21-10-2021 | 08:00

 

One of the longest standing public health nutrition recommendations has been the target of keeping dietary saturated fat at or below 10% of energy intake. This was based on a body of evidence developed from the 1950’s to the 1970’s, including metabolic ward studies, migrant studies, and prospective cohort studies (1–3).

 

This is a critical first point in light of the current scientific status quo in relation to low-density-lipoprotein cholesterol [LDL-C], which has been established as the primary causal factor in cardiovascular disease [CVD] (4,5). A revisionist narrative of heart disease frames the initial emphasis on saturated fat as if it was derived exclusively from the Seven Countries Study; this is plainly incorrect. Human evidence for the influence of diet on blood lipids began to develop more earnestly from the late 1940’s, with the acceptance at that time that atherosclerosis was not merely a byproduct of ageing, but an overt pathology (6). The first robust metabolic ward feeding studies comparing the effects of vegetable fat and animal fat on blood lipids found that, while vegetable fat resulted in significant reductions in blood cholesterol levels, substituting the vegetable for animal fat in the patients resulted in increased blood lipids (7,8). Reverting the patients to the high vegetable fat diet lowered the concentration of blood cholesterol again.

 

These findings were repeatedly confirmed, in particular with the metabolic ward studies by Ancel Keys [yes, he contributed significantly to the body of knowledge, not merely the Seven Countries Study], which robustly demonstrated that saturated fats have a 2-fold greater effect on raising blood cholesterol levels compared to the cholesterol lowering effect of polyunsaturated fat (3). The Keys Equation, developed from these studies to model changes in blood cholesterol levels from changes in saturated and polyunsaturated fat, still stands to this day (9).

 

With the benefit of hindsight, this evidence from robustly controlled metabolic ward studies showed that saturated fat increased the causal biomarker for CVD. This is relevant to the early epidemiology on saturated fat and coronary heart disease [CHD] because levels of saturated fat intake were far greater than population averages today in many countries. The current target of 10% energy is based on the risk reduction from decreasing saturated fat from higher levels of intake when both absolute intake and percentage energy were high. To put this issue of percentages vs. absolute intake into the historical context of saturated fat literature, it is instructive to look at certain cohorts from the Seven Countries Study [SCD] (1,10):

 

• East Finish cohort: 88g = 22% SFA
• West Finish cohort: 73g = 19% SFA
• Dutch cohort: 60g = 20% SFA
• Croatian cohort: 69g = 17% SFA
• US cohort: 55g = 21% SFA

 

Detecting effects of saturated fat on CHD in a population, mediated by effects on the causal LDL-C pathway, was clearer with such high levels of intake. In the 25-year follow-up of the SCD, only saturated fat, smoking, and dietary flavonoids were independently associated with CHD, but of these three factors saturated fat explained 73% of the variance, i.e., were the major determinant of CHD (1).

 

There is more context here, in particular the role of replacing saturated fat in the diet in modifying the effect on risk reduction. We will come back to this point in relation to more up-to-date epidemiology and controlled intervention trials, in due course. But first, we need to tackle the supposed ‘controversy’ regarding saturated fats head on.

 

Meta-Analysis, Schmeta-Analysis

The title of this subheading is borrowed from the title of a paper by the late epidemiologist Professor Samuel Shapiro, which criticised the manner in which meta-analysis could produce sloppy results (11). As an a priori statement, it is worth bearing in mind that while the meta-analysis may be the gold standard in the medical model of evidence, the quality of any meta-analysis will depend on the included studies, and with nutritional epidemiology if the populations vary widely it may attenuate true associations that would be more evident in a single cohort. In this regard, looking at individual cohort studies as standalone research may be more informative of the interface between diet and health.

 

Meta-analyses have become a tool for misuse in nutrition science, wherein included studies encompass a broad spectrum of different populations with divergent diets, fail to model the effects of replacement of a nutrient or substitution, and reduce statistical power due to the significant heterogeneity of included studies (12). And poorly conducted meta-analyses of nutritional exposures, lies at the heart of recent “null” associations between saturated fat and CVD/CHD.

 

Let’s take them in turn, starting with the most cited and the paper that started much of the more recent supposed controversy; Siri-Tarino et al. (13), a meta-analysis of 16 prospective cohort studies looking at associations between saturated fat and CHD/CVD. A more problematic issue arises in the potential for over-adjustment to have obscured any true association between SFA and CHD; 42% of the weight of cardiovascular events in the paper was derived from studies which controlled for blood lipids. This is problematic because the effects of SFA [or any other dietary constituent] on CVD is always indirect, mediated via effects on different physiological processes, in this case both the impact of SFA on blood lipids, specifically LDL, and the well-established causal role of LDL in atherosclerosis (4,14). By including such weight from studies adjusting for LDL, which accounted for nearly half of all events – 9,382 out of 22,012 – in the meta-analysis, would have had the effect of biasing the results towards a lack of association between SFA and CHD (15).

