Revision as of 14:43, 1 September 2020

Work In Progress By Matt Madore, BSc

Introduction

Recently a “State-of-the-Art” review entitled Saturated Fats and Health:A Reassessment and Proposal for Food-Based Recommendations was published in The Journal of the American College of Cardiology. The authors presented the argument that current evidence does not support the dietary guidelines recommendations to limit saturated fatty acid (SFA) intake to less than 10% of daily calories on the basis of reducing morbidity and mortality from common chronic diseases, most notably cardiovascular disease (CVD). They remark that although SFAs raise low-density lipoprotein cholesterol (LDL), this is due to increases in large (and not smaller, dense) particles, which aren’t as strongly related to CVD risk. Further, they exclaim that not all sources of fatty acids impart similar effects on health due to differences in their overall structure and the complex matrices of the foods they are found in, specifically emphasizing that dark chocolate, unprocessed meat, and whole-fat dairy are not associated with the risk of CVD and recommendations to limit their intake solely due to their SFA content are unsubstantiated1. Although some of the sentiments they offer are agreeable, and despite their claims otherwise, the totality of the available evidence does not support many of their arguments. Accordingly, their publication will likely cause greater confusion to the american population already struggling to decide who they can trust among the disordered field of nutritional science, and result in more harm than benefit.

The review begins by briefly discussing the history behind the initiation of dietary goals and recommendations to lower saturated fat intake dating back to the 1970s, and details that since the 80s there have been specific goals of reducing saturated fat intake to less than 10% if total calories to reduce CVD risk. The authors declare that their main intention is to answer the question posed by the United States Department of Agriculture and Health and Human Services’ in 2018; “What is the relationship between saturated fat consumption (types and amounts) and the risk of CVD in adults?” by reviewing the effects of saturated fats on health outcomes, risk factions, and mechanisms underlying CVD and metabolic outcomes. Having clearly defined their objective, the question then becomes whether their review provides a sufficient answer that is backed by a solid body of evidence, which will become quickly apparent is far from the case.

In the following paragraph, they say the following: “The relationship between dietary SFAs and heart disease has been studied in about 400,000 people and summarized in a number of systematic reviews of observational studies and randomized controlled trials (RCTs). Some meta-analyses find no evidence that reduction in saturated fat consumption may reduce CVD incidence or mortality (3–6), whereas others report a significant—albeit mild—beneficial effect (7,8).<2-7> ” Based upon this collection of research they conclude that the basis for recommending a low saturated fat diet is unclear and that they intend to propose an evidence-based recommendation for intake of SFA food sources. Right from the start the authors have demonstrated that they aren’t truly reaching their conclusions by considering the totality of the evidence. They mention 5 publications designed to observe the relationship between saturated fat and CVD that contain about 400,000 subjects. In reality, there are actually dozens of systematic reviews and meta analyses of both observational studies and RCTs encompassing millions of people that indicate reducing or replacing saturated fat with other nutrients results in significantly decreased CVD morbidity and/or mortality8-19. In fact, a couple of the more recent publications on the subject include over double the amount of people they imply this relationship has been studied in16,18. While there are also a few additional reviews suggesting that it has no observable effect20,21, along with those that the authors of the JACC review mention2-5, they involve critical flaws that impair their ability to effectively assess the relationship between SFAs and CVD morbidity/mortality, and as such have been heavily criticized. Following is a discussion of each of these trials, their respective pitfalls, and additional comments from other parties where appropriate.

Harcombe et al, de Souza et al, Siri-Tarino et al, and Zhu et al.

Overadjustment

Since all four fall victim to the same issue (among a few others), it will be best to first address the problems with the reviews on prospective cohort studies and case-controls assessing the relationship between saturated fat intake and CVD by Harcombe et al., de Souza et al., Siri-Tarino et al., and Zhu et al. The major methodological problem with these four reviews is the inclusion of an appreciable amount of cohorts which adjusted for serum cholesterol or baseline hypercholesterolemia (5/10, 1/3, and 5/11 cohorts in de Souza for total CHD incidence, CVD mortality, and CHD mortality, 7/16 and 4/8 in Siri-Tarino for CHD and stroke events, 3/6 in Harcombe et al., and 14/40 and 7/22 in Zhu et al. for CHD in the highest vs. lowest comparison and dose response analysis, respectively). This is particularly concerning because the action of adjusting for a moderator variable (in this case serum cholesterol, or more specifically LDL-c, which is increased in response to saturated fat consumption and increases the risk of CVD) that lies on the causal chain of the outcome of interest pulls the results of the analyses towards null, creating a biased and inaccurate observation of the true relationship. Given that almost half of the cohorts in each of these reviews make such adjustments, any effect would be especially muted. Scarborough et al. actually discuss this very issue in their comment responding to the authors of Siri-Tarino et al. closely following its publication22. While there are additional issues that may also contribute to the lack of effect (little to no variance in saturated fat intake among cohort’s sample population, inclusion of multiple cohorts with intakes all above or below the threshold where the majority of the increase in CVD risk is observed, failure to disclose review protocols, and inclusion of only CVD mortality metrics), just this alone is enough to invalidate the results of these reviews. Lastly, despite these over-adjustments, trans fat was still associated with significant increases with CHD mortality and CVD in Zhu et al. and de Souza et al., which will prove to be an important consideration with respect to some of the other reviews.

Apart from the 4 reviews just discussed, two additional reviews have suggested there may not be an association between saturated fat intake and CVD, one of which the authors of the JACC mentioned in their brief comments on the subject. These two reviews were carried out by Ramsden et al. and Steven Hamley, both including randomized controlled trials focused on determining the potential benefit of replacing saturated fatty acids with mostly polyunsaturated fatty acids. Ramsden et al.’s review included discussion of recovered data from the Minnesota Coronary Experiment (MCE) and also carried out a meta-analysis of an additional 4 RCTs, the Sydney Diet Heart Study (SDHS), the Rose Corn Oil Trial (RCOT), the Los Angeles Veterans Trial (LA Vet), and the Medical Research Council Soy Oil Trial (MRC-Soy), and a sensitivity analysis on the previous 5 in addition to 3 more, the Diet and Re-Infarction Trial (DART), the Oslo Diet Heart Study (ODHS), and the St. Thomas Atherosclerosis Regression Study (STARS). Not only was the MCE flawed in numerous ways that prevented meaningful conclusions being drawn from its results, there were also multiple issues with the other smaller trials included in their analysis (for which MCE ended up being weighed the most). As for the MCE, the high dropout rate (>75%) and subsequently insufficient power to detect effects on mortality, the utilization of a likely trans fat-containing margarine in the intervention group, the fact that the main difference in mortality was observed only in subjects over 65 years of age, and the lack of important metrics such as smoking status, LDL cholesterol, detailed dietary intake data, weight loss, and coronary disease status, were the main problems. The smaller size (and weaker statistical power), exclusion of mortality as a main endpoint, and inclusion of a trans fat based margarine in the experimental group of another trial (SDHS), were further issues that rendered the findings of the analyses unuseful. As for Hamley’s review of RCTs, he chose to exclude certain trials on the basis of “inadequate control” and other factors that he posits would impact the results, including suspicions that the control group had higher trans fat intake, were exposed to cardiotoxic medications, and had lower vitamin E intake. His meta analysis ended up incorporating the exact same trials as Ramsden et al.’s with the one exception being LA VET, which he replaced with DART. Ironically, this means he included both MCE and SDHS, which exposed the intervention groups to higher trans fat intake, and other small studies underpowered to detect meaningful effects on his chosen endpoints total and major CVD events.

Directly contradicting both of these trials is the recent Cochrane Review on reductions in saturated fat for cardiovascular disease, which was subject to far more rigorous pre-review protocols and analyzed the results of 15 RCTs (even including SDHS) to find that long term reductions in saturated fat intake resulted in significant reductions in the incidence of combined cardiovascular events17. Furthermore, they conducted a meta regression that demonstrated larger reductions in saturated fat (and consequently greater reductions in cholesterol) elicited greater reductions in events. Unfortunately, no such regression was carried out for CVD mortality, but in the subgroup analysis stratifying by absolute saturated fat reduction a clear trend towards significant decreases in mortality can be observed, with the trial in which the greatest reduction was achieved reaching significance (Veterans Admin).

Taking into account the incredibly large body of high quality evidence from RCTs and observational trials demonstrating the beneficial effect of reducing saturated fat intake on CVD morbidity and mortality, and considering the problematic aspects of reviews suggesting a null effect, it should be incredibly clear the JACC author’s statement that there is a lack of clarity regarding the basis for reducing saturated fat intake is preposterous.

