achieve an optimal blood pressure of less than 115/75 mmHg. Although a number of lifestyle changes including exercise and weight loss can lower blood pressure, a number of dietary changes can also effectively lower blood pressure.27 28 This includes reducing intake of salt and increasing intake of dietary fiber rich foods including whole grains, flavonoid rich foods including berries, soy, cocoa solids, and vitamin C and magnesium.29 30 31 32 33 34 35 36 37 38 These nutrients derived primarily from whole-plant foods may in-turn explain why intervention and observational studies have found that vegetarian diets, in particular vegan diets have favorable effects on blood pressure.39 40 41 42 43 44 45 46

The Better Way to Lower Cholesterol

As statins provide little appreciable protection against cancer, and like all drugs have adverse effects including but not limited to an increased risk of developing type II diabetes and memory loss or impairment, a significantly greater benefit would be achieved by lowering LDL cholesterol with a whole-foods plant based diet combined with regular exercise in order to not only lower the risk of cardiovascular disease but many other chronic and degenerative diseases.47 48 49 50 In Part II I review the evidence of dietary factors and the risk of stroke.

Diet heart retvist

In 2010, Jeremiah Stamler published the editorial Diet-heart: a problematic revisit in the American Journal of Clinical Nutrition addressing a number of very serious flaws in a meta-analysis paper supported by the National Dairy Council and authored by Siri-Tarino et al. that concluded that there was insufficient evidence from prospective cohort studies to suggest that the intake of saturated fat increases the risk of coronary heart disease and cardiovascular disease.1 A number of researchers including Stamler, who has played a prominent role in the diet-heart hypothesis for over 60 years found that a number of serious flaws in this meta-analysis would have likely biased the association between saturated fat and coronary heart disease towards null.1 2 3

In the editorial Stamler produced a meta-analysis based on the same papers included in the Siri-Tarino et al. meta-analysis and calculated that saturated fat was associated with a 32% increased risk of fatal coronary heart disease, an end point ignored, perhaps intentionally by the authors of the original meta-analysis.1 It would seem almost implausible for anyone citing the Siri-Tarino et al. meta-analysis with an interest in saving lives to fail to mention the findings for this fatal end point, the single most leading cause of death in the world.4 Perhaps the cholesterol skeptics do not share Stamler’s interest of saving lives, explaining why they have chosen to refrain from informing their audience of Stamler’s findings. 

Another shortcoming of the Siri-Tarino et al. meta-analysis paper was the lack of acknowledgement in the assessments and conclusions that major cross-population studies with a prospective (future looking) design, such as the Seven Countries Study found that saturated fat was associated with a significantly increased risk of fatal coronary heart disease (Fig. 1).1 5 Consistent with the trend of the findings from the Seven Countries Studies, the nomadic Kirghiz plainsmen who subsist on a diet of enormous amounts of organic grass-fed milk and meat experience severe vascular disease at a very young age [reviewed previously].

Figure 1. Saturated fat as % of calories and fatal coronary heart disease in 16 cohorts from the Seven Countries Study

In this series of posts I will review the diet-heart hypothesis and the arguments against the hypothesis raised by known cholesterol skeptics. Note that in this review the diet-heart hypothesis refers to the hypothesis that dietary change, such as the substitution of individual dietary fats for carbohydrate influences serum (blood) lipids (including serum total and LDL cholesterol), and therefore at the very least indirectly influences the risk of developing coronary heart disease.

Stephan Guyenet, the author of the Whole Health Source blog has produced some very informative posts dispelling Gary Taubes’s misleading claims regarding carbohydrate metabolism, insulin and obesity.6 Unfortunately, like Taubes rather than embracing the preponderance of evidence that has established the diet-heart hypothesis, Guyenet has chosen to confuse the subject in a series of blog posts. I have previously commented on Guyenet’s blog regarding one such concerning post in May 2011 where I raised my concerns regarding Guyenet’s arguments against the evidence that saturated fat raises serum cholesterol, and increases the risk of coronary heart disease.7  

One of my main concerns I presented in my comments on Guyenet’s blog was his lack of acknowledgement that saturated fat was associated with an increased risk of fatal coronary heart disease in the Health Professional’s Follow-up Study and in Stamler’s meta-analysis. Guyenet was less than appreciative of these comments, stating:

I find it disturbing that you continue to cite the Health Professionals follow-up study to support your position despite the fact that there was no statistically significant association between SFA intake and any measure of CHD after maximum adjustment. If there were really a relationship between the two factors, you wouldn't have to cite non-significant findings to support your position.

In the paper from the Health Professional’s Follow-up Study cited by Guyenet, for men in the top verses the lowest fifth of saturated fat intake the relative risk for fatal coronary heart disease was 1.72 (95% confidence interval 1.01 to 2.90) after maximum adjustment.8 In other words this study found that saturated fat intake was associated with a statistically significant 72% increased risk of fatal coronary heart disease for high compared to low intake. Guyenet avoided directly responding to my comments regarding the finding in Stamler’s meta-analysis for fatal coronary heart disease, and simply referred back to the Siri-Tarino et al. meta-analysis which failed to address this fatal end point.

In this particular post that I commented on, Guyenet made several misleading statements in reference to the findings from the Siri-Tarino et al. meta-analysis: 

Nearly every high-quality (prospective) observational study ever conducted found that saturated fat intake is not associated with heart attack risk. So if saturated fat increases blood cholesterol, and higher blood cholesterol is associated with an increased risk of having a heart attack, then why don't people who eat more saturated fat have more heart attacks?

Apart from the failure to acknowledge that Stamler demonstrated that the cohort studies included in this meta-analysis found that saturated fat intake was actually associated with an increased risk of fatal coronary heart disease, there are several other points in this statement that are problematic that will be addressed separately.

Guyenet’s suggestion that the Siri-Tarino et al. meta-analysis should have found a positive association between saturated fat and coronary heart disease if saturated fat raises serum cholesterol and serum cholesterol increases the risk of coronary heart disease is misleading. One of the most serious flaws in this meta-analysis was the inclusion of overadjustments for serum lipids and dietary lipids, which would have obscured this diet-cholesterol-heart relationship that Guyenet referred to. Stamler addressed this flaw in the editorial:1

…the issue of whether SFA relates to CHD in univariate analyses is relevant. If findings on this subject are positive but the association is markedly reduced or ceases in multivariate analyses, this may be due to confounding (eg, by dietary cholesterol) and/or overadjustment (eg, by inclusion in analyses of serum total or LDL cholesterol, a major CHD risk factor influenced by SFA intake)… Of 15 studies that unequivocally concern the SFA-CHD relation, 4 did not include other dietary lipids or serum lipids among covariates. Their CHD relative risks (RRs) ranged from 1.22 to 2.77—ie, >1.07, which was the estimated CHD RR in the meta-analysis. Do these larger RRs reflect freedom from confounding and overadjustment?

As Stamler demonstrated, the studies that that did not include overadjustments for dietary and serum lipids were more likely to find a positive association between saturated fat and coronary heart disease, reaffirming that the influence that saturated fat has on coronary heart disease is partly dependent on serum lipids.

Guyenet’s suggestion that the Siri-Tarino et al. meta-analysis found that the majority of high-quality prospective studies failed to find an association between saturated fat and heart disease is also misleading. Another serious flaw in the meta-analysis was the overreliance on poor quality dietary assessment methods, which was addressed by Katan et al.:2

A major weakness of the meta-analysis is the imprecision of dietary assessment methods used in the underlying studies. About half of the studies used 1-d dietary assessments or some other unvalidated method. Food intake varies from day to day, and there is a substantial literature showing that a single 24-h recall provides a poor estimation of the usual dietary intake of an individual. Such methods cannot reliably rank individuals by their long-term intake, especially within populations with a uniformly high saturated fat intake. Such imprecision in the assessment of disease determinants systematically reduces the strength of association of determinants with the disease. This is referred to as attenuation or regression dilution bias.