 

A further issue with this paper was the failure to compare “hard” outcomes, i.e., fatalities from CHD with “soft” or total incidence CHD. In a response to the paper, Stamler reanalysed the 11 studies included in the meta-analysis that reported on fatal CHD, revealing a significant 32% increase in risk of CVD mortality from saturated fat intake, weighted by person years of exposure (16). In a follow-up paper by Siri-Tarino et al. published later the same year, which purported to look at the modulation of CHD risk by the nutrients replacing SFA, the authors acknowledged the response, but minimised the finding by stating that in their own subgroup analysis of 7 studies the association was a “borderline significant” 18% increase in death from CHD (17). However, this subgroup analysis was performed with studies that reported only on fatal CHD, meaning that data on fatalities from the remainder of studies reporting on total CHD was omitted, again attenuating any true association between SFA and CHD, a questionable subgroup analysis given the significant increase observed for death from CHD from 11 studies in response.

 

The Siri-Tarino 2010 meta-analysis was followed up in 2014 by a further meta-analysis published in the Annals of Internal Medicine by Chowdhury et al. (18), which is arguably one of the most cited of these meta-analyses concluding no association between SFA and CHD. This meta-analysis examined both dietary and circulating fatty acids, however, it provides a case-in-point as to the issues that arise with sloppy inclusion of studies. In the meta-analysis on circulating saturated fatty acid levels, eight studies were included and yielded a weak but positive 6% increase in CVD risk. However, the two studies focused specifically on markers of dairy fat intake, in particular odd-chain fatty acids C15:0 pentadecanoic acid and C17:0 heptadecanoic (margaric) acid, finding protective effects. Two issues arise. First, we have evidence supporting an inverse association between odd-chain dairy saturated fatty acids and CHD (19). Secondly, not only are C15:0 and C17:0 low in circulatory measures of fatty acids, relative to the predominant composition of C16:0 palmitic acid and C18:0 stearic acid in phospholipids, but many non-ruminant high saturated fat foods contain no C15:0 or C17:0 – thus they are poor biomarkers for non-ruminant, high saturated fat foods (20). It was therefore inappropriate to mix studies assessing specifically the effects of odd-chain SFA as markers for dairy fat consumption with studies assessing the effects of other, longer-chain SFA, as these studies biased the results of the meta-analysis on circulating saturated fatty acids toward a non-significant association, which is ultimately what the authors concluded. In a reanalysis of the studies included by Chowdhury et al. in their meta-analysis of circulating saturated fatty acids, but excluding the NSHDS and VIP studies, there was a 21% increase in risk of CHD (20).

 

In 2015, de Souza et al. (21) published a further meta-analysis purporting to show a lack of association between SFA and CHD. However, caution is warranted when interpreting this paper as many of the criticisms of the two prior papers apply to this meta-analysis. First, the authors state in their methods that where risk estimates were unavailable in relation to SFA intake and CHD/CVD, they used estimates taken from the Siri-Tarino et al. 2010 meta-analysis. Given the significant weight of over-adjustment in the Siri-Tarino meta-analysis, using risk estimates from that study appear to have biased the results toward the null hypothesis; on removal of the four studies for which risk estimates were based on the Siri-Tarino meta-analysis, the risk ratio increased to a 26% increase in risk for CHD mortality. This should be interpreted in the context of the results as presented in this meta-analysis being those from models adjusted for blood cholesterol, with the potential for over-adjustment to obscure any true association between SFA and CHD. It should also be noted that in their subgroup analysis of US cohorts – analogous in dietary composition to the UK diet – of subjects under 60-years and with <25% smoking prevalence [two independent risk factors], there was a significant association between higher quintiles of SFA and CHD mortality.

