Epidemiology can be Interesting

      Hat tip to Nigel Kinburn for pulling up two studies from Siri-Tarino et al.’s 2010 saturated fat meta-analysis that did show correlations with heart disease. These were also the studies with the widest range of intakes. So what can they tell us?
      The first is by Jim Mann and colleagues from 1993, and straight up I am surprised that this has been included in any meta-analysis, because it uses a self-selected vegetarian cohort, with friends and family standing in for the rest of the population.
      “The study differs from previous prospective studies of diet and IHD in that the volunteers were individuals whose self-selected diet resembled, in nutrient content, current dietary recommendations rather than the relatively high saturated fat diet typical of most affluent societies. The findings may not only help to explain which attributes of a vegetarian diet protect against IHD but also which foods and nutrients are important in the aetiology of IHD in populations who modify their diets along the lines of present guidelines.”
      It’s odd that such high-bias methodology isn’t excluded from meta-analysis, and makes me wonder what else is included.
      What does Mann et al. tell us?
“Results—IHD mortality was less than half that expected from the experience reported for all of England and Wales. An increase in mortality for IHD was observed with increasing intakes of total and saturated animal fat and dietary cholesterol—death rate ratios in the third tertile compared with the first tertile: 3.29, 95% confidence interval (CI) 1.50 to 7.21; 2.77, 95% CI 1.25 to 6.13; 3.53, 95% CI 1.57 to 7.96, respectively. No protective effects were observed for dietary fibre, fish or alcohol. Within the study, death rate ratios were increased among those in the upper half of the normal BMI range (22.5 to under 25) and those who were overweight (BMI over 25) compared with those with BMI 20 to under 22.5.
(Relative risk figures have been converted from 100 to 1.0)

      IHD was significantly associated with higher consumption of eggs, cholesterol, animal fat, and saturated fat.
      But, here’s the surprising finding; none of those dietary factors was associated with any increase in total mortality, significant or non-significant. People who avoided dying of IHD by following the healthy eating guidelines were dying at the same rate – the same ages - as their less health-conscious friends and family. This wasn’t pinned down to any particular cause of death.

      The fact that BMI under 20 was associated with as much increased risk of overall mortality as BMI over 25 (“total mortality was significantly higher in those with an initial BMI under 20, and a similar though not statistically significant trend is apparent for IHD mortality.”) wasn’t mentioned in the abstract, and is underplayed in the text (if it can be explained by undiagnosed pre-existing disease, so can the correlation with higher BMI). A bit like this dodgy AHF BMI calculator. Set this to BMI 7 (maximum height, minimum weight) and you still look healthy; muscular or curvy depending on gender. Results in real life may vary.

      The main dietary finding pertaining to all-cause mortality in Mann et al.;
“all cause mortality for all subjects was significantly lower in the middle and highest intakes of green vegetables (0.62, 95% CI 0.46–0.83; and 0.74, 95% CI 0.56–0.99) and among those consuming the highest intake of nuts (0.76, 95% CI 0.60–0.97) compared with the lowest intakes of these foods.”

     The second paper is by Bonniface et al., and unfortunately doesn’t supply all-cause mortality data.
      “Not consuming alcohol, smoking, not exercising and being socially disadvantaged were related to high saturated fat intake and CHD death. Cox survival analyses adjusting for these factors found that a level of saturated fat 100 g per week higher corresponded to a relative risk for CHD death for men of 1.00 (0.86-1.18) and 1.40 (1.09-1.79) for women. This difference between the effects of saturated fat in men and women was statistically significant (P=0.019).”

     Mean intakes of SFA in Bonniface et al. - Men: 47.0 g/d Women: 34.4 g/d. A respectable ~20%E (similar to the consumption by Indians eating food prepared with ghee in Raheja et al. 1995).
“The cut-off points for the quintiles of saturated fat in grams per week were 220, 276, 337 and 427 for men and 159, 202, 252 and 319 for women. There was a clear trend to higher CHD death rates associated with higher total and saturated fats and Keys' fat difference in women.”

      Keys' fat difference? This is the ratio between SFA and PUFA.
      “The result for the Keys statistic indicates that a higher level of saturated fat can be compensated by a lower level of polyunsaturated fat, in the ratio 2:1.”
      PUFA by itself showed no correlations, but the Keys difference did. In fact, the correlation between Keys' difference and CHD in table 3 is pretty striking.

     Both populations were in Britain. Perhaps the take-home is, that in Britain, at least at a certain point in time, you could choose how you wanted to die to some extent by choosing your diet around heart guidelines. Or by watching your Keys' ratio if you were female (women today, with vegetable oil diets, would not have ideal Keys' ratios by these tables). But living longer than those around you by restricting saturated fat is not a prediction supported by this epidemiology, or by any meta-analysis, as was discussed by Simon Thornley, Grant Schofield and I in our letter to the NZMJ.