Next, the review moves on to discuss the variation in chemical structures of saturated fatty acids found in a wide variety of foods, explaining that SFAs vary based on their carbon chain length, their subsequent melting point and state at room temperature (solid vs. liquid), the presence or absence of methyl branches (branched vs. straight chain fatty acids), and their origin (exogenous vs endogenous). Furthermore, they exclaim that food sources of such SFAs contain different proportions of certain fatty acids, as well as other nutrients that have an impact on their physiological and biological effects. They continue on, saying “Branched-chain SFAs are found primarily in dairy, beef, and other ruminant-derived foods (13), and have similar physicochemical properties as unsaturated fatty acids, in particular lower melting point (or more accurately, phase transition temperature). In experimental animal studies, branched-chain fatty acids alter the microbiota composition in the direction of microorganisms that use these fatty acids in cellular membranes (14), and because they are normal constituents of the healthy human infant gut (15), these fatty acids could play a role in normal colonization.” It seems odd for them to be focusing on mechanistic studies in animal models (given the variability in their relevance to humans) in order to insinuate some sort of innate requirement for these fatty acids, especially given that they also bring up the ability of intestinal flora and the liver to synthesize them shortly thereafter. That being said, the comment is followed by a remark that fatty acids are synthesized de novo from “excess carbohydrate and protein” and reference to a study linking certain plasma phospholipid concentrations of fatty acids and adverse cardiovascular outcomes, seemingly hinting at the notion the process is inherently harmful, though that may not be the case. They then re-emphasize the earlier point that different circulating saturated fatty acids exert differing effects on blood lipids, glucose-insulin homeostasis, insulin resistance, and diabetes. While this is certainly a valid point, it does not purely suggest such effects follow changes directly resulting from consumption of the respective fatty acids given the potential for de novo synthesis and pathophysiological processes of certain conditions to also exert an effect on plasma concentrations. In the final paragraph of this section, they raise concerns regarding the failure to distinguish between fat and fatty acids, saying that the former are composed of fatty acids in differing proportions and other components such as glycerol. Another valid point, but not necessarily pertinent to any of the claims they’ve put forth so far.

 The next section of the review directs its focus towards the evidence on the health effects of saturated fat, and similar to the earlier paragraph briefly discussing the matter, the authors make numerous claims that are extremely misleading and not backed by the majority of the scientific literature on the subject. They begin by offering up common rhetoric about current guidelines being based upon observations from ecologic research (including the Seven Countries Study) throughout the 1950s on diet and coronary heart disease. Next, they exclaim, “In recent decades, however, diets have changed substantially in several regions of the world. For example, the very high intake of saturated fat in Finland has decreased considerably, with per capita butter consumption decreasing from ∼16 kg/year in 1955 to ∼3 kg/year in 2005, and the percent energy from saturated fat decreasing from ∼20% in 1982 to ∼12% in 2007 (28). Therefore, the dietary guidelines that were developed based on information from several decades ago may no longer be applicable.” First, the fact that diets have changed in recent decades is not at all reason to completely dismiss previously established guidelines, and even more astonishing, the specific country they mention (Finland) is a prime example of evidence cutting directly against their position. The exact article they reference explains the implementation of a widespread preventative health intervention originating in North Karelia (and later expanding to other regions in Finland) that aimed to modulate citizen’s dietary habits, mainly focusing on reducing saturated fat intake and replacing it with unsaturated fat, as well as increasing vegetable intake, and reducing sodium intake. The results of this program, which have been demonstrated to be attributed almost entirely to dietary changes, were that the working age population experienced a large reduction in blood cholesterol levels and a remarkable 80% reduction in annual CVD mortality rates23, yet the authors of the JACC review make no mention of this whatsoever. 

After this, they bring up what they claim to be a few large and well-designed prospective cohorts carried out recently that supposedly demonstrate replacing saturated fat with carbohydrate doesn’t result in a lower risk of coronary heart disease, and may increase risk8, 24,25. However, one of these is an editorial (Hu 2010), and echoes what the results from the other two (Jakobsen et al. 2009 and Liu et al. 2000) demonstrate, which is that replacing saturated fat with refined carbohydrate does not reduce, and may increase, the risk of CVD. Additionally, Jakobsen et al. showed that the replacement of SFAs with PUFAs elicited significant reductions in both CVD events and mortality, and Hu’s editorial declared that increased intake of refined carbohydrates and saturated fat were independent risk factors for CVD, and states that either a low fat, high complex carbohydrate, or moderately restricted carbohydrate diet rich in vegetable fat and protein may confer protection against CVD (although he believes that a focus on reducing refined carbohydrate intake may be most important). Not only is this ironic given that the authors spent quite a bit of time discussing the importance of not looking at saturated fat as a single uniform nutrient, yet they’re willing to do it for carbohydrates, but this also once again shows they are making misleading statements, and providing evidence that either doesn’t relate to their position or actually invokes evidence contradicting it. They continue on to say, “Furthermore, a number of systematic reviews of cohort studies have shown no significant association between saturated fat intake and coronary artery disease or mortality, and some even suggested a lower risk of stroke with higher consumption of saturated fat (3,6,32,33).” The major issues with three of these have been previously addressed (Zhu et al., de Souza et al., and Siri-Tarino et al.), and the fourth is on saturated fat intake and its potential protective effect against stroke26, which is a separate consideration entirely. To end this paragraph, they comment on a meta analysis of prospective cohorts demonstrating that biomarkers of long chain SFAs in plasma or serum were not associated with CHD27. It’s completely unclear as to why this was even included, given that previous similar publications have noted these SFAs in plasma are unlikely to result from diet28, and the authors go on to claim that “it is important to distinguish between dietary saturated fat and serum SFAs” themselves shortly after.

After this, they bring up the PURE study, and although this study was an incredibly ambitious undertaking, it is unfortunately ridden with numerous critical flaws that dozens of researchers have discussed via comments responding to the original publication. As the JACC review’s authors discuss, 80% of the sample population was from low- and middle-income countries, which explains the origin of one of its largest blunders; bias from malnutrition. This arises due to fact that alongside focusing on lower income countries, authors included energy intakes down to as low as 500 kcal/day, and higher carbohydrate consumption as a percentage of energy, as well as the consequential lower percentage from fat, were strongly correlated with low income, food availability, pollution, and healthcare access29,30. Therefore, comparing increasing quintiles of fat consumption to the lowest quintile is essentially comparing to a likely malnourished population, so even just minor decreases in incidence of death and disease would deem fat intake protective when in reality an unfair comparison is just skewing the results. Adding to this issue, others include failure to report the type of food frequency questionnaire used, lack of baseline health status and adjustment, failure to distinguish between types of carbohydrates, and large differences in the data from PURE and that from the China Health and Nutrition Survey (CHNS) on China’s fat intake31-33. Finally, it seems the JACC review’s authors again selectively choose to showcase the observations they feel support their assertions and ignore those that don’t, remarking that stroke incidence is reduced with increased saturated fat consumption, but not that rates of myocardial infarction are actually highest in the top quintile (though this doesn’t factor in adjustments prior to calculation of a HR, which is unfortunate, it would certainly be of interest to see the resulting values). Further, mortality and incidence of all other observed outcomes were lowest in the third and fourth quintiles of saturated fat intake, which are unsurprisingly those where subject’s intakes were below 10% of their total caloric intake. In a demonstration of consistency, they then cite a recent prospective cohort of UK Biobank participants, exclaiming that it doesn’t show an association between saturated fat and incident CVD, and that “Although there was also a positive relation of saturated fat intake with all-cause mortality, this became significant only with intakes well above average consumption”. While the former was shockingly correct, the latter was not, as the relation between saturated fat intake and all cause mortality became significant at above around 12% of calories (Figure 1), with the average intake of the study’s sample being over 13% (seen in Table S2)34. To follow that up, in a sentence mentioning the macronutrient distributions associated with the lowest hazard ratio for all cause mortality, they conveniently leave out a few lines following what they quote, which happened to be, “...5-10% from SFA (2.66 v 3.59 per 1000 person years, 0.67 (0.62 to 0.73) compared with high (20% of energy) intake)...”, clearly emphasizing the benefit of reducing saturated fat intake to 5-10% of calories. Lastly, they declare that for dietary carbohydrate, higher consumption (from starch and sugar) is associated with higher CVD and mortality, and that there is little need to restrict intakes of total or saturated fat for most populations in the context of contemporary diets, whereas reducing refined carbohydrates may be more relevant for decreasing the risk of mortality in individuals with insulin resistance and type 2 diabetes. While their final point is an important consideration, these conditions and the contribution of refined carbohydrates to adverse health outcomes aren’t being ignored at all, and it’s odd they don’t recommend reductions in both refined carbohydrates and saturated fat, especially given the pattern with the lowest hazard ratio for all cause mortality involves exactly that. The dietary guidelines their entire review has set out to criticize and suggest changes to actually call for decreasing refined carbohydrate and saturated fat intake, and also highlight healthy food patterns that will assist in achieving such reductions35, leaving one questioning what actual problems they have with them are.

