Abstract

BACKGROUND: Advisory committees worldwide state that saturated fat consumption increases serum 'bad' LDL-cholesterol levels, and therefore increases risk of cardiovascular disease (CVD). This is a simplistic approach, not taking into account the effects of saturated fat intake on 'good' HDL-cholesterol. If saturated fat intake is to increase CVD risk, than it would be expected that epidemiological studies show increased rates of CVD from consumption of saturated fat, and from consumption of dietary sources of saturated fat (such as animal fat, meat fat, and dairy fat).
Over the years, systematic reviews were published relating several types of dietary fats to CVD. But effects from animal/vegetable fat, specific fatty acids, and dietary cholesterol were not examined.
OBJECTIVES:

• The primary objective was to review all prospective studies which published information about dietary fat, dietary cholesterol, and specific types of dietary fat in relation to cardiovascular disease, coronary heart disease (CHD), and stroke.
• To examine if results from randomized trials about substitution of dietary fats can be attributed to the changes in saturated fat intake.
• To examine if changes in serum cholesterol - caused by changes in consumption of dietary fat - can predict subsequent changes in CHD.
• To examine if conclusions from advisory committees regarding saturated fat intake in relation to CVD are valid, and based on the data available from the literature.

DATA SOURCE: The Pubmed database was searched (No start date - Dec 13, 2010) for relevant articles using the keywords "dietary cholesterol, dietary fat, monounsaturated fat, omega 3, omega 6, omega 9, polyunsaturated fat, saturated fat, or trans fat" combined with "prospective, cohort, follow-up, or longitudinal". The exact search term is described Here.
Prospective studies published in the English language were included. Reference lists were searched for additional articles.
RESULTS FROM THE SYSTEMATIC REVIEW OF PROSPECTIVE STUDIES: 106 articles were found which provided information about 47 different cohorts. Of these, 0 articles were excluded.
Results are described when any evidence for an association - as defined in the Methods - was found.

• Saturated fat Very low consumption (≤ 17-20 g/day) of saturated fat possibly increases risk of intraparenchymal hemorrhage. No evidence was found for an association with total cardiovascular disease and coronary heart disease.
• Trans fat Suggestive evidence was found that trans fat consumption increases coronary heart disease risk (+ 22%). Stratified analysis showed that an increased risk was found for processed/vegetable trans fat at high consumption (+ 39% at ≥ 5.1-5.7 g/day), but not for ruminant/animal trans fat. No evidence was found for an association with total cardiovascular disease and stroke.
• Dietary cholesterol Suggestive evidence was found that dietary cholesterol increases total cardiovascular disease risk (+ 41%). But 4 out of 5 available cohorts were of very small size, and no evidence was found for an association with coronary heart disease and stroke.
• Other dietary fats Inconclusive/no evidence was found that total fat, animal fat, vegetable fat, total omega-3 fatty acids, total omega-6 fatty acids, monounsaturated fat, polyunsaturated fat, total long-chain omega-3 fatty acids from all dietary sources, or long-chain omega-3 from fish sources are associated with total CVD, CHD risk, CHD mortality, and stroke.

RESULTS FOR THE SECONDARY OBJECTIVES:

• Analysis of randomized trials about substitution of dietary fats showed that a large amount of confounders was able to influence the effects on CVD. None of the intervention trials was able to isolate the effect from saturated fats on CHD.
• Analysis of randomized trials about substitution of dietary fats showed that changes in serum cholesterol, caused by changes in dietary fat intake, are not predictive of CHD risk.
• Analysis of the validity of conclusions from 3 advisory committees (Institute of Medicine. 2005; USDA/USDHHS. 2010; and EFSA. 2010) shows that all advisory committees ignored results from the majority of both randomized trials and prospective cohort studies. Effects from 'good' HDL-cholesterol on CVD, caused by saturated fat intake are ignored consistently. And true results from the scientific literature were manipulated to better fit advices in 2 out of 3 reports.