     Diet epidemiology is interesting stuff. It’s incredibly hard to do well, and the things we can take away from it are sometimes unexpected. The papers that go into meta-analyses, even for something like SFA, are wildly heterogeneous in design and in quality. Jim Mann et al.’s 1993 paper told me just about everything I wanted to know that it was possible to tell from the data collected. Bonniface et al. were more obscure; critical data points for the Keys' difference were not included. What use are quintiles without means or cut-offs?
      I was surprised, as I said, that the Mann et al. paper, good though it is, is being included in meta-analysis, because of the self-selection bias (so, self-selection in Paleo or LCHF diet studies shouldn't be a barrier to being taken seriously either). That it was included speaks to the impartiality of meta-studies like Siri-Tarino et al. 2010 that exculpate saturated fat. Meta-studies give the overall truth that is relevant for public health planning, but miss the finer details of what is happening in specific communities at specific times. For example:
      In Mann et al., nuts are protective. This is a common finding, e.g. in Hu et al. 1998. In Bonniface et al. PUFA is not associated with harm, but the Keys' difference is. In Britain at the time of this study, among the mainly middle and upper classes, perhaps vegetable oils were not in common use. Perhaps nuts were a major source of linoleic acid, enough to attenuate its relationship with disease. And in Bonniface et al., with its more working class catchment (and this being Britain, class distinctions do matter), perhaps the ideal Keys' difference of 2:1 is what you get closer to eating nuts and fish with meat and dairy fat, and the adverse lower and higher ratios are what you get either not eating nuts and fish, or using vegetable oils and spreads instead of animal fats.
(the mean PUFA intake of 63.1g/week for women is ~4%E).
     Because it may turn out that when diet-heart epidemiologists one day separate PUFA in nuts and fish from PUFA in oils they will get very different values, as these AMD researchers did.

     Take home: For someone who has the disease of CHD, especially someone following a moderate fat, higher carbohydrate diet like most of the population (the dietary pattern at the heart of all epidemiology) it makes sense to follow these clues, as well as recognising the modern risk factors of sugar and refined flour; eat some nuts, fish, don’t eat red meat every day, eat only a few eggs per week, eat some full-fat dairy, and so on.
      On the other hand, for the average person to eat a pleasurable diet that has been designed around avoiding CHD risk factors from animal foods risks inviting in a host of other diseases that they may be susceptible to in ways they were never susceptible to CHD. Advice to the general population should be limited to recommending those protective factors for CHD that a) supply micronutrients, and b) are also protective factors in a wider sense (nuts, fish, fruit and vegetables, and full fat dairy), instead of messing with Keys' difference based on theories about blood lipids, as opposed to consistent findings based on real food inputs and hard endpoints.

Another Reason why the Lipid Hypothesis is Bunk

The lipid hypothesis, as evry fule kno, predicts that eating saturated fat causes elevation of serum cholesterol or LDL which then plays a causal role in cardiovascular heart disease. How or why no-one knows but the feeling out there is that saturated fat causes bad cholesterol and heart disease. The notion is, as they say, entrenched; it is a meme more widely believed now than any religious dogma.

Unlike the unknowable nature of God, the lipid hypothesis can be disproved by multiple lines of evidence. Here is one.

Animal fat is a blend of saturated fats, monounsaturated fats, and polyunsaturated fats. Polyunsaturated fats lower serum cholesterol, monounsaturated fats have no effect on serum cholesterol, and some saturated fats also have no effect on cholesterol. William Barendse describes the set-up eruditely and eloquently in his epic review “Should Animal Fats be Back on the Table? A critical review of the human health effects of animal fat” as follows;

“As an example from one of the hardest animal fats, approximately only 27% of tallow from pasture-fed beef is cholesterol-increasing saturated fatty acid (CISFA) (Yang et al. 1999b), i.e. chain length of 12–16 carbons, and which would raise serum cholesterol, 1% is polyunsaturated, ~4% is conjugated linoleic acid (CLA), and the rest is either MUFA or is the saturated fatty acid (SFA) stearic acid that causes the same effect on total serum cholesterol (TSC) as MUFA (Keys et al. 1965; Grande et al. 1970; Bonanome and Grundy 1988; Tholstrup et al. 1994a, 1994b; de Roos et al. 2001; Mensink et al. 2003). By comparison, in butter from pasture-fed cows, 42% of the fat is CISFA (Couvreur et al. 2006) and would raise serum cholesterol despite butter having a total of more than 60% SFA.”
(FYI, butter also supplies twice as much cholesterol as tallow.)