Following discussion of PURE and the UK Biobank data, the review moves on to another common talking point among skeptics of the diet-heart hypothesis; that most RCTs of nutrient intake are small in size and those which the dietary guidelines recommendations to limit dietary saturated fat had important methodological flaws. Authors then bring up the Women’s Health Initiative (WHI), one of the larger and more recent trials on reducing CVD via lifestyle intervention, and briefly remark that the low fat diet providing 9.5% of calories from saturated fat did not reduce the risk of heart attack or stroke. Again, numerous relevant details are being left out, the major one being that based on failure of subjects to reach adherence assumptions (that the intervention group would reduce percentage of energy from total fat 13% and 11% compared to the control group at 1 and 9 years, respectively, and the control group incidence rate would be one third greater), the projected power to detect differences in CHD was only 40%36. Based upon this limited power, the chance of the researchers detecting a difference between the intervention and control group was already incredibly low, and was further compounded by the less than moderate beneficial changes in the intervention group (and even some potentially detrimental ones) in comparison to the control group. Such paltry changes included a difference of weight loss of about 1 kg after 3 years, a less than 3% and 1% reduction in calories from saturated and trans fat respectively, a 1 serving difference in fruit and vegetable intake, and harmful alterations were an increased in refined grain consumption and decrease in intake of nuts. As such, the changes in biomarkers of interest, especially LDL-c, were similarly small, with the reduction in the intervention group being 3 mg/dl greater than the control. Given these factors, it’s unsurprising that no significant reduction in risk was seen. However, despite the extremely limited power, when authors directed their attention towards subjects who achieved the lowest intake of saturated fat (<6% of energy), they remarkably still observed a marginally significant reduction in the risk of CHD, again demonstrating the value of reducing intake of saturated fat, even in a relatively healthy population with a lower baseline intake (~13% of energy) and a lower overall incidence of CHD (<1% of the subjects over about 8 years of follow up). Moving onward, they bring up PREDIMED, saying “Despite an increase in total fat intake by 4.5% of total energy (including slightly higher saturated fat consumption), major cardiovascular events and death were significantly reduced compared with the control group.” It’s unclear how they even came to this conclusion, given that the supplementary data from the study itself shows that both the intervention groups reduced their intake of saturated fat as a percentage of calories from 10% to just about 9% (Table S9)37. Also worth noting was that they reduced red meat and dairy consumption, both of which are foods this review’s authors seem to emphasize there shouldn’t be limits to the consumption of. To close out this paragraph, they then claim that the 6 most recent reviews and meta analyses of RCTs demonstrated that replacing saturated fat with polyunsaturated fat does not significantly decrease coronary outcomes or total mortality, citing three publications, two of which have major problems that have been previously addressed; Ramsden et al. 2016, Hooper et al. 2015, and Hamley 2017. Aside from the fact that that they only cite three reviews, the one of the highest quality that included the largest amount of trials (Hooper) actually demonstrates a significant benefit of reducing saturated fat intake on CVD events, and similar to in their updated 2020 review mentioned earlier, their meta regression indicated that the extent of saturated fat reduction and the corresponding decrease in serum cholesterol were responsible for said effect. After the previous comment, they then state, “Even if these analyses were to be challenged, for example, based on the criteria for study selection or other lines of evidence (42), an important possibility to consider is that an apparently lower risk of CVD with substitution of SFAs by polyunsaturated fatty acids could be attributed to a possible beneficial effect of polyunsaturated fatty acids and not necessarily to an adverse effect of SFAs”, followed by, “...the evidence from both cohort studies and randomized trials does not support the assertion that further restriction of dietary saturated fat will reduce clinical events.” Firstly, the initial statement is quite an incredible speculation given the consistency with which reducing saturated fat alone, and/or replacing it with PUFAs, certain MUFAs (such as olive oil and nuts in PREDIMED), and whole grains have shown to elicit significant reductions in CVD events38. Second, even if this were the case, why would one choose to consume a nutrient that doesn’t lower the risk of the leading cause of death in the United States over almost all of the others (with the exception of refined carbohydrate) that do? Finally, after considering that almost everything the authors have cited up to this point has had extraordinary flaws they failed to disclose, and that many of their own sources actually cut against their own position, hopefully the erroneous nature of the closing statement for this section is incredibly clear.

In the next section, the authors attempt to instill doubt in the reader as to the utility of LDL cholesterol as a biomarker for assessing the effect of saturated fat on cardiovascular risk. After declaring that it is quite clear LDL plays a causal role in the development of CVD, they stipulate that the reduction of LDL through diet cannot be inferred to result in CVD benefit without having the means to assess other biological effects that accompany this reduction. Whether or not there are means to assess other biological effects (which there are), as repeatedly displayed throughout this entire commentary, saturated fat reduction does consistently and reliably reduce the incidence of CVD, so this point is entirely tangential. To follow up this stipulation, they note that postmenopausal estrogen plus progestin therapy and cholesteryl ester transport protein (CETP) inhibitors elicit no CVD benefit despite decreasing LDL cholesterol, as well as that mediterranean style interventions and pharmaceutical inhibition of sodium-glucose cotransporter type 2 reduces CVD risk while increasing LDL, suggesting that these supposedly unexplained deviations from the typical pattern somehow denigrate the relationship between dietary reductions of LDL and CVD risk. As for the increased risk associated with estrogen and progestin therapy, subgroup analysis showed that the risk was driven by those with the highest baseline LDL, for whom even the observed maximum reduction in LDL wouldn’t bring close to a normal value (Figures 1 and 4)39. For CETP inhibitors, the reference they cite clearly describes reasons for discrepancies in results of four different CETP-inhibitor trials, and actually highlights the success of anacetrapib (which did significantly reduce CVD events) being due to the trials longer duration, and its sustained effect on LDL-c (or non-HDL-C/apoB). The other trials were of substantially shorter duration, or resulted in less notable reductions in LDL-c, explaining the variance in observed results40. Regarding the mediterranean-style interventions reducing CVD risk, the two trials they cite are the Lyon Diet Heart Trial and a subgroup study of LDL oxidation biomarkers in PREDIMED participants, which is odd given that both established significant reductions in LDL from reducing/replacing dietary saturated fat confer protection against CVD, exactly the opposite of what they claimed these interventions show. Finally, given the positive benefit of SGCT2 on blood glucose and blood pressure, as well as its ability to offer nephroprotection in CKD (all of which can compound the risk of CVD events in those with established disease), and the “minimal changes in lipids” it causes, all directly described in the publication linked by the authors, it is unsurprising they’ve also shown benefit with respect to the risk of adverse cardiovascular outcomes41. None of these change the existence of the relationship between LDL-c and CVD, they just highlight the multifaceted nature of cardiovascular disease and the existence of other risk modifiers. Therefore, it is inappropriate to suggest they somehow indicate that diet-induced reductions in LDL can’t be inferred to result in CVD benefit.

The following paragraph brings up a few more common talking points, being that because saturated fat restriction “does not decrease smaller dense (triglyceride rich) LDL particles (sdLDL) in the majority of individual” and, “...also lowers the level of high-density lipoprotein cholesterol, and hence has a relatively small effect on the ratio of total to HDL cholesterol”, which have stronger associations with CVD risk than large LDL particles, that the reduction in saturated fat can’t be inferred to yield a proportional reduction in CVD risk. While it has been pretty consistently shown that small dense LDL and the total cholesterol to HDL ratio do indeed correlate well with CVD risk, in no way does this indicate that sdLDL is inherently more atherogenic or that HDL and cholesterol are the main dictators of cardiovascular disease risk. Accordingly, most studies show that while sdLDL shows a significant univariate association with CHD risk, it is seldom an independent predictor after multivariate adjustment for triglycerides and HDL, suggesting that “the increased risk associated with smaller LDL size in univariate analyses is a consequence of the broader pathophysiology of which small, dense LDL is a part (e.g. high triglycerides, low HDL cholesterol, increased LDL particle number, obesity, insulin resistance, diabetes, metabolic syndrome).”42 Furthermore, a recent pre-print of a mendelian randomization awaiting peer review that observed the effects of various lipoprotein subfractions on CVD risk provides additional support that sdLDL is not inherently more atherogenic, with the authors concluding, “LDL and VLDL subfractions appear to have nearly uniform effects on CAD across particle size. Therefore, the results do not support the hypothesis that small, dense LDL particles are more atherogenic.”43 While the point being raised here is important (i.e., that LDL cholesterol reductions aren’t necessarily the only metric that should be considered with respect to CVD risk reductions via dietary interventions), the other metrics aren’t being ignored, and even in most of the trials the JACC review authors claim changes in LDL didn’t correspond with reductions in cardiovascular events (PREDIMED and WHI), they actually did, as they do across a wide variety of therapeutic interventions44.

