Cardiovascular Disease Risk Assessment and Management for Primary Care.
https://www.health.govt.nz/system/files/documents/publications/cvd-risk-assessment-and-management-for-primary-care-v2.pdf

Its the same stuff – saturated fat is bad for you. Avoid it, and replace it with polyunsaturated and monounsaturated fats

But hang on minute, is this still the best advice you have?  And will it really prevent people getting cardiovascular disease?

The advice to limit saturated fat misses more important effects?

We think there are a few holes in the argument. Or at least we aren’t getting the full story.

They say……

“Substituting dietary saturated fat with mono and polyunsaturated fats is the most effective dietary approach to reducing low-density lipoprotein cholesterol (LDL-C) while maintaining or increasing high-density lipoprotein cholesterol (HDL-C).”

But we think this misses the mark – polyunsaturated and mono-unsaturated fats lower LDL because of their effect on the LDL-receptor and on ApoB catabolism. But they only raise HDL when substituted for carbohydrate, because they are fats, and fats in general stimulate the release of ApoA1, the seed of HDL, from gut and liver cells.

A high intake of linoleic acid lowered LDL and raised HDL when it was added to the baseline fat intake (e.g. replaced carbohydrate in the diet), but lowered both LDL and HDL when it replaced saturated fat.[1]

This might seem to be picking on the details, but we think it is important. As it stands above replacing saturated fats isn’t the most effective way of changing the fats in your diet to improve your chances of avoiding clogged arteries.

We think better advice might to be to replace the carbs your eat with fats from minimally processed foods.

The classic feeding study meta-analysis of Mensink et al. makes clear the benefits of replacing carbohydrate with various fats. This is worth quoting at length.[2]

The cis MUFAs had a modest but significant LDL cholesterol–lowering effect relative to carbohydrates. All 3 classes of fatty acids increased HDL cholesterol relative to carbohydrates. Unsaturated fatty acids increased HDL cholesterol less than did SFAs. As a result, the replacement of 1% of energy in the form of SFAs with an equal percentage in the form of cis MUFAs is predicted to lower HDL-cholesterol concentrations by 0.002 mmol/L. A similar decrease is expected when 1% of energy in the form of MUFAs is replaced with an equal percentage in the form of PUFAs. These effects, however, are small compared with those of replacement of carbohydrates with any of the 3 classes of fatty acids. Replacement of carbohydrates with any class of fatty acids decreased fasting serum TG concentrations (Table 1). The effect was slightly but not significantly larger for PUFAs than for other fatty acids. This contrasts with the powerful TG-lowering effect of n−3 PUFAs from fish, which is evidently not shared by linoleic acid, the major n−6 PUFA. Replacement of carbohydrates with SFAs did not change apo B concentrations. The cis unsaturated fatty acids, however, decreased apo B, and this effect was slightly stronger for PUFAs. SFAs and MUFAs increased apo A-I concentrations relative to carbohydrates. PUFAs did not significantly change apo A-I concentrations.

In other words, all benefits expected in terms of increasing unsaturated fats are seen when fat replaces carbohydrate, and this has the additional benefit of decreasing triglycerides – it’s better for the TG/HDL ratio. We explained how this effect plays out in terms of ApoB and ApoA1, even if saturated fat increases, in an earlier blog.

The substitution meta-analysis of Farvid et al makes it clear that a similar effect – an association with risk here, not just risk markers – is even seen in prospective cohort studies, confounded though those are.[3]

“9 cohort studies evaluated substitution of LA for carbohydrate showed that substituting 5% energy intake from LA for carbohydrates lowered risk with about 10%. A slightly lower risk benefit was seen for substitution of LA for SFA.”

So if it’s better, or at least not worse, to replace carbs with unsaturated fats and leave saturated fats as they were, why isn’t this offered as advice?

The most at risk benefit the least from current advice

The problem with the existing advice is is, that even the expected effects of replacing SFA with unsaturated fats are unlikely to be seen if you are overweight or insulin resistant. The studies being relied on for guidelines are based, overall, on healthy volunteers – unfortunately for people depending on these results, insulin sensitive people are at very low risk of CVD, and LDL has little correlation with their risk, but the opposite is true for the insulin-resistant.[4]

Design: A randomized, double-blind, 3-period crossover controlled feeding design was used to examine the effects on plasma lipids of 3 diets that differed in total fat: the AAD [designed to contain 38% fat and 14% saturated fatty acids (SFAs)], the Step I diet (30% fat with 9% SFAs), and the Step II diet (25% fat with 6% SFAs). The diets were fed for 6 wk each to 86 free-living, healthy men aged 22–64 y at levels designed to maintain weight.
Results: Compared with the AAD, the Step I and Step II diets lowered LDL cholesterol by 6.8% and 11.7%, lowered HDL cholesterol by 7.5% and 11.2%, and raised triacylglycerols by 14.3% and 16.2%, respectively. The Step II diet response showed significant positive correlations between changes in both LDL cholesterol and the ratio of total to HDL cholesterol and baseline percentage body fat, body mass index, and insulin. These associations were largely due to smaller reductions in LDL cholesterol with increasing percentage body fat, body mass index, or insulin concentrations. Subdivision of the study population showed that the participants in the upper one-half of fasting insulin concentrations averaged only 57% of the reduction in LDL cholesterol with the Step II diet of the participants in the lower half.

Whereas the drops in HDL and rise in TG (from the stepwise reductions in fat and replacement with carbs) probably cancelled out any benefit from lower LDL in responders here, the most IR subjects weren’t even getting the benefit of lower LDL! That’s where a low carb approach to lipid management would have come in handy –  if insulin and body fat % became lower, these subjects would experience a greater response to any PUFAs and MUFAs in their diet.

What is LDL anyway?

The LDL-cholesterol (LDL-C) in a standard lipid panel is just a calculated proxy for ApoB. On a low carb diet, with low TGs, you’ll start to get discordance between LDL-C and ApoB. That is, sometimes the LDL-C count can go up even when there’s a reduction in ApoB; this is because the ApoB particles become larger and less atherogenic. We see this in the Virta Health type 2 diabetes study – there’s a 9% rise in LDL cholesterol but ApoB has decreased non-significantly, LDL-P (the actual number of LDL particles) has decreased,  small LDL-P (the actual number of the most atherogenic type of LDL particle) has decreased massively, and of course everything else has improved.[5]

Curiously, triglycerides are only mentioned in the new guidelines as a risk factor for pancreatitis, which is one pathway to diabetes, and not as a CVD risk factor (and the cut off here is 11 mmol/L. Wow). We’re not sure why this is. Has the new shift to non-fasting tests made it impossible to use the old risk calculations, which clearly defined risk in terms of LDL, TG, and HDL? Is there an assumption that because everyone in NZ should be eating a high carb diet, there is no point giving advice to lower TGs? It’s a mystery. TGs (with more reasonable cut-offs) are still a risk factor for people with LDL controlled by statins.[6]

Triglycerides are important

Here’s a rare, good quality study (n= 3590) from the Framingham Offspring Cohort that actually looked at risk based on all 3 lipid measures, in a population not taking any lipid-lowering drugs. The high/low cut of for HDL was 40 mg/dL for men and 50 mg/dL for women, which some labs will tell you is still too low (we can do better !). The lowest TG cut-off of 100 mg/dL is also a bit high (again, we can do better !) – the 2 cut-offs combined give a TG/HDL ratio of 2.5 for men and 2 for women, whereas the insulin-sensitive groupings in other studies tend to have a mean TG/HDL ratio of ~1.1 (consistent with LDL particle size in people with type 2 diabetes improving below a TG/HDL ratio of 1.5).
Even so, you can see that if HDL is high and TG low, risk is low, and any difference in the LDL level has little effect. Note that this population wasn’t screened for familial hypercholesterolaemia genes, which would have impacted risk across all higher LDL categories.[7]

Statins – good for some?

When statins (okay we will wade into this just a little) are prescribed in secondary prevention (i.e. after a heart attack), they are very effective in preventing a second event in the most insulin-resistant people, calculated by the TG/HDL ratio. The NNT (number needed to treat) over 6 years in the IR group in the 4S study was 6, which is amazingly good – but statins didn’t really make much difference to the most insulin-sensitive, who are at an almost equally low risk if taking a placebo – their NNT in 4S was 36.[8]
Remember, these insulin sensitive cases, who don’t seem to benefit much from LDL lowering, are also the ones likely to see the biggest LDL drop if they replace saturated fats with unsaturated fats (it’s the opposite with statins, so the insulin-sensitive people below were actually on a higher statin dose to get the same LDL reduction – so much for extrapolating between diet and drug effects).

Age increases risk?

It’s also worth questioning the use of age as a continuous variable in risk calculations. Of course your risk of dying from any disease goes up as you age, but trials of statins in elderly populations for primary prevention are few, and include 1) the ALLHAT open-label trial where statin use was not beneficial in a post-hoc analysis of the elderly patients (n=2867): this was a rare trial not funded by industry and came closest to a real-world model of prescribing.

The hazard ratios for all-cause mortality in the pravastatin group vs the UC group were 1.18 (95% CI, 0.97-1.42; P = .09) for all adults 65 years and older, 1.08 (95% CI, 0.85-1.37; P = .55) for adults aged 65 to 74 years, and 1.34 (95% CI, 0.98-1.84; P = .07) for adults 75 years and older. Coronary heart disease event rates were not significantly different among the groups.[9]

2) The PROSPER RCT (n=5804) in which CHD was reduced, but all-cause mortality was not affected (0·97 (0·83–1·14)) due to increases in other causes of death.[10]

3) The JUPITER and HOPE3 trials, in which a recent post-hoc sub-group meta-analysis has revealed benefit for the elderly patients. (JUPITER was a statin trial targeted at patients with low LDL but high CRP, i.e. inflammation, and had most clear evidence of benefit in cases with low HDL at baseline, which again is evidence of statins being far more effective in the insulin-resistant). The older people were, the more likely they were to stop taking statins, but we can’t say how much of this is due to increasing side effects with age, because side effects were poorly recorded in these early statin trials.[11]

Risk management in the elderly may also be complicated by the fact that total cholesterol and LDL are often protective risk markers in older populations. For example, in the Danish registry of people without pre-existing heart disease or diabetes higher LDL is associated with lower mortality, compared with LDL under 2.5 mmol/L, in those over 50. That this included those with very high LDL – above 4 mmol/L – rules out reverse causality. Though statin use (by about 1 person in 4) was also associated with lower mortality in this population, there was no interaction between statin and cholesterol (i.e. statins didn’t explain the LDL difference either way). HDL between 1-2 mmol/L was protective compared with HDL <1 mmol/L (39 mg/dL); HDL ≥ 2 mmol/L was protective in women but not men (very high HDL levels can reflect heavy drinking), and higher TG was associated with increased mortality. In other words, the TG/HDL ratio – which correlates with fasting insulin, the 2-hour insulin response to glucose, and measures of insulin resistance – still predicted the risk of dying even in a population where LDL was pointing the other way.[12]

 

Better diet prescription?

If we’re going to prevent diabetes and cardiovascular disease, it’s obvious we need to identify insulin resistance and prescribe diets accordingly. Prescribing diets that seem to lower LDL based on studies in healthy, insulin-sensitive people isn’t going to achieve much for the insulin-resistant who are most at risk, especially if these are still high carb, fat-phobic diets. At the very least, people at risk should be told to cut out sugar and refined starches, the products driving their insulin and triglycerides.

Whichever way you look at it – whether you think low carb is best, or you just favour a real food or Mediterranean diet with less sugar and processed food – the diet advice given in these guidelines, and supposed to be passed on by every GP in the country, represents a wasted opportunity.

References

[1] Rassias G, Kestin M, Nestel PJ. Linoleic acid lowers LDL cholesterol without a proportionate displacement of saturated fatty acid. Eur J Clin Nutr. 1991 Jun;45(6):315-20.

[2] Ronald P Mensink, Peter L Zock, Arnold DM Kester, Martijn B Katan; Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials, The American Journal of Clinical Nutrition, Volume 77, Issue 5, 1 May 2003, Pages 1146–1155, https://doi.org/10.1093/ajcn/77.5.1146

[3] Farvid MS, Ding M, Pan A, et al. Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Circulation. 2014;130(18):1568-1578. doi:10.1161/CIRCULATIONAHA.114.010236.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334131/

[4] Michael Lefevre, Catherine M Champagne, Richard T Tulley, Jennifer C Rood, Marlene M Most; Individual variability in cardiovascular disease risk factor responses to low-fat and low-saturated-fat diets in men: body mass index, adiposity, and insulin resistance predict changes in LDL cholesterol, The American Journal of Clinical Nutrition, Volume 82, Issue 5, 1 November 2005, Pages 957–963, https://doi.org/10.1093/ajcn/82.5.957

[5] Nasir H. Bhanpuri, Sarah J. Hallberg, Paul T. Williams, Amy L. McKenzie, Kevin D. Ballard, Wayne W. Campbell, James P. McCarter, Stephen D. Phinney and Jeff S. Volek.
Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study.
Cardiovascular Diabetology. 2018; 17:56 https://doi.org/10.1186/s12933-018-0698-8

[6] Gregory A Nichols, Sephy Philip, Kristi Reynolds, Craig B Granowitz, Sergio Fazio; Increased Cardiovascular Risk in Hypertriglyceridemic Patients with Statin-Controlled LDL Cholesterol, The Journal of Clinical Endocrinology & Metabolism, https://doi.org/10.1210/jc.2018-00470

[7] Bartlett J, Predazzi IM, Williams SM, et al. Is Isolated Low HDL-C a CVD Risk Factor?: New Insights from the Framingham Offspring Study. Circulation Cardiovascular quality and outcomes. 2016;9(3):206-212. doi:10.1161/CIRCOUTCOMES.115.002436.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871717/

[8] Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.
Circulation. 2001 Dec 18;104(25):3046-51.
http://circ.ahajournals.org/content/104/25/3046

[9] Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, Pressel SL, Blaum CS; ALLHAT Collaborative Research Group. Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial. JAMA Intern Med. 2017 Jul 1;177(7):955-965. doi: 10.1001/jamainternmed.2017.1442.

[10] Lloyd SM, Stott DJ, de Craen AJM, et al. Long-Term Effects of Statin Treatment in Elderly People: Extended Follow-Up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Kiechl S, ed. PLoS ONE. 2013;8(9):e72642. doi:10.1371/journal.pone.0072642.

[11] Paul M Ridker, Eva Lonn, Nina P. Paynter, Robert Glynn, Salim Yusuf. Primary Prevention With Statin Therapy in the Elderly: New Meta-Analyses From the Contemporary JUPITER and HOPE-3 Randomized Trials. Circulation. 2017;135:1979-1981.
https://doi.org/10.1161/CIRCULATIONAHA.117.028271

[12] Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scandinavian Journal of Primary Health Care. 2013;31(3):172-180. doi:10.3109/02813432.2013.824157.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750440/

 

You might have noticed claims in the media in the last few days that

New research conducted by Deloitte Access Economics and Nutrition Research Australia shows that if every New Zealand adult adds three serves of high fibre grain food to their daily diet, it could save the economy an estimated $607 million a year in reduced healthcare costs and lost productivity, and potentially avert 34,000 new cases of cardiovascular disease and 68,000 new cases of type 2 diabetes.

This is from a report (dae-nz-fibre-economics) that Deloitte produced for Kellogg’s. Industry funding was a conflict of interest properly reported by media. We have a rough rule of thumb around this – when industry funds basic research in labs – experiments – that’s not necessarily a bad thing, because science always needs funding, and we want answers to questions. When industry funds reviews and modelling, these are more likely to be subject to cherry-picking to favour the sponsor – they are questions of interpretation, so the risk of bias is higher.

The causes of disease and mortality that grain fibre is supposed to be able to prevent are cardiovascular disease and type 2 diabetes.

Based on data from published meta-analyses, the number of cases averted was estimated by assuming that a one-gram increase in grain fibre reduces the risk of CVD by 1.1% and T2D by 2.5% (Threapleton, 2013; InterAct Consortium, 2015).

We took a closer look at the evidence used to calculate the larger of the two benefits, that for type 2 diabetes. This was the EPIC-InterAct study and meta-analysis; the EPIC-InterAct study was a multicentre European observational study that didn’t find a protective association for grain fibre once adjusted for BMI (but there are some interesting details we’ll discuss later), so the authors added a meta-analysis (a statistical method that pools all available studies world-wide) that did find a protective association with grain fibre.[1]

“However, the findings from our updated meta-analysis of prospective studies do support an inverse association between total fibre and cereal fibre intake and risk of type 2 diabetes, with a 9% and 25% lower RR per 10 g/day, respectively, independent of BMI.”

So an extra 10g of grain fibre reduces your risk of type 2 diabetes by 25%. Or does it? Actually, it depends on where you live.