 

Two more recent meta-analysis are worth mentioning, as they have become popular to cite as evidence that higher saturated fat intake reduces risk of stroke and CVD. Before highlighting the papers, let’s discuss a methodological factor which is consistency overlooked in citing cohort studies, and in meta-analysis, but is fundamental to any finding in nutrition science: the contrast in the exposure of interest. As there is no “zero exposure” in nutrition, no nutrient-free state, standard methodology is to compare high vs. low levels of intake. But what is “high”? What is “low”? And what is the magnitude of difference between high and low, is it a sufficient exposure contrast [i.e., variability in intake of an exposure of interest]? And if a substitution analysis is conducted, what is the effect of the replacement nutrient? We’ll come back to the context of substitution analysis in the next section, but for now we’ll consider these recent meta-analysis in the context of the former issue: the variance in exposure contrast and relevance for results. This issue of exposure contrasts and high vs. low comparisons is evident in two recent meta-analyses – Kang et al. 2020 (22) and Zhu et al. 2019 (23) –  cited for evidence of a reduced risk of stroke with, quote, “higher consumption of saturated fat.” Let’s look at this “higher”, shall we? The two studies cited are studies which derived the majority of their statistical weight from Japanese cohorts, in which the median “highest” intake was 18-24g – GRAMS – a day, compared to ~5-7g in the lowest. Interpreting these studies as evidence of a “high” saturated fat intake conferring a benefit, without quantifying the actual dose exposure contrast in the primary included studies, is completely misleading. A more appropriate interpretation would be:

 

“Studying mostly Japanese cohorts with less saturated fat in the whole diet than a full English breakfast reduces risk of stroke.”

 

Or

 

“Study confirms saturated fat intake within guideline recommendations reduces risk of stroke.”

 

But those appropriate interpretations don’t quite fit sensationalist revisionsim.

 

The place of meta-analysis atop the hierarchy of evidence generates naïve assumptions regarding the veracity of the findings derived from this statistical technique. However, to quote epidemiologist Professor Sander Greenland, the “mindless agglomeration of study results into a single summary estimate” (24) is not a useful approach for nutritional exposures which are dependent on exposure contrasts and moderating factors. Unless care is taken in the modelling, spurious ‘null’ findings are often the output, generating controversy in the evidence-base.

 

Substitution Effects

One such critical modelling factor is the effect of substitution of saturated fat. Recall that initial guidelines were introduced in many Western industrialised countries with >18% saturated fat in the diet. By the nature of nutrition, where increasing or decreasing any food or nutrient means corresponding replacement with others, this raises a critical point to observed effects of saturated fat relative to other nutrients. And in this regard, the totality of evidence demonstrates a clear hierarchy in the effect of substituting saturated fat: polyunsaturated fat > plant-derived monounsaturated fat > complex carbohydrate (14,25–28).

 

The replacement of SFA with PUFA is categorically the most protective substitution of one nutrient for another in relation to CHD/CVD, observed at every level from epidemiology to controlled interventions. Convincing evidence from RCT’s exists to support a lower blood cholesterol level from PUFA-rich diets compared to diets high [i.e, 18-20%] in SFA, and that the substitution of SFA for PUFA reduces CVD risk (29). This relationship between PUFA, blood lipid levels, and CVD risk is consistently observed in RCT’s. In a meta-analysis of controlled feeding studies, the isocaloric replacement of 5% energy from SFA with 5% PUFA reduced LDL-cholesterol by 10mg/dL, and the mean reduction in total cholesterol of 29mg/dL corresponded to a 12% reduction in heart disease risk for each 18mg/dL reduction in TC (29). Ultimately, the meta-analysis found that for each 5% of energy from SFA replaced by PUFA, CVD risk decreased by 10%. A further meta-analysis of 15 RCT’s found that the replacement of SFA with PUFA reduced CVD events by 15% (30). Or particular relevance to the context of nutrients being ‘high’ or ‘low’ in a diet, this meta-analysis demonstrated that reductions in CVD mortality were found where baseline SFA intake was >18%, and where the reduction of SFA was >8% (30). This is consistent with the totality of the literature, including the epidemiology.

 

The replacement of SFA with monounsaturated fats [MUFA] has been unclear to a degree, due to the fact that MUFA exist in both plant sources, and also animal meats and produce. At the level of epidemiology, this has generated some misleading results . In a meta-analysis of 11 cohort studies, the substitution of 5% energy from SFA with MUFA appeared to show a significant and pronounced increase in risk of myocardial infarction (31). However, this was a misnomer: in the included studies the primary source of MUFA was animal fat, and prior to industrial trans-fats being distinguished as a sole, and particularly deleterious fat subtype, TFA were included within the definition of MUFA (31). More recent evidence has distinguished between food sources of MUFA using substitution modelling finding that replacement of 5% energy from SFA with 5% from plant-sourced MUFA was associated with a significant reduction in heart disease risk (32). In March of 2018 an analysis of the Nurses’ Health Study and Health Professionals Follow-Up Study demonstrated that substitution of 5% of the sum of SFA and animal-based MUFA with plant-based MUFA lowered heart disease risk by 8%, and the substitution of animal-MUFA for plant-MUFA lowered risk by 12% (26). The effects of dietary enrichment with plant-sourced MUFA has been demonstrated in landmark intervention studies, in particular the Lyon Diet-Heart Study and the PREDIMED trial, which yielded 73% and 30% reductions in risk in secondary and primary prevention, respectively (27,28).