The next paragraph begins with a description of insulin resistant states, their increasing prevalence in the US, and a brief discussion of how they can increase atherogenesis. Authors then exclaim that individuals with insulin resistance experience impaired skeletal muscle glucose oxidation, increased hepatic de novo lipogenesis, and atherogenic dyslipidemia after a high carbohydrate meal. They also remark these individuals have higher propensity to convert carbohydrate to fat, which further aggravates the insulin resistant phenotype, including increases in circulating SFAs and lipogenic fatty acids such as palmitoleic acid. This is an incredible oversimplification that seems to imply once an individual is insulin resistant that any carbohydrates will exacerbate obesity, hypertension, hyperglycemia, hyperinsulinemia, and numerous other adverse effects associated with this phenotype. Additionally, the statement that subjects experienced significant detriments following a high carbohydrate meal is grossly misleading, as the diets fed in the study the authors linked were both high in fat (35% of kcal) and carbohydrate (55% kcal), contained an additional 25% of subjects daily energy requirements in the form of sucrose, and the quality of the foods and nutrients provided was unclear45. While refined carbohydrates are certainly the last thing that an insulin resistant individual should center their diet around, diets including appreciable amounts of whole food complex carbohydrates such as legumes, whole grains, fruits, and vegetables have been repeatedly demonstrated to exert a host of beneficial effects on metabolic function, including but not limited to improvements to insulin resistance, reductions in HbA1c, weight loss, decreased blood pressure, and improvements in lipids46-58. This lack of acknowledgement of important differences in food/macronutrient quality and their impacts on health again seems quite hypocritical given that one of the authors’ main contentions with dietary guidelines recommending reductions in saturated fat is that it fails to do so.

The next two paragraphs put a lot of effort into distinguishing between dietary saturated fat and circulating SFAs, starting by saying while some studies suggest increased saturated fat intake doesn’t increase chronic disease risk, people with higher circulating even-chain SFAs have an increased risk of numerous chronic diseases. While the latter may be true, the former is most certainly not, and unsurprisingly they cite two studies mentioned previously that don’t support such an assertion (Siri-Tarino et al. and Jakobsen et al.). They then proceed to say that circulating SFAs in the blood tend to track closer with dietary carbohydrate intake (again, no specification of quality here), and that changes in saturated fat intake of 2-3 fold have no effects on serum SFAs in the context of diets lower in carbohydrate. Adding on to this, they explain that the primary fatty acid product of de novo lipogenesis (DNL), palmitoleic acid, is a good proxy of DNL due to its low presence in the diet and that larger proportional increase when carbohydrates are converted to fat. Following this preface, they then discuss how multiple studies show a close link between increased dietary carbohydrate intake and increased serum palmitoleic acid levels independent of changes in body weight and saturated fat intake, referencing four studies59-62, after which they exclaim how increased palmitoleic acid levels are associated with substantial increases in the risk of stroke, heart failure, and coronary artery disease. What they don’t mention is that every single one of these studies involves diets high in refined carbohydrates, and only one trial62 reduced saturated fat intake below the limit recommended by the dietary guidelines and numerous other nutritional science organizations. Interestingly, the aforementioned trial only looked at serum FA content and select inflammatory markers, and the low carbohydrate intervention involved a reduction in calories accompanied by an increase in MUFA, no significant change in SFA intake, and reduced refined carbohydrate, whereas the low fat intervention also decreased calories, slightly reduced SFA intake, increased refined carbohydrate intake, and increased alcohol intake. Not only are results pertinent to actual metabolic function lacking, the comparison seems unfair, and the potentially detrimental changes in the dietary patterns of the low fat intervention aren’t representative of those that would be recommended by any competent nutritional organization. This whole discussion seems to be founded on portraying carbohydrates as inherently harmful to those with insulin resistance by referencing trials involving consumption of highly processed sources accompanied by other negligible changes in diet, which appears very disingenuous. Finally, they conclude that, “Clearly, the impact of dietary SFAs on health must consider the important role of carbohydrate intake and the underlying degree of insulin resistance, both of which significantly affect how the body processes saturated fat. This intertwining aspect of macronutrient physiology and metabolism has been consistently overlooked in previous dietary recommendations.” As stated previously, it is obviously important to consider these factors, yet it is unclear how the studies they brought up in this section showing excess refined carbohydrate intake is harmful to health (insinuated to be in part via increases in DNL reflected in increased serum palmitoleic acid, which is very reductionist and ignores the complexity of changes in DNL commonly observed with metabolic syndrome63) change the well established harmful effects of excess saturated fat on health. As repeated almost ad nauseam up to this point, the irony of mentioning intertwining aspects of macronutrient physiology and metabolism is astounding given the continued indiscriminate vilification of carbohydrates displayed just prior.

The review’s subsequent section begins with comments on the failure of the scientific community to determine “the one diet” that achieves optimal metabolic health for all, and brings up the heterogeneity of dietary intervention outcomes, which they postulate to be a result of the fact some individuals have better outcomes from specific diets than do others. According to them, the objective should be to match each person to their individual best diet, that is culturally appropriate. While it is incredibly important to consider that some individuals may indeed have appreciable variations in their responses to certain diets, and that modifications may need to be made dependent upon one’s life stage, the presence of some health conditions, and food availability among other factors, results of well controlled dietary intervention studies for improving health status have been fairly consistent, as well as results from observational studies on dietary patterns that are associated with substantial chronic disease risk reductions. Heterogeneity is typically well explained by differences in macronutrient quantity and quality, adherence to interventions, age, baseline disease presence, and other important external factors, things that the authors have repeatedly highlighted the importance of considering, yet seem to selectively ignore when it’s convenient. Individualizing nutrition is something that is most definitely valuable, and it’s odd to think someone within the field of nutritional science would dismiss this.

Moving onward, the authors begin to discuss nutrigenomics, which is a fascinating up and coming field of study, however their discussion is very narrow and seems focused almost entirely on exonerating saturated fat. They preface this discussion by saying that “the once apparently tight link between dietary SFAs and CVD appears to be loosening as a result of mounting evidence that casts doubt on previously established belief”, which is once again, blatantly incorrect. Then they say that some of the debate centers on the role of variation in food sources of SFAs (more on this to come), and some on interindividual variation in biological and clinical effects of saturated fatty acids, which is suggested in part to be a result of genetic variants that result a modulation of the relationship between dietary SFA and CVD-related biomarkers. One of the variants discussed is APOE4 allele of the apo E gene, which predisposes individuals to an increased risk of CVD, hypothesized to result due to greater fasting plasma and postprandial responses to saturated fat. Further, another study observing that saturated fat intake interacts with a weighted genetic risk score for obesity to modulate body mass index is mentioned, along with an apo A2 promoter gene for which saturated fat is associated with higher average body mass in those homozygous for the T allele. Appropriately, they don’t put too much weight on the latter associations, but they do state that current information suggests that genetic predisposition modulates the association between saturated fat intake. They then state this segment of the population, which they deem “SFA-sensitive”, may experience a benefit in reductions of saturated fat intake, so it could therefore be recommended for them specifically. There doesn’t seem to be any other way to classify this position than absolutely absurd. It is completely ridiculous to suggest that only a subgroup of people with genetic predispositions to an even higher CVD risk resulting from higher intake of saturated fat should consider reducing their intake. The existence of this subgroup in no way suggests an absence of risk in those outside of it, as evidenced by the reduced risk of CVD elicited from reducing/replacing saturated fat below levels it is currently consumed in millions of people both in epidemiological studies and RCTs. That being said, this section is concluded with a few statements that are similarly problematic. The authors emphasize that type 2 diabetes and obesity are major contributors to CVD risk, and declare that the “optimal diet” (what happened to there not being such a thing as “the one diet” based on current research?) should be based on an individual's “carbohydrate tolerance”, apparently determined by insulin resistance and insulin secretion capacity. Next they claim that a diet higher in fat and fiber seems to be optimal for type 2 diabetics, only based on a single trial64, and that a diet lower in total and saturated fat may solely be optimal for carbohydrate tolerant, or insulin sensitive individuals. While the dietary pattern they described as optimal can absolutely be beneficial to those with diabetes, it doesn’t necessitate higher intake of saturated fat, and individuals would serve to benefit from keeping it lower. Also, given the aforementioned success of high complex carbohydrate, low fat diets in improving glycemia, lipids, blood pressure, and other disease risk factors in both healthy individuals and those with type 2 diabeties55-58, the suggestion that only carbohydrate tolerant individuals would serve to benefit from a diet low in saturated and total fat is unwarranted. The end of this section echoes the author’s earlier points about the increasing prevalence of type 2 diabetes and the need for a more personalized and food based approach in recommending levels of total and saturated fat in the diet. As stated earlier, this is surely something considered by health professionals that have expertise in providing nutritional advice, and it doesn’t indicate a need for any major alterations in general dietary recommendations currently in place.