There are many countries in EPIC-Interact without a protective association between grain fibre and type 2 diabetes, including France with a non-significant HR of 1.72 (that’s 72% worse). Another exception is the UK with a non-significant HR of 0.74 (26% better).

What are the differences in these populations? The French cohorts, for some reason, are all 100% female, which isn’t the case for any other country. And the largest of the two UK cohorts is EPIC-Oxford. “The majority of participants recruited by the EPIC Oxford (UK) centre consisted of vegetarian and “health conscious” volunteers from England, Wales, Scotland, and Northern Ireland”.[2] So these health conscious volunteers are probably being compared with people with lower fibre intakes in the less health-conscious UK cohort.

Sweden always interests us because one of their two cohorts is the Malmö Diet and Cancer Study, which unlike the usual observational diet studies in this, or any other meta-analysis, uses the more accurate 7-day food diary for all subjects, and in Sweden the HR is a more reasonable 0.96. So less confounding by conscientiousness and more accurate diet recall tends to minimize the cereal fibre and type 2 diabetes association. If cereal fibre prevented type 2 diabetes in any important or unique way, it should probably show up in most of these populations, not just a few.

What about the other countries in the meta-analysis? Most of the weighty studies in favour of fibre for type 2 diabetes prevention in the EPIC-Interact meta-analysis come from the USA. There are two important facts about the USA – low fibre intakes are lower than they are anywhere else (so basically a high intake of deep fried food, white breads, and sweetened soda in these low-fibre groups), and conscientiousness is an identifiable confounding factor in many populations. For example, the Nurses’ Health Study and Health Professionals’ Follow-up Study; here we have the populations not only given the most advice about fibre being healthy, but also given the job of passing it on to the other US populations. In other words, grain fibre – like red meat – is one of the signifiers separating conscientious Americans from other Americans (it’s harder to eat fruit and vegetables without their fibre, and vegetables in the US includes fried potatoes). It’s almost a class distinction.

Closer to home, there are 3 Australian studies, two small ones with protective associations between grain fibre and type 2 diabetes (smaller studies have less weight in a meta-analysis) and a large one, Hodge 2004, with none.[3] However Hodge 2004 finds that white bread is associated with type 2 diabetes, and that lower GI carbs, including sugar, aren’t.

White bread in Australia is so bad that even sugar looks good by comparison.

Does it follow that putting a few grams of bran in white bread will make it safe, or even good for you? Why not just say “avoid white bread”? This would definitely be our advice! Anyway, if fibre isn’t associated with type 2 diabetes in a fairly large sample of Australians, who tend to have fairly high fibre intakes anyway (by OECD standards), do Kiwis still need to take their lead from the USA?

“The mean±SD fibre intake in the [European] subcohort was 22.9± 6.2 g/day (ranging from 19.9 g/day in Sweden to 25.2 g/day in Denmark; data not shown).”[1]

These figures for European countries are very similar to the averages for New Zealand – 22.8 g/day for men and 17.9 g/day for women.

Germany (7.40%) and Denmark (7.20%) have higher diabetes prevalence rates than Sweden (4.70%).  USA’s mean total fibre intake is 16.1 g/day and diabetes prevalence is 10.80%. This would suggest that there is a suboptimal fibre intake, or perhaps just a protective effect of the real food, higher fat diets eaten in a place like Sweden, where (in Malmö) dairy fat has a protective association with type 2 diabetes, total fat has a protective association with CVD mortality in men, and fibre is protective against heart attacks only in combination with saturated fat (most of this is grain fibre in Malmö, probably from rye bread).[4,5] Sucrose – sugar – is the only nutrient/food/ingredient significantly associated with increased heart disease risk in Malmö.[6]  Its effect on the lipid profile is to increase triglycerides.[7]

Participants who consumed >15 % of their energy intake (E%) from sucrose showed a 37 (95 % CI 13, 66) % increased risk of a coronary event compared with the lowest sucrose consumers (<5 E%) after adjusting for potential confounders. The association was not modified by the selected lifestyle factors.

There are no nutrients unique to grains. But some grain fibres, especially oat bran, are a very good source of silicon, a mineral which might be more important for cardiovascular health than is currently recognised.[8] Other good sources of silicon are mineral water (the higher the total dissolved solids, the higher the silicon content is likely to be), green beans (especially) and other crunchy fibrous vegetables, bone broth, red wine and beer, and some herb teas, especially horsetail, oatstraw, and nettle. Oat bran is low in digestible carbohydrate and could definitely be included in the LCHF diet if anyone thought this necessary (it makes a great binder for mince patties).

The push from Kelloggs is to increase fibre by eating more grains and cereals – this is conflating any benefit of fibre with the effect of starch (and sugar if we’re talking breakfast cereals). Indeed fibre might be healthful but if you get it by adding extra bread and breakfast cereal what does that mean? for example, from EPIC-Netherlands:[9]

Dietary GL was associated with an increased diabetes risk after adjustment for age, sex, established diabetes risk factors, and dietary factors [hazard ratio (HR) per SD increase: 1.27; 95% CI: 1.11, 1.44; P < 0.001] [corrected]. GI tended to increase diabetes risk (HR: 1.08; 95% CI: 1.00, 1.17; P = 0.05). Dietary fiber was inversely associated with diabetes risk (HR: 0.92; 95% CI: 0.85, 0.99; P < 0.05), whereas carbohydrate intake was associated with increased diabetes risk (HR: 1.15; 95% CI: 1.01, 1.32; P < 0.05). Of the carbohydrate subtypes, only starch was related to increased diabetes risk [HR: 1.25 (1.07, 1.46), P < 0.05]. All associations became slightly stronger after exclusion of energy misreporters.

And don’t forget the PURE study, as well as the Czech ecological analyses (below) – there are protective effects from moderate amounts of high fibre foods, but replacing fat with lots of carbohydrate is overall associated with a worsened metabolic profile and higher mortality.[10, 11]

The aim of this study was a large-scale ecological analysis of nutritional and other environmental factors potentially associated with the incidence of cardiovascular diseases (CVDs) in the global context. Indicators of CVDs from 158 countries were compared with the statistics of mean intake (supply) of 60 food items between 1993 and 2011, obesity rates, health expenditure and life expectancy. This comparison shows that the relationship between CVD indicators (raised blood pressure, CVD mortality, raised blood glucose) and independent variables in the global context is influenced by various factors such as short life expectancy, religiously conditioned dietary customs, the imprecision of some statistics and undernutrition. However, regardless of the statistical method used, the results always show very similar trends and identify high carbohydrate consumption (mainly in the form of cereals and wheat in particular) as a dietary factor most consistently associated with the risk of CVDs. These findings are in line with the changing view of the causes of CVDs.

 

From this evidence, it might be better to get the fibre from the low-starch foods; but if you do eat grains (not everyone is or needs to be low-carb), eating only whole grains, i.e. grains that you can see are whole or minimally broken, in relatively small amounts, and avoiding refined grains as far as possible is the pattern associated with most benefit.

 

 

The Bottom line: there are almost certainly people at higher risk of type 2 diabetes and cardiovascular disease because their diets are too dependent on refined and processed carbohydrate foods, especially sugars and grains. Their risk would indeed be lower if they replaced these with whole grains – brown rice, barley, oats and so on. This may be due in part to the fibre content, but it may also be due to the slower release of glucose and thus healthier insulin response to a grain when it hasn’t been powdered; fibre in a powdered grain doesn’t do much to reduce its impact. Yer dreamin if you think that just adding bran to processed carbs – which is what Kellogg’s products do – is going to make an impact on disease rates. Eating whole foods instead of food products might give us a chance.

For people with carbohydrate intolerance, grains are too carbohydrate-dense a food to consume in any quantity, but other fibre-rich foods are available to substitute.

However, to say that high-fibre diets are better is a generalisation – the benefits of fibre require the cooperation of gut bacteria and the gut, and quite a few people who look to diet to improve their health find that lower-fibre diets such as FODMAP exclusion diets and occasionally even zero-carb carnivore diets give significant improvement where high-fibre diets fail.

The What The Fat? diet is high-fibre because fibre increases satiety and there is some evidence for other health benefits, but fibre isn’t necessarily something there should be a bulk ruling about.

P.S. Ironically, when the Herald ran a news story on the Deloitte/Kellogg’s report, the high fibre success story they spoke to was a low(er) carber! There are only a couple of slices of brown bread in this story.

 

 

References

[1] The InterAct Consortium. Dietary fibre and incidence of type 2 diabetes in eight European countries: the EPIC-InterAct Study and a meta-analysis of prospective studies. Diabetologia. 2015;58(7):1394-1408. doi:10.1007/s00125-015-3585-9.ghb
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472947/

[2] The InterAct Consortium, Langenberg C, Sharp S, et al. The InterAct Project: An Examination of the Interaction of Genetic and Lifestyle Factors on the Incidence of Type 2 Diabetes in the EPIC Study. Diabetologia. 2011;54(9):2272-2282. doi:10.1007/s00125-011-2182-9.

[3] Hodge AM, English DR, O’Dea K, Giles GG. Glycemic index and dietary fiber and the risk of type 2 diabetes. Diabetes Care. 2004;27:2701–2706. doi: 10.2337/diacare.27.11.2701

[4] Wallström P, Sonestedt E, Hlebowicz J, et al. Dietary Fiber and Saturated Fat Intake Associations with Cardiovascular Disease Differ by Sex in the Malmö Diet and Cancer Cohort: A Prospective Study. Obukhov AG, ed. PLoS ONE. 2012;7(2):e31637.
doi:10.1371/journal.pone.0031637
[5] Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat intake and early mortality patterns–data from The Malmö Diet and Cancer Study. J Intern Med. 2005 Aug;258(2):153-65. link

[6] Warfa K, Drake I, Wallström P, Engström G, Sonestedt E. Association between sucrose intake and acute coronary event risk and effect modification by lifestyle factors: Malmö Diet and Cancer Cohort Study. Br J Nutr. 2016 Nov;116(9):1611-1620. Epub 2016 Oct 24.

[7] Sonestedt E, Hellstrand S, Schulz C-A, et al. The Association between Carbohydrate-Rich Foods and Risk of Cardiovascular Disease Is Not Modified by Genetic Susceptibility to Dyslipidemia as Determined by 80 Validated Variants. Müller M, ed. PLoS ONE. 2015;10(4):e0126104. doi:10.1371/journal.pone.0126104.

[8] Loeper J, et al. Study of fatty acids in atheroma induced in rabbits by an atherogenic diet with or without silicon IV treatment . Life Sciences 1988, 42:2105-2112.

[9] Sluijs I, van der Schouw YT, van der A DL, Spijkerman AM, Hu FB, Grobbee DE, Beulens JW. Carbohydrate quantity and quality and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) study. Am J Clin Nutr. 2010 Oct;92(4):905-11. doi: 10.3945/ajcn.2010.29620. Epub 2010 Aug 4.

[10] Dehghan M, Mente A2, Zhang X, et al. Prospective Urban Rural Epidemiology (PURE) study investigators. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017 Nov 4;390(10107):2050-2062. doi: 10.1016/S0140-6736(17)32252-3. Epub 2017 Aug 29.

[11] Grasgruber P, Cacek J, Hrazdíra E, Hřebíčková S, Sebera M. Global Correlates of Cardiovascular Risk: A Comparison of 158 Countries. Preprints 2018, 2018020066 (doi: 10.20944/preprints201802.0066.v1).
https://www.preprints.org/manuscript/201802.0066/v1

Cholesterol is a molecule required by every cell of the body in fairly large amounts. It can be easily synthesised by these cells, or taken up by them from LDL and other ApoB lipoproteins, but cannot be broken down. Cholesterol is not soluble in water, and thus must be carried through the blood on lipoprotein particles. When the cholesterol produced or taken up by the cells of the body becomes surplus to requirements it is extracted by HDL (ApoA1 lipoproteins) and carried back to the liver for disposal as bile salts and acids (most of this cholesterol is reabsorbed and recycled, but there is also a variable amount lost in faeces). Reverse cholesterol transport (RCT) is the term used for this extraction of unneeded cholesterol. Here we describe a simplified version of reverse cholesterol transport, how this has been modified by new research into HDL, and we explain the effect of raising or lowering insulin and insulin sensitivity on RCT.

This video gives a good overview of the systems we’ll be describing. (The brain has its own, largely separate cholesterol system which we’ll ignore for now).

Cholesterol and insulin

We have about 30g of cholesterol in our bodies, and synthesise well over a gram a day. Only 10% of this is synthesised in the liver, and even less if we eat cholesterol or have a reduced requirement. Our requirement goes up when we are growing (cells are expanding and new cells being made) and down when we are fasting or losing weight (when fat cells and glycogen cells are shrinking, and autophagic processes are clearing unwanted cells). Thus it makes sense, and helps to keep cholesterol in balance with requirements, that cholesterol synthesis is stimulated by insulin (the fed state hormone) and inhibited by glucagon (the fasting state hormone).[1] An additional check on cholesterol synthesis in the fasting state is the activation of AMPK by the ketone body B-hydroxybutyrate.[2] No surprises then that cholesterol synthesis is found to be increased in type 2 diabetes.[3]

If scientists want to create the early signs of heart disease in animals, they need to feed them doses of cholesterol much larger than the total capacity of the body to make cholesterol.[4] However, Jerry Stamler, one of the founding fathers of the diet heart hypothesis, found in the early 1960’s that animals treated in this way got better when the cholesterol feeding stopped – unless they were given extra insulin.[5] This vital clue was missed in the later rush to change our diets – Jerry Stamler advised the population to avoid egg yolk and replace fat with refined carbs, yet human diets never supplied the amount of cholesterol he fed his animals – unfortunately, the new, modified human diet would start to increase insulin to the high levels seen in those chickens once the diabesity epidemic got underway.

Reverse Cholesterol Transport

Fortunately our gut and liver cells make a protein called ApoA1, which the liver turns into something called a nascent HDL particle. Unlike VLDL and the other ApoB particles, which are released from the liver as large, fat and cholesterol laden spheres, HDL is produced in an embryonic state, just a few proteins with little if anything in the way of lipids (lipid-poor ApoA1), and only becomes what we call HDL by performing its cholesterol-gathering role out in the body.

If we focus on the cells believed to play the major role in atherosclerosis, macrophages (large immune cells) which can turn into foam cells if they become overloaded with cholesterol, we can see HDL at work. Macrophages clear the blood of infectious agents and damaged particles, and have a particular affinity for oxidised LDL particles (oxLDL).[6] LDL becomes oxidised if it stays in the blood too long (more likely with higher levels or small, dense particles) and is exposed to excessive glucose and fructose levels after meals, or to smoking and other oxidative stressors.[7,8,9] Brown and Goldstein, who won the Nobel Prize for discovering the LDL receptor, estimated that 30-60% of LDL is cleared from circulation by macrophages. (Macrophages exposed to excess insulin increase their uptake of oxLDL by 80%).[10] The oxLDL is then broken down and the cholesterol stored – remember it can’t be broken down. As in other cells, any excess is sent to the surface of the cell, to transporters and other structures that make it available for HDL to pick up, as free cholesterol (cholesterol efflux). If this doesn’t happen for some reason, over a long period, there’s a risk of foam cell formation and atherosclerosis. (Macrophages exposed to excess insulin decrease their efflux of cholesterol to HDL by 25%).[10]

LCAT and esterification

After HDL picks up free cholesterol, this is esterified by an enzyme called lecithin cholesterol acyltransferase (LCAT), making the HDL particle larger. Cholesteryl ester (CE) is cholesterol joined to a fatty acid, usually an unsaturated fatty acid, which is supplied from the phospholipids also picked up from cells by HDL. The more effectively HDL can esterify cholesterol, the sooner it can return to pick up more from the macrophage (or other cell) – this is called HDL efflux capacity – and the phospholipids found in egg yolk have been shown to increase HDL efflux capacity.[11] Phospholipids, found in all whole foods, especially fatty ones like eggs, nuts, seeds, liver, shellfish, and soya beans, are good things to have in your diet; you won’t get them from eating flour, sugar, and oil.