Therefore, if the lipid hypothesis were true, we would expect butter and other forms of dairy fat (of which butter is merely the concentrate) to cause, or at least be associated with, more heart disease than meat fat, especially considering that most meat fat is less saturated than tallow.

To the contrary, the 2012 epidemiological analysis, Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis, one of the few studies to separate saturated fats according to their dietary sources, found a strong protective (inverse) association between dairy fat and CVD, and a weaker positive association with the less saturated fat from meat, across a multi-ethnic population (this ruling out the possibility of the results being unduly influenced by genetic factors);

“When we evaluated risk across quintiles of SF consumption from each food source, a significant inverse association was seen for dairy SF [HR (95% CI) for extreme quintiles: 0.56 (0.38, 0.82); P-trend = 0.01], whereas meat SF was not statistically significantly associated with risk [HR (95% CI) for extreme quintiles: 1.40 (0.94, 2.08); P-trend = 0.12] (Figure 1). Butter and plant sources of SF were not associated with CVD risk, but ranges of SF consumption from these sources were quite narrow, which limited our ability to detect differences in risk across quintiles.”
“In sensitivity analyses in which angina was excluded from CVD endpoints, inverse associations of total, dairy, and plant SF with hard CVD were somewhat stronger, whereas the positive association of meat SF with hard CVD was slightly attenuated (data not shown).”

In case it is thought that the sample size in the MESA study (5,209) was too small, it is a common finding that dairy fat is either not, or is inversely, associated with CVD incidence.

An argument could be made that some factor associated with dairy fat, such as (hypothetically) calcium, reverses the harmful effect of saturated fat. If such were in fact the case, how nugatory would that harmfulness then need to be?

There may be things that raise cholesterol and that are associated with CVD. Industrial trans fatty acids seem to meet this case, as well as various organic toxins and heavy metals that are not fatty acids, and that are likely to be bad for you quite independently of any perturbations of your lipids. Sugar and high-GI starches are other potential candidates, which takes us into the intricacies of lipoprotein classes beyond the cartoon characters of cholesterol and LDL. There are also bound to be fatty acids, as well as other factors, which can increase CVD risk while lowering cholesterol. There have certainly been enough trials of cholesterol-lowering drugs, and cholesterol-lowering diets, where more people have died in the treated group, and sometimes died with lower cholesterol.

Yet people still believe this thing. It is nonsense. There are other things that better deserve the energy that has been poured into making people worry about saturated fat, and about the influence of dietary fats on cholesterol. The lipid hypothesis, and consequent pious attempts to respect or enforce the magical 10% saturated fat limit, have had a mischievous influence over the modern diet. Belief in it has not made us, in the majority, healthy, wealthy, or wise. It has made us saturate our bodies in polyunsaturated fats without considering whether they are omega 6 or omega 3, cis or trans, oxidised or unoxidised, or how far they are in fact necessary, or whether they bring anything in the way of nutrition to the diet to make up for the choline, carotenoids, cholesterol, retinol, menaquinone, and cholecalciferol we miss out on by not eating as much butter or fatty animal parts as our ancestors did. We have been fools, and we are making our society sick. It is time to stop.

Diabetes as an Iatrogenic Disease - the Second Hit

Why does dairy fat, and perhaps other similar fats like tallow and coconut, seem to prevent diabetes?
A broken omega 6:3 ratio becomes more likely with higher PUFA intakes. There is something about having a low PUFA intake that preserves the balance, even at relatively low omega 3 intakes.
We can see this in the recent fatty liver study comparing olive oil with canola oil and soy/safflower oil (control). For 6 months 20g of oil per day was used to cook food; this is not much (and it seems likely to me that many participants would have used more than they were directed to, if only to increase the palatability of their meals). There was no change in fatty liver and insulin resistance scores in those using soy/safflower oil, which is presumably what all subjects cooked with before.

The pre- and post-intervention difference in liver span was significant only in the olive (1.14 ± 2 cm; P 0.05) and canola (0.66 ± 0.33 cm; P 0.05) oil groups. In the olive and canola oil groups, post-intervention grading of fatty liver was reduced significantly (grade I, from 73.3% to 23.3% and from 60.5% to 20%, respectively [P 0.01]; grade II, from 20% to 10% and from 33.4% to 3.3%, respectively [P 0.01]; and grade III, from 6.7% to none and from 6.1% to none, respectively). In contrast, in the control oil group no significant change was observed. 