In the following section, authors begin by highlighting that the health effects of fats and oils may depend on the content of saturated and unsaturated fats, but is not only a sum of its lipid components, and depends on the interacting effects from naturally occurring components and unhealthy components introduced by processing. They then reference the “trans-fat” story, which is a fairly appropriate example, but just seems to be an aside that doesn’t lead anywhere. Following a discussion of the history of suggestions to replace dairy fat with vegetable oils and the origin of the legislation that drove the saturated vs unsaturated debate, they mention that the major component of vegetable oils (polyunsaturated linoleic acid) was recognized to decrease plasma cholesterol concentrations by the 1950s, whereas saturated fat could raise it, therefore the former was estimated to have a more favorable effect on atherosclerosis. Incredibly, they then jump to state that despite being high in saturated fat, that dairy does not promote atherogenesis, with a single reference. The reference they cite happens to be an analysis of the relationship between dairy fat and incident CVD from 3 pooled cohorts with over 5 million person years of follow up, showing that when compared to carbohydrates (excluding fruits and vegetables - so likely mostly the refined grains that the authors have spent so much time using to paint carbohydrates in a bad light) that dairy fat wasn’t associated with a significant increase in total risk of CVD for a 5% increase in energy by a very small margin, as the RR was 1.02 with a 95% confidence interval of 0.98 to 1.0565. However, in their analysis on the effect of isocaloric replacement of dairy fat with other nutrients/foods, with the exception of carbohydrates from refined grains/starches and other animal fat, every single replacement elicited a significant reduction in the risk of CVD, including vegetable fat, omega 6, ALA, marine omega 3, and carbohydrates from whole grains, ranging from RRs of 0.9 (0.87 to 0.93) to 0.72 (0.69 to 0.75) for vegetable fat and whole grains respectively. Henceforth, the authors very conclude, “The results suggest that, compared with dairy fat, vegetable sources of fat and PUFA are a better choice for reducing risks of CHD, stroke, and total CVD, although other animal fat (e.g., from meats) may be a less healthy choice than dairy fat. In addition, we showed that types of carbohydrates made a difference; the replacement of dairy fat with high-quality carbohydrates such as whole grains was associated with lower risk of CVD, but the replacement with refined starch and added sugar did not appear beneficial.” How this supports their assertion dairy fat is not atherogenic, or the larger overall point that saturated fat reduction is not warranted, is unknown, as it strongly suggests the opposite.

After this, they begin to bring up an even stranger point, that due to the fact the ability of humans to digest lactose in milk has evolved separately numerous times, it is unequivocal that humans “required continuous dairy consumption for survival to reproductive age.” It seems as if they’re attempting to suggest this “requirement” for dairy milk, which was based on the fact that it may have offered a survival advantage in previous years (unsurprising given it is a concentrated source of calories), extends to present day, which is just outright false, and especially problematic given that the prevalence of lactose intolerance worldwide has been suggested to exceed 65% of the population66. Expanding upon this, the authors also mention how bovine, goat, and sheep domestication coincided with the emergence of lactase persistence, and that the meat from these species was likely a major contributor of saturated fat to human diets, supplemented with some low polyunsaturated fruit oils (olive, avocado, and palm) where available. Continuing, they state that seed oil consumption would have been negligible back then, and that these historical facts demonstrate saturated fats were abundant, key parts of the ancient human diet. Along with the lack of any research to support these final few assertions, there are numerous issues with this rhetoric, the main one being that any argument extending from this reasoning would be entirely founded on the logical fallacy “appeal to tradition”. Additionally, as they explicitly stated for milk consumption, these choices were likely made on the basis that they supported survival until reproductive age more than anything else, and therefore they wouldn’t necessarily have any relevance to constructing dietary patterns supporting a long, (at least mostly) disease-free life, which is the goal of countrywide dietary guidelines. Interestingly, reviewing the best estimates we have on nutrient intakes of paleolithic populations (which are more of a “true” ancestor if that’s the metric by which the authors feel is appropriate to base dietary recommendations on) intakes of saturated fat were substantially lower than current day populations, with estimates ranging from 7.5 to 12% of energy, indicating that a large fraction of the populations likely had intakes within the range recommended by dietary guidelines. Funnily enough, the JACC review authors specifically mention that domestication originated around 10,000 years ago with the advent of modern day agriculture, which is when the same publication mentions that some have hypothesized to be the origin of notable discordance between “older” and “newer” populations’ health67. That being said, this is the farthest thing from what we should be using to formulate current day guidelines on, especially when we have decades of recent high-quality data available.

Next, the authors talk about 1970s animal experiments that used coconut oil of “unspecified origin”, which caused dramatic increases in hepatic and blood cholesterol and were therefore deemed atherogenic. They mention these oils were usually highly processed and fully hydrogenated (without a source), and that “virgin” coconut oils produced in recent years using gentler preparation methods don’t possess the same LDL cholesterol raising properties, citing a study apparently demonstrating this lack of effect in humans68. While there was indeed no significant change in LDL following 4 weeks of consuming coconut oil daily, there are quite a few concerning factors that make this trial at least a bit suspect. First, baseline saturated fat intake was already relatively high (~15% kcal) in the coconut oil group, and there was no information available on post trial intake, making it impossible to gauge the overall change in saturated fat intake, which is of critical importance. Given that the change in calories and total fat from baseline were only 71 kcal and 29 g, when the coconut oil should have theoretically added about 430 kcal and 50 g of fat, it is very likely significant alterations in dietary patterns were made, and that absolute saturated fat intake may have hardly changed, if at all. Regardless, another trial on virgin coconut oil69 showed that it did indeed significantly increase LDL cholesterol over 30 days, and a recent meta analysis70 including these two trials along with 14 others demonstrated a significant increase with coconut oil consumption in trials over 2 weeks, so this matter is clearly far from settled.

After mentioning these trials, the authors discuss the recent realization that high-temperature treatment of oils in the presence of trace metals generates process contaminants, and describe an in vitro trial demonstrating that direct administration of different coconut oil samples subject to various leveling of processing elicited different effects on cholesterol metabolism, with greater processing being associated with greater increases in cellular cholesterol. It’s strange that after criticizing others for not basing their decisions on high quality evidence that the authors defer to mechanistic studies, one of the weakest forms of evidence, in order to support a speculation about the effect of potential oil contaminants. Subsequently, they bring up a study using (mostly non-enzymatic) oxidation resistant linoleic acid and claim that it supports the hypothesis that oxidation products and not specific fatty acids cause plaque formation in mouse models71. Such a statement is very misleading, as the di-deuterated linoleic acid in this study only partially reduced atherogenesis when mice were fed a high saturated fat and cholesterol diet, and alongside a reduction in oxidation products it also elicited significant decreases in LDL cholesterol. Pinning the entire process on oxidation products, especially when substitution of standard sources of PUFAs significantly reduces the incidence of CVD in humans, is unbecoming. Furthermore, placing so much weight on speculations stemming from rodent models such as this is a major issue given the remarkable inconsistency in the predictive ability of said models with respect to humans72, there is a reason they reside near the bottom of the evidence hierarchy.