 

CETP – swapping cholesteryl esters for triglycerides

HDL renews itself in the bloodstream by moving cholesteryl esters onto VLDL and other ApoB particles, in more-or-less equal exchange for triglycerides (TGs), through a banana-shaped protein tunnel called Cholesteryl Ester Transport Protein (CETP) which docks between ApoA1 and ApoB particles. HDL can then shed the TGs picked up to help feed cells along its path (as ApoB particles also do), turning them into free fatty acids and glycerol by the action of lipase enzymes. However, the CETP exchange is another place where things can go wrong. If there are too many TGs on VLDL, and too many TG-rich VLDL particles, and fats are not being burned by the body (yes, we’re talking about insulin resistance again), then the piling of TGs onto HDL via CETP will result in its recall to the liver after limited efflux.[12] Carrying lots of TGs back to the liver that made them is not a good use of HDL’s time. And the cholesterol esters being transferred to former TG-rich VLDL is what makes the “Pattern B” lipoproteins, small dense LDL, which are more likely to oxidise and more easily taken up by macrophages. LDL really, once it’s done its job of delivering fat, cholesterol, antioxidants and proteins to cells that need them, ought to be helping in reverse cholesterol transport by ferrying the extra cholesterol esters it received from HDL back to the liver. Large, cholesterol-dense LDL particles – “Pattern A” – are better at this. Small, dense LDL particles aren’t taken up as avidly by the liver, so tend to stay in circulation and oxidize. Hence the TG/HDL ratio is a critical predictor of cardiovascular risk, whether or not we factor in LDL.

The exchange via CETP action is thought responsible for the inverse relationship between levels of TG and HDL-C. Specifically, the larger the VLDL pool (higher TG level), the greater the CETP-mediated transfer of CE from HDL to VLDL in exchange for TG, resulting in TG-rich small, dense HDL which are catabolized more rapidly, leading to low levels of HDL-C. These small, dense HDL also have reduced antioxidant and anti-inflammatory properties. Thus, the greater the increase in hepatic VLDL-TG synthesis and secretion that characterizes insulin-resistant/hyperinsulinemic individuals, the lower will be the HDL-C concentration.[12]

 

Fasting, weight loss, and LDL

People who are naturally lean and active and have good insulin sensitivity are at very low risk of cardiovascular disease; they tend to burn fat and have low TG/HDL ratios on any diet. Paradoxically, LDL rises sharply when such people fast for long periods.[14] Despite this, no-one as far as we know has ever suggested that not eating enough causes atherosclerosis. Of course TGs and insulin also fall, while HDL stays the same. But strangely, this rise in LDL does not happen in obese people or people with atherosclerosis.[15]

 

Phinney and colleagues found that LDL first fell, then rose significantly, during major weight loss. They calculated that this was due to the delayed removal of around 100g extra cholesterol from the adipose of obese people. LDL became normal when a weight maintenance diet replaced the (low fat, reduced calorie) weight loss diet.[16]
Think about this – all of this extra 100g of cholesterol, 3x the usual whole body content, was eventually removed by reverse cholesterol transport. Some of it ended up on LDL, increasing the LDL count to the level where statins would be indicated according to guidelines. This did not prevent its removal. There is no “LDL gradient” that forces cholesterol back into the body. The LDL level doesn’t tell you whether cholesterol is coming or going – the TG/HDL ratio is the best guide to that.[17]

Hepatic lipase – burning fat.

ApoA1 and HDL production increases the release of hepatic lipase, so in a sense ApoA1 is a fat-burning protein, which helps to explain why eating fat increases ApoA1 output.[18, 19] More lipase means lower TGs all round. So, making more HDL can lower TGs, just as making too many TGs can lower HDL – but only the latter is likely to be harmful.

Of course, a low fat, high carbohydrate diet decreases ApoA1, but this doesn’t mean it’s bad if you’re insulin sensitive and have low TGs (and low LDL) eating such a diet, as many people do; the lower lipid circulation all round probably just means that less ApoA1 will be required for equilibrium. However, the old assumption that the lower fat higher carb diet is the “Prudent” diet hasn’t aged well.

We have previously reported that apoA-I and HDL directly affect HL-mediated triacylglycerol hydrolysis, and showed that the rate of triacylglycerol hydrolysis is regulated by the amount of HDL in plasma.

The antioxidant and antiinflammatory benefits of HDL.

Reverse cholesterol transport is the core business of HDL, but it isn’t the only business; HDL is like a busy doctor with a useful bag of healing tricks trundling up and down your bloodstream. For example, HDL carries an antioxidant protein, PON1. When a fatty hamburger meal rich in lipid peroxides was fed to 71 subjects, those with higher HDL experienced a much smaller rise in oxLDL.[20]

The pre-meal HDL level was associated with the extent of the postprandial rise in oxidized LDL lipids. From baseline to 6 h after the meal, the concentration of ox-LDL increased by 48, 31, 24, and 16 % in the HDL subgroup 1, 2, 3, and 4, respectively, and the increase was higher in subgroup 1 compared to subgroup 3 (p = 0.028) and subgroup 4 (p = 0.0081), respectively. The pre-meal HDL correlated with both the amount and the rate of increase of oxidized LDL lipids. Results of the present study show that HDL is associated with the postprandial appearance of lipid peroxides in LDL. It is therefore likely that the sequestration and transport of atherogenic lipid peroxides is another significant mechanism contributing to cardioprotection by HDL.

Tregs or T regulatory cells are a type of immune cell that switches off inflammatory responses. They are also a type of cell that takes up HDL, and HDL selectively promotes their survival. This is a good thing.[21]

Can LDL help in reverse cholesterol transport?

 

The answer is yes – if it’s large LDL particles (Pattern A), not so much small dense ones. Triglycerides and VLDL, on the other hand, are no help at all.

There are two pathways by which RCT can occur. In the first, the scavenger receptor class B type 1 (SRB-1) mediates hepatic uptake of CE from HDL particles without uptake of apoA-I or the whole HDL particle [74]. In the second pathway, cholesteryl ester transfer protein (CETP) catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL) in exchange for TG from the apoB-containing lipoproteins (Fig. 1) [21, 75]. This exchange results in apoB-containing lipoproteins which are enriched with CEs and depleted of TGs, and HDL particles which are depleted of CEs and enriched with TGs. The TG-rich and CE-poor HDL particles are catabolized faster than large, CE-rich HDL (apoA-I FCR is increased as noted in Fig. 1), a finding resulting in lower levels of HDL-C in the setting of high TG levels [76]. The apoB-containing lipoproteins, now enriched in CE, can also be taken up by the liver receptors as previously described [75]. When TG levels are high, the apoB particles are TG-enriched and hepatic lipase then hydrolyzes the TGs within the TG-rich LDL to release FFAs, a process which remodels the LDL particles into smaller and denser LDL particles which can enter the arterial intima more easily than larger LDL particles, thus making them more atherogenic (Fig. 1). Small, dense LDL particles also bind less avidly to the LDL receptor, thus prolonging their half-life in the circulation and making these particles more susceptible to oxidative modification and to subsequent uptake by the macrophage scavenger receptors [12].

An unusual experiment (using a radioactive nanoemulsion mimetic of LDL) showed that LDL cholesterol is removed from circulation more rapidly in resistance-trained healthy men than in sedentary healthy men. oxLDL was 50% lower in the resistance-trained men – but total LDL levels were the same, probably as a result of increased beta-oxidation (fat burning).[22]

Why are doctors being confused about HDL and reverse cholesterol transport?

There’s a trend in mainstream medicine to be dismissive of HDL and treat reverse cholesterol transport as unimportant; LDL lowering is the thing. New evidence from genetics, epidemiology, and drug trials is increasingly misinterpreted in this way – probably because drugs that increase HDL have, with some exceptions, been failures. However, drugs that raise HDL, and lower LDL, by inhibiting CETP are not helping either particle do its job; so far, they have neither decreased nor increased the rate of heart attacks in people taking them. Drugs that raise HDL by increasing ApoA1 and nascent HDL output, like the fibrates (e.g. gemfibrozil), do decrease CHD – but only in people with lower HDL and higher TGs! Moderate alcohol use, which also increases ApoA1 output, seems to have a similar effect, though the first randomised controlled trial of this observational hypothesis is only beginning.[23, 24] Even statins help with RCT by decreasing the synthesis of cholesterol in peripheral tissues, thus leaving more room on HDL for efflux cholesterol – again, statins only seem to reduce CHD in the subgroup of people with lower HDL. Clearly reverse cholesterol transport is very important, and efficient reverse cholesterol transport can best explain why so many people with high LDL and high cholesterol do enjoy long lives free from cardiovascular disease. Some ApoA1 genes that especially promote RCT are associated with reduced CVD risk, notably ApoA1 milano – which is actually associated with low HDL, because HDL clearance is so rapid – a paradox which highlights the trickiness of measuring a dynamic process across all tissues only by what appears in the blood.[25] Efficient RCT is associated with lean genes, but it’s largely something you have to work for – eating right, exercising, and looking after yourself in various ways – including giving up smoking, or not starting – which may be why the drug industry has largely given up on it.[26]

We observed that normolipidemic smokers present higher total plasma and HDL phospholipids (PL) (P < .05), 30% lower postheparin hepatic lipase (HL) activity (P < .01), and 40% lower phospholipid transfer protein (PLTP) activity (P < .01), as compared with nonsmokers. The plasma cholesteryl ester transfer protein (CETP) mass was 17% higher in smokers as compared with controls (P < .05), but the endogenous CETP activity corrected for plasma triglycerides (TG) was in fact 57% lower in smokers than in controls (P < .01). Lipid transfer inhibitor protein activity was also similar in both groups. In conclusion, the habit of smoking induces a severe impairment of many steps of the RCT system even in the absence of overt dyslipidemia.

The latest study on very, very high HDL – why isn’t it good?

Last year we wrote about the CANHEART study, which seemed to show adverse health effects of higher HDL. We wrote then that this was probably showing an effect of alcoholism, hereditary CETP defects, and other factors, and not an increase in heart disease. A new study allows us to look at this problem in more detail.[27]

When compared with the groups with the lowest risk, the multifactorially adjusted hazard ratios for all-cause mortality were 1.36 (95% CI: 1.09–1.70) for men with HDL cholesterol of 2.5–2.99 mmol/L (97–115 mg/dL) and 2.06 (1.44–2.95) for men with HDL cholesterol ≥3.0 mmol/L (116 mg/dL). For women, corresponding hazard ratios were 1.10 (0.83–1.46) for HDL cholesterol of 3.0–3.49 mmol/L (116–134 mg/dL) and 1.68 (1.09–2.58) for HDL cholesterol ≥3.5 mmol/L (135 mg/dL).

Those are some very high HDL levels, and not surprisingly fewer than 4% of men and even fewer women had HDL levels so high that they were associated with any extra risk.
Compare that with 40% of both men and women having low HDL levels that were associated with an equally elevated risk!
Further, the risk associated with very high HDL, though it does include cardiovascular deaths, doesn’t seem to include much increased risk of heart attacks and strokes.

This is consistent with alcoholism (a confounder not measurable with accuracy, as we described in the CANHEART analysis) increasing deaths from heart failure, cancer, and other causes, and with no further benefit (but maybe not much harm overall) from CETP variants elevating HDL.[28] Furthermore, interactions between heavy alcohol consumption and genes associated with higher HDL have been noted in some populations.[29]
Note that the HDL level associated with lowest heart disease and stroke incidence in this study is well to the right of the bell curve of population HDL distribution. Most of these people could have done with more HDL.
Madsen et al discuss their results soberly; although they fail to discuss the potential role of alcohol, which would explain the exact pattern of increased mortality seen well, and don’t highlight the 10-fold larger impact associated with low HDL in their study, there is nothing biased about their analysis. The European Heart Journal’s editorial was also worth reading.[30]

However, as reported in medical media, the message changed a bit.

“It appears that we need to remove the focus from HDL as an important health indicator in research, at hospitals and at the general practitioner. These are the smallest lipoproteins in the blood, and perhaps we ought to examine some of the larger ones instead. For example, looking at blood levels of triglyceride and LDL, the ‘bad’ cholesterol, are probably better health indicators,” he notes.

Well yes, looking at everything is good, and TGs and the TG/HDL ratio as well as LDL will give you extra information about the likely reasons for low HDL and whether you need to worry about it. However, Denmark, where the extremely high HDL study was done, is a place where high LDL (the ‘bad’ cholesterol, remember) is associated with lower all-cause mortality in those over 50 free from diabetes or CVD at the start of the study.[31] Over 50 is when most CVD and type 2 diabetes is diagnosed, so LDL might not be all that informative unless you can look at the subclasses of oxLDL, sdLDL, particle number, and so on (of course part of the effect of LDL in Denmark will be due to that country’s higher dairy fat intake, which will also raise HDL and LDL particle size, maybe helping to explain why the association is so favourable in that population).

If we look at the PURE study, higher fat consumption is associated with both higher LDL and higher ApoA1 and HDL, with saturated fat (like all fat types) tending to improve the ApoB/ApoA1 ratio.[32] This is consistent with many other lines of evidence.

Intake of total fat and each type of fat was associated with higher concentrations of total cholesterol and LDL cholesterol, but also with higher HDL cholesterol and apolipoprotein A1 (ApoA1), and lower triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ratio of apolipoprotein B (ApoB) to ApoA1 (all ptrend<0·0001).

This is just what fat-burning does, and there’s maybe not a lot of reason to think it’s good or bad per se. What is good about it is, that fat burning lowers insulin. Insulin is what makes your cells hoard cholesterol, and it’s also one of the things that can mess with reverse cholesterol transport. If you’re making or using excess insulin, the switch to a fat burning metabolism allows the insulin to normalise and causes your cells, including the macrophages, to let go of cholesterol – and when they do, the lipoproteins are there ready to carry it away.

Takeaways

Reverse cholesterol transport manages cholesterol flux through all cells and helps us reach a healthy old age.

LDL cholesterol is not a reliable guide to the state of cholesterol flux unless TG/HDL (and HbA1c) are factored in as well. LDL may increase when cholesterol is being removed or in states where it is not being taken up by cells.

Reverse cholesterol transport can remove prodigious amounts of cholesterol from the body during weight loss.

Excessive triglycerides due to insulin resistance can impair reverse cholesterol transport, as can smoking.

Various nutritional factors found in whole food diets have been found to assist in reverse cholesterol transport (including phospholipids, CLA, and polyphenols).

HDL in the high (if not the “extremely high”) range usually correlates with efficient reverse cholesterol transport and has benefits for cardiovascular health, inflammation, antioxidant status etc, but people with HDL outside (higher or lower than) the ideal range can be equally healthy if their overall metabolic health (insulin sensitivity) is good.

The TG/HDL ratio is a good measure of insulin sensitivity, and if excessive can be improved by lowering excessive insulin levels. A low carb diet, intermittent fasting, exercise, or weight loss are all effective ways to correct the TG/HDL ratio.

References

[1] https://themedicalbiochemistrypage.org/cholesterol.php

[2] Bae HR, Kim DH, Park MH, et al. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016;7(41):66444-66454. doi:10.18632/oncotarget.12119.

[3] Gylling H, Hallikainen M, Pihlajamäki J, et al. Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study. Journal of Lipid Research. 2010;51(8):2422-2427. doi:10.1194/jlr.P006619.

[4] Regulation of hepatic LDL metabolism in the guinea pig by dietary fat and cholesterol.
Lin ECK, Fernandez ML, Tosca MA, McNamara DJ. Journal of Lipid Research. 1994; 35:446-457

[5] Stamler J, Pick R, Katz LN. Effect of Insulin in the Induction and Regression of Atherosclerosis in the Chick. Circulation Research. 1960; 8:572-576.
Stamler Chick

[6] Brown MS, Goldstein JL. Lipoprotein Metabolism in the Macrophage: Implications for Cholesterol Deposition in Atherosclerosis. Annual Review of Biochemistry 1983 52:1, 223-261
brown1983

[7] Kopprasch S, Pietzsch J, Kuhlisch E et al. In Vivo Evidence for Increased Oxidation of Circulating LDL in Impaired Glucose Tolerance. Diabetes 2002; 51(10): 3102-3106. https://doi.org/10.2337/diabetes.51.10.3102

[8] Vos MB, Weber MB, Welsh J et al. Fructose and Oxidized LDL in Pediatric Nonalcoholic Fatty Liver Disease: A Pilot Study. Archives of pediatrics & adolescent medicine. 2009;163(7):674-675. doi:10.1001/archpediatrics.2009.93.

[9] Medina-Navarro R, Durán-Reyes G, Díaz-Flores M, Kumate Rodríguez J, Hicks JJ. Glucose autoxidation produces acrolein from lipid peroxidation in vitro. Clin Chim Acta. 2003; 337(1-2):183-5.. PMID: 14568199

[10] Park YM, Sangeeta R Kashyap SR, Major JA, Silverstein RL. Insulin promotes macrophage foam cell formation: potential implications in diabetes-related atherosclerosis. Laboratory Investigation. 2012; 92, 1171-1780.
doi:10.1038/labinvest.2012.74

[11] Andersen CJ, Blesso CN, Lee J, et al. Egg Consumption Modulates HDL Lipid Composition and Increases the Cholesterol-Accepting Capacity of Serum in Metabolic Syndrome. Lipids. 2013;48(6):10.1007/s11745-013-3780-8. doi:10.1007/s11745-013-3780-8.

[12] Welty FK. How Do Elevated Triglycerides and Low HDL-Cholesterol Affect Inflammation and Atherothrombosis? Current cardiology reports. 2013;15(9):400. doi:10.1007/s11886-013-0400-4.

[13] Bertsch RA, Merchant MA. Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk. The Permanente Journal. 2015;19(4):4-10. doi:10.7812/TPP/14-237.

[14] Sävendahl L, Underwood LE. Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans. J Nutr. 1999 Nov;129(11):2005-8.

[15] Ende N. Starvation studies with special reference to cholesterol. Am. J. Clin. Nutr. 1962. 11:270-280.

[16] Phinney SD, Tang AB, Waggoner CR, Tezanos-Pinto RG, Davis PA. The transient hypercholesterolemia of major weight loss. Am J Clin Nutr. 1991 Jun;53(6):1404-10.

[17] da Luz PL, Favarato D, Faria-Neto JR Jr, Lemos P, Chagas ACP. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary disease. Clinics. 2008; 64:427-32

[18] Ramsamy TA, Boucher J, Brown RJ et al. HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol. The Journal of Lipid Research. 2003; 44: 733-741.
http://www.jlr.org/content/44/4/733.long

[19] Chatterjee C, Sparks DL. Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia. The American Journal of Pathology. 2011;178(4):1429-1433. doi:10.1016/j.ajpath.2010.12.050.

[20] Tiainen S, Ahotupa M, Ylinen P, Vasankari T. High density lipoprotein level is negatively associated with the increase of oxidized low density lipoprotein lipids after a fatty meal. Lipids. 2014; 49(12): 1225-32. doi: 10.1007/s11745-014-3963-y. Epub 2014 Oct 31.

[21] Rueda CM, Rodríguez-Perea AL, Moreno-Fernandez M et al. High density lipoproteins selectively promote the survival of human regulatory T cells. J Lipid Res. 2017 Aug;58(8):1514-1523. doi: 10.1194/jlr.M072835. Epub 2017 Apr 4.

[22] da Silvaa JL, Vinagrea CGCM, Morikawa AT et al. Resistance training changes LDL metabolism in normolipidemic subjects: A study with a nanoemulsion mimetic of LDL.
Atherosclerosis. 2011; 219(2): 532-537.
http://www.sciencedirect.com/science/article/pii/S0021915011008185

[23] Mukamal KJ, Clowry CM, Murray MM, et al. Moderate Alcohol Consumption and Chronic Disease: The Case for a Long-Term Trial. Alcohol Clin Exp Res. 2016 Nov;40(11):2283-2291. doi: 10.1111/acer.13231. Epub 2016 Sep 30. Review.

[24] Moderate Alcohol and Cardiovascular Health Trial (MACH15) . https://clinicaltrials.gov/ct2/show/NCT03169530

[25] Leite JO, Fernandez ML. Should we take high-density lipoprotein cholesterol levels at face value? Am J Cardiovasc Drugs. 2010; 10(1):1-3. doi: 10.2165/11319590-000000000-00000.

[26] Zaratin AC, Quintão EC, Sposito AC et al. Smoking prevents the intravascular remodeling of high-density lipoprotein particles: implications for reverse cholesterol transport. Metabolism. 2004 Jul;53(7):858-62.

[27] Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. European Heart Journal,. 2017; 38(32): 2478–2486, https://doi.org/10.1093/eurheartj/ehx163

[28] Devenyi P, Robinson GM, Roncari DA. Alcohol and high-density lipoproteins. Canadian Medical Association Journal. 1980;123(10):981-984.

[29] Volcik K, Ballantyne CM, Pownall HJ, Sharrett AR, Eric Boerwinkle E. Interaction Effects of High-Density Lipoprotein Metabolism Gene Variation and Alcohol Consumption on Coronary Heart Disease Risk: The Atherosclerosis Risk in Communities Study. Journal of Studies on Alcohol and Drugs, 68(4), 485–492 (2007).

[30] Barter PJ, Rye K-A. HDL cholesterol concentration or HDL function: which matters? European Heart Journal. 2017; 0: 1–3
doi:10.1093/eurheartj/ehx274
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[31] Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scandinavian Journal of Primary Health Care. 2013;31(3):172-180. doi:10.3109/02813432.2013.824157.

[32] Mente A, Dehghan M, Rangarajan S et al. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study.
Lancet Diabetes Endocrinol 2017 Published Online August 29, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30283-8
PURE lipids and BP

 

 

 

These days most people associate the word “Presidential” with a lot of bluster that tends to disguise real problems and do more harm than good, as well as a partisan approach to any question. In the US at least, being “presidential” means a pathological inability to admit error, and a cavalier approach to the evidence and the scientific method.

The question is whether this trait is moving elsewhere?  We’d say that these vices are on full display in the new American Heart Association (AHA) position statement on saturated fat and cardiovascular disease.[1]

First, we do find some common ground

1. It seems reasonable to us that specific saturated fats, most notably palmitic acid, can have adverse cardiometabolic effects when combined with refined carbohydrates and eaten by people with an excessive postprandial insulin response.
2. It also seems reasonable that the effects can be quite different outside of this context, and in fact the AHA has cited evidence that shows this, which we will get to later.

We’re not poo-pooing the whole idea or the body of evidence on display here, just pointing out that the AHA’s single-minded obsession with the 10-15% of saturated fat in the average diet has completely blinded them to the effect of the 50-60% of mostly refined carbohydrate, and the value of replacing that with almost anything. We think that in this case the naturally occurring saturated fat in the diet will be harmless and quite possibly somewhat beneficial at a population level.

So how do you wade through and make any sense of the research evidence the AHA has presented? Here’s our attempt.

Meta-analysis of RCTs (we like)

We can start with the new meta-analysis of saturated fat substitution RCTs that the AHA team has done. We’ve never seen a meta-analysis like this. There seems to be no prearranged protocol. What we get instead is the four most favourable studies of PUFA replacing saturated fat, now designated “core studies” and analysed separately from all the RCTs that failed to confirm the hypothesis, using the fixed-effects model. The unfavourable RCTs are dismissed because of confounders that favoured the control diets. However, confounders that favoured the interventions go unmentioned. Controls in the Sydney Diet Heart study may in fact have consumed more trans fats [TFA] than the intervention group for example, which is consistent with the intervention lowering LDL cholesterol; the AHA hypothesis is that lowering LDL cholesterol reduces heart attacks and heart attack deaths, but this is the opposite of what happened in Sydney.[2]

The AHA has rehabilitated the Finnish Mental Hospital Study and included it as a “core study”, and this tells you a lot about their attitude to the scientific method, which Gary Taubes demolishes here. In the FMHS the populations in two hospitals were allocated to different diets, and the patients who ate a high intake of PUFA (from rapeseed oil) replacing SFA saw fewer heart attacks and cardiovascular deaths. This is the SFA-replacement study with the largest reduction in CHD and CVD mortality in the intervention arm (0.59), which may be why the AHA choose to revive it. However, non-CVD deaths rose and the all-cause mortality rate didn’t go down (1.01).
In any case, it’s our view that this study has  important confounders that the AHA hasn’t mentioned. For example, the patients were treated with a cardiotoxic medicine, thioridazine, with overall greater use in the control diet groups (0.63 vs. 0.97 standard doses/day).[2] Thioridazine is an antipsychotic  drug that causes heart attacks as a side effect, which is why it was withdrawn worldwide in 2005. The control diet groups were also fed more trans fats than the intervention groups (2%E vs 0%E in hospital K, 0.6%E vs 0.2%E in hospital N).[2] So the people eating more PUFA may have had fewer heart attacks because of the PUFA, which is plausible because this diet supplied plenty of omega 3 to a population possibly lacking in it, but for all we know it could have been due to the fact that they were being poisoned less often. Or, of course, just due to chance, because this study wasn’t fully randomised a a patient level. Patients were allocated diets on admission to hospital and there were only two hospitals; this is called a cluster trial and it takes more clusters than were in FMHS to equate to a randomised trial.

Now, either the AHA knows about the confounding, and they should, it’s been mentioned in discussions of this trial for years (including their ref. 35) and Steven Hamley covers it in his own recent meta-analysis – the one that tried hardest to account for confounders, and they’ve chosen not to mention it. The alternative is that they don’t know, and are sleepwalking through the science with blinkers on. In general – and probably in toto – the AHA meta-analysis covers only half the evidence on confounders, the half that suits the AHA position, as Gary Taubes found when he analysed the Oslo study. We ask how this gets past independent peer-review?

Fat intolerance and its causes

We don’t have time to check every reference, but as usual we checked the ones that claimed to prove something of interest to us. One of these is the primate studies in which saturated (and monounsaturated) fat is more atherogenic than PUFA (studies in mice and rabbits don’t show this consistently enough to validate the hypothesis). The AHA states:

“To induce hypercholesterolemia and atherosclerotic lesion formation, one group of monkeys typically was fed lard or palm oil at 35% of their daily energy intake and dietary cholesterol to raise serum cholesterol levels into the 300- to 400-mg/dL range to model hypercholesterolemia in human beings at high risk for CHD. A second group of monkeys was fed a monounsaturated fat, high-oleic safflower oil, and a third group was fed a polyunsaturated fat linoleic acid–rich diet using safflower oil. Saturated fatty acids promoted higher LDL cholesterol concentrations and more coronary artery atherosclerosis. Linoleic acid lowered LDL cholesterol concentrations and decreased the amount of coronary artery atherosclerosis.”

How much cholesterol do you need to feed to monkeys to make them intolerant of saturated (and monounsaturated) fat? 0.8mg/Kcal; the equivalent of 1,600mg for a human eating 2,000kcal/day.[3] This is more cholesterol than you should make in an average day, so the monkey cannot downregulate cholesterol synthesis enough to compensate. Humans, with natural diets higher in cholesterol, can usually decrease absorption of cholesterol and increase excretion enough to tolerate such amounts. Indeed in some cases much larger amounts –  but these monkeys can’t.[4] However, the test monkeys were chosen for their response to saturated fat and cholesterol in the first place, they weren’t chosen at random from the monkey population. Monkeys that didn’t respond as desired were excluded from the study.[3] It’s not the saturated fat causing atherosclerosis, or these monkeys would only have needed to be fed saturated fat.

Here’s a question; what factor, if any, could possibly make a human as intolerant of fat as a cholesterol-fed monkey? Surely not fat itself, nor the minor amounts of cholesterol in the average human diet. How about the insulin response to refined carbohydrate? High refined carb diets cause heart disease in monkeys without any need to feed them cholesterol. This is the elephant in the room with the AHA. They do mention that replacing SFA with refined carbs is a bad idea (despite the AHA having recommended this substitution for many decades). You get the impression that they only think it’s bad because it has no effect, not because it’s harmful – more on this later.

Another cause of high cholesterol

In a 1991 cross-over trial, 147 non-obese normotensive subjects (60 females and 87 males) aged 19-78 were placed alternately on high-sodium and low sodium diets. The high sodium diet raised mean arterial blood pressure by a mean of 7.5 mmHg in 17% of the subjects (salt sensitive) – the low sodium diet raised mean arterial blood pressure by a mean of 6 mmHg in 16% (reverse reactors). With dietary salt restriction serum total- and LDL-cholesterol as well as serum insulin and uric acid concentrations increased significantly in all three groups. The largest increases in total (10%) and LDL- (12%) cholesterol occurred in the reverse reactors.[5]

So it would appear that the salt restriction advice the AHA has been giving generally for years, in the face of growing contradictory evidence, can raise cholesterol as much as eating butter can if taken to extremes. Again this is ignored.

Evidence that SFA is safe in low carb diets is cited but concealed

As an example of the AHA”s approach to evidence, consider the reference for this claim.

“Therefore, the effects of replacing carbohydrates with various kinds of fats qualitatively at least may be similar by increasing larger and decreasing smaller LDL sizes. In another study, monounsaturated fat, replacing carbohydrates, reduced medium and small LDL, also shifting the distribution to the larger size.78”

In the context in which it occurs, the statement is far from exciting, but the reference 78 is actually a very valuable experiment and one of the few that answers the question “what is the difference between high saturated fat and low saturated fat in a low carb diet?” This should be something that interests the AHA, but the blinkers mean they can only use this paper to buttress their own position on some minor point while ignoring the main outcomes from this research.

Ref 78 is a Ron Krauss paper in which a low fat diet (54% CHO) is compared with a moderate fat diet (39% CHO) and two low carb (26% CHO) diets, one with 15% SFA, one with 9% SFA. The diets are isocaloric, and the 15% SFA diet is superior to all other diets for four cardiometabolic results. Lower triglycerides, higher HDL, lower total cholesterol/HDL ratio, lower ApoB/ApoA1 ratio, larger LDL particle size.[6,7]

Now, the AHA is quite churlish about particle size. Maybe they’re right, maybe they’re wrong. However, every LDL particle only has one ApoB lipoprotein. The larger the particles, the less ApoB you have at any given LDL concentration. The ApoB/ApoA1 ratio (only slightly) favours the 15% SFA diet. Of course, 26% CHO is a little outside the upper edge of low carb, but this is the best evidence we have to show whether SFA in a low carb diet is a worry or not. The evidence says it’s not. In fact, what this study shows is that carbs are are mechanistic in causing poor lipid profiles as related to cardiometabolic health.

The evidence on carbohydrate

The AHA review also cites observational studies, including the Jakobsen et al and Farvid et al meta-analyses, in which a substitution analysis appears to show that replacing saturated fat with mostly linoleic acid is beneficial. The logic of this is impeccable – “because we can’t find the evidence that we wish existed, that saturated fat is independently associated with heart disease (which would suggest a causal relationship), we are going to compare it with the essential fatty acids, because that makes it look worse”. These studies are out of date because they do not include the two Praagman et al studies from last year, in the larger of which (n=35,597) replacing SFA with PUFA was associated with an increase in ischemic heart disease events.[8]

“Total SFA intake was associated with a lower IHD risk (HR per 5% of energy: 0.83; 95% CI: 0.74, 0.93). Substituting SFAs with animal protein, cis monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), or carbohydrates was significantly associated with higher IHD risks (HR per 5% of energy: 1.27-1.37).”

In the smaller (n=4,722) study there was no association.[9]

Even so, what do the substitution meta-analyses tell us? That every benefit, if there is a benefit, of replacing SFA with PUFA can also be achieved by replacing carbohydrate with PUFA. By carbohydrate is meant the total carbohydrate from the mixture of refined (flour, sugar) and unrefined (potato, fruit, whole grains, legumes) sources in the usual diet. The AHA fastens on this distinction – not made in the substitution metas – to tell us that replacing 5% of energy from saturated fat with 5% of energy from whole grains will produce some huge associational benefit.

If your diet was about 50% refined carbohydrate, as is normal in Western countries these days, you’d be looking to replace some of that with unrefined carbs, PUFA, MUFA, anything at all, rather than worrying about the 10-15% of saturated fat left in these diets!
Let’s look at this again – you have maybe 50% of energy from junk carbs to replace in the Standard Western Diet. You don’t need any of it – you can replace every last bit of it and only feel better for the effort.

On the other hand you have around 15% of saturated fat at most. Much of this is attached to whole foods – some of it is even in nuts, fish, and vegetable oils!
Priorities, people, priorities.

Even Harvard’s NHS/HPFS study, which has its issues but which the AHA relies on heavily here, predicts that replacing carbs (which includes some unrefined) with fat (which includes some saturated) will be associated with lower mortality, 0.84 (0.81-0.88) and cardiovascular mortality, 0.86 (0.79, 0.93).[10] Similarly, the Malmo Diet and Cancer Study found a significantly lower risk of CVD death (RR 0.65, p=0.028) in men eating the most fat, an average of 47%E.  “No deteriorating effects of high saturated fat intake were observed for either sex for any cause of death”.[11]

But supposing there is a benefit of PUFA? The Farvid meta-analysis predicted that “A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% CI, 0.86-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.82-0.94).”[12] One good wholefood source of linoleic acid is nuts. According to a 2016 meta-analysis, just eating 28g of nuts per day was associated with greater decreases in mortality from coronary heart disease, 0.71 (95% CI: 0.63–0.80), cardiovascular disease, 0.79 (95% CI: 0.70–0.88), and all-cause mortality, 0.78 (95% CI: 0.72–0.84) than those predicted by Farvid et al for total PUFA.[13] We have this evidence that PUFA from nuts is beneficial, or at least not harmful. We don’t actually have the same evidence when it comes to PUFA from plant seed oils – no-one has looked at these specifically.

Coconut oil – the rush to judgement

When Ancel Keys chose his 7 countries to study from the 22 or 23 available, he chose Japan as an example of a country with a low fat intake and a low rate of heart disease; but he could have chosen Ceylon, very close to it on the graph, with a similar low rate of heart disease but 4x as much saturated fat as Japan, because the Ceylonese cooked with coconut oil.