 

The replacement of saturated fat with carbohydrate has been particularly contentious of late, given that dietary carbohydrates are the current scapegoat for chronic lifestyle disease. However, similar to MUFA, closer scrutiny of this issue reveals a distinct and divergent effect of carbohydrate quality, wholegrain or refined, as the replacement nutrient for SFA. This has been muddied by certain epidemiological studies concluding that replacing SFA with carbohydrate either has no effect on lifestyle disease risk, or in fact increases it (33,34). However, uniformly these studies failed to distinguish between carbohydrate type. This is a critical omission, as the effects of replacing saturated fat with either wholegrain or refined carbohydrates are diametrically oppositional, and the substituting of SFA for refined carbohydrate does not modify CVD risk, which remains unchanged or increases risk (17,34). Correspondingly, in reducing the contribution of energy from SFA in the diet, replacing that energy with carbohydrates from wholegrain sources significantly reduces risk of heart disease (25). That the primary replacement nutrient for SFA in population diets has been refined grains and added sugars, which do not alter risk, should not – as many attempt to portray – be taken to mean that SFA are not an issue, when elevated in the diet.

 

When it comes to the issue of saturated fat and cardiovascular health, the purpose of the desired reduction to 10% energy is due to the clear reduction in total cardiovascular events observed with a decrease to that threshold (30,35). The question is to what extent is health improved by the various options for replacement nutrients? An overall analysis of the literature reveals a clear hierarchy and the most pronounced reductions in cardiovascular risk occur when SFA are substituted for:

 

1. Unsaturated fats (polyunsaturated fats, followed by plant- based monounsaturated fats);
2. Unrefined, wholegrain carbohydrates.

 

“But dairy tho”

The unique effects of certain dairy foods, cheese and potentially yogurts in particular, and the fact that their fatty acid content is primarily saturated, has become a popular misdirection for the overall effects of dietary saturated fat in relation to CVD risk. And it is certainly evident in the literature that, compared to butter for example, cheese has a largely neutral or slightly positive effect on blood lipids (36). But the dose is low – 40-60g/d – and not an exception to the general associations between an overall diet high in total saturated fat. The fact is that the benefit to certain dairy foods is only observed when comparing dairy to other food sources of SFA.

 

For example, in the Multi Ethnic Study of Atherosclerosis which investigated the effects of different foods rich in saturated fat on CVD risk over a 10-year follow-up period, dairy SFA were associated with a significant reduction in risk [HR 0.62; 95% CI 0.48-0.82], but red meat was associated with an increase in CVD risk [HR 1.48, 95% CI 0.98-2.23] (37). In modelling the effects of substitution, replacing 2% of energy from meat sources of SFA with dairy sources was associated with a significant 25% reduction in CVD risk [HR 0.75, 95% CI 0.63-0.91]. A recent review in the Journal of the American College of Cardiology emphasised dairy in positing a lack of association between SFA and CVD, stating that “despite its high content of SFAs, dairy fat does not promote atherogenesis” (38). This was misdirection: “atherogenesis” describes the formation of fatty deposits, i.e., the actual pathophysiology of atherosclerotic CVD. The paper cited [reference 89] doesn’t mention atherogenesis once, because it didn’t measure atherogenesis; it was an observational analysis with CVD events and mortality as outcomes. The semantics are important here. In this analysis of the major US cohorts, the Nurses Health Study I and II, and the Health Professional’s Follow-up Study, the effects of dairy fat, and of replacing dairy fat with other fat sources, was examined (39). Dairy fat was not associated with risk, but look at the relative risks: 1.02 [95% CI 0.98-1.05) for CVD, 1.03 [95% CI 0.98-1.09) for coronary heart disease [CHD], and 0.99 [95% CI 0.93, 1.05] for stroke. ’Not associated with risk’ with insignificant effects differs substantially from ‘does not promote atherogenesis’.