In the following paragraph, authors state that human studies assuming all foods high in saturated fat are similarly atherogenic in many cases stem from an era prior to the recognition of process contaminants, which seems as if they’re suggesting this is the only atherogenic characteristic of saturated fat rich foods, and if so is quite a seriously disturbing conjecture. Next it is claimed that the recent Presidential Recommendation to avoid saturated fats from the American Heart Association was based on studies in the 60s and 70s, 3 in Europe, and 1 in America. This is an extremely uncharitable and blatantly incorrect characterization of the AHA’s Presidential Recommendation, which actually evaluated evidence from these 4 trials, 6 smaller, lower quality “non-core trials”, the Lyon Heart study, PREDIMED, additional observational studies on populations following similar mediterranean diets, RCTs reducing saturated fat intake and decreasing LDL-c (and vice versa), multiple meta analyses of observational studies on SFA intake and CVD incidence, large scale cohorts observing the effects of replacing saturated fat on CVD incidence, and additional supplementary genetic and mechanistic evidence73. These considerations aside, the JACC review’s authors discuss that the 3 European trials are confounded due to the fact that they used customary diets as comparisons, and supposedly partially hydrogenated fish oils were major constituents of European margarines during the 1960s and 70s, for which they cite a book titled “The Story of Margarine”, that unfortunately was inaccessible. They declare that The Oslo study explicitly estimated intake of partially hydrogenated fish oil at 40 to 50 g/day. Whether this pertains to the control or experimental group is unclear, however the only information given in the publication is for the experimental diets’ composition, which was the following: “In an analysis of the experimental diet as consumed by 17 selected dieters, the mean daily intake was: protein, 92 gm.; fat, 104 gm.; carbo-hydrates, 269 gm.; and cholesterol, 264 mg. Daily intake of calories was 2,387. Calories derived from fat constituted 39 per cent of the total. The sources of fat were: soybean oil (72 per cent), fish fat (11.6 percent), animal fat (8.8 per cent), cereal fat (s.o per cent), and fat from other sources (2.6 per cent).74” Given these numbers, and assuming “fish fat” is entirely partially hydrogenated fish oil, 11.6 percent of 104 g fat is still only 12 grams, way off from what they claim, so this bit is pretty confusing. Continuing in this vein, they assert that since the three European trials used customary diets as comparisons, it can be inferred that they were tests of polyunsaturated fats against trans-plus-saturated fats, and the effects can’t be ascribed to saturated fat alone. Henceforth, excluding these trials as they see fit, only the (smaller and underpowered) U.S. trial75 remains, which didn’t show a significant difference between the control and intervention group for its primary endpoint, although for all endpoints combined and fatal atherosclerotic events, results were significant despite the relatively low total event rate and consequential low statistical power. A few things merit discussion here. First, the entire reason they suggest the European trials should be excluded is an inference they are confounded that isn’t conclusively proven. Second, even if this were the case, the large body of evidence from other RCTs and observational studies discussed in the AHA’s Presidential Report are sufficient to underscore the importance and benefit of reducing/replacing dietary saturated fat.

Finally, they conclude this section by saying, “...these observations strongly support the conclusion that the healthfulness of fats is not a simple function of their SFA content, but rather is a result of the various components in the food, often referred to as the “food matrix.”...ample evidence is available from research on specific foods that other food components and the food matrix likely dominate over saturated fat content, as discussed in the following section. Recommendations should, therefore, emphasize food-based strategies that translate for the public into understandable, consistent, and robust recommendations for healthy dietary patterns.” Once again, the evidence they’ve brought forth does not seem to strongly suggest that the saturated fat content of foods is negligible with regard to a food’s healthfulness and impact on CVD risk. As for the food components and matrix, their actual relevance and implications for a foods’ impact on health will be addressed accordingly. Finally, as mentioned a few times previously, the current (and hopefully future) dietary recommendations are arguably already understandable, consistent, and robust, although there is certainly always room for improvement.

At last in some of the final paragraphs of the review the authors specify their reasons as to why they feel a few specific foods with high saturated fat content are unfairly discouraged. These foods include yogurt and cheese, dark chocolate, and red meat, discussed in that order. For yogurt and cheese, authors begin by describing that dairy is the major source of SFAs in most diets, and that major dietary guidelines recommend low or fat-free versions to limit SFA, but that food based meta-analyses consistently find the two are inversely associated with CVD risk, citing a cohort76, a literature review77, another cohort on type 2 diabetes78, and one actual meta analysis79. This seems as if it was just a citation error, but regardless the meta analysis they cite actually provides weak, if any, evidence suggesting an inverse association of cheese and yogurt with CVD. The inverse association was only actually found for cheese, and was attenuated when a single large study was removed in a sensitivity analysis. Furthermore, the subgroup analyses demonstrated the strongest inverse association with subjects below 50 years of age, a group in which CVD incidence would be lower and would therefore possess far less of an ability to effectively gauge the true effect on CVD risk. Even more concerning, numerous trials adjusted for hyperlipidemia, serum cholesterol, or saturated fat, which would also strongly impair their ability to pick up on an increased risk of CVD. One final consideration is that they chose to exclude one of the largest, and perhaps best quality studies (Hu et al. 1999), from their analysis, which demonstrated a significantly increased risk of CVD within the highest quintile of full fat dairy consumption, a higher ratio of full to low fat dairy consumption.

To the author’s benefit, another earlier meta analysis80 showed a similar neutral association of yogurt and cheese with CVD, and another published this year demonstrated a significant inverse association81, however no detail on the fat content, amount of intake, and overall diet composition of subjects was provided. This is problematic given that the details on the amounts, what the two are replacing, and the actual fat content are incredibly important to consider and could meaningfully influence the observations. The cohort they cite even exemplifies these points, showing that a higher intake of saturated fat from dairy (equivalent to 1-2 servings in the highest quintile depending on the source) is associated with a slight reduction in CVD risk, and that replacement of an equivalent amount from meat elicited a substantial RR of 0.7576. This definitely does give some merit to their statements about the saturated fat content of foods not being the only determinant of its overall effect on health, yet it doesn’t eliminate the possibility that cheese and yogurt have any contribution to CVD risk as they seem to suggest.

They also refer to a meta analysis on circulating biomarkers of dietary fat intake, specifying that data from 4 cohorts showed those in the top vs bottom third of plasma measures of C17:0 (heptadecanoic acid) had a decreased risk of CHD82. In addition to the issues present in the previously discussed meta analyses, it has been acknowledged that C17:0 (along with C15, pentadecanoic acid) are poor indicators of dairy intake, and that caution should be taken in interpreting any findings related to observations in epidemiological studies83. Alongside their discussion centered around cheese/yogurt and CVD, authors briefly mention that some studies indicate higher whole-fat dairy consumption is associated with a lower risk of diabetes, again providing an odd selection of citations; two literature reviews84,85, the de Souza meta analysis discussed earlier (which observed implications of serum Ct16:1n7 concentrations), and a cohort on circulating fatty acids (C15:0, C17:0, and Ct16:1n7) associated with dairy consumption and their relation to type 2 diabetes risk86. While the latter two did suggest an inverse association between serum values of these fatty acids and T2D, and although it is much more likely that Ct16:1n7 correlates with dairy intake, others have raised concern that it is also unreliable87, and these studies both fall victim to the numerous problems just discussed for those on CVD.

As an addendum, it is only fair to note that one of the sources the authors cited to support their claims on CVD was a cohort pertinent to the assessment in changes of diabetes risk resulting from substitutions between subgroups of dairy78. This particular study had more data that allowed for further investigation, which revealed a few interesting details. Most striking was that the consumption of full fat dairy products in general was incredibly low for yogurt, and a little less so for cheese. For yogurt and cheese, mean intakes were 0.05/0.08 and 1.38/1.47, and ranges were 0.01-0.88/0.01-0.60 and 0.48-3.39/0.46-3.44 servings per day for the two in men/women respectively. No notable associations were found for cheese with respect to all the substitutions tested, however substitution of low for whole-fat yogurt increased the risk of T2D, whereas substitution of whole fat yogurt for low-fat milk, whole-fat milk, and buttermilk all significantly reduced the risk. Given the low mean and ranges of intake, it seems highly likely that these findings are spurious at best, and further details only increase the likelihood of this. Looking over the radar charts provides insight as to the differences in the dietary profiles of those in the lowest and highest intakes of full-fat dairy. They reveal that higher intake of full fat dairy was associated with reduced intakes of red and processed meats, sugar sweetened beverages, and butter, along with greater intake of fruit and vegetables. Taking this into account, although variables related to dietary factors are considered, given the extent of the differences in the low vs high full-fat dairy intake groups in conjunction with the very low range, it is unreasonable to make any strong conclusions from this particular study. A few additional meta analyses had discordant results, with some showing inverse associations for cheese88,89 another demonstrating no effect90, and one showing an increase in risk91. Unfortunately none of these stratified by fat content, although when dividing dairy foods up between full and low-fat, three of four showed no significant association. Results for yogurt were similarly inconsistent, showing an inverse association with T2D in three meta analyses90-92, and no association in two88,89. Also like those on cheese, none of these were divided up into low and high-fat content sources. Factoring in all of these studies, it becomes quite clear that the association isn’t nearly as strong as the authors make it out to be, many being questionable at best.

