How ‘State of the Art’ is the JACC Saturated Fat Review?

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

But that doesn’t quite fit the thème du jour.

This issue again rears its head in the heavy emphasis on the PURE trial, in which the authors state the individual’s in the “highest” quintile of SFA intake [~14%] had lower risk for stroke. But hold on: in PURE, 4/5 quintiles had <10% SFA, and the ‘high carb’ risk was predominantly derived from low-middle income Asian countries with a high reliance on dietary staples, like white rice. The benefit to the “highest” SFA quintile is not a benefit per se, but a benefit by reference to the exposure contrast, i.e., the comparative lowest quintile group: which was 2.9-5%, with the lower end of that reflecting nutritionally inadequate diets in low-middle income Asian countries that formed a predominance of the data in PURE.

The authors also make the common circular reasoning argument that if there is a benefit to replacing SFA with PUFA, that, quote, “this could be attributed to a possible beneficial effect of polyunsaturated fatty acids and not necessarily to an adverse effect of SFAs.” What is interesting in this regard is that in the paper, they cite the Finnish example, which in effect contradicts this point regarding SFA alone. The Finnish public health campaign targeted SFA intake specifically through reductions in butter, which constituted the primary food source of SFA in the population. Over a 35-year period, CHD mortality decreased by 80%, of which reductions in blood cholesterol accounted for 67% of the mortality decrease. The population-wide reductions in blood lipids were primarily attributable to achieving a decrease in SFA intake from the average of 23% to 12-13%. What lends more weight to the Finnish example is that the changes in SFA intake, blood lipids, and CHD risk, occurred in the context of relatively no change in smoking rates in women [men declined], and an increase in BMI across the population. Let’s also consider that, with the exception of trans-fats and refined carbohydrate, replacing SFA with anything else – PUFA, plant-derived MUFA, wholegrain carbohydrates – is consistently associated with reduced CVD risk, across populations. Because reducing one food group will inevitably mean adding others, the argument that a benefit to replacement may not reflect an adverse effect of the nutrient being replaced is practically moot. Nevertheless, we have consistent evidence of the increase in risk that occurs with higher – >18% – SFA intakes.

>LDL reductions from diet and LDL particle size

This thrust of the argument posited regarding LDL-C and SFA appears to be that a reduction in CVD risk from lowering SFA cannot be inferred from the [well-established] effects of SFA increasing blood lipids [SFA raise LDL-C levels to a greater degree than any other nutrient]. This argument is factually incorrect. As stated above, in Finland between 1972 and 2007, population average cholesterol levels fell by 1.4mmol/L [56.7mg/dL], only 0.14 mmol/L [0.54mg/dL] of which was attributable to increasing statin use, i.e., the effect was driven almost entirely by the population-wide reductions in SFA. Of course, before someone imperceptibly declares “association isn’t causation”, allow me to quote from the most recent Hooper et al. 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.” [Emphasis added]

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

Another point made is that reductions in LDL-C can’t be inferred to result in a benefit to CVD when there could be other biological effects of diet, and the the example of cholesteryl ester transport protein [CETP] inhibitors is cited, which may lower LDL-C but have shown no benefit to reducing CVD risk. With respect, this mechanistic example of CETP is misconceived. CEPT inhibitors act on the transfer of cholesterol between HDL and LDL particles, purported to result in greater cholesterol clearance. But this isn’t the unifying mechanism by which all other interventions have been shown to work, which is via upregalation of the LDL-receptor. Lowering LDL-C levels through different mechanisms [statins via HMGCR, which influences liver production; ezetimibe via NPC1L1, which influences intestinal absorption; PCSK9-inhibitors via PCSK9, which influences LDL uptake into cells], the unifying factor is that each results in increased LDL-receptor activity, and increased clearance of LDL-C in the blood. That is the same mechanism through which saturated fats impact LDL-C levels, downregulating the LDL-receptor and resulting in increased blood LDL-C levels. Cholesterol transport = no effect; cholesterol uptake into cells and out of circulation = effect. The PUFA:SFA ratio has the effects it has on LDL-C levels precisely through the latter mechanism.

The authors also cite two studies to suggest that CVD risk may be reduced through diet without reducing LDL-C levels. However, one study – Lyon Diet Heart – was in secondary prevention patients – and the other was a subgroup of PREDIMED in high-risk CVD patients, with participants in both studies being on a range of drugs, from lipid-lowering medications to antihypertensives, and the PREDIMED subgroup showing significant reductions in oxidised-LDL. Changes in LDL-C through diet alone in this context may not necessarily be as pronounced as the effects of lower reductions, earlier in life, with the greatest magnitude of CVD event risk reduction in RCTs was observed where baseline levels of SFA were >18% energy, and were reduced on average by 8%. And the benefit to CVD risk in secondary prevention cannot exclude the effect of polypharmacotherapy.

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. While the authors acknowledge that large LDL particles are more enriched in cholesterol, they contend that small LDL are more strongly associated with CVD risk, and reducing SFA may not change small LDL. However, this emphasis on major differences in the risk of particle size appears to have been waning, particularly as evidence increasing suggests it is the cholesterol payload of lipoproteins into the artery that is the prime culprit in atherosclerosis. Allow me to quote from a recent review by Sniderman et al. 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.” [Emphasis added]

Again, the particle size point is used to contend that a reduction in SFA cannot be assumed to result in a reduction in CVD risk from lowering LDL-C. The recent Hooper et al. analysis cited above indicates that it is precisely through reductions in cholesterol that restricting SFA results in lower CVD risk.

>The “Our Ancestors”/whole foods argument

I’ve always found this view of ancestral diets interesting regarding animal fats, given SFA are estimated to have provided about 6% of the average total energy intake for humans in the Paleolithic period. And it was Loren Cordain, godfather of the ‘Paleo’ diet, who co-authored a 2004 JACC paper indicating, by reference to hunter-gatherer populations, that physiologically normal LDL is likely in the range of 1.2-1.8mmol/L [50-70mg/dL]. In the present review, the contention that SFA were an “abundant” part of the ancestral diet is not exactly a reflection of the “historical facts” as alleged: saturated fatty acids, in particular C14:0 myristic and C16:0, were not major contributions to diet in the Paleolithic period, reflecting the fat composition of wild game meat in free-living African mammals. This average intake would be consistent with dietary patterns associated with heart health today, in particular the Mediterranean and traditional Japanese diets.

The authors are right to point out the deleterious effects of hydrogenation and industrialised trans-fats, but this is no longer is dispute, and through regulation or industry cooperation, levels of trans-fats in the food supply have been drastically reduced.

Finally, we come to the real thrust of the review: to shift to whole-food based recommendations. This also is not necessarily a new idea, and I doubt you would find anyone in nutrition who doesn’t think this would be a positive step. However, when we look at the evidence for dietary patterns, and factor in interventions, what these recommendations would inevitably come to would be oily fish, nuts, seeds, olive oil, rapeseed oil, etc. You know, foods generally low in SFA. There are exceptions to this, as highlighted in the review, in particular certain dairy foods, and dark chocolate. Nonetheless, were these ‘Med diet’-style recommendations followed in the whole population, SFA intake could conceivably end up lower than current levels, in the ~6-8% range that characterises that dietary pattern.

>The Precautionary Principle

Whether academics like it or not, publishing papers in nutrition is not merely to publish to the wider academy and policymakers, but to publish into a cesspool of ideology that is currently dominated by two diametrically opposed belief-systems characterised by a plant:animal divide. With social media, we end up with an uncoordinated misunderstanding and misapplication of evidence in support of various positions in nutrition, through multiple channels. One end of that dietary extreme, which may perhaps be most problematic, is the cholesterol-denialist, fibre-denialist, heart-disease revisionist group of evangelicals, for whom the Abstract of this study alone is sufficient to confirm their bias. But let’s be objective about what this paper does and does not call for. Here is what isn’t in this review: a recommendation to increase SFA intake. Rather, the gravamen of the author’s case is that there may be no need to recommend further limits relative to current levels on intake in Western countries. Keep that in mind when you see the gross overreach which has inevitably accompanied the reception to the paper.

Let’s be clear: there is a distinct difference, by orders of magnitude, between stating that current SFA levels are around a threshold at which there may be little addition benefit to risk CVD from further reductions vs. saying there is no evidence that lowering SFA benefits risk, and as a corollary, there is no risk to increasing levels of intake. To be fair, the authors do not make the latter case, but this how the study will be – and is being – interpreted by the bacon-and-butter brigade.

What is somewhat ironic is the statement in the paper that the research upon which the dietary recommendations were based had “methodological flaws”, given that the basis for abandoning said recommendations are based off arguably more ‘methodological flaws’. These flaws are, however, state of the art, particularly when based on mishap meta-analyses.

>How to Write a ‘There is No Association’ Paper

It appears there is actually a formula to putting papers together that question the relationship between saturated fat, blood cholesterol, and CVD. Follow these steps, not necessarily in order.

Here is your formula:

1. Make lipid language soup with effects of individual fatty acids on lipoproteins
2. Select from any number of methodological mishap meta-analyses
3. Emphasise exceptions to rule in the form of dairy yogurts & cheese
4. Cite PURE study
5. Leave out any comparisons of higher thresholds of intake, discussion of exposure contrasts, or analysis of sigmoidal relationships
6. Did we say cheese? How about PURE?
7. Conclude by recommending the need to abandon guidelines for lower saturated fat in favour of food-based recommendations for foods low in saturated fat by reference to dietary patterns with <10% saturated fat.

Be sure to submit to either the British Journal of Sports Medicine or BMJ Open Heart, it’ll confirm their biases, too.