Stamler noted that the studies included in the Siri-Tarino et al. meta-analysis that used more precise dietary assessment methods were more likely to find a positive association between saturated fat and coronary heart disease:1

...the meta-analysis reported its findings as independent of a quality score including diet assessment. Of the 16 CHD studies, 4 relied on one 24-h dietary recall; the SFA-CHD RR was >1.00 for only one of these studies. Seven used a food-frequency questionnaire (FFQ); the RR was >1.00 in 3 of these studies. Five used dietary history or multiday food record; the RR was >1.00 in all 5 studies, even though 3 were adjusted for serum or dietary lipids. These facts, which were unnoted in the meta-analysis, prompt the question: Did low-level reliability (reproducibility) of dietary SFA data drive RR values toward 1.00 (the regression-dilution bias problem)? No data on SFA reliability are given

It could actually be concluded from this data that the majority of the cohort studies that used ‘high-quality’ dietary assessment methods, in particular those that did not include overadjustments for dietary and serum lipids found that saturated fat was associated with an increased risk of coronary heart disease.

In the Seven Countries Study dietary intake was measured with high quality assessment methods including a seven day food record and for a subsample of participants the diets were also chemically analyzed.5 Another strength of the Seven Countries Study is that dietary intake was assessed between groups of individuals which has been shown to result in less measurement error than assessing dietary intakes between individuals as was done in the cohort studies included in the Siri-Tarino et al. meta-analysis.9 A further strength of the Seven Countries Study was that saturated fat intake ranged from 3% to about 22% of calories, a far greater range than the studies on mostly homogeneous populations included in the Siri-Tarino et al. meta-analysis, providing greater statistical power to detect a significant relationship. 

Stamler also addressed the problem related to participants making voluntary dietary changes, including the reduction of saturated fat intake in response to elevated serum cholesterol that could have also obscured the findings of the Siri-Tarnio et al. meta-analysis:1

Also, the meta-analysis says nothing about the problem for the 16 studies of possible bias in SFA-CHD findings due to dietary change (eg, reduced SFA intake) in people with higher serum total cholesterol seeking to lower total cholesterol/CHD risk (as occurred for the earliest of the 16 studies).

Even over 50 years ago in the Chicago Western Electric Company study, the earliest of the studies included in the Siri-Tarino et al. meta-analysis, participants were reducing intake of saturated fat and dietary cholesterol in response to unfavourable serum cholesterol concentrations.10 In studies where participants measured their lipid profile and subsequently lowered saturated fat intake in response to unfavourable results before entering the study, the saturated fat intake of these potentially high risk participants measured during the study could have been significantly lower than their lifetime averages. This could have resulted in an artificial increase in number of coronary events in the groups of participants classified as having a low intake of saturated fat. Similarly, the participants who lowered saturated fat intake in response to unfavourable serum lipids after completing their dietary assessment for the study may have artificially lowered the number of coronary events in the groups of participants classified as having high intake.

Few studies included in the Siri-Tarino et al. meta-analysis adequately addressed this problem, with the Health Professionals Follow-up Study perhaps being one of these few.8 In addition to the problem of imprecise dietary assessment methods, this problem further obscures the classification of the participants ranges of usual saturated fat intake potentially biasing the findings further towards null.11 Another problem that could have potentially obscured the findings in these studies, especially those that lasted into the statin era is that participants with higher serum cholesterol as a result of a high saturated fat intake maybe more likely to have received aggressive medical intervention in order to prevent cardiovascular disease. It should be emphasized here that Stamler found in a meta-analysis that saturated fat was associated with a 32% increased risk of fatal coronary heart disease despite such problems.1

Guyenet’s suggestion that the Siri-Tarino et al. meta-analysis addressed the ‘association’ between saturated fat and coronary heart disease independent of other caloric sources is also misleading, a point that was addressed by Katan et al.:2

First, the notion that there exists such a thing as “the effect of saturated fat” is flawed. A lower intake of saturated fat implies an increased intake of some other source of calories to maintain caloric balance. Different substitutions for saturated fat have different effects on risk of coronary heart disease (CHD) and need to be discussed separately.

One of the greatest contributors to unnecessary confusion in nutritional research has resulted from studies that failed to compare foods or macronutrients with other suitable sources of energy. The majority of participants studied in developed nations typically consume only negligible amounts of whole plant foods, and therefore a lower intake of one particular food typically results in a higher intake of other processed or animal foods.12 Without giving this important fact careful consideration most foods that are less than optimal for human health will appear harmless in studies as they are typically compared with other unhealthy foods. This problem was elaborated on in a research panel including Ronald Krauss, the senior researcher of the Siri-Tarino et al. meta-analysis:13

For example, it may not be useful, as is usually done, to compare a specific food to all other sources of energy, which are usually mainly refined starches, sugars, red meat, and fat-rich dairy products in typical Western diets.

Hu FB and Sun Q, two of the authors of the Siri-Tarino et al. meta-analysis also addressed this shortcoming of the meta-analysis in a paper they co-authored, describing what sources of energy saturated fat was substituted for:14

…however, in this meta-analysis saturated fat was compared with other calorie sources, primarily refined carbohydrates, and high intake of refined carbohydrates has been associated with a high risk of CHD.

As the Siri-Tarino et al. meta-analysis failed to find a lower risk of saturated fat compared primarily to foods rich in refined carbohydrates even after adjusting for serum lipids, these findings hardly justify increasing the intake of saturated fat any more than they do to increasing the intake of refined carbohydrates. As expected from these findings, meta-analysis and systematic reviews that compare foods to all other sources of energy combined have also failed to find a clear association between refined grains and cardiovascular disease and all-cause mortality, even without the inclusion of such significant overadjustments.15 16 If Guyenet and the other cholesterol skeptics applied the same methodology they use to judge the health properties of saturated fat to all foods, they would not be able to justify their recommendation of limiting intake of refined grains in order to reduce the risk of cardiovascular disease and other non-communicable diseases. 

In Guyenet’s post I commented in regards to a pooled analysis of 11 large prospective cohort studies which found that replacing 5% of energy from saturated fat with an equivalent of polyunsaturated fat was associated with a 26% decreased risk of coronary heart disease mortality.17 Here again Guyenet was less than appreciative of such comments, stating: 

That's not how epidemiology works. What you do is you examine if people who eat more SFA have more heart attacks than people who eat less, while controlling for other variables-- and the studies have nearly all found no association. That's how epi works in other disciplines. Moving the goalposts to Keys score, SFA/PUFA ratios and using fancy math to model nutrient substitutions will only fool people who don't know any better or are desperate to believe that there's an association.

It appears that Guyenet is either desperately trying to confuse his audience or is suggesting that a change in saturated fat intake in the general population will not influence the intake of any other sources of energy for which he has provided no evidence for. Examining saturated fat intake is meaningless without considering what sources of energy it is replacing, which is why models of macronutrients substitution is preferred. The study of nutrition epidemiology is different than the study of other exposures such as tobacco smoke in the respect that energy is required in order to maintain life, and therefore it essential in nutrition science to compare one source of calories with suitable alternatives. 

Additional Findings from Observational Studies

Even if one were to judge the health properties of saturated fat on the basis of findings from prospective cohort studies that compared saturated fat intake with all other sources of energy combined, it would still be implausible to conclude that saturated fat is not disease promoting. The finding from Stamler’s meta-analysis that saturated fat intake was associated with a 32% increased risk of fatal coronary heart disease by itself is a cause for concern, however other findings from cohort studies also raise significant concern. 

A meta-analysis of 12 cohort studies of 418,816 women found that saturated fat intake was associated with an increased risk of breast cancer, consistent with the findings from more recent cohort studies of 319,826 and 188,736 women.18 19 20 In addition, a pooled-analysis of 12 cohort studies of 523,217 women found that a high intake of saturated fat was associated with an increased risk of ovarian cancer.21 Furthermore, a large cohort of 525,473 men and women found that saturated fat intake, especially that from animal sources increased the risk of pancreatic cancer and a cohort of 494,000 men and women found that saturated fat intake was associated with a greatly increased risk of small intentional cancer.22 23 Another cohort study of 137,486 women found that saturated fat intake was associated with an increased risk of hip fracture, consistent with other lines of evidence [reviewed previously].24

Siri-Tarino et al. excluded cohort studies of type II diabetics patients from the meta-analysis which should be addressed. Two such studies found a very strong association between saturated fat and cardiovascular disease, including the Nurses’ Health Study which also found a significant association for dietary cholesterol and the Keys score.25 26 Furthermore, although typically considered lower in the hierarchy of evidence than prospective cohort studies, a number of case-control studies have also found a positive association between saturated fat and coronary heart disease.27 28 29 30

In regards to the association between saturated fat intake and the risk of stroke, the Siri-Tarino et al. meta-analysis failed to address the possible influence that blood pressure has on the association between saturated fat and the risk of stroke despite finds from large cohort studies including the Nurses’ Health Study that suggest the association is dependent on blood pressure. Without consideration of these important details the Siri-Tarino et al. meta-analysis should not be considered as providing a clear interpretation of the association between saturated fat intake and the risk of stroke. I have addressed this matter in further detail in Part I and Part II of a review addressing blood pressure, blood cholesterol, diet and the risk of stroke, which also addresses the Northern Manhattan Study which found that saturated fat was associated with a trend towards an increased risk of ischemic stroke that was excluded from the Siri-Tarino et al. meta-analysis despite apparently meeting the requirements for the inclusion criteria.31

The disease promoting properties of saturated animal fat cannot be ascribed purely to the substitution of saturated fat for other macronutrients, but also to other nutritional factors including the content of dietary cholesterol, ruminant trans-fat and the lack of dietary fiber and other phytonutrients. For example, a study on an apparently health conscious population included in the Siri-Tarino meta-analysis found that while saturated fat was associated with 2.77 fold increased risk of coronary heart disease which was the value used in the meta-analysis, the association for animal fat was even stronger, a 3.29 fold increased risk.32

In the pooled analysis of 11 large cohort studies, compared to saturated fat, monounsaturated fats which was predominantly derived from animal fat was associated with the greatest increased risk of coronary events out of all the studied macronutrients. Furthermore this pooled analysis adjusted for dietary fiber, dietary cholesterol and possibly ruminant trans-fat, which also needs to be taken into consideration as this could have potentially underestimated the adverse effects of increasing saturated animal fat intake at the expense of whole plant foods.33

As foods contain not only macronutrients but also tens of thousands of different bioactive constituents which can potentially influence health, it would therefore be more informative to compare the effect of substituting different foods rather than isolated macronutrients on disease outcomes.34 35 Arguably the highest quality prospective cohort study to have published a paper addressing the substitution of foods on the risk of coronary heart disease was the Nurses’ Health Study (Fig. 2).14 As suggested by this study, the benefits of replacing animal foods with whole plant foods to lower the risk of coronary heart disease can be explained partly but not entirely by the displacement of saturated fat with other macronutrients.

Figure 2. Coronary heart disease associated with replacement of a major dietary protein source with another in the Nurses' Health Study

Another paper that also addressed the substitution of foods on the risk of coronary heart disease was from the Iowa Women’s Health Study, which found that substituting foods rich in refined carbohydrates with dairy was associated with a increased the risk of fatal coronary heart disease and substitution with red meat was associated with a increased risk of both fatal coronary heart disease and all-cause mortality.36 These findings raise significant doubt towards the cholesterol skeptics claims that certain animal foods appear disease promoting in studies only because they act as a marker of refined food intake. This study actually found that dairy and red meat are disease promoting even when compared to foods rich in refined carbohydrates. 

It is well documented that the conclusions of studies that receive industry funding, including from the dairy, soda and tobacco industries are far more likely to bias in favor of the invested industry than studies without apparent industry funding.37 The Siri-Tarino et al. meta-analysis was funded by the National Dairy Council and the senior researcher,  Ronald Krauss has reported receiving grants from the National Dairy Council, the National Cattleman’s Beef Association and the Robert C. and Veronica Atkins Foundation. Although such conflicts of interests do not necessarily prove that the meta-analysis is flawed, it does at the very least suggest however that the author’s lack of acknowledgement of the positive association between saturated fat and fatal coronary heart disease and of the very serious flaws in the meta-analysis may have been intentional. 

Like diet, it is notoriously difficult to accurately measure environmental tobacco smoke exposure which has obscured the findings for passive smoking and smoking related diseases in observational studies. In a similar fashion as the dairy industry has done to downplay and distort the relationship between saturated fat and cardiovascular disease, the tobacco industry has taken advantage of measurement error in order to scrutinize the association between passive smoking and lung cancer in part due to the fact that the majority of observational studies failed to find a statistically significant association.38 However, it is clear that when all of the evidence is considered there is convincing evidence that passive smoking increases the risk of lung cancer, just as the substitution of whole plant foods with saturated animal fat increases the risk cardiovascular disease.39

In 2003, tobacco affiliated researchers Enstrom and Kobat published findings from a 39 year follow-up of a prospective cohort study in the British Medical Journal and concluded that exposure to environmental tobacco smoke does not likely significantly influence the development of lung cancer and coronary heart disease. This paper received a lot of attention from the mass media, including the Wall Street Journal, and was used by the tobacco industry to criticize government sponsored ‘junk science’.40

This study was criticized by a number of researchers and by the American Cancer Society which addressed a number of the very serious flaws in the study.41 42 The prominent flaw that was emphasized was the lack of a suitable comparison group. The analysis only took into account whether never smokers who had a smoking spouse were more likely to develop lung cancer and coronary heart disease compared to never smokers without a smoking spouse, and did not account other forms of environmental tobacco smoke. This was an issue because in 1959 when the participants were enrolled there was tobacco smoke virtually everywhere leaving no group unexposed. Furthermore this study only measured the spouses smoking status at study baseline and did not account for whether the spouse quit smoking, ended the marriage or died during the follow-up period. 

To summarize some of the shortcomings of this tobacco industry influenced study, it suffered from a lack of suitable comparison group, lack of  high quality assessment methods to precisely measure exposure, and the lack of assessment of changes to exposure during the follow-up period. These shortcomings remarkably resemble those of the Siri-Tarino et al. meta-analysis. This paper has even been cited in a lawsuit against tobacco companies by the US District Court as ‘a prime example of how nine tobacco companies engaged in criminal racketeering and fraud to hide the dangers of tobacco smoke.’43 

This was unfortunately not the last time that the researchers of an industry influenced study would publish a paper that has the potential to jeopardize the health of so many. What is also unfortunate is that many cholesterol skeptics have also chosen to exploit these findings in an attempt to advocate disease promoting diets to an uninformed audience. Follow-up posts in this series will critically examine other lines of evidence of the diet-heart hypothesis that cholesterol skeptics have chosen to misinterpret and exploit in an attempt to confuse the general population.

Grass-fed Animal meet

Vilhjalmur Stefansson was an Artic explorer known for his observations on the traditional living Inuit-Eskimo, which he lived together with in the winter of 1906-1907 in the Mackenzie Delta of Canada. Stefansson asserted that during this time he subsisted on traditional Inuit fare, based almost exclusively on flesh. In part based on less than extensive observations of the health of the Inuit, Stefansson hypothesized that a number of chronic and degenerative diseases, including cancer are diseases of civilization which can be prevented by adherence to a pre-modern diet and lifestyle. However, Stefansson did not suggest that only flesh based dietary patterns, such as that consumed by the traditional living Inuit, but also primarily vegetarian diets, such as that consumed by the Hunza may protect against such diseases.1 

The term diseases of civilization, which Stefansson has contributed to the popularization of is frequently referred to by proponents of Low-Carb, Paleo, Primal and Weston A. Price Foundation type diets. Many of these proponents have extrapolated limited suggestive evidence that obesity, type 2 diabetes, coronary heart disease, certain cancers, and a number of other chronic and degenerative diseases were uncommon during the Paleolithic period to suggesting that foods derived from naturally raised, grass-fed animals, as was consumed by Paleolithic humans must therefore somehow provide protection against these so-called diseases of civilization. Many of these proponents have also claimed that a vast number of scientific studies that have been used as evidence to conclude that animal foods increase the risk of such diseases have been complicated by confounding of other unhealthy foods and lifestyle factors, or by the use of unnaturally raised animal foods. This series of posts will examine the evidence to help determine whether these claimed confounding variables can actually explain the evidence linking animal foods with certain chronic and degenerative diseases, often referred to as diseases of civilization, but also as western diseases, lifestyle diseases and diseases of affluence.

In 1928, Stefansson and his colleague Karsten Anderson participated in a monitored experiment partly funded by the meat industry in which they consumed a flesh exclusive diet for the period of one year. Although the researchers concluded that these two men were in good health throughout the experiment, Anderson experienced a severe elevation in blood cholesterol, with measurements as high as 800 mg/dl on one occasion, which returned to pre-experiment levels after resuming a higher carbohydrate diet.2 A glucose tolerance test carried out immediately after the termination of the meat based experiment showed a marked rise in blood sugar in both men compared to a subsequent test carried out after resuming a higher carbohydrate diet. Glucose was detected in the urine of Anderson in the test following the meat based experiment, a marker of untreated diabetes. This abnormality was not detected in the subsequent test after resuming a higher carbohydrate diet.3

Short-term experiments such as this cannot provide adequate insight into the long-term consequences of following such a diet, as it can take many decades for diseases caused by exposure to harmful substances to become clinically significant. For example, the greatest risk of excess death from radiation-related solid cancers among the atomic bomb survivors of Hiroshima and Nagasaki was more than half a century after exposure.4 Furthermore, other flesh based experiments have resulted in considerably more unfavorable outcomes. For example, in 1906, Russell noted an even earlier experiment: 

A recent instance occurred in South Africa, where about twenty natives out of some hundreds who were supplied with a large amount of flesh, as an experiment, by mine-owners, died, and many others were ill.5

Cardiovascular Disease in Ancient Civilizations

The traditional living Inuit's were certainly
not immune from atherosclerosis

If a diet rich in naturally raised animal foods provides protection against cardiovascular disease as many proponents of Low-Carb type diets claim, it would be expected that traditional living populations consuming such a diet, particularly those living prior to the rapid westernization of the globe would demonstrate evidence of superior cardiovascular health compared to those populations who subsisted primarily on starchy staples, including grains, legumes and tubers. Populations who have inhabited the arctic, where scant plant matter is available throughout most parts of the year, such as the Inuit and Aleut were forced to subsist almost exclusively on hunted marine animals for extensive periods of time.1 6 This should make these populations suitable to study the hypothesis that naturally raised animal foods protect against cardiovascular disease.

Contrary to claims of the traditional living Inuit being immune from cardiovascular disease, evidence of severe atherosclerosis has been identified in several frozen mummies of Alaskan Inuit dating back to 400 CE and 1520 CE, both instances predating European contact.7 8 Atherosclerosis has also previously been identified in several artificially prepared mummies of Aleut-Unangan hunter gatherers who lived in the 18th century in the Aleutian Islands in Alaska.9 10 Recently the HORUS study, which examined an additional five recovered mummies of Unangan hunter gatherers who lived in the mid and late 19th century found definite evidence of atherosclerosis in several major arteries in all three who were over the age of 25.11

When considering the findings from all of these Alaskan Inuit and Aleut mummies it becomes evident that these Alaskan natives likely experienced a greater incidence of atherosclerosis, especially given the young mean age compared to the three other ancient populations studied in the HORUS study. Unlike the Alaskan natives, these other three populations, which were the ancient Egyptians, ancient Peruvians and Ancestral Puebloans practiced agriculture and consumed grains. 

In addition to evidence of atherosclerosis from native Alaskan mummies, reports from medical officers provide further evidence of unfavorable rates of cardiovascular disease among the Inuit before the rapid transition to the western diet. In 1940, based on decades of clinical practice and reviewing reports of medical officers dating all the way back 175 years ago, Bertelsen, who is considered the father of Greenland epidemiology stated in regards to the mortality patterns among the Greenland Inuit that: 

...arteriosclerosis and degeneration of the myocardium are quite common conditions among the Inuit, in particular considering the low mean age of the population.12

Bjerregaard and colleagues performed a literature review for studies addressing the incidence of atherosclerosis and cardiovascular disease among the Inuit of Alaska, Canada and Greenland spanning from the 1930s to more recent decades. The researchers found that the incidence of atherosclerosis was generally similar to that of other western populations that suffered from high rates of cardiovascular disease. Mortality from stroke was found to be even higher, and mortality from all cardiovascular diseases combined was found to be similar or even higher among the Inuit. The researchers also found that mortality from coronary heart disease among the Inuit was not significantly different after adjusting for ill-defined causes of cardiovascular death, suggesting that the substantial proportion of cardiovascular deaths being classified as ‘garbage codes’, particularly in Greenland may have hidden a significant portion of deaths from coronary heart disease. The researchers concluded: 

The mortality from all cardiovascular diseases combined is not lower among the Inuit than in white comparison populations. If the mortality from IHD [ischemic heart disease] is low, it seems not to be associated with a low prevalence of general atherosclerosis. A decreasing trend in mortality from IHD in Inuit populations undergoing rapid westernization supports the need for a critical rethinking of cardiovascular epidemiology among the Inuit and the role of a marine diet in this population.12

A similar phenomenon to the misclassification of deaths from coronary heart disease among the Inuit populations has also been observed in France, which may largely explain the so-called French Paradox. Data from the World Health Organization MONICA Project suggests that the official mortality statistics for France significantly underreport deaths from cardiovascular disease compared to other countries, with deaths from coronary heart disease being underestimated by 75%. Other reports suggest that this is likely explained by a much higher rate of French doctors classifying deaths as due to ‘other causes’ than in other countries.13 14

It has been observed that among the Alaskan Inuit a higher intake of saturated fat is associated with elevated blood pressure, insulin resistance, glucose intolerance and carotid atherosclerosis, suggesting that the traditional Inuit foods relatively rich in saturated fat were likely to have been detrimental to the cardiovascular health of the Inuit.15 16 17 It has also been observed that among Alaskan Inuit elevated LDL cholesterol is associated with a greater than fourfold increased risk of cardiovascular disease.18 Furthermore, rheumatic disorders that have been linked to cardiovascular disease, such as gout and rheumatoid arthritis have been found to be just as, or even more common among the Eskimo populations compared to that of the general North American population.19 20 Established risk factors, a number of which are likely adversely affected by the traditional Inuit diet can probably in part explain the evidence of severe atherosclerosis and unfavorable rates of cardiovascular disease observed among the traditional living Inuit and Aleut populations. 

In the HORUS study it was found that two of the four Ancestral Puebloan who lived in southwestern United States dating between 1500 BCE and 500 CE exhibited probable evidence of atherosclerosis, the two other both being under the age of 30. These Ancestral Puebloans were identified as being from a time when they were transitioning from hunter-gatherers to farmer-foragers, and were likely to have relied on hunted animal foods to supply at least a modest portion of their diet. An additional Ancestral Puebloan mummy aged 18-22 found from a later period after a greater transition towards agriculture did not exhibit any evidence of atherosclerosis.11

In the HORUS study the ancient Egyptian mummies exhibited the next greatest frequency of atherosclerosis, with 29 (38%) of the 76 of the mummies exhibiting at least probable evidence of atherosclerosis.11 In their book Protein Power, Michael and Mary Eades assert that the ‘diet of the average [ancient] Egyptian consisted primarily of carbohydrates’, which they suggest was ‘a veritable nutritionist’s nirvana… rich in all the foods believed to promote health and almost devoid of saturated fat and cholesterol'. These authors go on to suggesting that the carbohydrate rich diet of the ‘average Egyptian’ which they describe as being based on whole-grain wheat and barley supplemented by a variety of fruits, vegetables, legumes, nuts and some goats milk is responsible for the atherosclerosis and obesity exhibited by the ancient Egyptian mummies.21

The authors of Protein Power suggest that complex carbohydrates, such as wheat made the ancient Egyptians obese

There is much evidence that casts doubt on these authors description of the diets of the ancient Egyptian mummies. For example, Macko and colleagues have shown that isotope analyses of the amino-acid composition of hair from the ancient Egyptian mummies far more closely resemble that of modern westerners following an omnivorous diet than a vegetarian, and especially vegan diet.22 In addition, David and colleagues showed that evidence from hieroglyphic inscriptions on ancient Egyptian temples suggest that the elites of ancient Egyptian society, being those who were primarily mummified consumed a diet rich in flesh and saturated animal fat. These researchers addressed the confusion surrounding the diet and atherosclerosis of the ancient Egyptian mummies, asserting: 

It is important to point out that there was a marked difference between the mainly vegetarian diet most Egyptians ate and that of royalty and priests and their family members whose daily intake would have included these high levels of saturated fat. Mummification was practised by the elite groups in society, ensuring that their remains have survived to provide clear indications of atherosclerosis; by contrast, there is a lack of evidence that the condition existed among the less well-preserved remains of the [mainly vegetarian] lower classes.23

The findings of a lower incidence of atherosclerosis among the lower classes of ancient Egypt who subsisted primarily on a carbohydrate-rich vegetarian diet are consistent with observations in Egypt in the early 20th century. In 1934, Rosenthal asserted:

Of interest is the report of Ismail in Egypt, who has communicated that among his private patients, whose diet is similar to that of the Europeans, the incidence of atherosclerosis is high, while in his hospital practice, composed mainly of natives, who subsist largely on a carbohydrate diet, the incidence of atherosclerosis is low.24

It is clear that the authors of Protein Power have confused the diet of the elites of the ancient Egyptian society, who certainly cannot be considered as the 'average Egyptian' with the largely vegetarian diet of the of the lower classes who exhibit a lack of atherosclerosis, and which scant evidence suggests were obese. The findings from ancient Egyptian mummies do not support the claimed benefits of a low carbohydrate, high saturated fat diet promoted by these authors.

In the HORUS study, despite having the highest mean age, nearly 10 years older than that of the Unangan and Ancestral Puebloans mummies, the ancient Peruvians exhibited the lowest incidence of atherosclerosis, being evident in 13 (25%) of 51 of the mummies. Compared to these other studied ancient populations, the Peruvians likely relied more on staple plant foods, such as corn, beans and tubers, although did consume some domesticated and hunted animals.11

The researchers of the HORUS study suggested that exposure to smoke from fire used for cooking and25

heating may help explain some of the degree of atherosclerosis identified in these ancient populations. However, the description of the use of fire for cooking in ancient Egypt provided by these researchers would apply primarily to the lower classes of ancient Egypt which exhibit a lack of atherosclerosis, rather than the mummified elites that these researchers examined who would typically have had servants to cook for them.

Gout was known to be common among 

the Mongols of the Golden Horde

In regards to the traditional living Inuit and Aleut, it has been suggested that the extensive exposure to seal oil lamps may help explain the relatively severe degree of atherosclerosis in these populations.  These findings should however be considered in light of evidence of atherosclerosis in other populations which have high exposure to hazardous smoke but consume contrasting diets. For example, it has been observed that the Papua New Guinean highlanders have a smoking prevalence of greater than 70% for males and 20% for females while also being exposed to smoke for up to twelve hours a day due to the use of centrally placed open wood fires in their houses which lack both ventilation and chimneys. Despite such a high exposure to hazardous smoke it has been observed that the Papua New Guinean highlanders have among the lowest age-adjusted incidence of atherosclerosis of any studied population. However, unlike the Inuit, the Papua New Guinean highlanders traditionally consumed a plant based diet with carbohydrate supplying more than 90% of total energy intake, predominantly derived from sweet potatoes.26 27

Another population that have historically been documented to subsist almost exclusively on a diet derived from grass-fed, free-ranging animals are the largely nomadic Mongolians. John of Plano Carpini who visited the Mongols in the mid-13th century noted:

[The Mongols] have neither bread nor herbs nor vegetables nor anything else, nothing but meat… They drink mare’s milk in very great quantities if they have it; they also drink the milk of ewes, cows, goats and even camels.28

Smith reviewed the literature regarding the health of the Mongols from the 13th century and noted that a number of unfavorable cardiovascular risk factors, including obesity and gout were both common disorders. Smith went on to state:

Cardio-vascular problems, although not then subject to diagnosis, may be suspected as well.29

In 1925, Kuczynski reported on the nomadic pastoralists of the Kirghiz and Dzungarian Steppes in Central Asia and northern China that were of Mongolian descent. Similar to the observations of the diet of the nomadic Mongols of the 13th century, Kuczynski observed that these nomadic pastoralists subsisted almost exclusively on enormous quantities of meat and milk from grass-fed, free-ranging animals. Other authors have also come to the same conclusions regarding the composition of the diet of the nomadic pastoralists of the Central Asian Steppes. For example, Tayzhanov asserted:

…the people [of the steppe] lived exclusively on meat, fat and sour milk. Bread was added only later and even then some households did not adopt or consume this food.30

Similarly, Barfield asserted:

In good legendary style, the pure Central Asian nomads eat only meat, marrow, and milk products {preferably ferments}. They despise farmers, farming, and grain…31

These findings suggest that the diet of these nomadic pastoralists of the Central Asian Steppes was almost exclusively animal based, virtually devoid of grains, legumes and refined carbohydrates. This should make these populations also suitable to study the hypothesis that naturally raised animal foods protect against cardiovascular disease. However, not only did Kuczynski observe that these nomadic pastoralists suffered from high rates of obesity and gout similar to the Mongols of the 13th century, Kuczynski's observations further extended to the diagnosis of cardiovascular disease and other dietary related disorders. Kuczynski asserted:

They get arteriosclerosis in an intense degree and often at an early age as shown by cardiac symptoms, nervous disordes, typical changes of the peripheral vessels, nephrosclerosis and, finally, apoplectic attacks. Even in men thirty-two years old I frequently observed arcus senilis.32

It was also observed that in the 1960s the prevalence of coronary heart disease among the nomadic pastoralists in Xinjiang in northern China who consumed large quantities of animal fat from grass-fed, free-ranging animals was more than seven times higher than that of other populations both within Xinjiang and throughout China which consumed significantly less animal fat.33 These observations support the suggestion that cardiovascular disease was common among the Mongols of the 13th century who subsisted almost exclusively on a diet based on grass-fed, free-ranging animals.

Dispelling Grass-Fed Fairy Tales

These findings from populations living before the 20th century suggest that similar to the findings from people studied in more modern times, a greater intake of minimally refined plant foods strongly predicts a lower prevalence of atherosclerosis and cardiovascular disease. These findings cast doubt on the hypothesis that foods from organic, naturally raised animals protect against cardiovascular disease compared to staple plant foods. Furthermore, these findings suggest that the traditional living populations that relied predominantly on naturally raised animal based foods suffered from complications related to cardiovascular disease at a relatively young age and are poor role models for health.

Future posts in this series will further address how naturally raised animal foods influence cardiovascular disease, as well as other so-called diseases of civilization.

Do vegetariens really live longer

Proponents of Paleo and Low-Carb diets suggest that plant-based diets, particularly those rich in grains and legumes, promote disease, ultimately resulting in premature death. However, there is a substantial amount of evidence casting doubt on such suggestions, with many studies providing evidence that plant-based diets increase longevity. This review will focus on studies examining the longevity of plant-based populations, and some of the criticisms of these studies, particularly in reference to Denise Minger's recently published book, Death By Food Pyramid.

It is not news that Denise Minger has a tendency to downplay the health benefits of plant foods and plant-based diets. In her critique of the China Study, Minger claimed that “as a plant-nosher”, she was hoping to find evidence to support Dr. T. Colin Campbell's findings from the China Study linking dietary fiber to lower rates of colorectal cancer.1 Somehow, however, despite her vegan bias apparently creeping into her critique, Minger suggested that she was unable to find sufficient evidence outside of the China Study supporting the hypothesis that dietary fiber protects against colorectal cancer. And yet, several months later the omnivorous panel of experts of the World Cancer Research Fund concluded based on a review of over 1,000 publications that there was convincing evidence that dietary fiber protects against colorectal cancer.2 In Death By Food Pyramid, Minger continues this trend of downplaying the health benefits of plant-based diets. 

In the chapter of her book, Herbivore’s Dilemma, Denise Minger provides a brief overview of the history and the growth of the popularity of vegetarian diets, bringing into picture the earliest of the studies on the Californian Seventh-day Adventists. Loma Linda, California which is highly concentrated by Adventists is considered to be a Blue Zone because of the greater life expectancy compared to other parts of North America. Loma Linda shares the title of Blue Zone with four other populations which are all characterized by traditionally consuming plant-based diets, typically rich in legumes and grains.3 These other Blue Zones include, Ikaria, Greece; Nicoya, Costa Rica; Okinawa, Japan; and Sardinia, Italy. It seems that Minger was not even able to get these simple details right in her book, claiming that the Greek island of Crete is considered a Blue Zone, while citing an article that clearly refers to Ikaria.

Minger hypothesizes that the longevity of the Adventists maybe unrelated to their low meat diet, and may rather reflect the discouraged use of tobacco and alcohol. To illustrate this, Minger points out that the Mormons who are also discouraged from the use of tobacco and alcohol, "but whose founder never endured any meat-abstinence visions"[p.194] have a greater life expectancy than the average population. Although Joseph Smith, Jr., the founder of Mormonism may not have demanded followers to completely abstain from meat, the Word of Wisdom (section 89 in The Doctrine and Covenants) which he delivered, apparently received as a revelation from god, states that:4

Yea, flesh also of beasts and of the fowls of the air, I, the Lord, have ordained for the use of man with thanksgiving; nevertheless they are to be used sparingly;

In regards to longevity, Minger then goes onto state that:

But what’s even more telling is the fact that meat-eating Mormons and vegetarian Adventists tend to live equally as long. When compared to ethnically matched folks outside their religious groups, both Adventist and Mormon men—once their birthday-cake candles start numbering in the thirties—can expect to live about seven years longer than the rest of the population.[p.194]

Unlike what Minger appears to have the reader believe, the 7 years greater life expectancy referred to in the study she cites is for the average Adventist male, and not specifically for vegetarian Adventist men. Less than one third of the men in the cited study were considered vegetarians, with more than half considered regular meat eaters.5 What these studies specifically found was that the life expectancy for active Mormon men who reached the age of 35 was about 7.5 years greater than the average U.S. white male, whereas the life expectancy of the average Californian Seventh-day Adventist male who reached the age of 30 was about 7.3 years greater than the average Californian white male.5 6 When specifically looking at the average vegetarian Californian Adventist male, their life expectancy was found to be about 9.5 years greater than the average Californian white male. It is important to note that the Californian whites that the Adventists were compared to have one of the highest life expectancies of any American state, and are expected to live up to a year longer than the average U.S. white that the Mormons were compared to.7

The more recent 25 year follow-up of the Mormons may allow for a more informative comparison, as like the Adventist study, it included both men and women from California, and examined the effects of other lifestyle factors on mortality. Mormon men and women over the age of 25 with four favorable lifestyle factors associated with significantly reduced mortality were expected to live about 9.8 and 5.6 years longer, respectively, compared to U.S. whites.8 In comparison, vegetarian Adventist men and women over the age of 30 with three favorable lifestyle factors were expected to live about 13.2 and 8.9 years longer, respectively, compared to non-Adventist Californians whites.5 9 Compared to the average U.S. white however, this difference in life expectancy would be expected to be closer to about 14 and 10 years.7 However, and more importantly, a later paper on the Californian Adventists found that those who adhered to a vegetarian diet for at least 17 years were expected to live 3.6 years longer than those who adhered for fewer years.10 This suggests that when restricting the analysis to long-term vegetarian Adventists, the difference in life expectancy compared to the Mormons would be even greater.

There are also other lines of evidence lending support to the observed greater life expectancy of the vegetarian Seventh-day Adventists compared to health conscious Mormons. For example, one study in which vegetarian Adventists and Mormons were matched for strength of religious affiliation, and consumption of tobacco, alcohol, tea and coffee, the vegetarian Adventists were found to have significantly lower levels of serum cholesterol, blood pressure and rates of obesity (Fig. 1).11 12 The difference in blood pressure remained significant even after controlling for BMI, and could not be explained by differences in sodium intake. Another study also found that vegetarian Adventists had lower blood pressure than Mormons, and that the difference increased with age, suggesting a greater favorable effect of long-term adherence to a flesh-free diet.12 

Figure 1. All percentiles of distribution of blood pressure were found to be lower in the vegetarian Adventists compared to health conscious omnivorous Mormons.

Although some of the many factual errors in Minger’s book may be passed off as sloppy research rather than as being intentional (one example perhaps being when she confuses Crete for Ikaria), given the number of occasions she has discussed the Adventist studies previously, it is difficult to believe that she was truly being honest and simply was not even aware of the data in the very studies she cites. Furthermore, Minger acknowledges in this book that she had others with knowledge in this field review her manuscript and assist her with the completion of this book (almost exclusively individuals who have demonstrated an anti-vegetarian stance), allowing for little excuse for these misleading statements.

 

As there are no published meta-analyses examining all of the current available prospective cohort studies comparing mortality in vegetarians and health conscious non-vegetarians, I performed a simple meta-analysis using the results for the fully adjusted model from the most recent follow-up of each cohort. For mortality from all-causes, based on 7 cohorts, the vegetarian group had a statistically significant 7%, and a borderline significant 6% reduced risk, using the fixed effects and random effects models, respectively (Fig. 2).10 13 14 15 16 The 6 cohorts that stratified data by sex suggested an even stronger protective effect of a vegetarian diet for men.16 17

Figure 2. All-cause mortality for vegetarians compared to health conscious non-vegetarians in a meta-analysis using the fixed effects model. 

*Indicates that participants classified as semi-vegetarians were included in the vegetarian group

It should be stressed that the meat intake in the non-vegetarian group in most of these studies was significantly lower than that of the general population. As described in a different review, the selection criteria for the non-vegetarians in these studies generally included being affiliated with vegetarians in some way or another, likely explaining their relatively low meat intakes. Furthermore, evidence suggests that many of the self-proclaimed vegetarians in these studies actually consumed meat on a regular basis, resulting in minimal differences in meat intake between the groups.10

Considering the lack of difference in meat intake between the vegetarian and non-vegetarian groups, it would only be expected that these studies would not have the statistical power to demonstrate a significant benefit of a vegetarian diet. Two studies which may be considered as especially having limited statistical power due to such limitations were the Heidelberg Study and Health Food Shoppers Study. In the Heidelberg Study, the non-vegetarian group were predominantly semi-vegetarians, while in the Health Food Shoppers Study, a validity assessment of the survey used to classify the participants vegetarian status suggested that 34% of the participants classified as vegetarians actually consumed meat. In fact, a slightly greater percentage of participants classified as vegetarians in the Health Food Shoppers Study were found to consume meat 3 or more times a week than the non-vegetarians in the Heidelberg Study (7.6% and 6.9%, respectively).14 18 Taking this into consideration, I performed a sensitivity analysis excluding either the Heidelberg Study or Health Food Shoppers Study from the meta-analysis. Excluding the Health Food Shopper Study alone reduced heterogeneity and strengthened the association between vegetarian status and a reduced risk of mortality from all-causes (RR 0.91 [95% CI, 0.87-0.94], and 0.92 [95% CI, 0.86-0.98] using the fixed effects and random effects model, respectively).

Most of these studies did not provide separate data for length of adherence to a vegetarian diet. As already described earlier in this review, evidence from several of these studies suggest a stronger effect on mortality would have been observed if the analysis was restricted to long-term vegetarians.10 Another important limitation was that most studies also did not verify changes to vegetarian status of the participants throughout the follow-up, which may in part explain why the association between a vegetarian diet and a reduced risk of mortality weakened over time in several of the studies.9 10

Another important potential limitation of these studies described in detail in the next section, is that some of the participants likely adopted a vegetarian diet in order to improve poor health, such as symptoms of an undiagnosed or developing illness that would ultimately became fatal. Each of these limitations described are expected to have either biased these findings towards null, or even in favor of the non-vegetarian group, suggesting that the findings of this meta-analysis may have significantly underestimated the benefits of an appropriately planned vegetarian diet.

In order to determine which factors may have contributed to the observed reduced risk of death in vegetarians, I also performed separate meta-analyses for the major causes of death. This included mortality from coronary heart disease and cardiovascular disease, and the incidence of all cancers combined. For mortality from coronary heart disease, based on 7 cohorts, the vegetarian group had a statistically significant 25% and 24% reduced risk, using the fixed effects and random effects models, respectively (Fig. 3).13 14 15 16 17 For mortality from cardiovascular disease, based on 7 cohorts, the vegetarian group had a statistically significant 17% and 14% reduced risk, using the fixed effects and random effects models, respectively (Fig. 4).13 14 15 16 17 For the Adventist Mortality Study and Adventist Health Study, mortality from cardiovascular disease was derived from pooling the relative risk for mortality from coronary heart disease and stroke.17 Excluding the Adventist Mortality Study and the Adventist Health Study, the vegetarian group had a statistically significant 8% reduced risk of mortality from cardiovascular disease, using both the fixed effects or random effects model (0.92 [95% CI, 0.85-0.99]).

Figure 3. Coronary heart disease mortality for vegetarians compared to health conscious non-vegetarians in a meta-analysis using the fixed effects model. 

*Indicates that participants classified as semi-vegetarians were included in the vegetarian group

Figure 4. Cardiovascular disease mortality for vegetarians compared to health conscious non-vegetarians in a meta-analysis using the fixed effects model. 

*Indicates that participants classified as semi-vegetarians were included in the vegetation group

As described in a previous review, the degree of reduction in risk of mortality from coronary heart disease observed in vegetarians in these cohort studies was generally in proportion to the expected reduced risk based on the differences in levels of total and non-HDL cholesterol, and blood pressure. There is a plethora of evidence, not only from epidemiological studies, but also clinical trials that plant-based diets and nutrients have favorable effects on total and LDL cholesterol, blood pressure, among several other factors which are established risk factors for cardiovascular and all-cause mortality.19 20 21 22

In the Oxford Vegetarian Study, high compared to low intake of saturated animal fat was associated with a nearly 3-fold increased risk of coronary heart disease mortality.23 Similarly, in a meta-analysis of 11 cohort studies, high compared to low intake of saturated fat was associated with a 32% increased risk of coronary heart disease mortality, despite the inclusion of over-adjustments for dietary and serum lipids.24 It was also found in the Oxford Vegetarian Study that high compared to low intake of total animal fat and dietary cholesterol was associated with a greater than 3-fold increased risk of coronary heart disease mortality.23 Furthermore, evidence from thousands of experiments carried out over the last century have shown that the feeding of dietary cholesterol and saturated fat has accelerated the development of atherosclerosis in virtually every animal species in which researchers were able to find a method to sufficiently elevate cholesterol concentrations. This includes herbivores, omnivores and carnivores from mammalian, avian and fish species, and over one dozen different species of nonhuman primates.

In both the Oxford Vegetarian Study and the Adventist Mortality Study, high compared to low intake of eggs was associated with an increased risk of coronary heart disease mortality.23 25 However, for ill-defined reasons, these studies were excluded from several recent meta-analyses. In the Adventist Mortality Study and Heidelberg Study, high compared to no intake of meat was associated with a 50% and almost 5-fold increased risk of coronary heart disease mortality, respectively.14 25 Similarly, in the Adventist Health Study, high compared to no intake of beef was associated with a greater than 2-fold increased risk for men.26 In addition, recent meta-analyses of prospective cohorts found that an increment of 1 mg/day of heme iron, found only in animal tissue, is associated with a 16% and 27% increased risk increased risk of type II diabetes and coronary heart disease, respectively.27 28 Therefore, the totality of evidence strongly suggests that the observed greater longevity of vegetarians can be explained, at least in part, by the reduced risk of cardiovascular disease as the result of the replacement of animal foods with minimally processed plant foods.

For incidence of all cancers combined, based on 5 cohorts, the vegetarian group had a statistically significant 8%, and borderline significant 6% reduced risk, using the fixed effects and random effects model, respectively (Fig. 5).13 14 29 30 Excluding the Health Food Shoppers Study removed evidence of heterogeneity and strengthened these findings (RR 0.90 [95% CI, 0.85-0.99] using both the fixed effects and random effects models).

Figure 5. Cancer incidence for vegetarians compared to health conscious non-vegetarians in a meta-analysis using the fixed effects model. 

*Indicates that participants classified as semi-vegetarians were included in the vegetation group

The finding of a decreased risk of cancer in vegetarians may also be explained, in part, by a diet devoid in heme iron. Controlled feeding trials have established that NOCs (N-nitroso compounds) arising from heme iron in meat forms potentially cancerous DNA adducts in the human digestive tract, likely in part, explaining the significant association between heme iron and an increased risk of colorectal cancer in recent meta-analyses of prospective cohort studies.31 32 33 Heme iron has also been associated with numerous other cancers. These lines of evidence also provide confidence in the validity of the findings of greater longevity in vegetarians.

Which came first,
vegetarianism or ill health?

In health research, the reasons why some people chose to become health conscious is critically important when interpreting data from observational studies. This is because it is possible that it may not have been the health conscious lifestyle that caused the examined outcome, but rather the outcome that caused the health conscious lifestyle, ie. reverse causality. As previously described in a different review, reverse causality occurs when the studied effect precedes the cause. An example in health research is the frequent paradoxical observation that former smokers have worse health outcomes than current smokers. These unfavorable outcomes are not explained as being caused by smoking cessation, but rather that those who quit smoking tend to have done so because they were showing symptoms of illness, illnesses that ultimately resulted in the observed unfavorable health outcomes. A similar phenomenon has been observed in nutritional research where sick people tend to adopt a more plant-based diet, suggesting that this would bias observational studies towards showing an unfavorable effect of plant-based diets and nutrients, and therefore a favorable effect of animal based diets and nutrients.34

Although Denise Minger suggests that the favorable health outcomes for vegetarians observed in many studies maybe unrelated to dietary factors, but rather explained by other healthy habits associated with vegetarianism, she fails to consider the possibility that these vegetarians may have become health conscious, including adopting a vegetarian diet, in order to improve poor health. The results of a recent study from the Netherlands illustrates the critical importance of considering reverse causality in research on plant-based diets. The researchers found that 75% of the vegetarian participants with cancer adopted a vegetarian diet after diagnosis, consistent with previous research which found that cancer survivors are highly motivated to adopt a more plant-based diet with the intention of improving poor health.35 36

Although health researchers often attempt to partially control for reverse causality by excluding participants who were diagnosed with cancer, cardiovascular disease and other life threatening conditions prior to baseline of a study, it is nearly impossible to fully control for reverse causality, as participants may make dietary changes due to symptoms or unfavorable risk factors that act as markers of an undiagnosed or developing disease. For example, it is known that in studies carried out as far back as the late 1950s, participants with unfavorable blood cholesterol levels tended to reduce the intake of dietary cholesterol and saturated fat (ie. in part, by abstaining from animal foods). This resulted in paradoxical findings where participants who consumed more dietary cholesterol and saturated fat actually had lower serum cholesterol levels. These paradoxical findings were produced, in part, because those participants who continued to consume a diet rich in these lipids were choosing to do so because they were able to maintain lower cholesterol levels despite consuming such a diet (ie. due to favorable genetics).37 Many individuals who attempt to downplay the harmful effects of these lipids, such as Minger has done in her book have chosen to ignore this critical factor when reviewing research on the diet-heart hypothesis.24

In the chapter Herbivore’s Dilemma, Minger reviews several prospective cohort studies that compared the mortality rates of vegetarians to health conscious non-vegetarians, carefully selecting only those studies in which vegetarians were not found to live longer. These studies were the Oxford Vegetarian Study, the Health Food Shoppers Study and the Heidelberg Study, all included in my meta-analysis. Minger emphasizes the lack of reduced risk of mortality in the vegetarian groups, while neglecting to mention that the difference in intake of meat between the groups was relatively small. Minger especially focuses on the Heidelberg Study, happening to be the smallest study, which found a non-significant increased risk of all-cause mortality in the vegetarian group. Minger points out that in this particular cohort, the vegetarians had greater levels of physical activity, consumed less alcohol and smoked less. Minger then states “Mortality and disease rates, in this case, might be expected to turn up in favor of the vegetarian crowd, even though the opposite ended up happening”[p.270]. This statement is outright misleading as all these factors were controlled for in the analysis. One could also correctly point out that the vegetarians tended to be older than the meat eaters, but suggesting that this would be expected to turn up in favor of the meat eaters would also be misleading, as age was also controlled for. Either way, the differences in mortality between the groups did not even come close to being statistically significant.

There are several important findings that Minger neglected to mention that cast doubt on the suggestion that a vegetarian diet had a harmful effect on the participants in the Heidelberg Study. For example, it was shown in an earlier follow-up of this study that, similar to the Adventist studies, the participants who adhered to a very low meat diet for at least 20 years had a 29% lower risk of all-cause mortality compared to those who adhered to such a diet for fewer years.10 Excluding the first 5 years of follow-up significantly strengthened this association, resulting in a 45% lower risk of all-cause mortality, suggesting that reverse causation may have attenuated the results for the entire follow-up.38 This difference in mortality was considerably stronger than the mortality difference between vegetarians and non-vegetarians. Unfortunately the researchers appear to not have provided any data comparing mortality in long-term vegetarians and non-vegetarians. Indeed, in other cohorts it has been observed that compared to non-vegetarians, short-term vegetarians had a higher rate, whereas long-term vegetarians had a lower rate of all-cause mortality.34 These findings suggest that those who adopted a vegetarian diet more recently had done so due to deteriorating health, biasing the results in favor of the non-vegetarians. 

Also as already briefly mentioned, in this study it was also found that intake of meat 3 or more time per week was associated with an almost 5-fold increased risk of mortality from ischemic heart disease, whereas there was a greater than 2-fold risk increase for those who consumed fish more than once per month. One of the reasons that this did not translate into an increased risk of all-cause mortality in the non-vegetarian group may have been due to the very low intake of meat, with less than 7% of the non-vegetarians consuming meat 3 or more times a week.14 Another important finding was that there was a trend towards a favorable effect of a vegetarian diet on mortality in the early years of follow-up, which declined over time (Fig. 6).14 This suggests the likelihood of undocumented changes in vegetarian status in a portion of the participants throughout the follow-up, which would be expected to have attenuated a possible favorable effect of a vegetarian diet. A similar phenomenon was also observed in several other studies included in my meta-analysis.9

Figure 6. Standard Mortality Rates (SMRs) and their 95% CIs for all-cause mortality, dietary group, and 5-year follow-up period, separately for males and females. (○, female vegetarians; •, female nonvegetarians; □, male vegetarians; ▪, male nonvegetarians).

Minger also points out that there was a trend towards a higher rate of mortality among the vegans in the Heidelberg Study, which included only 60 vegans, while neglecting to mention that in the Adventist Health Study 2, which included almost 100 times many vegans found that compared to the non-vegetarians, the vegans, especially male vegans experienced a lower rate of mortality.16 In the Heidelberg Study, while current smokers had the same mortality rate from cancer as never smokers, past smokers suffered from a 70% greater risk of cancer mortality than current smokers. This strongly suggests that many of the past smokers in this cohort quit smoking because they had deteriorating health.14 This raises the question as to whether the participants in this cohort also had a tendency to adopt a vegetarian diet after becoming ill, possibly explaining the unfavorable mortality rates in the vegetarian group. Perhaps the reason why the vegetarians in this group tended to be older, was not because they were becoming more ethical with old age, but because they were becoming more health conscious, which included adopting a vegetarian diet due to deteriorating health with old age. As these lines of evidence described suggest, the trends towards elevated mortality in the vegetarian groups in the Heidelberg Study may be explained by reverse causation. It is more than possible that it was not the vegetarian diet that caused these unfavorable outcomes, but deteriorating health, which would ultimately resulted in these unfavorable outcomes that caused a portion of the participants to adopt a vegetarian diet.

There is strong evidence that plant-based diets, including those rich in whole-grains and legumes reduces the risk of premature death from chronic and degenerative diseases, which in-turn helps explain the longevity of a number of plant-based populations. Contrary to the findings for plant-based diets, there is a plethora of evidence demonstrating the harms of popular carbohydrate restricted diets. For example, meta-analyses of clinical trials have found that low-carbohydrate diets elevate LDL cholesterol and impair endothelial function.39 Furthermore, a recent meta-analysis of prospective cohort studies with more than 272,000 participants found that low-carbohydrate diets, particularly those rich in animal foods are associated with an increased risk of all-cause mortality.40 Evidence also shows that the hazardous effects of diets rich in animal foods are also applicable to that of organic, grass-fed animal foods. These, and other lines of evidence described throughout this review appear to have been almost entirely ignored by proponents of these diets, perhaps because they find it too difficult to explain. 

Although there is strong evidence that plant-based diets promote longevity, it is important to replace animal foods with minimally refined plant foods in order to achieve the maximum benefits. This may in part explain why the benefits of a vegetarian diet were more evident in the Adventists than other populations.9 In conclusion, the totality of evidence supports the hypothesis that appropriately planned whole foods, plant-based diets promote longevity.