CONCLUSIONS : Few effects were found. Very low consumption of saturated fat possible increases risk of intraparenchymal hemorrage, and high consumption of processed/vegetable trans fat possibly increases CHD risk. Both findings should be interpreted with care since no evidence was found for an association with total CVD. Suggestive evidence was found that dietary cholesterol intake increases CVD risk. This association should also be interpreted with care since no evidence was found for an association with either CHD or stroke. Inconclusive evidence was found for an association between any other type of dietary fat and any type of CVD.
All available evidence from randomized trials and prospective cohort studies relating saturated fat to CVD should be taken into account. When effects from saturated fat intake on both intermediate end points (such as cholesterol), and direct end points (CVD) are considered, no evidence at all can be found that saturated fat intake influences CVD risk. Ignoring the majority of the available evidence, and manipulation of true results from the scientific literature were necessary to make advisory committees conclude that saturated fat intake increases CVD.
PERSPECTIVE: Some conclusions may contradict findings from other authors. This is probably caused by the fact that a different methodology was used for the definition of evidence. Meta-analysis may "create" a significant effect from heterogeneous data including many nonsigificant associations. In the case of long-chain omega-3 fatty acids, some significant associations were found with CHD. But if these associations are found in cohorts in which the cumulative amount of cases captures only a small minority of the total amount of cases from all cohorts, we should ask ourselves if an effect found by meta-analysis can lead to valid conclusions. The same uncertainty comes from small effects after meta-analysis of data including significant results from cohorts of very small size only, while no associations are found in cohorts of moderate-large size. I suggest a methodology in which both the effect size after meta-analysis, and results from individual studies should be taken into account. Conclusions based on data gathered this way are less likely to fluctuate over time, decreasing the chance that dietary advices need to change every now and then.
THE FUTURE OF ADVICES: A large international team of researchers, including Walter Willett, recently reviewed the evidence relating the advice to reduce saturated fat intake in order to reduce CHD risk (Astrup A. 2011). They came to the following conclusions:

Introduction.

Consumption of saturated fat increases levels of LDL- (bad) cholesterol. And LDL-cholesterol increases risk of heart disease. These correlations have led to worldwide recommendations to decrease consumption of saturated fat in order to decrease risk or heart disease.
Generally, advisory committees/scientists use 3 types of support for these recommendations:

• Results from randomized studies have shown that saturated fat consumption increases cholesterol levels.
• Intervention studies have shown that the decrease of saturated fat, and simultaneous increase of polyunsaturated fat in the diet, decreases CHD risk.
• Prospective cohort studies have shown that saturated fat intake increases coronary heart disease risk.

All types of support will be discussed, and brought into perspective with data from other types of evidence.

Theory 1: Results from randomized studies have shown that saturated fat consumption increases cholesterol levels.

Often, advisory committees and scientists use the same article to prove that saturated fat intake negatively influences cholesterol: A meta-analysis of 60 randomized studies examined the effects of replacing carbohydrates by different types of fat (Mensink RP. 2003). The feeding studies included lasted between 13 and 91 days.
What did this meta-analysis find?
The analysis showed that replacing carbohydrates by saturated fat increased cholesterol levels, but contrary to what is often suggested, this effect is not necessarily disastrous. Both the levels of 'bad' LDL-cholesterol, and 'good' HDL-cholesterol increased significantly. Saturated fat consumption increased HDL-cholesterol to an even larger extend than both monounsaturated-, and polyunsaturated fat. Saturated fat significantly increased total cholesterol levels, but the ratio of total:HDL-cholesterol was not influenced.
The authors found that replacing carbohydrates with any food source rich in dietary fats will improve the ratio total:HDL cholesterol:

And the predicted changes were calculated:

Do subjects with higher cholesterol levels have an increased risk of cardiovascular disease?
A meta-analysis of 61 prospective studies examined the relation between cholesterol, and mortality from cardiovascular disease (Prospective Studies Collaboration. 2007). Subjects with higher cholesterol levels had a significantly increased risk of CHD mortality, but the ratio total:HDL-cholesterol was the strongest predictor of CHD mortality. And both HDL-cholesterol, and LDL-cholesterol levels were independent predictors of mortality from CHD.
Is focusing on effects on cholesterol causes by increased saturated fat intake a reliable way to predict effects on heart disease?
The researchers from the meta-analysis about effects of fat on the cholesterol (Mensink RP. 2003) warn against focusing on the effects of intermediate end point:

They also warn against focusing on just one single intermediate end point:

And long-term effects are unknown:

Conclusion: Saturated fat consumption increases both HDL-, and LDL-cholesterol levels compared to carbohydrates, without changing the ratio total:HDL-cholesterol. Subjects with higher cholesterol levels probably have increased risk of mortality from CHD compared to subjects with lower cholesterol levels, but the ratio total:HDL-cholesterol was a much stronger predictor of this association. Dietary fats will probably - apart from their effects on cholesterol levels - also influence other intermediate end points for CHD, and how the sum of the different effects from the various intermediate end points will eventually influence risk of CHD, can not be predicted.

Theory 2: Intervention studies have shown that the decrease of saturated fat, and simultaneous increase of polyunsaturated fat in the diet, decreases CHD risk.

In the past years, several systematic reviews of randomized studies were published which looked at the effect of replacing saturated fat by polyunsaturated fat (Hooper L. 2000/2001; Skeaff CM. 2009; Mozaffarian D. 2010; Ramsden CE. 2010). Results of these systematic reviews can be seen in the following table. Studies examining the effects of polyunsaturated fat consumption from fish were mostly not included in these systematic reviews. Since results from all randomized trials were published well before the year 2000, all authors were able to include data from all available trials.

Results from the 4 systematic reviews were similar for CVD/CHD risk, but differed for CVD/CHD mortality, and mortality from all causes.
The 4 reviews included different randomized trials:

• The Finnish Mental Hospital Trial (Turpeinen O. 1979; Miettinen M. 1983) was only included by Skeaff CM, and Mozaffarian D. In this trial, subjects were not randomized to the dietary trial group, or the control group on an individual level. Instead, all subjects in one hospital were allocated to the experimental group, while all subjects in another hospital were allocated to the control group. Six years later, the hospitals switched their diets.
• The Rose Corn Oil Trial (Rose GA. 1965) was included in all reviews, except the one from Mozaffarian D. Except for this trial, Skeaff CM and Mozaffarian D included the same 7 trials.
• The DART Study (Burr ML. 1989) was included in all reviews, except the one from Ramsden CE. This author stratified effects by differences in the type of dietary polyunsaturated fats included in the experimental diets. And the DART Study did not provide data about the specific n-6 and n-3 PUFA composition of the study diets.
• The Sydney Diet-Heart Study (Woodhill JM. 1978) was only included by Hooper L, and Ramsden CE. The trial provided data about all-cause mortality, but not about CVD/CHD. But Ramsden CE pointed out that all-cause mortality increased by 49% in this study, and 61 of 67 deaths were attributed to CHD. Therefore, failure to publish the full dataset of this negative study probably led to an overestimation of the beneficial effects of cholesterol-lowering polyunsaturated fat diets on CHD.
• Note: Results for mortality from all causes differed between Skeaff CM, and Mozaffarian D, while the same cohorts were included for this analysis. This may be caused by the possibility that Skeaff CM interpreted results from "The Finnish Mental Hospital Trial" incorrectly (Miettinen M. 1972). Skeaff CM found a significant protective effect against mortality (- 26% for men, and - 27% for women), while the authors from this trial themselves found no effect among women, and a small non-significant protective effect among men. It is possible that Skeaff CM overlooked the fact that the control group was followed for a longer period of time (3.13 y for women, and 2.93 y for men, respectively) compared to the invervention group (2.60 y for women, and 2.38 y for men, respectively.
• Note: The analysis by Hooper L differed to a large extend from the analysis by Mozaffarian D, and Skeaff CM. More studies were included, while less subjects died. This is partly because no subjects got sick or died in 13 out of 27 included studies during the trial period, and this is partly because "The Finnish Mental Hospital Trial" was excluded from the analysis. The latter trial included 1,285 deaths from all causes.

It seems that results from the "The Finnish Mental Hospital Trial" can explain the differences between the 4 systematic reviews to a large extend. This trial was excluded in 2 reviews (Hooper L. 2000; Ramsden CE 2010), and the size of the protective effect against all-cause mortality is probably overestimated in another review (Skeaff CM. 2009).

Results from the 4 systematic reviews of randomized trials:
All 4 reviews found a protective effect against risk of CVD/CHD from replacing saturated fat by polyunsaturated fat. Risk decreased by 15-19%. Hooper L (2000) showed that all effects lost significance when "The Oslo Diet-Heart Study" (Leren P. 1970) was excluded in which the intervention group was additionally randomized to fish consumption. This study was included in all 4 systematic reviews. After exclusion of this study the RR's became (0.86; 95% CI = 0.72-1.03 for CVD risk, 0.94; 95% CI = 0.79-1.11 for CVD mortality, and 1.02; 95% CI = 0.91-1.14 for mortality from all causes).
Only one out of four systematic reviews found a nonsignificant protective effect against all-cause mortality from replacing saturated fat by polyunsaturated fat (Skeaff CM. 2009). And as can be seen above, the author probably overestimated the size of this effect. All other authors found no effect on all-cause mortality (RR's of 0.98, 0.99, and 1.02 for Mozaffarian D, Ramsden CE, and Hooper L, respectively).
Does it matter which type of polyunsaturated fats is used to replace saturated fat?
Ramsden CE showed that effects differed by type of polyunsaturated fats used for the substitution of saturated fats. RR's for all end points were > 1 when trials examining n-6 specific polyunsaturated fats (linoleic acid) were used, and RR's for all end points were < 1 when trials examining both n6 and n3 polyunsaturated fats (alpha-linolenic acid) were used:

In all trials saturated fat intake lowered, while polyunsaturated fat intake increases. So which type of fat was responsible for the effect on CHD found in the systematic reviews?
None of the 4 systematic reviews analyzed the probability that any of the given effects was caused by any specific type of dietary fat. At least in the articles mentioned above......
The systematic review by Hooper L was published twice (2000, 2001). The version mentioned above was published in 2000, and was included in the Cochrane Database. In 2001 the review was published again. And in this second version the author tried to explore the relation between change in proportion of total fat, saturated fat, polyunsaturated fat, and monounsaturated fat on cardiovascular events. This analysis showed no evidence for an effect by total fat, saturated fat, and polyunsaturated fat, while monounsaturated fat significantly increased risk of cardiovascular events. The author warns that these results should be treated with caution, but clearly this analysis does not fuel the hypothesis that saturated fat consumption plays a major part in risk of cardiovascular events.

Can changes in serum cholesterol - which are caused by changes in consumption of dietary fat - predict subsequent changes in CHD in a reliable way?
Randomized studies consistently showed that dietary changes, aimed at substitution of polyunsaturated fat for saturated fat, decreased serum cholesterol levels. A global look at the subsequent effect on CHD suggests that these decreased levels of serum cholesterol, often correspond fairly well with the predicted decrease in CHD rates. But when more detailed findings are taken into account, little evidence remains that changes in serum cholesterol created by changes in dietary fat intake are predictive of CHD rates. Full details about this analysis can be found here: link.
Results from randomized trials of substitution of dietary fats are often used to "prove" a causal relation between consumption of saturated fat and CHD. But can results from these trials be attributed to the changes in saturated fat intake, or could other dietary and non-dietary changes have contributed to these results?
Various confounders were able to influence the effect of replacing saturated fats by polyunsaturated fats. Sometimes, experimental groups were randomized to a complete mediterranean diet, including increased consumption of vegetables and fruits. The effect of reduced trans fat intake in the experimental groups, is likely to have attributed to the protective effects against coronary heart disease in all 8 trials. Saturated fat was replaced by polyunsaturated fat in all trials, and dietary cholesterol intake correlated strongly to saturated fat intake. Subsequently, none of the trials involved in the analysis was able to isolate the effect from saturated fats on CHD. Full details about this analysis can be found here: link.

Conclusions by the authors from the 4 systematic reviews of randomized trials to decrease saturated fat consumption, and simultaneously increase polyunsaturated fat consumption:
1) In 2000 Hooper L published his systematic review in the Cochrane Database. The following recommendation was made:

But neither in the "results", nor in the "discussion" part of the article is any information given that an examination was done of the specific part of saturated fat in this effect. This suggest that his conclusion was based on an assumption, rather than on actual research.
In 2001 Hooper L published the same systematic review again and - as shown above - not saturated fat, but monounsaturated fat was found responsible for the increased risk of CVD events. This made the author come to another conclusion:

2) In 2009, Skeaff CM concluded the following:

Also, this author concluded that substitution of saturated fat for carbohydrates, probably will not effect CHD events, and fatal CHD (see table 4 in the related article).
3) In 2010, Mozaffarian D, concluded the following:

4) In 2010, Ramsden CE did not mention the specific effect of saturated fat.

Conclusion: In the past, several dietary interventions trials were done to decrease consumption of saturated fat, and simultaneously increase consumption of polyunsaturated fat. Systematic reviews of these trials show that such an intervention may decrease risk of CVD/CHD by 15-19%, but will probably not increase survival. When only randomized trials were included, and when dietary interventions with fish consumption were excluded, no significant associations were found of replacing saturated fat by polyunsaturated fat (- 14% for CVD risk, - 4% for CVD mortality, and + 2% for all-cause mortality).
An analysis of randomized intervention trials showed that total fat, saturated fat, and polyunsaturated fat did not influence risk of CVD events. Instead, monounsaturated fat consumption was found to significantly increase risk of CVD events. Furthermore, changes in serum cholesterol, caused by changes in dietary fat intake are not predictive of coronary heart disease risk. Finally, a large amount of confounders was able to influence the effects on CVD from substitution of dietary fats. None of the intervention trials involved was able to isolate the effect from saturated fats on CHD.

Theory 3: Prospective cohort studies have shown that saturated fat intake increases coronary heart disease risk.

According to the Institute of Medicine, the majority of epidemiological studies have reported an association between saturated fat intake and risk of CHD (Institute of Medicine. 2005). This conclusion is based on incorrect citing of true results from these studies: Read
In the past 3 systematic reviews of prospective studies were published, examining the relation between consumption of saturated fat and CHD or stroke (Skeaff CM. 2009; Mente A. 2009; Siri-Tarino PW. 2010). These were all published recently. In a fourth systematic review the effects of replacing saturated fat by other macronutrients were examined (Jakobsen MU. 2009).

High vs low consumption of saturated fat: Results from the first three systematic reviews are shown in the table below. None of these reviews found a significant association with CHD or stroke of high vs low consumption of saturated fat.
Replacing saturated fat by unsaturated fat or carbohydrates: In 2009, Jakobsen MU published a systematic review about the effects on CHD of replacing saturated fat by 3 other macronutrients. Eleven cohorts were included in this analysis. Replacement by polyunsaturated fat decreased both risk-, and mortality from CHD. Replacement by monounsaturated fat or carbohydrates increased CHD risk - but not CHD mortality - among men.

Conclusion: In the past, 3 systematic reviews examined the effect of high vs low consumption of saturated fat on CHD or stroke. None of these reviews found a significant association. A fourth review shows the effect of lowering saturated fat is probably related to the nutrient it is replaced by. In this case polyunsaturated fat may decrease CHD risk and mortality, while monounsaturated fat and carbohydrates may increase CHD risk among men.

Meat fats and dairy fats in relation to cardiovascular disease and all-cause mortality.

Previously, I examined the relation between both meat- and dairy fats in relation to both CVD and all-cause mortality, based on results from prospective studies. The literature search covered the period until may 25, 2010.
In short, results are as follows:

• Meat fats and CVD None of the articles presented data about the relation between lean meats vs fatty meats for any type of meat.
• Dairy fats and CVD No consistent differences in effect were found between full-fat and low-fat versions of total dairy products, milk, and cheese.
  Butter and margarine were not independently related to CHD, but within cohort comparisons showed RR's were lower for butter than for margarine in 5 out of 6 cohorts. In contrast, margarine possibly protects against stroke mortality among women, and butter possibly increases risk of intracerebral hemorrhage. Other fat dairy products were not linked to increased CVD rates: Cheese possibly decreases risk of ischemic stroke, and cream might protect against the sum or CHD and stroke.
• Meat fats and all-cause mortality No associations were found.
• Dairy fats and all-cause mortality no evidence was found for a modifying effect of dairy-, milk-, and cheese fat on the association between the related items and mortality. And no evidence was found for a difference in effect between butter and margarine.

Conclusion: Results from prospective studies show that full-fat dairy items and low-fat dairy items do not consistently differ in their effects on CVD. Certainly, no conclusion can be drawn that margarine intake decreases CHD rates relative to butter. No data is available about the relation between meat fats and CVD.

Are the conclusions from advisory committees, about the relation between saturated fat and cardiovascular disease, valid?

Advices are based on conclusions and summaries of findings from literature searches. Ideally, these literature searches cover all relevant data available, according to a predefined set of criteria. This is called a systematic review. By standard, a systematic review never excludes results from individual studies found without a clear motivation.
As mentioned before, advisory committees include 3 types of data to judge the evidence relating saturated fat intake to cardiovascular disease:

• Randomized trials examining the effect of saturated fat intake on serum cholesterol.
• Randomized trials examining the effect of substitution of polyunsaturated fat for saturated fat in relation to cardiovascular disease.
• Prospective cohort studies examining the direct effect of saturated fat intake on cardiovascular disease.

If advisory committees want to make valid conclusions based on all available evidence, they have to use data from systematic reviews covering these 3 topics, or they have to do a systematic literature search themselves.
The table below is an overview of the criteria used to judge the evidence linking saturated fat intake to CVD/CHD in 3 different reports. The reports included are as follows. Full details about missing data and incorrect citations in these reports can be seen by clicking on the related item:

• The dietary reference intakes for macronutrients 2005, by the Institute of Medicine (Read full details).
• The dietary guidelines for Americans 2010, by the USDA, and the USDHHS (Read full details).
• The scientific opinion on dietary reference values for fats 2010, by the EFSA (Read full details).

Did the 3 European and US reports include all data available?

• The EFSA report based it's evidence for the relation between saturated fat intake and serum cholesterol on a systematic review of randomized trials (Mensink RP. 2003). Both other reports only included only a small amount of the available evidence.
• All 3 reports mentioned that saturated fat intake increases serum LDL-cholesterol and that serum LDL-cholesterol increases risk of CVD/CHD.
• Only 2 out of 3 reports mentioned that saturated fat intake increases serum HDL-cholesterol. All reports failed at mentioning that serum HDL-cholesterol decreases CVD/CHD risk. None of the reports discussed the reason for this. One report cited the effect of saturated fat intake on serum HDL-cholesterol incorrectly.
• The EFSA report was the only report to include data from randomized trials about the effect of substitution of dietary fats in relation to CVD. It failed at defining results from available systematic reviews (Hooper L. 2000, 2001), and it failed at describing the true dietary interventions used in these trials.
• All 3 reports failed at systematically reviewing the available results from prospective cohort studies. The EFSA report included just one single cohort study. Both other reports did not only fail to include data from all available cohorts, but they also failed at correctly citing the true results from this limited amount of data.

Conclusion: None of the 3 European and US reports evaluated all available evidence. Instead most of the available evidene from both randomized trials and prospective cohort studies were ignored. Though 2 reports mentioned the fact that research has shown that saturated fat increases HDL-cholesterol to an even larger extend than unsaturated fats, none of the reports found it necessary to discuss the finding that HDL-cholesterol decreases CHD mortality (Prospective Studies Collaboration. 2007). Both US reports did not find it necessary to define results from prospective cohort studies, the way they were defined in the articles referred to. Instead, incorrectly defined results fitted their "advice" better.

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