To wrap up this paragraph, authors conclude, “Cheeses and yogurts consist of complex food matrices and major components include different fatty acids, proteins (whey and casein), minerals (calcium, magnesium, phosphate), sodium, and phospholipid components of the milk fat globule membrane (115). Yogurt and cheese also contain probiotics and bacterially produced bioactive peptides, short-chain fatty acids, and vitamins such as vitamin K2. The complex matrix and components of dairy may explain why the effect of dairy food consumption on CVD cannot be explained and predicted by its content in SFAs.” One immediate point that warrants attention is the authors make no effort to provide evidence that any of the components discussed here have relevance to dairy’s influence on health, CVD, or other notable outcomes. As such, any insinuation regarding these nutrients or other components is purely speculative. Also, quite ironic is the fact that the majority of them are also present in low fat yogurt/cheese (many even in greater amounts, i.e., whey and casein, calcium, magnesium, phosphate, etc.), so even if the saturated fat content was irrelevant they make no real case for consuming full fat over low-fat/fat-free alternatives, and from the evidence discussed here the latter seem to be associated with far more favorable outcomes.

Despite these points, it is only fair to acknowledge the authors do indeed appear to be correct that at the very least cheese and yogurt cannot be directly equated to other foods containing similar amounts of saturated fat. This is shown by the fact that feeding trials have consistently demonstrated that when compared to a diet lower in SF and higher in MUFA, PUFA, or carbohydrate, cheese raises LDL cholesterol to a lesser degree than butter providing an equivalent amount of saturated fat93,94. However, this discrepancy seems to be present only in subjects with a high baseline LDL, as discussed by Brassard et al. in their 2017 publication. Furthermore, in a meta analysis95 observing comparisons to other foods, including reduced fat cheese, tofu, and egg white, full fat cheese also tended to elicit significant increases in LDL cholesterol. Unfortunately, data on the impact of full fat yogurt in isolation on LDL is pretty scarce, however two trials including a three or four week intervention with high fat cheese, yogurt, and milk resulted in a significant increase in LDL95, or mitigation of the decrease observed following a lower fat intervention, even when coinciding with a large increase in overall fiber intake and reduction in sugar intake compared to the low-fat intervention96. If the food matrix or nutrient content of full fat dairy such as cheese and yogurt affects their impact on cardiometabolic risk factors, the magnitude appears to be small, and would likely not be of substantial importance. Taking into account the highly inconsistent associations of full fat cheese and yogurt with CVD/T2D outcomes, that they can negatively influence LDL cholesterol, the similar (and in some cases superior) nutrient profile of low-fat alternatives, and the findings from the pooled cohorts showing replacement of dairy fat with virtually all other sources of fat and carbohydrate significantly reduces the risk of CVD, it is abundantly clear that current recommendations to limit saturated fats from these two foods are appropriate.

After cheese and yogurt, the authors direct their attention to dark chocolate, stating that it contains stearic acid, which has a neutral effect on CVD risk, as well as that it contains other nutrients that may be more important with respect to CVD/type 2 diabetes. They note that it possesses potential preventative effects on the two, supported by both experimental and observational studies. While they provide no source for the stearic acid claim, the three meta analyses they link97-99 do actually offer consistent evidence confirming a small protective effect of chocolate with respect to CVD and type 2 diabetes, in agreement with a meta-analysis100 on dark chocolate and cocoa powder’s effects on serum lipids and an RCT101 of its impact on insulin sensitivity.

The final food the authors remark that there is insufficient evidence to suggest reducing intake of based on saturated fat content is (unprocessed) red meat. To back up this claim, they give four references; a meta analysis of cohort studies102, two meta analyses of RCTs, one on surrogate biomarkers103 and one on actual outcomes104, and a small cohort105. Aside from the fact that these publications don’t even represent a modicum of the evidence on red meat intake and CVD, type 2 diabetes, and cancer, the three they gave to justify their claims are weak at best. The first meta analysis they cite only includes 4 and 5 cohorts observing the effect of red and processed meat intake on CHD and type 2 diabetes incidence, respectively. Furthermore, three of the four observing the effect of red meat intake on CHD made adjustments for serum cholesterol, which as discussed previously is incredibly problematic given its role as a casual intermediate. Finally, although the association with diabetes was non-significant, it was by an incredibly small margin. Due to the limited number of studies considered and range in intakes observed, it would be ill-advised to draw a conclusion on the matter from this publication alone.

The first of the two meta analyses of RCTs they refer to investigated how one half or more servings per day of red meat impacted CVD risk factors, particularly serum lipid and blood pressure values. The authors of this publication conclude that red meat did not significantly impact LDL, HDL, triglycerides, systolic blood pressure, and diastolic blood pressure. This is a perfect example of the importance of not just taking results from RCTs at face value simply because it is referred to as the “gold standard” for nutritional science research. First, many of the trials intentionally used lean red meat for their comparison, which isn’t representative of consumer’s typical choices, and also detracts from the ability to actually determine the impact of naturally occurring saturated fat on a subject's lipid and blood pressure values. Second, well over half of the trials involved the addition of red meat to one’s habitual diet or a diet designed to elicit weight loss. While the former isn’t necessarily an issue, failure to consider the baseline diet (energy intake, saturated/trans fat intake, cholesterol intake, and refined carbohydrate intake, among other factors) would prevent a reliable assessment of the impact of adding red meat from being made. If subjects maintained or decreased intake of the aforementioned nutrients in the intervention, or lost weight, this would bias the results towards a null or even positive outcome given that weight loss and changes in these nutrients can affect blood pressure and lipids. Third, the comparators (food given to the control group) varied significantly, another potential source of issues since different foods or overall dietary patterns could impact lipid and blood pressure parameters. Finally, mean final LDL concentrations of both groups were above the normal range (3.18 and 3.13 mmol/L for intervention and control), giving merit to the theory that initial nutrient intake was subpar and had already given rise to lipid values, and also indicating that the conclusion red meat supposedly does not increase LDL is of limited value in this context. In a recent and far more thorough meta analysis of RCTs on the same topic106, many of these issues and their impact on observations were well-documented. The main finding of this publication was that substitution of red meat for high quality non-meat protein sources significantly increases LDL cholesterol, even considering diets designed to decrease lipid values. Another important note was that the total saturated fat content of the intervention diet containing red meat modulated the results, with any differences between changes in LDL becoming non-significant from other comparator diets when total saturated fat intake was matched or great in the intervention.

The second meta analysis cited by the authors is shockingly even more concerning. The goal was to observe the effect of reducing unprocessed red meat consumption in RCTs of over 6 months duration on chronic disease morbidity and mortality (specifically cancer and CVD). First of all, an RCT is far from an appropriate model for assessing the impact of dietary habits on chronic disease incidence and mortality, as these are lifestyle diseases that take decades to develop and manifest. It is extraordinarily naive to believe that a randomized controlled trial would include enough participants or be carried out long enough in order to have the power to observe a significant change in these metrics. Further, the feasibility of doing so is reflected in the fact that this analysis includes a single trial, the Women’s Health Initiative trial. As expected, no significant impact of reducing red meat on the outcomes considered was observed. That being said, despite the immense limitations of using this approach, a difference of a single serving (~1.4) per week of red meat between groups, and adjustment for cholesterol in their analysis, the results were still borderline significant: “...all-cause mortality 0.99 [95% CI, 0.95 to 1.03]), cardiovascular mortality (HR, 0.98 [CI, 0.91 to 1.06]), and cardiovascular disease (HR, 0.99 [CI, 0.94 to 1.05])...little or no effect on total cancer mortality (HR, 0.95 [CI, 0.89 to 1.01]) and the incidence of cancer, including colorectal cancer (HR, 1.04 [CI, 0.90 to 1.20]) and breast cancer (HR, 0.97 [0.90 to 1.04]).” Once again, this fails to provide convincing evidence, if any at all, that red meat does not contribute to chronic disease risk.