As an aside, a recent cohort of 58,472 Japanese followed up 19 years with 11,656 deaths showed that Japanese women with the highest saturated fat intake, and higher total fat intake had lower mortality rates. So, for what is worth, there is some associational evidence that more fat could be protective in the Japanese population.[14]

We don’t know a lot more about coconut oil today than we did in Ancel Key’s day, but the AHA thinks that its effect on serum lipids warrants avoiding it. That makes sense in a country where having higher cholesterol increases the risk of being prescribed unnecessary drugs or having your insurance premiums raised. Viewed in that context, coconut oil could be truly hazardous to your health.

Most of the health claims made for coconut oil can’t be substantiated, because the research hasn’t been done. An exception is this recent paper, which shows that a meal high in coconut oil had a more favourable effect on postprandial lipids than either palm oil or rice bran oil.[15] It’s also interesting because it shows that higher insulin and a higher fasting TG/HDL ratio (1.8 vs 1.1) is associated with an adverse response to palm oil. We’d interpret this as meaning that carbohydrate intolerance (the meal supplied an OGTT dose of refined carbs) drives fat intolerance, as we would expect from the interaction between carbohydrate, insulin, and palmitic acid discussed here.
Another benefit of using coconut oil for meals such as stir fries is that it is much less likely than plant seed oils to produce carcinogenic fumes. Lung cancer risk is greatly increased in non-smokers exposed to heated seed oils in poorly ventilated kitchens, as we discussed here.

The Dog in the Manger

One of the defects of the modern “Presidential” personality type, as we mentioned in the introduction, is that every innocuous question is treated with a partisan bias. Nowhere is this more evident than in the handling of trans fats.

Industrial trans fats probably increase heart disease risk, more by their effect on the metabolism of omega-3 and -6 fatty acids and how this affects blood clotting and inflammation than by any effect on lipids or basic metabolism.

Fact – people were only exposed to industrial trans fats because animal fats were replaced with vegetable fats.

There are also trans fats in dairy – ruminant trans fats. These, as far as we can tell, are associated with better health not worse

The AHA really wants (you) to believe that the effects of ruminant trans fats are similar to those of industrial trans fats.

“Although most human trials were conducted with partially hydrogenated vegetable oil, emerging evidence suggest the ruminant trans fatty acids have similar adverse effects on blood lipids…Although industrial trans fatty acids were consistently associated with total CHD and CHD death in observational studies, ruminant trans fatty acids were generally not. The exact reason for these discrepant relationships remains unknown but may relate to the very low levels of ruminant trans fatty acids in these studied populations (mean intake, ≈0.7% of total energy),112 differences in trans fatty acid isomers between ruminant and industrial trans fatty acids that have diverse biological effects, or confounding by the high amount of saturated fat in the major source of ruminant trans fatty acids.”

Firstly, ruminant trans fats (present in both dripping and dairy fat at around 3%) are products of the fermentation of plants by bacteria. Does anyone still believe that such fermentation is bad for the heart? The dominant ruminant trans fat, CLA, is a cis-trans fat. The cis bond means that it cannot behave like an industrial trans fat in cell membranes. The metabolism of CLA in vivo involves elongation and further desaturation similar to that seen with long-chain polyunsaturates.

The “emerging evidence” that the AHA alludes to involves feeding doses of ruminant trans fats higher than those sourced from diet in supplement form, without their accompanying fats. This is a critical point; the myristic acid in ruminant fats raises the most beneficial forms of HDL, but the benefit of HDL depends on its functionality. Ruminant trans fats by themselves increase HDL functionality, but not mature HDL.[16] The similar benefit of olive oil and red wine polyphenols may also depend on their inclusion in foods that raise HDL.[17]
Whole foods beat supplements and refined foods every time.

Interventions in Children

The AHA review mentions a number of intensive healthy-lifestyle interventions in children that reduced saturated fat, always in the context of many other changes including reduced sugar, and had positive effects on various proxies for heart disease risk. We concur that healthy diet and lifestyle choices can overall reduce heart disease risk. What we don’t know is whether saturated fat intake from good-quality sources needs to be restricted to produce these benefits, and whether greater benefits will not in fact follow from a higher fat, lower refined carbohydrate diet that minimises insulin exposure after meals. The least-confounded RCTs of saturated fat reduction suggest that it contributes little if any benefit in adults, and the evidence that specifically relates to low fat vs whole milk, and to fat content overall in the diet of children (including breast-feeding infants, which eliminates reverse causality), suggests that lower fat foods and diets in the general population are associated with higher childhood BMI and therefore greater future cardiovascular risk.[18-23]

Summing up

The recommendation to eat less than 30% of energy as fat, applied to a population with easy access to refined carbohydrates, as promoted by the AHA (which did promote the use of sugar and flour in place of naturally fatty foods for many years) may have increased fat intolerance in the population, mostly with regard to specific saturated fats, mainly palmitic acid.[24] This intolerance, because it is driven by insulin, seems to go away when carbohydrate is restricted. It may also go away to some extent when genuinely unrefined carbohydrate replaces refined starch and sugar, due to the lower insulin AUC.

It would literally take a PhD thesis to fully dissect the AHA presidential advisory and its errors of interpretation and expressions of bias. We’ve only dipped into the areas we already know about, and found the AHA trying to pull a fast one. Which is not to say that every statement or idea in the document is false, but that half the story is hidden in darkness. The public needs bodies like the AHA to adjudicate fairly, not act like a prosecutor for one cause then a defense attorney for another. The AHA’s diet advice may be taken with a grain of salt by many in the know who can afford to ignore it, but not by those fed in institutions or by government programs, and the AHA’s stated positions also influence drug prescribing. If the AHA can’t balance the evidence wisely, and step well beyond the bias of defending their previous assumptions that a high carb, low fat diet low in saturated fat is best for all, we’re in trouble.

 

References

[1] Sacks FM, Lichtenstein AH, Wu JHY et al. Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation. 2017; CIR.0000000000000510. doi.org/10.1161/CIR.0000000000000510
AHA SFA 2017

[2] Hamley S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutrition Journal. 2017; 16:30 DOI: 10.1186/s12937-017-0254-5
https://nutritionj.biomedcentral.com/articles/10.1186/s12937-017-0254-5

[3] Rudel LL, Parks JS, Sawyer JK. Compared with dietary monounsaturated and saturated fat, polyunsaturated fat protects African green monkeys from coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1995;15:2101–2110.

[4] Kern F. Normal Plasma Cholesterol in an 88-Year-Old Man Who Eats 25 Eggs a Day — Mechanisms of Adaptation. N Engl J Med. 1991; 324:896-899. DOI: 10.1056/NEJM199103283241306

[5] Ruppert M, Diehl J, Kolloch R et al. Short-term dietary sodium restriction increases serum lipids and insulin in salt-sensitive and salt-resistant normotensive adults. Klin Wochenschr. 1991;69 Suppl 25:51-7.

[6] Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT.
Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia [published correction appears in Am J Clin Nutr. 2006;84:668]. Am J Clin Nutr. 2006;83:1025–1031; quiz 1205.

[7] Feinman RD, Volek JS. Low carbohydrate diets improve atherogenic dyslipidemia even in the absence of weight loss. Nutrition & Metabolism. 2006; 3:24 DOI: 10.1186/1743-7075-3-24

[8] Praagman J, Beulens JW, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.Am J Clin Nutr. 2016; 103(2): 356-365.
http://ajcn.nutrition.org/content/103/2/356.long

[9]Praagman J, de Jonge EAL, Kiefte-de Jong JC et al. Dietary Saturated Fatty Acids and Coronary Heart Disease Risk in a Dutch Middle-Aged and Elderly Population.
Arteriosclerosis, Thrombosis, and Vascular Biology. 2016;ATVBAHA.116.307578
https://doi.org/10.1161/ATVBAHA.116.307578

[10] Wang DD, Li Y, Chiuve SE, Stampfer MJ, Manson JE, Rimm EB, Willett WC, Hu FB. Association of Specific Dietary Fats With Total and Cause-Specific Mortality. JAMA Intern Med. 2016;176(8):1134-1145. doi:10.1001/jamainternmed.2016.2417.

[11] Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat intake and early mortality patterns–data from The Malmö Diet and Cancer Study. J Intern Med. 2005 Aug;258(2):153-65.

[12 Farvid MS, Ding M, Pan A et al. Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Circulation. 2014;CIRCULATIONAHA.114.010236
http://circ.ahajournals.org/content/early/2014/08/26/CIRCULATIONAHA.114.010236

[13] Aune D, Keum N, Giovannucci E et al. Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies. BMC Medicine. 2016; 14:207
DOI: 10.1186/s12916-016-0730-3
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0730-3

[14] Wakai K, Naito M, Date C, Iso H, Tamakoshi A. Dietary intakes of fat and total mortality among Japanese populations with a low fat intake: the Japan Collaborative Cohort (JACC) Study. Nutrition & Metabolism. 2014;11:12. doi:10.1186/1743-7075-11-12.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973975/

[15] Irawati D, Mamo JCL, Slivkoff-Clark KM et al. Dietary fat and physiological determinants of plasma chylomicron remnant homoeostasis in normolipidaemic subjects: insight into atherogenic risk. British Journal of Nutrition (2017), 117, 403–412. doi:10.1017/S0007114517000150

[16] Nicod N, Parker RS, Giordano E et al. Isomer-specific effects of conjugated linoleic acid on HDL functionality associated with reverse cholesterol transport. J Nutr Biochem. 2015 Feb;26(2):165-72. doi: 10.1016/j.jnutbio.2014.10.002. Epub 2014 Nov 12.
https://www.ncbi.nlm.nih.gov/pubmed/25468613

[17] Nicod N et al. Green tea, cocoa, and red wine polyphenols moderately modulate intestinal inflammation and do not increase high-density lipoprotein (HDL) production. J Agric Food Chem. 2014; 62(10):2228-32. doi: 10.1021/jf500348u. Epub 2014 Mar 4.

[18] Prentice P, Ong KK, Schoemaker MH, et al. Breast milk nutrient content and infancy growth. Acta Paediatrica (Oslo, Norway : 1992). 2016;105(6):641-647. doi:10.1111/apa.13362.

[19] Vanderhout SM, Birken CS, Parkin PC, Lebovic G, Chen Y, O’Connor DL, Maguire JL; TARGet Kids! Collaboration. Relation between milkfat percentage, vitamin D, and BMI z score in early childhood. Am J Clin Nutr 2016;104:1657–64.

[20] Rolland-Cachera MF, Maillot M, Deheeger M, Souberbielle JC, Peneau S, Hercberg S. Association of nutrition in early life with body fat and serum leptin at adult age. Int J Obes (Lond) 2013;37:1116–22.

[21] Alexy U, Sichert-Hellert W, Kersting M, Schultze-Pawlitschko V. Pattern of long-term fat intake and BMI during childhood and adolescence—results of the DONALD study. Int J Obesity Relat Metab Dis. 2004;28: 1203–9.

[22] Gunnell DJ, Frankel SJ, Nanchahal K, et al. 1998. Childhood obesity and adult cardiovascular mortality: a 57-year follow-up study based on the Boyd Orr cohort. American Journal of Clinical Nutrition 67: 1111–18.

[23] Ness AR, Maynard M, Frankel S, et al. Diet in childhood and adult cardiovascular and all cause mortality: the Boyd Orr cohort. Heart. 2005;91(7):894-898. doi:10.1136/hrt.2004.043489.

[24] Kuipers RS, de Graaf DJ, Luxwolda MF et al. Saturated fat, carbohydrates and cardiovascular disease. Neth J Med. 2011 Sep;69(9):372-8.
http://www.njmonline.nl/getpdf.php?id=1095

Our last post which questioned in passing aspects of the plant-based position on climate change caused quite a fuss in some circles. We were accused of being science-deniers, on a par with Trump and the anti-vaxxers, by some. There’s a recent blog about us here.

The atmosphere is warming, the sea levels are rising, species are dying and habitats becoming sterile, and the major contribution – certainly the largest modifiable contribution – is the fossil fuel combustion which has gone on since the beginning of the industrial era and shows no sign of decreasing. A secondary contribution is increased methane emissions from intensive agriculture and the huge quantities of landfill waste that modern consumerism is able to generate without thought or effort. No denying that!

This is not in question. What is in question are the most effective ways to deal with it and, with regard to agriculture, what to do also about the tsunami of metabolic diseases which threaten to swamp us here in the Pacific before the sea can. People will always need food and the world will always need animals; this may not always be true for fossil fuels, which can potentially be replaced almost completely by various other forms of energy.

We are not experts in climatology, energy, or agriculture – we can only point out the things that seem obvious. One of these facts is that as long as there have been animals on earth, they have breathed out CO2 and emitted methane. They have not always burned fossil fuels (coal, gas, oil, diesel, petrol) or burned down forests. According to a 2013 FAO report, farmed ruminants contributed 14.5% to the total greenhouse gas effect, a figure which did not take into account carbon sequestration in pasture (which has not been properly measured yet) and which included ongoing deforestation, which is not a current farming practice in NZ (although it may contribute to some imported feeds).[1,2,3]

A recent modelling of 10 possible dietary patterns found that 3 dietary patterns that included some animal foods were more environmentally sustainable than a diet of only plants.[4]

“Carrying capacity was generally higher for scenarios with less meat and highest for the lacto-vegetarian diet. However, the carrying capacity of the vegan diet was lower than two of the healthy omnivore diet scenarios.” 

However a limitation of this paper was that the environmental impact of meat was based on the US model of intensive beef production in feedlots, and that nutritional value was based on the US dietary guidelines, so that animal fat, full fat dairy, and organ meats were not included, making the use of animal foods much more wasteful than is necessary in the context of the LCHF diet.

One of the trends in NZ farming is that extensive farming of high country land for traditional meat and fibre herds like sheep is being replaced with intensive land use to produce dairy, with consequent harmful effects on our rivers and increased emissions. As a result of this, which is primarily to feed world markets, lamb and mutton are being priced out of the reach of New Zealanders. A further effect of this change on the environment is that wool production has decreased to be replaced with synthetic fleeces which shed minute plastic fibres into the environment when washed, killing fish and other small sealife.

Environmental benefits of LCHF

There are important ways in which the LCHF diet is more sustainable than the standard diets it replaces. Here are a few we can think of….
1) the appetite control effects of the LCHF diet mean that less food will be eaten overall at a population level, and if weight loss is an effect in an overweight person, their energy requirement thereafter also goes down.
(If someone exercises then, unless they are losing weight, their need for food will increase, but no-one is telling us not to exercise; besides, the cost of exercise is partly offset by a decreased use of fossil fuel for common exercises such as cycling, walking, and running).
2) the LCHF diet supplies a mechanism (reduction of serum SFA and increased LDL particle size) by which a higher intake of saturated animal fats is less likely to be harmful; the consumption of fats from animals reduces the need for plant crops, including palm oil. The production of palm oil is an environmental scandal, but the demand for it is entirely an unintended consequence of advice to avoid animal fat.
3) the LCHF diet is not a high protein diet, includes a variety of animal and plant protein foods, and allows the use of organ meats and bone broths, another way of preventing waste and reducing the numbers of animals required to feed a population that has been entirely overlooked in dietary guidelines.
4) the LCHF diet can easily be a lacto-etc-vegetarian diet, with more difficulty has been managed as a vegan diet, and is usually a plant-based diet if by that is meant a diet in which most food, by volume, is unprocessed plants and fruit oils (however the term plant-based, as used in the literature, does seem to be entirely interchangeable with vegan). Unlike the Paleo diet LCHF includes the use of legumes, a low-environmental impact protein source, for people with a sufficiently healthy carbohydrate tolerance.

You can read some criticisms of our last post from a plant-based consultant here. We must point out that their criticism of Zoe Harcombe is out-of-date to say the least. She does have a PhD now and is a published author of important peer reviewed articles in prestigious medical journals. Her expert analysis of the biased and error-ridden Naude et al meta-analysis, which when the errors were corrected said the opposite of what its authors, six supposed experts in their field, claimed it said, helped secure the acquittal of Tim Noakes and looks set to become a textbook case of forensic statistical analysis.[5]

The Zoe Harcombe article we linked to in our last blog post did not contain her own research but quotations from a published work written by an expert in sustainable agriculture, and her conclusions from this were so reasonable and climate-aware that only someone with an ideological agenda could ignore them in favour of an ad hominem dismissal.

We wanted to comment on the blog containing these plant-based criticisms of us, but comments were not allowed. However, the author complains in his post that we had censored comments he tried to place on this blog; we have never seen such comments in moderation and would not censor them. We welcome them, so please send them in.