So canola oil and olive oil were about equally good for reversing steatosis; this might be an expected effect of supplying fats with an omega 6:3 ratio of 2:1 for six months. But when it came to glucose and insulin, there was a marked difference:In a comparison of olive and canola oil, a significant decrease in fasting insulin level, HOMA-IR, HOMA-βCF, and DI (P 0.001) was observed in the olive oil group.
In fact, fasting insulin and blood glucose were normalised in the olive oil group, but not in the canola oil group. With regard to these measures of glycemic control, a 50% lower intake of linoleic acid (with substitution of MUFA from oleic acid) produced more benefit than a 20-fold increase in alpha linolenic acid.

Here we have a paper that compares the effect of LA restriction (from 8%E to 4%E) with the effect of DHA in immune-deficient mice bearing human breast cancer cells;
Tumor prostaglandin E2 concentrations were reduced by feeding the lower LA level; further dose-dependent decreases occurred in the DHA dietary groups and were accompanied by reduced levels of 12- and 15-hydroxyeicosatetraenoic acids.
According to Raheja et al. (1993) "prostaglandin E2 is a potent inhibitor of first-phase insulin release, whereas an arachidonic acid lipoxygenase product, possibly 12-hydroxyeicosatetraenoic acids (12-HETE) sustains increased second-phase insulin release". A pattern also known as insulin resistance, or if sufficiently elevated, NIDMM or type 2 diabetes. These elevated prostaglandins are also seen in type 1 diabetics.
And, what do you know, ghee reduces PGE2 in Wistar rats:Ghee, the anhydrous milk fat, is one of the most important sources of dietary fat in India. Male Wistar rats were fed diets containing 2.5, 5.0 and 10 wt% ghee for a period of 8 weeks. The diets were made isocaloric with groundnut oil. The results showed that serum thromboxane levels decreased by 27-35%, and 6-keto-prostaglandin F1alpha by 23-37% when ghee was incorporated at level of 10% in the diet. Prostaglandin E2 levels in serum and secretion of leukotrienes B4, C4 and D4 by peritoneal macrophages activated with calcium ionophore decreased when increased amounts of ghee from 2.5 to 10% were included in the diet. Arachidonic acid levels in macrophage phospholipids decreased when incremental amounts of ghee were fed to rats. These studies indicate that ghee in the diet not only lowers the prostaglandin levels in serum but also decreases the secretion of leukotrienes by macrophages.

(I haven't seen fulltext for that, but control, groundnut oil, is around 30% LA, and 10 wt% will be more than 10%E).

With regard to ALA, this epidemiological paper on prostate cancer, while perhaps  irrelevant, has an interesting line:ALA intake was unrelated to the risk of total prostate cancer. In contrast, the multivariate relative risks (RRs) of advanced prostate cancer from comparisons of extreme quintiles of ALA from nonanimal sources and ALA from meat and dairy sources were 2.02 (95% CI: 1.35, 3.03) and 1.53 (0.88, 2.66), respectively. The multivariate RR of advanced prostate cancer from a comparison of extreme quintiles of the ratio of LA to ALA was 0.62 (0.45, 0.86).
Do you have any idea how much dairy fat it takes to get into a high quintile for ALA? Anyway, just another epidemiological paper where animal fats come out safer than their vegetable equivalents. One of the ones you don't hear about.
As I mentioned previously here, in New Zealand per capita weekly butter consumption at the beginning of the Second World War was 415 grams. It is now 112 grams, which is half of the reduced 1940s wartime ration. Not much Type 2 diabetes in New Zealand prior to the Second World War. Not much consumption of heart-healthy oils either, but plenty of consumption of sugar and white flour.

The second hit: In children and young individuals, a high intake of n-6 PUFA is correlated with fasting hyperinsulinaemia, and dietary supplementation with n-3 PUFA leads to an improved lipid profile but not insulin sensitivity. In adults, high-carbohydrate meal consumption was reported to cause hyperinsulinaemia, postprandial hyperglycaemia and hypertriacylglycerolaemia. (Misra, A. 2009).
Take a child, and raise them on this high-LA, vegetable oil diet (because saturated fat and high cholesterol, don't you know, cause heart disease in toddlers). By the time they reach adulthood, they'e primed for the second hit:

Refined grain consumption and the metabolic syndrome in urban Asian Indians (Chennai Urban Rural Epidemiology Study 57).

Compared with participants in the bottom quartile, participants who were in the highest quartile of refined grain intake were significantly more likely to have the metabolic syndrome (odds ratio, 7.83; 95% confidence interval, 4.72-12.99). Higher intake of refined grains was associated with insulin resistance and the metabolic syndrome in this population of Asian Indians who habitually consume high-carbohydrate diets.

That's grains, by the way, not sugar, not HFCS.

Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans.