Does "Metabolically Healthy Obesity" Exist?

Obesity is strongly associated with metabolic alterations and negative health outcomes including diabetes, cardiovascular disease, and some types of cancer (1, 2, 3, 4).  Excess body fat is one of the primary causes of preventable health problems and mortality in the United States and many other affluent nations, ranking in importance with cigarette smoking and physical inactivity.  Obesity is thought to contribute to disease via the metabolic disturbances it causes, including excess glucose and lipids in the circulation, dysregulated hormone activity including insulin and leptin, and inflammatory effects.  This immediately raises two questions:

1. Does metabolically healthy obesity exist?
2. If so, are metabolically healthy obese people at an elevated risk of disease and death?

Does metabolically healthy obesity exist?

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The Asian Paradox: End of the Line for Low Carb Diets?

The fact that the populations of many parts of Eastern and Southeast Asia have traditionally been slim while consuming a high carbohydrate diet, typically rich in white rice is often considered as a ‘Asian Paradox’ by advocates and followers of carbohydrate restricted Low-Carb, Paleo and Primal type diets who hypothesize that such a dietary pattern promotes weight gain. Mark Sisson, a prominent Paleo diet advocate recently explained that the so-called ‘Asian Paradox’ is not a paradox because he believes that Asians have traditionally conformed to a lifestyle and diet that is comparable with his recommendations.1

Sisson attributes the leanness and health of the traditional living Asians to regular exercise and a diet rich in unprocessed foods including fresh meat, offal, bone broth as well as vegetables, with rice playing a neutral role. In addition, Sisson attributes much of the observed increases in rates of obesity, diabetes and coronary heart disease in Asia in more recent years to an increased intake of sugar, and the replacement of rice with wheat and saturated animal fats with omega-6 rich fats. However, Sisson provided scant evidence to support his claims regarding the composition of traditional and modern diets in Asia. Considering that obesity, diabetes and cardiovascular disease are major causes of disability and death throughout the world, this warrants an examination of these claims.2

Concerns of Low-Carb and Paleo Diets

Mark Sisson sells whey protein, among many 
other supplements. These supplements were 
certainly not available to Paleolithic humans.

Sisson advocates a diet that is rich in animal protein and fat and poor in carbohydrate. Sisson has an 80/20 rule which allows 20% of dietary intake from non-Paleolithic foods from his list of approved foods, including items such as full-fat dairy, chocolate, coffee and wine, as well as the supplements that he sells. Sisson would have his targeted audience believe that humans have conveniently adapted to many foods that were not typically available during the Paleolithic period which are popular among followers of low-carb diets, but not the foods that they typically shun. As such a dietary composition is probably not coincidentally all that different from other popular carbohydrate restricted diets, this makes the diet that Sisson promotes essentially in one variant or another a rebranded Atkins diet. Aside from the lack of originality, there is an ever-increasing amount of evidence demonstrating harm of such a diet. 

It is well established that weight loss has a modest favorable effect on many cardiovascular risk factors.3 4 5 Therefore the modest beneficial changes to cardiovascular risk factors observed in participants on carbohydrate restricted diets in some controlled trials can be either partly or wholly explained by weight loss. However, even in the presence of slightly greater weight loss, meta-analyses of randomized controlled trials have found that compared to diets rich in nutrient poor, low-fiber carbohydrates, carbohydrate restricted diets raise LDL cholesterol and impair flow-mediated dilatation, a measure of endothelial dysfunction which can increase the risk of cardiovascular disease.6 7 In addition, a recent intervention study on a Paleo type diet that contrary to previous intervention studies, did not focus on reducing saturated fat intake found that a Paleo diet significantly raised non-HDL cholesterol and the total cholesterol/HDL ratio despite weight loss and adherence to an exercise regime.8

The findings of a harmful effect on flow-mediated dilatation are consistent with several other controlled experiments which found that diets rich in saturated fat, including when consumed in a carbohydrate restricted diet impaired flow-mediated dilatation.9 10 11 12 13 These findings are also supported by experiments showing that diets rich in cholesterol and saturated fat cause endothelial dysfunction in numerous species of nonhuman primates.14 15 16 Taken together, these findings lend support to the findings that carbohydrate restricted diets adversely affect coronary blood flow, arterial wall function and cardiac efficiency.17 18 19

The findings of a harmful effect on LDL cholesterol are consistent with the findings from hundreds of controlled experiments establishing beyond plausible doubt that a diet lower in saturated fat, ruminant trans-fat, dietary cholesterol, and richer in soluble fiber and plant sterols significantly reduces total and LDL cholesterol.20 21 22 23 24 25 It has also been established beyond plausible doubt that lowering LDL cholesterol reduces the risk of coronary heart disease.26 However, this effect is likely to be considerably stronger the longer LDL cholesterol is maintained at a lower concentration.27 28