Finally, authors briefly mention that in a recent analysis of pooled prospective cohort studies unprocessed red meat was associated with a small, significant increase in all cause mortality and incident CVD, along with chicken and processed red meat. What they didn’t disclose is that this “small” association was for only 2 servings of red meat a week, under the average intake of all Americans, on top of almost 200 g processed meat and around 300 g chicken according to data for 1999-2016 from NHANES107.

After bringing up this study, they move on to make another point and close the paragraph, as if this is all the evidence that exists on the subject, which is an immense understatement. Red meat consumption has consistently been shown to significantly raise the risk of all cause mortality, CVD, diabetes, colorectal cancer, and stroke in numerous meta analyses and pooled results from large prospective cohorts108-127. The extent to which the existing literature pertinent to this discussion was ignored is inexcusable, and the conclusion drawn by the authors was highly misleading. In an attempt to reconcile the results of the one publication they did mention suggesting it may be harmful, they reason that it is a major source of protein, bioavailable iron, minerals, and vitamins that may comprise an important part of the diet for the elderly and low-income populations. Although considerations for certain demographics are important, the recommendations the authors are criticizing are meant to apply to the general population, which mostly isn’t composed of these individuals, so it seems odd to bring them up without any sort of prompting. Furthermore, focusing on nutrient content and cost of a food while ignoring strong, consistent associations with increased risk of the most prevalent, life-threatening or debilitating chronic diseases is short sighted. This is especially strange considering red meat isn’t typically seen as a cheap food, and that there other nutrient rich, low-cost foods with substantial health benefits, such as legumes, whole grains, and select nuts and seeds. A few studies on older populations underscore the protective effects of these, legumes especially, as well as the potential harm of higher meat intake128-131. Henceforth, with this in mind, their points appear even less convincing.

 Before wrapping up their review, the authors comment on what they feel to be gaps in current research and important considerations for future investigations. They initiate this paragraph by claiming that recommendations to reduce SFA intake without considering specific fatty acids and food sources is not aligned with current evidence. As a result, they suggest that these recommendations, “may distract from more effective food-based recommendations, and may also cause a reduction in the intake of nutrient-dense foods (e.g., dairy, unprocessed meat) that may help decrease not only the risk of CVD, type 2 diabetes, and other noncommunicable diseases, but also malnutrition, deficiency diseases, and frailty, particularly among “at-risk” groups.” This is both false and incredibly hyperbolic. As demonstrated throughout this entire commentary, with the exception of dark chocolate, they continually failed to substantiate any of these claims. Regarding nutrient intake, full fat dairy products hardly offer any advantage, if at all, over low-fat. Elimination of red meat does not necessitate decreased nutrient intake, especially given healthy substitutions such as fish, other lean meats, whole grains, legumes, and nuts/seed are made. Pertaining to disease risk, the full body of evidence shows the effects of full fat dairy are inconsistent at best, and effects of low-fat dairy actually appear to be favorable. Red meat has continually been shown to have adverse effects on the risk of the diseases they mentioned, so the intention of including it in their sweeping claims is unknown. Next, they suggest that a focus on SFAs has had an unintended consequence of misleadingly guiding government, consumers, and industry towards foods low in SFA but rich in refined starch and sugar, and that guidelines should consider the types of SFAs, and more importantly the foods containing them and their diverse effects on health outcomes. In addition to the fact that these choices were almost definitely motivated by factors other than the actual dietary guidelines, the consideration of different SFAs and foods containing them only seems to hold water to a very limited extent, with dark chocolate and potentially coconut (which the authors interestingly chose not to discuss) being the likely exceptions to the relationship between saturated fat intake and adverse health outcomes. 

Finishing up this section and transitioning into their final paragraph, they strongly recommend a more food-based translation of to achieve a healthy diet, reconsidering the guidelines on a reduction in total SFAs, and caution regarding incorporation of processed foods “until much more is known about the health effects of specific process contaminants so that their levels can be minimized.” Carrying on, they claim that there is a long-standing bias against foods rich in saturated fat that should be replaced with a view towards recommending diets consisting of healthy foods. Immediately following, they state, “We suggest the following measures: 1) enhance the public’s understanding that many foods (e.g., whole-fat dairy) that play an important role in meeting dietary and nutritional recommendations may also be rich in saturated fats; 2) make the public aware that low-carbohydrate diets high in saturated fat, which are popular for managing body weight, may also improve metabolic disease endpoints in some individuals, but emphasize that health effects of dietary carbohydrate—just like those of saturated fat—depend on the amount, type and quality of carbohydrate, food sources, degree of processing, etc.; 3) shift focus from the current paradigm that emphasizes the saturated fat content of foods as key for health to one that centers on specific traditional foods, so that nutritionists, dietitians, and the public can easily identify healthful sources of saturated fats; and 4) encourage committees in charge of making macronutrient-based recommendations to translate those recommendations into appropriate, culturally sensitive dietary patterns tailored to different populations.”

There are some excellent points here, however their relevance is questionable. Regarding their recommendations encouraging a food based translation of a healthy diet/a focus on diets consisting of healthy foods, it is almost certain that anyone interested in constructing policies for designing and implementing dietary guidelines would agree whole-heartedly. As a matter of fact, the panel in charge of creating the guidelines in 2015 were in such agreement, that’s exactly what they did. On the United States Department of Agriculture/Health and Human Service’s website, it is explicitly stated, “A healthy eating pattern includes: A variety of vegetables from all of the subgroups—dark green, red and orange, legumes (beans and peas), starchy, and other, fruits, especially whole fruits, grains, at least half of which are whole grains, fat-free or low-fat dairy, including milk, yogurt, cheese, and/or fortified soy beverages, a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), and nuts, seeds, and soy products, and oils”35, which leaves one questioning what exactly the JACC review’s authors are even contesting.

Moving on to their postulation about a “long standing bias” against foods with saturated fat and the subsequent plea for the creators of the guidelines to reconsider their suggestions to reduce total saturated fat intake, there is just no solid evidence for either of these. The suggestion there is existence of some sort of bias is completely unsubstantiated, and the totality of the evidence indicates that no such reconsideration is needed. In addition to the robust evidence from the numerous meta analyses already discussed here, the Scientific Advisory Committee on Nutrition’s recent 2019 report concluded that based on 47 systematic reviews, meta-analyses and pooled analyses on saturated fat intake (mainly from desserts, full fat dairy products, and meat/meat products) and various health outcomes, there is no need to modify the recommendations to limit saturated fat to less than 10% of calorie intake, and reduction to this amount would impose significant population level health benefits132. Next, their claim that many foods that play a role in meeting dietary and nutritional recommendations may also be high in saturated fat, is just as baseless, especially considering that low-fat and fat free versions of the products they are speaking about (dairy and meat specifically) are just as rich in nutrients, if not more so, than their higher fat counterparts. Furthermore, a large array of other nutrient dense and health promoting foods, many of which are recommended by the current guidelines, are available. Their second major point in the closing paragraph; that the public should be made aware that low carbohydrate diets high in saturated fat, popular for managing body weight, may also improve metabolic disease endpoints, and that health effects of dietary carbohydrate depend on the amount, type and quality of carbohydrate, food sources, degree of processing, etc., is of even less relevance. Not only did they provide absolutely no evidence in support of low carbohydrate diets eliciting weight loss or improvements in metabolic disease endpoints “in some people”, as discussed previously, the latter points are subsumed in the current recommendations for healthy eating patterns provided by the USDA/DHHS. Their third and fourth points once again falsely characterize the guidelines, both asserting that the current paradigm only emphasizes the saturated fat and macronutrient content of foods and fails to include culture sensitive dietary patterns, which as repeated numerous times at this point is just untrue.

While the authors of this State of the Art review make some bold claims, including that saturated fat limits are arbitrary, that numerous foods rich in SFAs have no association with CVD or diabetes, and that the guidelines should emphasize food-based recommendations for healthy dietary patterns, they continually fall short of corroborating them. The evidence they provide in an attempt to do so is weak, inconsistent, and many times even contradicts their own claims. They continually misrepresent the studies being presented and the current dietary guidelines, put forth speculative claims stemming from animal or in vitro/vivo models, and make misleading statements that will actually create more confusion amongst the public. Current evidence makes a strong and consistent case for a reduction in saturated fat, especially from red meat, to decrease morbidity and mortality from diabetes, cancer, and cardiovascular disease. Although they do raise the important point of factoring the quantity and quality of foods into dietary guidelines intended to minimize disease and support a long, healthy life, such considerations are already made by those currently in place. While the current guidelines may not be perfect, they are much better than this review’s authors make them out to be, and do not require the adjustments they suggest.

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