The author, who is friendly enough, engaged with one of us (GH) on twitter and informed us that glycotoxins from the flesh of animal species increase the risk of Alzheimer’s.

This seems to us like pseudoscientific scare-mongering  in pursuit of an ideological agenda. Firstly, even in the NIH-AARP study which was heavily weighted against red meat for mortality outcomes, red meat had a protective association with Alzheimer’s mortality alone. Secondly, the world’s oldest people have consistently been omnivores with red meat in their diets, not vegans, and have kept their wits about them to the end. Thirdly, Alzheimer’s is identified as an insulin resistance disease and the role of processed carbohydrate cannot be overlooked. Fourthly, there is no evidence that glycotoxins from meat have been related to any specific case of Alzheimer’s. Fifthly, glycotoxins are also known as AGEs and are formed from a wide variety of foods due to high-temperature cooking, not just from meat, and are also formed in the body under high-sugar conditions.

In fact the reduction of AGE exposure for health was the subject of a chapter in Dr Atkins; Age Defying Diet back in 2000AD.

Plant fibres and polyphenols normally thought to be beneficial can form large concretions called bezoars, familiar to fans of Harry Potter, in the intestines of people eating them, with deadly and painful consequences. This is a thing that actually happens – there is no doubt about it, it is not just a hypothesis like the meat->glycotoxin->Alzheimer’s claim. Should we then warn people against eating plants in case they get a bezoar? Of course not. Bezoars are extremely rare (which is why they are valuable to magicians) and result from very imbalanced diets.[6]

We’re going to stick our necks out here – you can safely eat plants without worrying about bezoars (but please don’t sue if we’re wrong).

What can we do?

Agricultural climate science, and agriculture’s role in nutrition and health, are too important to be captured by a special interest lobby which represents less than 1 percent of the population, a relatively privileged 1 percent at that, for whom climate control is not the primary motivation for the ideology, and who frequently resort to pseudoscientific scare-mongering tactics (“nutritional terrorism”) to influence people’s dietary choices.

But if you want to stop this happening, and to prevent the destruction of our planet in the most human-friendly way possible, everyone needs to take a bigger interest in the subject, and vote, shop, travel, and if necessary eat accordingly. Support farming methods you agree with and give feedback to industry when you can. Support the stalled campaign to label palm oil in food the next time you write to an MP or meet one (seriously, what is wrong with people that this didn’t happen?). We are not experts, you are not experts, but the future surely depends on what we all do much more than it depends on what the experts decree. If we sweep this issue under the rug, then we are giving away control of it.

The Bottom line – when we rediscover how to control our weight and appetite, and how to include animal fat and organ meats in our diets, we will need fewer animals and fewer plants per capita to be nourished and healthy.
Beyond this, attitudes to family planning, energy use, and the consumption of natural resources are at the root of our problems. Reduce, recycle, reuse, repair; use public transport or your own muscle power whenever possible, if not try to carpool. Use dinner leftovers for breakfast. All this will make you wealthier too – what’s not to like?

References

{1] Gerber, PJ, Steinfeld, H, Henderson B, Mottet A, Opio C, Dijkman J, Falcucci A and Tempio, G. Tackling Climate Change through Livestock – A Global Assessment of Emissions and Mitigation Opportunities, Food and Agriculture Organization of the United Nations, FAO 2013, Rome.

[2] Opio, C., Gerber, P., Mottet, A., Falcucci, A., Tempio, G., MacLeod, M., Vellinga, T., Henderson, B. and Steinfeld, H. (2013) Greenhouse Gas Emissions from Ruminant Supply Chains – A Global Life Cycle Assessment. Food and Agriculture Organization of the United Nations (FAO), Rome.

{3] There is a good discussion of the WHO estimates and other aspects of sustainable animal farming from Richard H Young, Policy Director of the Sustainable Food Trust and Beef cattle and sheep farmer Sustainable Food Trust, here http://www.bmj.com/content/357/bmj.j1957/rr-9

[4] Peters CJ, Picardy J, Darrouzet-Nardi AF et al. Carrying capacity of U.S. agricultural land: Ten diet scenarios. Elementa. 2016. DOI: 10.12952/journal.elementa.000116
https://www.researchgate.net/publication/305627253_Carrying_capacity_of_US_agricultural_land_Ten_diet_scenarios

[5] Harcombe Z; Noakes TD. The universities of Stellenbosch/Cape Town low-carbohydrate diet review: Mistake or mischief?. South African Medical Journal, [S.l.], v. 106, n. 12, p. 1179-1182, dec. 2016. ISSN 2078-5135.
http://www.samj.org.za/index.php/samj/article/view/11605/7753

[6] De Toledo AP, Rodrigues FH, Rodrigues MR, et al. Diospyrobezoar as a Cause of Small Bowel Obstruction. Case Reports in Gastroenterology. 2012;6(3):596-603. doi:10.1159/000343161.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529578/

 

 

By George Henderson and Grant Schofield

Disclaimer – we’re not recommending that people eat red meat in preference to white meat, anymore than we think people should eat red peppers instead of onions. A mixed diet of various types of animal and plant foods, as close to nature as is consistent with good hygiene, good digestion, and good eating, is the default option for good nutrition.

However, red meat epidemiology is the modern example of bad science which, because it panders to a vegetarian bias that runs along class lines, isn’t being properly criticised and is allowed to regularly misinform the public about nutrition.

This latest example is particularly worth examining because its faults are very clear and give an insight into what may have gone wrong with other studies of this sort behind the scenes.[1] They even allow us to make recommendations about how to improve these studies in future.

The BMJ has published a “new” epidemiological paper from the NIH-AARP study (based on FFQs sent in by mail from half-a million people, an impressive number) in which red meat – compared with white meat, which includes both chicken and fish – is associated with an increased risk of cancer, heart disease, and all-cause mortality.

This comes along with no less than two accompanying editorials one from Professor Potter, from Massey University NZ telling us to give up meat for the sake of our health and the planet’s.[2] Just what you’d expect, right? All those warnings about red meat couldn’t be for no reason, and all that stuff about TMAO, haeme iron, and saturated fat has to mean something, right? And those cow burps and farts have to be worse than dinosaur burps, mammoth burps, or bison burps ever were, right?

Not so fast – there are even stronger associations between unprocessed red meat and liver disease mortality and respiratory disease mortality. How did that happen? The authors are left floundering around for explanations – they settle on nitrites and nitrates. But hang on – the association is for unprocessed red meat, and not for processed white meat, so that makes no sense. And we know that saturated fat, as found in beef fat, protects against alcoholic liver disease, whereas polyunsaturated fat, as found in chicken, makes it worse – and this is a very strong, consistent, and reliable experimental finding – so, what gives?[3]

Luckily an earlier paper also looked at the same data sets, and this allows us to clearly see what went on.

In the 2009 paper that looked at the same aspect of the NIH-AARP data – red meat, white meat, and mortality – in a slightly different way (i.e. without the dodgy and unrealistic “substitution” analysis), the associations between unprocessed red meat and accidental death in men, HR 1.26 (1.04-1.54), were as great (albeit with slightly wider CIs) as the associations for cancer mortality, HR 1.22 (1.16-1.29) or CVD mortality, HR 1.27 (1.20-1.35). There was a comparable protective association between white meat and accidental death which was non-significant after adjustment.[4]

So what’s the biological mechanism by which red meat causes accidental death in men? If anything, the cognitive effects of deficiencies of red meat nutrients such as vitamin B12 suggest that an unconfounded relationship should run in the opposite direction. Men’s risk of accidental injury mortality in the US is 2-3x that of women, accidental death rates in NIH-AARP were low, and the association was not seen in women. However women’s accidental deaths may be less due to risk-taking behaviour than the deaths of men (for example if women are more likely to be victims in vehicular accidents caused by men than by women); so accidental death in men is by far the bulk of deaths caused by accidents in the NIH-AARP population (similar to the gender difference in deaths from heart attacks).

The finding for accidental death gives us some idea of the effect of healthy-user bias in this population. Perhaps men who ignored health warnings about red meat and did not replace it with white meats (or vegetable protein) were more likely to ignore basic health and safety advice, or work in dangerous workplaces. Dangerous workplaces are also places where one can be exposed to carcinogens and pollutants which increase cardiovascular risk. People who ignore health warnings about red meat are also likely to ignore warnings about sugar-sweetened beverages, and highest intake of fructose from SSBs was also associated with cardiovascular mortality in NIH-AARP.[5]

Who can spot the possible confounding in this sort of study? Give yourself a pat on the back if you can…..you’ll be ahead of some of the more claimed epidemiologists in modern nutrition science!

The potential for healthy user bias can clearly be seen in the baseline data (Table 1), with many more men, a more than doubled rate of smoking, and a mean BMI of 28.3 vs 25.8 in the highest red meat quintile.[1] Good luck adjusting for all that. And what does this adjustment mean in reality anyway? It is a mythical person.

For some reason accidental death was dropped as an outcome of interest in the current study, concealing important information about the likely effect of healthy-user bias on the results, and the analysis did not include adjustment for fructose, high-GI carbs, or other nutrients of interest.

Risk-taking behaviour and workplace safety are even more important considerations with regard to the two strongest associations in the BMJ paper, liver disease mortality (risk of both viral infection and hepatotoxicity from drug-taking) and respiratory mortality (pollutant exposure), causes of death which lack mechanisms sufficient to explain the strength of association with red meat in this paper.

Mechanisms run both ways

But what about the mechanisms? Doesn’t heme iron cause cancer, and TMAO from red meat cause heart disease?

The truth is probably more complicated than that. For example, heme iron can interact with other chemicals to increase production of the hydroxyl free radical, which can damage DNA, but it’s also needed for the catalase enzyme that turns peroxide radicals to water, and the CYP450 enzymes that detoxify most of the carcinogens we’re exposed to, among other things. This may help explain why, in those rare studies that control for healthy-user bias by matching sets of individuals, vegetarian and vegan diets are associated with more cancer, not less.[6,7]

Although TMAO levels in serum are associated with cardiovascular mortality, high TMAO levels are likely to be a warning sign of kidney disease, or some other metabolic disorder, rather than a causative agent.

The evidence for this is 1) that chemicals which are precursors for TMAO are found in large amounts in nuts and fish, which are negatively associated with CVD mortality, 2) that carnitine, the precursor of TMAO found in meat, prevents heart attacks when given in large doses as a supplement to patients with established heart disease.[8]
The evidence seems to say that, while there are mechanisms by which red meat can cause CVD and cancer, there are also mechanisms by which red meat can prevent CVD and cancer, and at a population level these mechanisms, if they are important, seem to cancel each other out anyway in health-conscious individuals who choose to eat meat.
There is however evidence for limiting red meat (or donating blood) in persons with high ferritin levels, especially with the genetic condition known as familial haemochromatosis.

But what about the planetary health?

In New Zealand, lamb and beef, venison and goat (but not so much dairy) are being farmed on pasture land established a couple of centuries ago, and watered with the rain, whereas pork and chicken, even free-range chicken, are being fed grains and soy, much like factory farmed beef in the US. Red meat (other than pork) as grown in NZ is thus not bad for the planet, but instead sequesters carbon, fertilises the land, and maintains the stability of topsoil undermined by plant monoculture farming (which is how plant crops are grown outside market gardens and organic or semi-organic mixed-farming model farms these days). We waste food by not eating as much organ meat, fat, and bone as we used to (because we’ve been indoctrinated by health experts to eat “lean meat”, i.e. the more expensive muscle meat, and throw the rest away), and this is not great for the planet. Zoe Harcombe has written a more detailed analysis of the environmental claims in Professor Potter’s editorial here.

New Zealanders do not eat “too much” red meat in any case. The 2008/9 NZ Adult Nutrition Survey showed that Kiwis consumed more iron and protein from grains than from all animal foods combined. When you consider that animal food including meat is a very good source of these nutrients and grains are (or ought to be, in the natural, whole grain, state) a very poor source, this might suggest that the average Kiwi diet is either badly out of proportion or over-processed or (our bet would be) both.

Improvements suggested

We can think of ways to protect future epidemiological studies from the inaccuracies likely to be in this latest one.
1) Always give results for accidental death, ideally for men and women separately, in any mortality analysis. This will allow some assessment of healthy-user bias. (Injury requiring hospitalisation rates could be given in papers without mortality outcomes).
In the BMJ paper, the authors already knew about the association with accidental death from their 2009 paper but chose not to include it when they were being funded by the WHO, an organisation that seems to have taken up an activist position against red meat to go with its already dated position on salt and saturated fat.
2) Where possible, give subgroup results for closely matched, and equally health conscious, subjects; those with the same income, BMI, smoking rates, ethnicity and gender balance, etc.
We also think it would be a good idea if professors of agriculture, preferably ones with farming experience, wrote more editorials about planetary health, if that’s what the medical journals are after.

References

[1] Etemadi A, Sinha R, Ward MH et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study BMJ 2017; 357:j1957 http://www.bmj.com/content/357/bmj.j1957

[2] Potter JD. Red and processed meat, and human and planetary health BMJ 2017; 357 :j2190 Potter 2017

[3] Kirpich IA, Miller ME, Cave MC, Joshi-Barve S, McClain CJ. Alcoholic Liver Disease: Update on the Role of Dietary Fat. Osna N, Kharbanda K, eds. Biomolecules. 2016;6(1):1. doi:10.3390/biom6010001. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808795/

[4] Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake and mortality: a prospective study of over half a million people. Archives of internal medicine. 2009;169(6):562-571. doi:10.1001/archinternmed.2009.6.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803089/

[5] Tasevska N, Park Y, Jiao L, Hollenbeck A, Subar AF, Potischman N. Sugars and risk of mortality in the NIH-AARP Diet and Health Study. The American Journal of Clinical Nutrition. 2014;99(5):1077-1088. doi:10.3945/ajcn.113.069369.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985213/

[6] Burkert NT, Muckenhuber J, Großschädl F, Rásky E, Freidl W. Nutrition and Health – The Association between Eating Behavior and Various Health Parameters: A Matched Sample Study.
PlosOne: February 7, 2014 https://doi.org/10.1371/journal.pone.0088278

[7] Key TJ, Appleby PN, Spencer EA et al. Cancer incidence in vegetarians: results from the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr. 2009 May;89(5):1620S-1626S. doi: 10.3945/ajcn.2009.26736M.
http://ajcn.nutrition.org/content/89/5/1620S.full

[8] DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O’Keefe JH. L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. Mayo Clin Proc. 2013 Jun;88(6):544-51. doi: 10.1016/j.mayocp.2013.02.007. Epub 2013 Apr 15.

 

The case study is a very important type of medical publication that’s overlooked in this age of big data. Unlike large statistical studies, which tell you the probability of something happening, the case study tells you whether something CAN happen at all, and under exactly which circumstances it has happened.

Case studies answer questions like “Can autoimmune diabetes, with lower insulin production, be managed long-term without insulin?”

Yes, it can, and this is described in full detail and a clear and simple style in a new case-study from Christchurch.[1]
2017 Nelson Jacobs Case report Management of autoimmune diabetes without insulin

This is published on Zenodo.org, an online data repostitory set up by people involved in CERN and other places. Warrick Nelson, the first author is the patient and is an operations manager at Plant and Food Research in NZ. The second author is his doctor. This is citizen science.  We love it.

So onto the topic of diabetes, and  management of the condition with low carb diets……

We reviewed the strong evidence for low carb diets in diabetes management in the New Zealand Medical Journal in a 2016 review cited in the current paper.[2]

Its case study is a great example of how the wisdom of Citizen Scientists, equipped with mass produced measuring devices and, in this case, a proven medicine, can discover the one way to treat a disease. It is written up by the patient and his doctor, who was wise enough to recognise this as the teachable moment it is.

The patient first presented with type 2 diabetes, non-alcoholic fatty liver disease, insulin resistance, and a high risk TG/HDL ratio. He was highly motivated and was able to lose weight and correct all of these issues with a better diet and metformin alone.

In early 2013 the patient, a white male 53 years of age, was diagnosed diabetic following a routine screening test, based on fasting glucose of 10.8 mmol/L and HbA1c of 58 mmol/mol (7.5%). Mild overweight, especially abdominal, mild hypertension, mild dyslipidaemia and elevated liver function panel (Table 1) indicated the onset of T2D. Metformin 500mg twice daily and 10kg weight loss were indicated. Advice on weight loss was primarily calorie control (particularly between-meal calories, as the patient self-reported a tendency to snack in the evenings on biscuits). Snacks were recommended to be reduced and cheese or almonds suggested as options. The patient was highly motivated and within nine months HbA1c test showed a pleasing result at 37 mmol/mol (5.5%) and BMI of 26 (Table 1).