A meta-analysis of 108 lipid intervention trials with 300,000 participants and a mean follow-up of only three years found that for each 1 mmol/l (38.7 mg/dl) reduction in LDL cholesterol, coronary heart disease and all-cause mortality was reduced by 24% and 15% respectively, independent of HDL cholesterol, triglycerides and non-lipid effects of specific interventions.29 Comparatively, a meta-analysis of mendelian randomization studies with more than 312,000 individuals found that for each genetically predicted 1 mmol/l reduction in LDL cholesterol maintained throughout life, coronary heart disease was reduced by 55%, independent of the mechanism by which LDL was modified and other known risk factors.30 Conversely, both randomized controlled trials and mendelian randomization studies have been unable to establish a causal relationship between HDL cholesterol and triglyceride concentrations and coronary heart disease.29 31 32

Experiments on animals have found that carbohydrate restricted diets accelerate the development of atherosclerosis independently of traditional risk factors.33 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 vertebrate species that has been sufficiently challenged. This includes mammalian, avian and fish species- herbivores, omnivores and carnivores, and over one dozen different species of nonhuman primates. 

Nations throughout Australasia, Europe and North America have experienced very dramatic declines in coronary heart disease mortality throughout the last half century, for which a substantial portion of the decline has been explained by a dietary induced reduction in serum cholesterol.34 35 After a decade of steady increases, the rates of coronary heart disease mortality in the Czech Republic and Poland fell almost immediately and halved within about 15 years following the abolishment of communist subsidies on meat and animal fats after the collapse of the Soviet Union. Nearly half of this decline has been explained by decreases in serum cholesterol.36 37 In the Nordic nations the rate of coronary heart disease mortality decreased by about 50-85% within three decades following Government initiatives which included a reduction in saturated fat intake. In Finland, Iceland, Norway and Sweden the decreases in serum cholesterol was the main contributor explaining between about one-third and more than half of this decline.38 39 40 41

Contrasting trends have however been observed in Tunisia and Beijing. Tunisia has recently experienced a significant increase in coronary heart disease mortality, of which half of this increase has been explained by an increase in serum cholesterol following a transition from the traditional wheat based diet to a diet richer in animal protein and fat.42 In Beijing where the rates of coronary heart disease mortality increased by more than 100% between 1984 and 1999, the great majority of the increase was explained by an increase in serum cholesterol following a five-fold increase in intake of meat and eggs (Fig. 1).43

Figure 1. Coronary heart disease mortality trends in Beijing 1984 to 1999

Over the last decade the population of Sweden has been shifting to a diet lower in carbohydrate and higher in fat, especially from animal sources following much positive media support for low carbohydrate-high-fat (LCHF) diets. However, despite promises of rapid weight loss, not only has there been no change to the constant increase in BMI, there has actually been an increase in serum cholesterol despite an increased use of cholesterol lowering medication.44

Following the dietary transition in Sweden there has been a sudden surge in heart attacks in women, and stoke in men and women aged 35-44 despite steady decreases in smoking prevalence in this age group, especially for women.45 This has been a great cause of concern for a number of prominent Swedish cardiologists who have attributed this to the significant increase in the popularity of LCHF diets.46 Similar concerns were raised when there was a sudden surge in sudden cardiac death among women, also aged 35-44 in the United States during the period of heightened popularity of the Atkins diet.47 48

As younger adults are considerably less likely to be treated for risk factors prior to a cardiovascular event, they may be more vulnerable to these dietary changes, possibly explaining why they have been the first group in the Swedish population to experience these adverse effects following the dietary transition. The finding that particularly young women were adversely affected may be because young women were among the first groups in the population to make this dietary transition, and also because LCHF diets are considerably more popular among Swedish women than men.44 49

Another concern with diets that are rich in meat and offal is an excess intake of heme iron, found exclusively in animal tissue. As iron is a pro-oxidant and excess iron cannot be excreted from the body, excessive absorption of iron can contribute to progressive inflammatory and degenerative diseases.50 It has been shown in controlled feeding experiments that the absorption of heme iron is considerably less regulated than that of non-heme iron, and therefore a high intake can lead to excess iron absorption.51

Recent meta-analyses of prospective cohort studies found that an increment of 1 mg/day of heme iron was associated with an 11%, 16% and 27% increased risk of colorectal cancer, type II diabetes and coronary heart disease respectively.52 53 54 When taking into consideration the fact that diets very rich in meat and offal can supply well over 10 mg of heme iron per day, these findings cast considerable doubt on the long-term safety of such diets.55 Heme iron intake has also been associated with oxidative stress and an increased risk of stroke, gestational diabetes, gallstones and cancers of the prostate, lung, stomach, esophagus, endometrium and kidneys.56 57 58 59 60 61 62 63 64 65 66 67 68 69

It has been shown in a randomized controlled trial that carbohydrate-restricted diets promote metabolite profiles that may increase the risk of colorectal cancer.70 This is compatible with the strong evidence from both controlled experiments and prospective cohort studies that diets richer in heme iron and poorer in dietary fiber increase the risk of colorectal cancer. Over a century ago, high rates of cancer were observed in Argentina which was inhabited by the Gaucho, a nomadic population that for months subsisted entirely on pasture raised beef. Similarly, a study carried out in Uruguay where livestock is predominantly grass fed, and the administration of hormones is banned by law found that a high intake of fresh red meat was associated with between a 87% and 290% increased risk of 13 different major cancers, independent of other food groups.71

Another concern of diets rich in animal protein is that they can have adverse effects on phosphorus balance in the presence of declining kidney function, contributing to very serious complications associated with kidney disease including cardiovascular disease and sudden death.72 A Cochrane review of randomized controlled trials with patients with chronic kidney disease found that compared to patients with unrestricted protein intake, patients who restricted protein intake had a 32% lower risk of kidney death.73 These findings are particularly concerning when considering that the prevalence of chronic kidney disease is estimated to be between 8-16% with approximately 735,000 deaths attributed to chronic kidney disease worldwide in 2010 alone.74 75 Even in developed nations a significant portion of chronic kidney disease cases go undetected.76

The potential harm of animal protein on kidney function is evidently only in part explained by the high phosphorus content. For example, it has been shown in several randomized controlled trials in patients with declining kidney function that even when protein and phosphorous intake is held constant, plant protein from grain and soy has a favorable effect on phosphorus balance and other markers of kidney function compared to animal protein.77 78 Consistent with these findings the Adventist Health Study 2 found that those who adhered to a vegetarian type diet had less than half the rate of kidney death compared to those who consumed meat regularly.79

Low-carb and Paleo type diets are often advocated as a means of weight loss. However, consistent with the long-term trends in Sweden, randomized controlled trials have found that compared to diets rich in nutrient poor, low-fiber carbohydrates, carbohydrate restricted diets provide little benefit in terms of weight loss in the long-term.80 81 As it has been shown in randomized controlled trials that an increase in intake of dietary fiber has favorable effects on body weight and a number of other cardiovascular risk factors, this suggests that had these trials focused on high-fiber carbohydrate rich diets, carbohydrate restricted diets would have been less likely to have compared favorably.82 83 84 85 Recently Don Matesz published an informative critique of the Paleo diet as a measure for weight loss. Notably Matesz mentions: 

Consequently, any Paleolithic humans who engaged in nutritionally motivated hunting would have done so in order to increase their food energy intake in order to maintain or gain weight, not in order to achieve weight loss… In view of this, the "Paleo diet" theory that overfed sedentary modern humans who need to lose excess adipose should regularly eat the fatty flesh and eggs found in supermarkets because active, underfed, extremely lean prehistoric people who struggled to meet their basic kcaloric needs ate lean game flesh or eggs whenever possible lacks basic credibility. 

Considering the evidence it is not surprising that many of the prominent proponents of Low-Carb and Paleo diets who unlike Sisson have not partaken in caloric restriction have gained considerable amounts of weight while adhering to such diets. 

Recently a meta-analysis of prospective cohort studies with more than 272,000 participants found that carbohydrate restricted diets was associated with a 31% increased risk of death from any cause.86 Sub-analyses suggested that carbohydrate restricted diets based on animal protein and fat was associated with an even stronger risk of death from any cause as well as death from cardiovascular disease. This was despite the evidence that animal protein and fat was primarily compared to refined rather than high-fiber carbohydrates, and there is data from over one million people in cohort studies demonstrating that dietary fiber and whole grain intake is associated with a significantly reduced risk of death from any cause. Although this meta-analysis was based on observational evidence, the abovementioned evidence from randomized controlled trials provides confidence for the validity of these findings, as do other lines of evidence cited previously. 

Considering the lack of evidence when compared to healthy alternatives of a significant long-term favorable effect on body composition and strong evidence of harm, especially when animal sources of protein and fats are chosen, there is little rational to promote these fad diets.