 

But let’s look at what this study also found in relation to replacing dairy fats, given that the biological effects of dairy SFA form the crux of the argument that SFA foods mandate different considerations. In this study, substituting 5% dairy fats with total PUFA was associated with:

 

• 24% reduction in CVD risk [RR 0.76, 95% CI 0.71-0.81]
• 26% reduction in CHD risk [RR 0.74, 95% CI 0.68-0.81]
• 22% reduction in stroke risk [RR 0.78, 95% CI 0.7-0.88]

 

Thus, the hierarchy of benefit appears to remain in terms of PUFA>SFA generally. Sources of dairy fat may show benefit when compared to other deleterious saturated fatty acid food sources, e.g., red meat, however substitution analysis of replacing dairy SFA with unsaturated fats, in particular PUFA, indicates that the established hierarchy of benefit to substitution of SFA with unsaturated fats remains. Heterogeneous effects of fatty acids, and SFA foods, may be evident, but it is a scale within the overall class of SFA foods, not an absolution of the effects of a total dietary pattern high in total SFA.

 

“But large fluffy cuddly LDL tho”

The “large vs. small” LDL particle argument is one frequently put forward, particularly in the context of refined carbohydrates precipitating the remodelling of LDL into smaller, dense particles. However, this emphasis on major differences in the risk of particle size appears to have been waning within the cardiovascular sciences community, particularly as evidence increasing suggests it is the cholesterol payload of lipoproteins into the artery that is the prime culprit in atherosclerosis. To quote from a recent review by Sniderman et al. (40) with regard to particle size:

 

“Low-density lipoprotein particles can differ in the mass of CE within their core and consequently can differ in size. However, as will be demonstrated later in this article, all have the same atherogenic potential….Thus, more smaller, cholesterol-depleted particles will be trapped than will a similar number of larger, cholesterol-enriched particles that have entered an arterial wall. On the other hand, the more cholesterol within an apoB particle that has been trapped within the arterial wall, the more cholesterol that will be released at that site to injure the wall. Therefore, there is an equivalence between greater injury per particle from trapping of cholesterol-richer particles but greater injury from trapping of more cholesterol-depleted particles.” 

 

And although reducing SFA likely benefits other parameters of cardio-metabolic risk, for example liver fat (41), the primary mechanism through which lowering SFA reduces CVD risk is through reductions in atherogenic lipoproteins, in particular LDL-C. To quote from the most recent Hooper et al. (35) meta-analysis of RCTs targeting reductions in saturated fat:

 

“Meta‐regression and subgrouping suggested that greater reductions in SFA intake, greater reductions in total serum cholesterol levels, higher baseline SFA intake and greater increases in PUFA and MUFA intakes reduced CVD events more, but the strongest factor was the degree of cholesterol lowering. This clearly indicates that the cardiovascular effects of reducing saturated fat rely on changes in atherosclerosis via serum cholesterol.” 

 

This is consistent with a body of evidence dating back to the 1950’s metabolic ward studies.

 

Converging Lines of Evidence

Part of the issue with looking at SFA in the diet now is that current levels are in a range at which differences in risk between narrow exposure contrasts – e.g., comparing 10% to 13% - may not be as demonstrably evident. This obscures the fact that much of the benefit has already been achieved in the population. The Finnish public health intervention serves as the strongest example of this. In the 1960’s Finland had the highest population SFA intake in the world at 23-25% energy, with the highest population blood cholesterol levels, and experienced the highest CHD/CVD mortality globally. Starting in 1972, a public health intervention to reduce mortality targeted population reductions in specific risk factors, in particular smoking rates, blood cholesterol, blood pressure, and adiposity (42,43). By 2007, CHD/CVD mortality had declined by 80% and of the cumulative risk factors, population reductions in blood cholesterol accounted for 67% of the decrease in mortality (42,43).

 

A primary determinant in the population-wide reduction in blood cholesterol was a reduction in dietary saturated fat from 23% to 13%, achieved through deliberate public health messaging regarding butter consumption [the most significant contributor to SFA in Finnish diets at the time]. Of particular note, this decrease occurred in the context of smoking rates remaining largely similar [slight decline in men, increase in women], and an overall increase in BMI across the population, both significant risk factors for CVD.

 

Controlled interventions corroborate these thresholds of effect. As stated above, the strongest reductions in CVD mortality have been observed in intervention trials where baseline SFA was >18%, and an average achieved reduction of >8% (30,35). The magnitude of this effect, reduced from this threshold, is greates when PUFA replace SFA (29,35). And these effects, both of SFA on causal risk factors for CVD, and of PUFA lowering LDL-C in replacing SFA, are supported by 70yrs of metabolic ward studies (3,9,14).

 

The general public health target of <10% energy for saturated fat is evidence-based, and is the threshold at which the greatest risk reduction for total CVD events is observed (30). The overall totality of literature is supported by consistency across ecological experiments, observational epidemiology, and randomised controlled feeding studies, and metabolic ward studies.

 

 

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