Meat as a Staple in Asian Diets

Traditional Kirghiz nomadic pastoralists

The evidence that Sisson provides to suggest that traditional Asian diets were rich in meat and offal is based on his observations of Chinese, Japanese, Korean, Thai and Vietnamese restaurants and Asian supermarkets in modern day United States. However, the food balance sheets from the United Nations for the early 1960s for these nations that Sisson makes special reference to, suggest that total animal food intake only amounted to between 2.5% and 10% of total caloric intake, with offal intake being almost non-existent.87 As earlier dietary surveys, especially prior to World War II suggest that intake of animal foods was even lower, this casts significant doubt on Sisson's suggestion that animal foods traditionally contributed to a large portion of these populations diets.88 89

Perhaps if Sisson would only visit a Mongolian Barbeque restaurant he would observe a meaty diet that is not only largely comparable with his recommendations, but also with the traditional diet of the nomadic pastoralists of Mongolia, Central Asia and northern China. It has been observed however that many of these nomadic populations who subsist largely on pasture raised animal foods have high rates of obesity and cardiovascular disease, and this has been frequently associated with their meaty diets.90 91 92 Some of these observations were made at least as far back as ninety years ago.

In the 1920s, it was observed that the nomadic pastoralists of the Kirghiz and Dzungarian Steppes in Central Asia and northern China subsisted almost exclusively on enormous amounts of fermented mare’s milk and meat from pasture raised animals. Not only was a high rate of obesity observed, but also high rates of premature extensive atherosclerosis, contracted kidney, apoplexy, arcus senilis, and gout. These pastoralists were often observed to suffer from complications related to cardiovascular disease even in their early thirties. In contrast, their urban counterparts who based their diet on soup, bread, pickles, and potatoes with very little meat were observed to be slim, free of cardiovascular disease and had very good health, even into their seventies when they were still sexually active.

It was observed that in the 1960s the rates of coronary heart disease of the nomads from Xinjiang in northern China who largely subsisted on pasture raised animal foods was more than 7 times higher than that of other populations both within Xinjiang and throughout China which had a much lower intake of animal fat.93 These findings from non-industrialized populations in Asia are compatible with the observations of a high rate of cardiovascular disease among the Inuit populations whose staple is marine animals.94 In 1940, based on decades of clinical practice and his review of reports of medical officers dating all the way back to 1838, 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.

It is clear that these populations who traditionally subsisted predominantly on large amounts of naturally raised animal foods that the Low-Carb and Paleo proponents such as Sisson promote are not a good role model of health.

Wheat as a Staple in Asian Diets

Unleavened bread, the traditional Bedouins
predominant source of food

There had been a considerable amount of research carried out in regards to diet and the health of populations within the greater Asia region that consumed a semi-vegetarian diet based largely on wheat. Examples include the Arab Bedouins and Yemenite Jews, both of which traditionally consumed on average more than 500 grams of bread per day.95 These populations are known for their exceptionally low rates of coronary heart disease and obesity when following their traditional wheat based diet. Perhaps the largest consumers of wheat that there is considerable data available for are the Bedouins from southern Israel. The great majority of the dietary intake of the traditional Bedouins comes from wheat, typically in the form of full-grain bread, which is especially the case for the poor who eat very little else. It was estimated that the Bedouins traditionally consumed on average 750 gm, or the equivalent of 25 slices of full-grain bread per day.95

The traditional Bedouins had many dietary traits besides an extremely high intake of whole-grain wheat that are considered by advocates of Low-Carb and Paleo diets as being primary causes of obesity and the so-called ‘diseases of civilization’, including diabetes and coronary heart disease. For example sugar intake was observed to be modestly high, a trait comparable to that of the populations in Colombia, Cuba and Venezuela who have traditionally had among the highest rates of per capita sugar consumption in the world and low rates of coronary heart disease mortality.96 97 It was estimated that dietary cholesterol intake was only 53 mg/day and saturated fat was less than 3% of caloric intake, suggesting that animal foods as a whole contributed very little to the Bedouins diet. Meat was consumed only about once per month, and virtually never eaten by the poor. Similarly egg and especially fish intake was very infrequent, although animal milk is frequently consumed. Fat intake only contributed to about 11% of total caloric intake, with a relatively low intake of omega-3 fat and a high ratio of omega-6/omega-3 fat. Vitamin A intake was very low, and for the many women who virtually never exposed their skin outside, blood concentrations of vitamin D would have likely been on the low side.96

It has been documented that diabetes and heart attacks were all but entirely absent in the traditional living Bedouins which had an average serum cholesterol of 4 mmol/l (155 mg/dl), and that the great majority of the population were exceptionally lean by western standards, both in terms of weight and skin thickness.96 98 The rates of inflammatory bowel disease were also considered to be very low.99 The few Bedouins that were observed to be obese were exclusively the wealthier elderly who rarely even walked. Being a semi-nomadic population that largely relied on walking as a means of transport, exercise has been suggested as one explanation for their exceptional low rates of obesity. However, many of the women were forced to stay inside their tents all day allowing for little exercise, yet these women with almost no exceptions were slim and free of vascular disease.96 

Researchers believe that it is the Bedouins small appetite that partly contributed to their exceptional leanness.96 Considering that about 90% of caloric intake was derived from full-grain wheat suggests that the wheat consumed was not a low satiety food, nor was it fattening. This hypothesis is consistent with the findings from a recent review of 38 epidemiological studies that found suggestive evidence that whole-grain bread intake favorably influences body weight.100 Similarly, a number of controlled experiments found suggestive evidence that wheat bread assists with satiety and weight loss in low-calorie diets.101 102 103 In addition, a recent large systematic review found that whole-grain cereals and bread are associated with a significantly decreased risk of colorectal cancer, type 2 diabetes and cardiovascular disease.104

One clear downside of the Bedouins traditional diet was a very low intake of fruits and vegetables. Although an increased intake of fruits and vegetables would likely have helped to prevent a number of potential vitamin deficiencies and improved overall health, it is clear that the traditional Bedouins were very slim and had very low rates of diabetes and heart disease despite consuming a diet that Sisson considers as a primary cause of diseases of civilization. 

Sisson referred to an article from a blogger, Ned Kock who analyzed the data from the China Study II with minimal control for confounding factors and found a positive association between wheat flour intake and cardiovascular disease mortality. However, Michel Blomgren, a statistics enthusiast who conducted a much more comprehensive analysis found that intake of wheat and a number of other staple grains were associated with a decreased risk of ischemic heart disease mortality.105 The opposite was found for animal protein and both animal and vegetable fat (Fig. 2).

Figure 2. Various foods and nutrients and risk of ischemic heart disease in a multivariate regression analysis in the China Study II, ages 35-69

Although these findings may contrast the more simple analyses produced by people like Ned Kock and Denise Minger, the greater consistency with other ecological studies, as well as other lines of evidence described previously does provide some confidence for the validity of these findings.106 107 This is not to say that this analysis is without its limitations, nor to say that an analysis with a similar degree of control examining all causes of cardiovascular disease mortality would not be more informative. However, when considered together with all other lines of evidence, this suggests that a modest intake of whole-grain wheat can be part of a health promoting diet for most people. These contrasting findings may not be considered to be all that surprising when considering that animal food intake was very strongly associated with favorable socioeconomic factors, with household income explaining up to 80% of the variance of intake between counties. Such favorable socioeconomic factors were not typically enjoyed in those counties with higher intakes of wheat, which would inevitably have had an unfavorable influence on cardiovascular disease mortality.108

In the China Study, a higher wheat intake can probably be considered as a marker of a higher concentration of certain ethnic groups, such as those from Central Asia living in northern China. Without specific data on the ethnic breakdown of each county, this makes it difficult to determine how ethnicity may have impacted these findings. However, a number of studies examining people within some of the major ethnic groups living in northern China have investigated the association between dietary factors and obesity and other cardiovascular risk factors. For example, a study found that within several ethnic groups living in Xinjiang, the region with the highest average BMI in the China Study and home to a number of nomadic populations, meat intake was associated with an increased risk of obesity, consistent with studies carried out in other regions of northern China.90 109

Although it is clear that a small portion of the population, such as those with celiac disease will benefit from eliminating wheat from their diet, there is no need to resort to making up nonsense as Low-Carb and Paleo diet advocates such as Sisson and Wheat Belly author William Davis have done about whole-grain wheat being a primary cause of obesity and diseases of civilization.110 111 The idea that whole-grain wheat should be replaced with fatty meats and eggs is clearly a step in the wrong direction, and there are certainly better alternatives for people who cannot tolerate wheat.

What is the evidence?

The assertion that the populations of Eastern and Southeast Asia were traditionally slim and healthy while consuming a high carbohydrate diet is somehow a paradox suggests that populations in other parts world have not thrived on a high carbohydrate diet. Such a suggestion ignores the evidence from healthy populations all throughout the world.

As Sisson correctly pointed out, there has been a surge in the rates of obesity, diabetes and other chronic diseases in Asia in recent decades (Fig. 1). Sisson suggests that this surge could partly be explained by changes to dietary habits, but provides scant evidence to support his claims. This merits further exploration into how the trends in dietary habits may have had an impact. As the intake of not only several of the items mentioned by Sisson, but also animal foods, especially meat has increased dramatically in Eastern and Southeast Asia over the last half century, naturally emphasis on how this has impacted the health of these populations has been the focus of much research. Part II of this review will focus on the composition of traditional diets in Asia and how certain dietary and lifestyle changes may help explain this epidemic of obesity and chronic diseases sweeping across Asia.


Please post any comments in the Discussion Thread.

Cracking Down on Eggs and Cholesterol: Part II

Recently two meta-analysis papers were published addressing the findings from population studies of the association between egg intake and the risk of cardiovascular disease.1 2 Unfortunately the authors of these two review papers reached contradictory conclusions regarding the dangers of egg intake which is likely to lead to unnecessary public confusion. The authors of the most recent meta-analysis paper reviewed studies on coronary heart disease, heart failure, diabetes and all cardiovascular diseases (CVD) combined and concluded:

Our study suggests that there is a dose-response positive association between egg consumption and the risk of CVD and diabetes.

In contrast to this conclusion, the authors of the earlier meta-analysis paper limited their review to studies that specifically addressed coronary heart disease and stroke and concluded:

Higher consumption of eggs (up to one egg per day) is not associated with increased risk of coronary heart disease or stroke. The increased risk of coronary heart disease among diabetic patients and reduced risk of hemorrhagic stroke associated with higher egg consumption in subgroup analyses warrant further studies.

The second meta-analysis paper is problematic in part because the authors failed to consider the relevant findings from dozens of rigorously controlled feeding experiments on humans and thousands of experiments on animals, including nonhuman primates that strongly support the recommendations to limit the intake of eggs and cholesterol [reviewed previously]. This paper is also problematic in part because the authors failed to consider many other relevant findings from prospective cohort studies which suggest that egg and cholesterol intake increases the risk of coronary heart disease, diabetes, heart failure, cardiovascular disease and all-cause mortality.

Firstly, the association between egg intake and the risk of cardiovascular disease is meaningless without considering suitable substitutes for eggs. As a lower intake of eggs implies a higher intake of other foods in order to maintain caloric balance, the effect that egg intake has on coronary heart disease depends on which foods eggs are substituted for. For example, data from the Nurses’ Health Study, one of the largest studies included in these meta-analyses suggested that replacing one serving of nuts, but not red meat and dairy with one serving of eggs per day is associated with a significantly increased risk of coronary heart disease.3 The authors of both meta-analyses failed to address this factor despite the fact that the importance of evaluating suitable food alternatives has been strongly emphasized by many prominent diet-heart researchers.4 The findings from these meta-analyses should therefore be interpreted with caution as eggs may have been primarily compared to processed foods and other animal foods which make up the majority of caloric intake in developed nations.4 5

Eggs, Cholesterol and Diabetics

The authors of the most recent meta-analysis paper found that among diabetics, frequent egg intake was associated with a 83% increased risk of cardiovascular disease, whereas the authors of the earlier meta-analysis paper found that frequent intake was associated with a 54% increased risk of coronary heart disease. The authors of the most recent meta-analysis paper excluded one, while the authors of the earlier meta-analysis paper excluded two additional cohort studies that found that among diabetics, high compared to low intake of eggs was associated with an approximately five-fold increased risk of cardiovascular disease.6 7 These additional studies had they been addressed by these authors would have potentially strengthened the association between egg intake and an increased risk of cardiovascular disease in diabetics.

The authors of the most recent meta-analysis found that frequent egg intake was associated with a 68% increased risk of type II diabetes, a major risk factor for cardiovascular disease. However, the authors of the earlier meta-analysis largely failed to address this evidence. A literature search I performed produced papers from 5 separate prospective cohort studies addressing egg intake and the risk of developing type II diabetes, including two additional studies that were not addressed in both meta-analyses papers.8 9 10 11 In addition, I also found one additional cohort study addressing egg intake and the risk of developing gestational diabetes.12 All except one smaller cohort found a statistically significant association after adjusting for potential confounders. These cohorts also found suggestive evidence that the increased risk persisted regardless of whether eggs were consumed in the presence of a higher or lower carbohydrate diet, and that the association was even stronger when repeated measurements of egg intake were considered.9 In addition, these cohorts also found suggestive evidence that the increased risk could partly be explained by the dietary cholesterol and protein content of eggs, and that substituting eggs with carbohydrate-rich foods, especially fiber-rich bread and cereals significantly decreases the risk of developing type II diabetes.8 9 11 12

In the one cohort that did not find a statistically significant association, average egg intake was relatively low and there was suggestive evidence of an increased risk when a follow-up measurement of egg intake was used to update exposure overtime.10 In addition to these findings, a paper from the Health Professionals Follow-Up Study also found suggestive evidence that egg intake is associated with an increased risk of type II diabetes.13 Furthermore, papers from an additional 5 cohort studies found that dietary cholesterol was associated with a significantly increased risk of developing either type II diabetes or gestational diabetes.14 15 16

Overall findings from 12 prospective cohort studies with 265,675 participants and 14,497 cases of type II diabetes and gestational diabetes strongly implies that egg and cholesterol intake are significant risk factors in the development of diabetes. In addition to the findings from cohort studies, 4 cross-sectional studies found that egg or cholesterol intake was associated with between a nearly two-fold and greater than four-fold increased risk of developing type II diabetes and gestational diabetes.12 17 18 19 Also consistent with these findings, in the Adventist Health Study 2 it was observed that vegans had a lower risk of developing type II diabetes compared to lacto-ovo vegetarians, and especially non-vegetarians.20

One cohort included in these meta-analyses that used repeated egg intake measurements to update exposure over time found that in diabetics, intake of at least 7 eggs compared to less than 1 egg per week was associated with a two-fold increased risk of all-cause mortality, whereas another cohort that did not use repeated measurements found suggestive evidence of a 30% increased risk of all-cause mortality.21 22 The authors of the first study stated:

…among male physicians with diabetes, any egg consumption is associated with a greater risk of all-cause mortality, and there was suggestive evidence for a greater risk of MI [heart attack] and stroke.

An additional study found that in diabetics, an increment of one egg per day was associated with a greater than three-fold increased risk of all-cause mortality.6

According to the International Diabetes Federation, globally approximately 183 million people, or half of those who have diabetes have not been diagnosed. Even in high-income countries about one-third of people with diabetes have not been diagnosed.23 Given this data and the data that egg and cholesterol intake is associated with a significantly increased risk of developing diabetes, and that in diabetics egg intake is associated with a significantly increased risk of coronary heart disease, cardiovascular disease and all-cause mortality, there is likely a significantly greater number of people at risk than suggested by the authors of these recent meta-analyses.

Eggs, Cholesterol and Non-Diabetics

The Nurses’ Health Study found that an increment of cholesterol equivalent to one medium size egg per day was associated with a 17% increased risk of all-cause mortality, consistent with the findings from several other studies.24 25 26 Another study included in these meta-analyses found that in non-diabetics, intake of at least 7 eggs compared to less than 1 egg per week was associated with a 22% increased risk of all-cause mortality.21 Also, another cohort from Japan found that frequent egg intake was associated with an increased risk of all-cause mortality in women, consistent with the findings from the Adventists Mortality Study.27 28 In addition, a cohort of elderly found suggestive evidence that egg intake was associated with a significantly increased risk of all-cause mortality, and that substituting eggs with fruits, vegetables and grains significantly decreases risk.29

The authors of the most recent meta-analysis paper found that in largely non-diabetic populations that frequent egg intake was associated with 19% increased risk of cardiovascular disease compared to all other sources of calories combined, which is predominantly processed foods and other animal foods. The authors of the earlier meta-analysis that did not reach this conclusion suggested that their findings are relevant for total cardiovascular disease but failed to address the findings from prospective cohort studies regarding the risk for heart failure. For example, two cohort studies which were included in the most recent meta-analyses found that intake of at least 7 eggs compared to less than 1 egg per week was associated with an approximately 30% increased risk of heart failure.30 31

Another potential important finding that has contributed to the knowledge of the dangers of eggs are the results from studies that were carried out on populations with a low habitual cholesterol intake, such as vegetarian populations. The authors of the most recent meta-analysis paper excluded one, while the authors of the earlier meta-analysis paper excluded two cohort studies that were carried out on largely vegetarian populations. Frequent consumption of eggs was associated with a more than 2.5 increased risk of fatal coronary heart disease in the Oxford Vegetarian Study and also an increased risk in females in the Adventists Mortality Study.28 32 The characteristics of the participants in these studies differ from that of most other studies, not only because of the their lower habitual intake of dietary cholesterol, but also because of their lower rates of obesity and typically healthier overall diet. Therefore separately analyzing egg intake in this subgroup of the population may be of significant importance. The authors of a paper from the Nurses’ Health Study and the Health Professionals Follow-Up Study cited in these meta-analyses described the potential importance of addressing egg intake in people with very low habitual cholesterol intake and how their study may have been inadequate to test this hypothesis: 33

One potential alternative explanation for the null finding is that background dietary cholesterol may be so high in the usual Western diet that adding somewhat more has little further effect on blood cholesterol. In a randomized trial, Sacks et al found that adding 1 egg per day to the usual diet of 17 lactovegetarians whose habitual cholesterol intake was very low (97 mg/d) significantly increased LDL cholesterol level by 12%. In our analyses, differences in non-egg cholesterol intake did not appear to be an explanation for the null association between egg consumption and risk of CHD. However, we cannot exclude the possibility that egg consumption may increase the risk among participants with very low background cholesterol intake.

As it is well documented that cholesterol intake has a much greater effect of raising serum cholesterol when baseline intake is very low, this may in part explain why egg and cholesterol intake was more strongly associated with coronary heart disease in studies on largely vegetarian populations.34 35 Another explanation for a possibly stronger association in vegetarian populations is that egg intake may have a greater effect in leaner people, and it has been well documented that vegetarians are generally leaner than their omnivorous counterparts [reviewed previously]. This hypothesis is supported by several dietary experiments which found that dietary cholesterol had a greater effect of raising serum cholesterol among leaner compared to overweight participants.36 37 This hypothesis is also supported by the findings from the Chicago Western Electric Study which found that while dietary cholesterol was associated with a significantly increased risk of coronary heart disease in lean men over and above the adverse effects it has on serum cholesterol, increased intake had little appreciable effect on men with a greater BMI and body fatness.38 Another explanation for these findings is that vegetarians may choose healthier substitutes for eggs, such as nuts which was associated with a significantly lower risk of coronary heart disease compared to eggs in the Nurses’ Health Study.3

It was found in a sub-analysis based on 4 cohorts included in the earlier meta-analyses that egg intake was associated with an 18% non-significant increased risk of fatal coronary heart disease. The addition of the mortality findings from the two largely vegetarian cohorts that were excluded from this meta-analysis would have likely strengthened this association.28 32 This suggests that similar to saturated fat intake, egg intake may increase the risk of fatal coronary heart disease more than non-fatal coronary heart disease [reviewed previously]. The lack of a significant association likely reflects the fact that eggs were not compared to healthy foods, and also likely due to misclassification of participants into ranges of usual dietary intake as the result of measurement error [reviewed previously].

In the video below Dr. Michael Gregor addresses recent research on choline when consumed from eggs and other animal foods and the risk of cardiovascular disease and cancer.

Carnitine, Choline, Cancer and Cholesterol: The TMAO Connection

Egg Intake and Stroke

In regards to a sub-group analysis of 5 cohort studies, the authors of the earlier meta-analysis suggested that egg intake was associated with a lower risk of hemorrhagic stroke. The authors suggested that the inverse association between egg intake and hemorrhagic stroke is supported by findings of an inverse association between serum cholesterol and hemorrhagic stroke in several cohort studies. However, in the largest cohort study the authors cited, the inverse association was confined to participants with elevated blood pressure.39 A similar interaction between blood pressure and serum cholesterol and hemorrhagic stroke was observed in much larger cohort studies in both Asian and Western populations that the authors of this meta-analysis conveniently failed to cite.40 41 In a meta-analysis of 61 cohort studies it was found that among participants with near optimal systolic blood pressure (<125 mmHg), lower serum cholesterol was actually associated with a significantly lower risk of hemorrhagic, ischemic and total stroke mortality [reviewed previously]. Furthermore, most mammalian species have very low LDL levels (mean value of 42 mg/dl in 18 species), and there is very scant evidence that these animals are at high risk of having a stroke.42

This data demonstrates that continued emphasis should be placed on lowering both LDL cholesterol and blood pressure which have been proven in hundreds of randomized controlled trials to lower not only the risk of cardiovascular disease, but also all-cause mortality.43 44 Increasing the intake of eggs after achieving a near optimal blood pressure is unlikely to reduce the risk of hemorrhagic stroke and will likely increase the risk of dying of any cause.

Unwarranted Mediocre Health Recommendations

The conclusions of the earlier meta-analysis are misleading and inconsistent with the body of literature. What is more concerning is that these findings will likely be used in marketing campaigns to confuse the general population, of which the great majority are already at risk of cardiovascular disease. The most recent meta-analysis paper while being overall informative and more clearly demonstrating the dangers of eggs for both diabetics and non-diabetics, the authors still failed to address many important findings that have been addressed in this series of posts. A greater emphasis on the effects of replacing eggs with other suitable foods is required, and the available evidence suggests a significant benefit of replacing eggs with whole plant foods, including fruits, vegetables, whole grains and nuts.3 11 29 As Spence and colleagues pointed out in regards to recent controversy surrounding dietary cholesterol and eggs:45

…the only ones who could eat egg yolk regularly with impunity would be those who expect to die prematurely from nonvascular causes.

Diet-Heart Posts

Part I - Diet-Heart: A Problematic Revisit
Part II - Diet-Heart: Saturated Fat and Blood Cholesterol
Part III - Diet-Heart: The Role of Vegetarian Diets in the Hypothesis
Part IV - Cracking Down on Eggs and Cholesterol

Please post any comments in the Discussion Thread.

Diet-Heart: A Problematic Revisit

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.

The Problem of Overadjustment 

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.

The Problem of Dietary Assessment Methods 

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. 

The Problem of Dietary Modification

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

The Problem of the Comparison Group

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 Problem of Reductionism

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. 

The Problem of Conflicts of Interests 

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. 

Diet-Heart Posts

Part II - Diet-Heart: Saturated Fat and Blood Cholesterol

Part III - Diet-Heart: The Role of Vegetarian Diets in the Hypothesis
Part IV - Cracking Down on Eggs and Cholesterol
Part V - Cracking Down on Eggs and Cholesterol: Part II


Please post any comments in the Discussion Thread.