A year later and the patient has signs of Type 1 Diabetes, this pattern is known as Latent Autoimmune Diabetes of the Adult (LADA).

However, a year later a routine HbA1c of 83 mmol/mol (9.7%) occurred, associated with unexplained weight loss and fatigue. By this time, the BMI target was very close to achievement. Anti-GAD tests were ordered on the assumption it was likely the patient had resolved to a Type 1 diabetic pattern. The result was unrecordably high autoantibodies and the patient was referred to a specialist diabetes clinic to begin insulin therapy.

But in the meantime the patient has begun testing post-meal blood sugars and eating accordingly – note that the doctors or dietitians had already recommended eating almonds or cheese instead of biscuits in the weight-loss phase, so he has a general idea of the alternatives.

In the interim, the patient had begun using a home glucose meter with nearly immediate resolution of blood glucose from the 15-23 mmol/L range to sub-10 postprandial tests (Figure 1). This was achieved by an immediate drastic reduction of bulk dietary carbohydrates, primarily experimenting with reducing carbohydrate intake to achieve acceptable postprandial glucose levels. A food diary indicated sub 100g carbohydrate per day, and more stringent dietary intervention from January 2015 suggests <75g/day is being achieved.
The patient attended two clinic visits, but expressed reluctance to begin insulin therapy while home blood glucose testing indicated dietary interventions were working. At this time, HbA1c had already reverted to 49 mmol/mol (6.6%) and by the second visit, 3 months later, was down to 38 mmol/mol (5.6%). Further autoantibody tests indicated both IA2 and ICA at the top of the measurable range. A fasting insulin test returned 66pmol/L.

But can it be healthy, eating such a restricted diet?

The patient reports the new diet is completely satisfying, tasty and easy to manage other than when faced with commercial food offerings eaten away from home. In particular, airline and hospital “diabetes” choices are completely incompatible with a low carbohydrate diet. The patient reports completely removing wheat flour products (such as breads, cake/biscuits, pasta, couscous), potato, rice, maize and other obvious high starch products (including gluten free options such as quinoa and buckwheat). The dietary bulk provided by these foods is largely replaced with salad and vegetable as appropriate. High carbohydrate vegetables (such as carrots, pumpkin, green peas) are not eliminated, but are eaten in moderation.

But surely the results are not sustainable?

Quarterly HbA1c tests have remained at ≤40 mmol/mol (≤5.8%) for two years on this diet. The patient has felt confident to reduce the frequency of home blood glucose testing to one day per week of pre/post prandial testing for one or two meals on that day plus occasional testing following introduction of new food items.

The authors discuss how failing islet beta-cells in late-onset diabetes tend to keep producing low levels of insulin (we think this might be more likely if they’re protected from lipotoxicity – excess fat – and glucotoxicity – excess sugar; the weight loss phase where NAFLD was reversed would have helped avoid the former, the low carb diet the latter).[3] We have theorised previously that the different gut hormone responses to a low carbohydrate meal, which include a lower release of glucagon and a higher release of somatostatin 28, can contribute to controlling post-prandial glycogenolysis, lipolysis, and proteolysis at a lower insulin level.

Reading this report, we are bystanders at a revolution in medicine. This patient has decompensated diabetes, and it’s unlikely any variation on a higher carbohydrate diet would be able to control their blood sugar without insulin. In fact, the hospital diabetes diet is completely unsuitable for this purpose. If the low carb diet is suitable, and the hospital diet isn’t, for this critical aspect of diabetes management, what then?

Hospital diabetes diets are generally the high-carb, low fat, dietary guidelines type of diet that was introduced into diabetes care without any RCT comparison with the low carbohydrate (<130g/day CHO) or very low carbohydrate (<50g/day CHO) diabetes diets that have outperformed it in RCTs ever since.[2] These diets are normally grain based, nutritionally poor, and high in glycemic load. Their only concession to diabetes management is that the carbs are counted and (supposed to be) spread throughout the day. They require higher insulin dosing than would be the case with low carb diets, and thus make it harder to maintain blood sugars safely within the normal, non-diabetic range, so higher cut-offs are accepted as “good management”.[2] This case, as well as the evidence we included in our review, and a more recent RCT of a low carb diet (70g/day CHO) for type 1 diabetes published by Jeremy Krebs’s team in New Zealand,[4] show that this approach needs to change.

References

[1] Nelson W, Jacobs P. Management of autoimmune diabetes for two years without insulin treatment: a case report. Zenodo.org May 7 2017 doi:10.5281/zenodo.572338.svg
2017 Nelson Jacobs Case report Management of autoimmune diabetes without insulin

[2] Schofield G, Henderson G, Thornley S, Crofts C.
Very low-carbohydrate diets in the management of diabetes revisited.
NZMJ. 2016;129:1432.
https://scienceofhumanpotential.files.wordpress.com/2016/04/henderson-1998-nzmj-1432-final.pdf

[3] Schofield G, Henderson G, Crofts C, Thornley S.
What are we to think when results from mouse research contradict those from human experiments and clinical practice? Nutrition & Diabetes (2016) 6, e224; doi:10.1038/nutd.2016.31

[4] Krebs JD, Parry Strong A, Cresswell P, Reynolds AN, Hanna A, Haeusler S.
A randomised trial of the feasibility of a low carbohydrate diet vs standard carbohydrate counting in adults with type 1 diabetes taking body weight into account.
Asia Pac J Clin Nutr. 2016;25(1):78-84. doi: 10.6133/apjcn.2016.25.1.11.

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By George Henderson and Grant Schofield

There are few diet trials published from New Zealand, so we’re always keen to see them; and there are even fewer vegan diet trials.

We are even more interested when they go beyond their data, and start in on a sort of zealot approach to running down low carb diets which this study gives no insight into.

So what did they do? They went vegan (plant only) That is, we think this was a vegan study, because it’s called a “whole food plant based diet”, well-known vegan doctors are cited in the supplementary materials, dietary fat intakes were, though not measured, intended to be very low indeed, and because B12 supplements were supplied, but few details about the intervention are given, and even fewer about the controls; these received “standard medical care” with no diet advice mentioned.

The study was small (n=65) and not as representative as the authors might have hoped for; “The intervention involved patients from a group general practice in Gisborne, the region with New Zealand’s highest rates of socioeconomic deprivation, obesity and type 2 diabetes” – however, after randomisation there were only 3 Māori with 30 NZ European in the intervention arm (n=33) whereas the control arm had 21 European, 5 Māori and 6 other (n=32).

The results were excellent in terms of weight loss, and good in terms of medication reduction, with a couple of people reversing diabetes. Weight lost was as great as in the best ketogenic diet trials, although the controls here, with no diet change (or else useless advice based on NZ government recommendations? It would be good to know) provided no competition.

“The mechanism for this is likely the reduction in the energy density of the food consumed (lower fat, higher water and fibre). Multiple intervention participants stated ‘not being hungry’ was important in enabling adherence.” In other words, de facto calorie restriction is likely to have occurred, due to greater satiety per calorie, the same as mooted in LCHF studies.

The weight changes at 3 months don’t compare too badly with the weight changes at 10 weeks in the first report from this long term ketogenic diet study. [2] The reductions in medication and reversals of diabetes are greater in the ketogenic diet study, with a similar intensity of intervention, but nonetheless the BROAD weight loss results are very good by the standards of most diet trials.

So the Whole food plant-based (WFPB) diet didn’t do too badly for weight loss; what about other parameters?

In our opinion this is where the BROAD study lets itself down; it’s not that these results are terrible, but that the discussion of them, such as it is, amounts to special pleading. HDL was low (“high risk”) at baseline – 1.3 mmol/l in the intervention arm; HDL didn’t change, but the TG/HDL ratio deteriorated from 2.835 to 3.170.

“CVD Risk Assessment tools are widely used in New Zealand, and although we saw intervention WC, BMI and HbA_1c improve, the between-group CVD RA (which does not account for some of these) did not change significantly. Also, HDL-cholesterol tends to decrease on a plant-based diet, and previous research had shown this ‘may not be helpful for predicting cardiovascular risk in individuals consuming a low-fat, plant-based diet’. Our analysis corroborates that this tool is not particularly appropriate for those consuming a WFPB diet.”

Now, this may well be true, but the reference for this claim is one 30-day cohort study (no comparison arm) using the same kind of wishful thinking.[3] What would be more convincing would be a mechanistic explanation of why lower HDL levels are tolerable on a very low fat diet, maybe through the diet’s effect on HDL subtype, or HDL efflux capacity, or an interaction with very low LDL, demonstrated in feeding studies. However, LDL in the intervention arm was 3 mmol/l at 12 months which though almost within target is not especially low, and the TG/HDL ratio predicts that the percentage of small dense LDL will be relatively high, so we do need more than wishful thinking before discounting the relevance of these scores. If we were to claim that a lack of effect on LDL didn’t matter in a low carb study, we would have no shortage of mechanistic evidence from feeding studies and risk factor studies to explain why; there is a huge body of scientific investigation about lipoproteins that can be relevant to these sorts of cases.

Where the discussion goes badly wrong is in attacking LCHF diets using evidence that is thin and irrelevant. The numbers of people in LCHF trials and feeding studies has become large enough that patterns of adverse outcomes can be decided by the evidence from these studies. As prior to recent years very few people in the general population ate LCHF diets, epidemiological studies don’t give us this evidence.

So what do we get, by way of a discussion of superiority?

Reviews comparing the WFPB approach to other diets show similar weight loss at 12 months for low-carbohydrate and low-fat diet approaches. However, studies on the effects of low-carbohydrate diets have shown higher rates of all-cause mortality,⁵⁴ decreased peripheral flow-mediated dilation,⁵⁵worsening of coronary artery disease,⁵⁶ and increased rates of constipation, headache, halitosis, muscle cramps, general weakness and rash.

This isn’t good enough. Reference 54, Noto et al, is a notorious mishmash of epidemiological studies, uses an idiosyncratic and unrealistic scoring system, is mostly concerned with protein (or at least certainly conflated with it),  and includes no evidence from low carbohydrate diet trials. In fact, because more recent evidence shows that higher fat intake was associated with lower mortality in the Nurses Health Study and Health Professionals Follow up Study, and lower cardiovascular mortality in the Malmo Diet and Cancer study, not to mention the forthcoming PURE study, this line of evidence, even were it admissible, is no longer supportive of the claim. Reference 55 combines 5 studies only one of which had significant results – in any case, FMD is an insulin-mediated response to glucose in the bloodstream and its reduction, while possibly undesirable and indicative of insulin resistance on a high-carb diet, would seem to be a normal adaptation to the absence of carbohydrate. Reference 56 relates to people eating high protein during an uncontrolled low fat, high carbohydrate intervention – how high, and what else did they eat differently? It’s impossible to tell from the paper, which is a singularly inappropriate piece of evidence to use in an attack on low carb.

What about “increased rates of constipation, headache, halitosis, muscle cramps, general weakness and rash”? Some of these are expected temporary effects of keto-adaptation or of insufficient salt intake during low-carb induced natriuresis. Rash can result from increased intake of unrefined plant foods in people who are salicylate-intolerant, so is a possible side effect of vegan diets too.

The greatest weakness of this paper is its failure to discuss at all two findings; firstly that blood pressure increased on the WFPB diet. This was not statistically significant (p=0.06) but as it is an underpowered trial and this result ran counter to expectations it is worth explaining; possibly a reduction in medication can account for it.

Secondly, one person in the intervention arm had their gallbladder removed due to gallstones at 5 months. This is a known adverse effect of weight loss on a very low fat diet.[4,5] It was the subject of a 2014 meta-analysis, which found that “diets high in fat content reduced gallstones, compared with those with low fat content (risk ratio, 0.09; 95% CI, 0.01-0.61)”.[6] This would seem to be more serious than the known side effects of low carb diets. Though the one event of this sort in BROAD cannot be statistically significant, the authors (and reviewers) should have been aware of similar occurrences in other trials, making this an important risk to discuss.

Adherence at 12 months was 70% but no-one’s reason for dropping out was given.
(The informed consent phase meant that people who agreed to be in the study were aware that a vegan diet would be the only diet they were likely to get. This could be seen as a different situation in terms of self-selection bias from those studies which offer an equal chance of getting a low carb diet or a calorie-restricted 30% fat diet; people who didn’t specifically want a vegan diet could opt out, knowing their care would be the same, whereas with a two-diet comparison people may be more likely to enter the study but drop out after learning what diet they have been randomised to.)

Although this study obtained very good results in terms of weight loss, a definite win for its participants, the authors’ unwillingness to discuss possible negatives and their over-eagerness to attack low carb interventions without real evidence (they should have saved their bile for the “usual medical care” that failed their patients) do not enhance this paper’s value.

Nor does the appeal to the environmental sustainability and greenhouse gas footprint, which depends on a 2014 UK modelling paper. It all depends what foods you eat – at present these models use the lean meat, low fat dairy recommendations; however, animal fat and organ meat are wasted products, adding up to a lot of energy and nutrition, of producing these that we could use a lot more wisely. A vegan diet will have a larger environmental impact if you need to eat more imported food and out-of-season (not a problem with NZ beef and lamb) and food with a higher water content, which isn’t a very economical use of land. Raising monoculture plant crops uses more fossil fuels and has a worse effect on the land than raising ruminants the way we do in New Zealand (something you might miss with a UK model, where a lot of meat is imported). It is early days for that kind of research and all we have so far is speculative models based on assumptions.

Take homes? This trial tells us little about eating meat. It shows that getting off sugar, and refined foods has a good effect on short and medium term weight loss on this intensive intervention group compared to usual care. However an effect may be the worsening of some CVD risk factors, although what this really means isn’t clear. It says nothing about low carb healthy fat eating.

References

[1] Wright N, Wilson L, Smith M, Duncan B, McHugh P. The BROAD study: A randomised controlled trial using a whole food plant-based diet in the community for obesity, ischaemic heart disease or diabetes. Nutrition & Diabetes. 2017; 7(e256) doi:10.1038/nutd.2017.3. http://www.nature.com/nutd/journal/v7/n3/full/nutd20173a.html

[2] McKenzie AL, Hallberg SJ, Creighton BC, Volk BM, Link TM, Abner MK, Glon RM, McCarter JP, Volek JS, Phinney SD
A Novel Intervention Including Individualized Nutritional Recommendations Reduces Hemoglobin A1c Level, Medication Use, and Weight in Type 2 Diabetes
JMIR Diabetes 2017;2(1):e5. DOI: 10.2196/diabetes.6981

[3] Kent L, Morton D, Rankin P, et al. The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study. Nutrition & Metabolism. 2013;10:58. doi:10.1186/1743-7075-10-58.

[4] Festi D, Colecchia A, Orsini M, et al. Gallbladder motility and gallstone formation in obese patients following very low calorie diets. Use it (fat) to lose it (well). Int J Obes Relat Metab Disord. 1998; 22(6):592-600.

[5] Gebhard RL, Prigge WF, Ansel HJ, Schlasner L, Ketover SR, Sande D, Holtmeier K, Peterson FJ. The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology. 1996; 24(3):544-8.

[6] Stokes CS, Gluud LL, Casper M, Lammert F. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2014 Jul;12(7):1090-1100.e2; quiz e61. doi: 10.1016/j.cgh.2013.11.031. Epub 2013 Dec 7.

 

In our last post, we went into a lot of detail about specific types of saturated fat and their effects on HDL. Here, we’ll try to summarise that information, and highlight some interesting conclusions, in simpler language.

But first, a short chemistry lesson. Nothing too hard, hopefully – we’ll just focus on the main dietary saturated fats (technically, fatty acids), the 4 “even numbered, long-chain saturated fats”.

Lauric acid – a 12 carbon saturated fat (C12:0). This is the rarest of these 4 fats. It is mainly found in the diet in coconut oil (49% lauric acid) and dairy fat. Lauric acid also has some properties of  the shorter medium-chain fats (C6:0 – C:10:0), making it especially ketogenic.

Myristic acid – a 14 carbon saturated fat (C14:0). This is found in coconut oil, palm kernel oil, dairy fat, and the fats of ruminants and fish.

Palmitic acid – a 16 carbon saturated fat (C16:0). This is the most common of the saturated fats, and the second most common fat in nature after oleic acid (C18:1, a monounsaturated fat). It is found in all fats and oils.

Stearic acid – an 18 carbon saturated fat (C18:0). This is the second most common saturated fat, and is found in animal fats, cocoa butter, and palm oil.

The reality is that dietary fats, as they occur in actual foods, contain combinations of lots of different fatty acids; saturated, polyunsaturated, and monounsaturated. More, within each group they contain different combinations of each sort.

For example here’s what is in beef fat and butter*

These fats are also made in the body; they can be made from glucose and other sugars, and a shorter fat can also be converted to a longer one. Thus, palmitic acid (C16:0) is easily converted to both stearic acid (18:0) and oleic acid (18:1) in the carbohydrate fed state, myristic acid (C14:0) is less easily converted to palmitic acid (C16:0), and lauric acid (C12:0) is only with difficulty converted to myristic acid (C14:0).

The reason for these differences is that, the shorter the chain-length of a saturated fat, the quicker it is converted to energy (oxidised) and thus the less it is available for conversion to a longer fat (elongation).[1]

Dietary carbohydrate inhibits the oxidation of saturated fats and promotes their retention and elongation.[2]

This may explain why people eating low carbohydrate diets are able to eat a larger amount of energy from saturated fat without adverse effects – if indeed there are adverse effects to be experienced by saturated fats. Not only do all the blood markers of “cholesterol” improve (apart from rises in LDL cholesterol in a minority of cases), but the saturated fat content of the blood either decreases or, in a person where it was already low, stays the same.[3]

This is important because most of the health problems associated with saturated fat today are associated, not with saturated fat in the diet, but with a high level of saturated fat in the blood. High levels of palmitate and stearate are linked to insulin resistance, metabolic syndrome, and heart disease.[4,5,6] High levels of myristic acid and palmitate are linked to low levels of HDL and to NASH (non-alcoholic steatohepatitis), the inflammatory liver disease that is a dangerous consequence of NAFLD (non-alcoholic fatty liver disease).[7,8]
High plasma levels of palmitoleic acid (C:16:1 n-9), a rare monounsaturated fat formed when myristic acid is elongated to palmitate, are associated with increased future risk of new-onset type 2 diabetes.[9] This is a good indication that diets high in refined carbohydrate do play a causal role in this pathology, because levels of C16:1 drop once carbohydrate is restricted.[3]

When carbohydrate is restricted, and more fat including saturated fat eaten, the serum level of myristic acid falls more than that of palmitate, probably because its shorter chain-length means that its oxidation was less subject to carbohydrate control to begin with.[3]

It’s also the case that the shorter the chain length of a saturated fat, the more it raises HDL.[10]

And thus a very interesting set of correlations appears:

1: The shorter-chain the saturated fat, the faster it is converted to energy, and the harder it is to elongate.

2: The shorter-chain the saturated fat, the more it increases both HDL and LDL cholesterol at a normal carbohydrate intake.

3: The shorter-chain the saturated fat, the more the serum level in the blood drops when fat replaces carbohydrate

4: As a general rule, when fat replaces carbohydrate, both HDL, and the HDL: total cholesterol ratio, rise.

 

So, what is the connection? Well, it’s a mystery. So far, none of the references we’ve found actually indicates a mechanism by which some saturated fats raise HDL levels more than others.

We know that dietary fat (both saturated and monounsaturated) replacing carbohydrate increases the transport rate of ApoA-1 in liver cells, and that the decrease in triglyceride-rich VLDL with saturated fat in a low-carbohydrate diet, and the decrease in myristic acid levels, will help retain HDL in circulation long enough to do its job.[11,12]

(Interestingly, alcohol increases the transport rate of both ApoA-1 and ApoA-2, a type of HDL which has “no known function”, but which seems to be beneficial in moderate amounts, but to interfere with ApoA-1 function in larger amounts.)[13,14]
But we don’t yet have a mechanistic, nor an evolutionary, explanation as to why the chain-length of a C12-18 saturated fat and its rate of oxidation should make as much difference as it does to its effect on your HDL level. (Answers on a postcard please).

The bottom line: 
– all dietary fats are a mixture of saturated, monounsaturated, and polyunsaturated fats, and monounsaturated fat will make up the largest share of energy in the average low-carb diet (with the exception of coconut-based traditional diets), as it does in your body fat stores.
– It’s possible to eat a diet very high in lauric acid, but only if coconut or coconut oil is a major source of dietary energy. It’s impossible to eat a diet very high in myristic acid. These two fatty acids have the largest impact on HDL levels.
– Eating less carbohydrate will make less saturated fat appear in your blood between meals, even if you do eat more saturated fat, and this is most true for the lauric acid and myristic acid in your diet.
– There will also be benefits in terms of HDL (less) and reduced saturated fat in the blood (more)from a low-carb diet that is higher in monounsaturated fat, and lower in saturated fat than the average, if that’s what you like.

The bottom bottom  line: Don’t blame the butter for what the bread did!

*We have some evidence from New Zealand dairy fat expert Joycelyne Benatar that New Zealand dairy fat is, or was, higher in myristic acid than palmitic acid.[15,16] This is consistent with palmitic acid in milk being more the result of carbohydrate feeding (in grain-fed animals), or of animals being fed palm kernel expeller, and myristic acid being more the product of the synthesis of fatty acids from acetate supplied by fermentation.

References

[1] DeLany JP, Windhauser MM, Champagne CM, Bray GA. Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr. 2000 Oct;72(4):905-11.

[2] Lossow WJ, Chaikoff IL. Carbohydrate sparing of fatty acid oxidation. I. The relation of fatty acid chain length to the degree of sparing. II. The mechanism by which carbohydrate spares the oxidation of palmitic acid. Arch Biochem Biophys. 1955; 57(1):23-40.

[3] Volk BM, Kunces LJ, Freidenreich DJ, et al. Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome. PLoS ONE. 2014;9(11):e113605. doi:10.1371/journal.pone.0113605.

[4] Sokolova M, Vinge LE, Alfsnes K, et al. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochim Biophys Acta. 2017; 1862(2):234-245.

[5] Lu Z, Li Y, Brinson CW, Kirkwood KL, et al. CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate. Oral Dis. 2016; Oct 18.

[6] Eulàlia Montell, Marco Turini, Mario Marotta et al. DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. American Journal of Physiology – Endocrinology and Metabolism. 2001; 280(2): E229-E237.

[7] Tomita K, Teratani T, Yokoyama H et al. Plasma free myristic acid proportion is a predictor of nonalcoholic steatohepatitis. Dig Dis Sci. 2011 Oct;56(10):3045-52. doi: 10.1007/s10620-011-1712-0. Epub 2011 Apr 23.

[8] Martínez L, Torres S, Baulies A, et al. Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaining de novo ceramide synthesis. Oncotarget. 2015;6(39):41479-41496.

[9] Mozaffarian D, Cao H, King IB. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr 2010;92:1350–8. LINK

.[10] Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr May 2003
vol. 77 no. 5 1146-1155. http://ajcn.nutrition.org/content/77/5/1146.full

 

[11] Brinton EA, Eisenberg S, Breslow JL. A Low-fat Diet Decreases High Density Lipoprotein (HDL) Cholesterol Levels by Decreasing HDL Apolipoprotein Transport Rates. J. Clin. Invest. 1990; 85: 144-151. Circulation. 2000;102:2347-2352.

[12] Noto, D et al. Myristic acid is associated to low plasma HDL cholesterol levels in a Mediterranean population and increases HDL catabolism by enhancing HDL particles trapping to cell surface proteoglycans in a liver hepatoma cell model. Atherosclerosis. 2016; 246:50 – 56.

[13] De Oliveira e Silva ER, Foster D, Harper MMcG, et al. Alcohol Consumption Raises HDL Cholesterol Levels by Increasing the Transport Rate of Apolipoproteins A-I and A-II.

[14] LW Castellani, Lusis AJ. ApoA-II Versus ApoA-I: Two for One Is Not Always a Good Deal. Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1870-1872.

[15] Benatar JR, Stewart RAH. The effects of changing dairy intake on trans and saturated fatty acid levels- results from a randomized controlled study. Nutrition Journal. 2014; 13:32. LINK

[16] Palmitic acid increased from 15% to 30% of NZ dairy fat, and oleic acid increased from less than 10% to 30%, between 2011 and 2013, matching changes in palm kernel expeller use, at the expense of other saturated fats including myristic acid. Jocelyne Benatar quoted in Listener article by Jonathan Underhill, The Price of Palm Oil, 3 March 2017 LINK

 

 

 

 

The nutrients that raise and lower HDL and ApoA1.

So is getting your HDL high a good thing?  It probably depends if you earned it or not…..and what you eat especially myristic acid

This very interesting study from 2014 brings into focus many of our recent posts about HDL, TG/HDL, ApoB/ApoA1 in the context of our more food-focused posts about butter and the dietary guidelines.[1]
hdl-diet

This is a very readable paper which covers a lot of interesting ground.
It looks at the associations between reported intake of micronutrients and macronutrients and a variety of HDL-associated measurements (HDL, HDL-2, HDL-3, and ApoA1) in a case-control cohort (n=1566) selected for a study of coronary artery atherosclerotic disease (CAAD) – the CLEAR study.

The authors are coming off the back of a series of drug trials in which raising HDL had no benefit for CHD outcomes, and also the Mendelian randomisation research showing that genes associated with high HDL aren’t protective, whereas those associated with low LDL are.

The quick bottom line In our opinion this just means that HDL benefit isn’t a gift, but something you might need to work for through diet and exercise – especially keeping your insulin down. A low fasting TG/HDL ratio denotes low-normal insulin levels and the absence of insulin resistance, and that’s why higher HDL is protective against cardiovascular disease (because the higher triglyceride levels associated with insulin resistance on a high carb diet will force HDL down. Interestingly people sometimes get high TG and thus a high TG/HDL ratio when losing weight quickly, but this doesn’t seem to depress HDL).

(our post on the TG/HDL ratio)

The CLEAR study used the Harvard Food Frequency Questionnaire, so the amounts entered weren’t as exact as in feeding studies, but the authors have compared results to feeding studies where available and found the results are very consistent. To allow for inaccuracy of the method, the stronger correlations should be taken as more reliable, as well as more clinically meaningful. The FFQ analysis didn’t measure inessential or non-nutritive phytochemicals, so can’t tell us anything about their effects on HDL.

The strongest positive correlations with all HDL measurements were for myristic acid (C14 – a 14 carbon saturated fat) and alcohol, folate and magnesium were also associated with HDL, EPA (a fish omega 3) with HDL-2, and vitamin C with ApoA1, and fibre with HDL3 (the antioxidant form of HDL that may be most beneficial).[2]

The strongest negative association was with carbohydrate, and there were weak negative associations for iron and animal fat, as well as for arachidonic acid, the long-chain omega 6 found in animal foods, with HDL2.

The latter deserves an explanation – the sample was in a US population and in the US animal fat mainly comes from chicken, with some pork and other processed meats (that are usually associated with carbohydrate, e.g. on pizzas or in hotdogs). Chicken fat has almost no myristic acid or EPA, and is high in AA.

Myristic acid is 16% of coconut oil and palm kernel oil, 7-12% of butter fat, 2-4% of beef and lamb fat, 3% of salmon fat, 2% of lard, and less than 1% of chicken.

Other vegetable oils supply no myristic acid, including the palm oil that’s in junk food.
In a recent Listener article Otago professor Murray Skeaff stated that myristic acid is “far more cholesterol-raising than palmitic acid”. Be that as it may, and we will refrain from asking how much of that cholesterol-raising effect depends on HDL, we note than in every epidemiological study where different types of saturated fat have been measured in isolation, myristic acid has been associated with less harm , or more benefit, than palmitic acid or even stearic acid (which doesn’t raise LDL cholesterol).[3,4,5,6]

This difference is small and statistically insignificant, but it is always consistent, and doesn’t support a view that myristic acid is worse than other saturated fats.

As far as we can see, the main problem with myristic acid is that it can be elongated to palmitic acid by de novo lipogenesis when consumed in a high-carbohydrate diet.[7] The control of C16 and C18 levels by carbohydrate and insulin explains both the higher associations of these fats with disease (or lower protective associations in positive saturated fat studies) and the failure of low fat diets.[8] The rate of oxidation of saturated fats also depends on their chain length, thus C14 will be converted to energy faster than C16 – if fats are being oxidised.[9] This explains why MCT oil (which is mostly C8 and C10 saturated fats) is especially ketogenic. (the rate of oxidation of unsaturated fats, on the other hand, depends on their number of unsaturated bonds; the more they have, the faster they are oxidised and the more ketogenic they are).[9]

If we were designing a diet to raise HDL based on the CLEAR study, the diet would be low in carbohydrate, and its fat would supply myristic acid (not necessarily a very high amount – the CLEAR study subjects were average US dairy fat users) and EPA. Vegetables and fruit would also be encouraged as sources of magnesium, vitamin C, fibre, and folate. Salmon, eggs, and dairy, as foods supplying desirable fats, would replace some of the red meats supplying iron (avoiding processed grains would also reduce the iron content of the diet – note though that the iron correlation, though consistent with other evidence, is not very strong; and that lamb supplies appreciable amounts of EPA).
The animal fat correlation was weak, and the authors didn’t bother to explain it or treat it as meaningful, probably due to a lack of supporting evidence. It is almost certain to be due to confounding from the Harvard FFQ program and the US diet, where animal fats are found together with processed carbohydrate foods. The omega-3/6 balance of animal foods was strongly correlated with HDL2; linoleic acid wasn’t included in the analysis because it correlated too strongly with other dietary fats to be isolated, but ALA (omega-3) was and wasn’t associated with HDL.

Although whole grains are a source of folate, and folic acid is added to most bread today (and to white rice in the USA), iron is also added to refined grains. Legumes supply more folate by weight and per carbohydrate calorie than whole grains, as well as more magnesium and fibre. Organ meats and leafy green vegetables are also good sources of folate.

Interestingly alcohol was dose-dependently correlated with HDL and ApoA1, supported by the cardioprotective associations of moderate drinking. However, there were only a few (21) heavy drinkers (>60g day) in the sample. Because heavy drinking is associated with cancer, accidental death, and heart failure, and is very likely to make you and everybody else miserable in the long run, we don’t recommend this approach to HDL-raising, except for people who already enjoy alcohol in moderation (defined as 10-30g/day, that’s 1 or 2 small glasses of wine or standard drinks).

However, the protective associations between moderate alcohol consumption and CHD clearly show that not every drug that elevates HDL fails to reduce risk. Of course, alcohol is also a food, which might help. Note that, if you do drink, the types of fat that supply most myristic acid in the diet – coconut oil, dairy fat, and beef and lamb dripping – are (along with cocoa butter) those that are most protective against alcoholic liver disease.[10]

Myristic acid raises HDL and LDL cholesterol

Where does the idea that myristic acid is harmful come from? This feeding study showed that myristic acid raised cholesterol, both HDL and LDL – however, to get this amount of myristic acid, 11% of diet, which was supplied by a special 50% myristic acid margarine, from ordinary foods, you would have to eat nothing but butter. Carbohydrate intake in the study was 47% of energy, fat was 39%.[11]

Myristic acid is the third most common saturated fat in the diet. Average intake levels are about 1 g/d in Japan, 6 g/d in the United States, 8 g/d in the Netherlands, and 14 g/d in eastern Finland (D. Kromhout et al, unpublished data, 1988). Major sources are butter fat, which is also rich in palmitic acid, and two vegetable oils, coconut oil and palm kernel oil; the latter two also contain large amounts of lauric acid. Palm oil, another vegetable oil that is high in saturated fatty acids, is low in myristic acid and high in palmitic acid. Palm oil is the number one edible oil worldwide, and its consumption is rising. If much of the cholesterol-raising effect of saturated fatty acids is indeed specifically due to myristic acid, then palm oil would be a suitable substitute for animal fats and hydrogenated vegetable oils in a wide range of products for cholesterol-lowering diets. Moreover, modern biotechnology could be applied to replace myristic acid with palmitic acid in other fats.

The diet, not mentioned in that study, with the most myristic acid – over 20g/day – would have been that of the Tokelau islanders who got most of their energy from coconuts, had a high percentage of myristic acid in adipose tissue (4x that of Europeans) and had very low rates of cardiovascular disease – on a lower carbohydrate diet. [12]

Carbohydrate controls the HDL response to Myristic acid

What happens to myristic acid on a low carb diet? This study by Jeff Volek et al measured fatty acids in the blood on a 1500 kcal 12% carbohydrate diet (about 50g carbohydrate), compared with a 1500 kcal low fat diet (24% fat, 56% carbohydrate).[13]
(This initial finding was supported by a series of other experiments by this group, including one in which a dose-response effect of carbohydrate on serum C14 levels was demonstrated, and another in which the effect was shown in the absence of calorie restriction or weight loss.)[8,14]

The dietary intake of saturated fat was threefold higher on the CRD (36 g/day) compared to the LFD (12 g/day). Remarkably, the CRD showed consistently greater reductions in the relative proportions of most circulating SFAs in TAG and CE fractions (16), mainly attributed to greater reductions in myristic (14:0; 47% reduction) and palmitic (16:0; 10%) acids. With the exception of those with a low level at baseline, nearly all subjects consuming the CRD had a decrease in total saturates (17 of 20 subjects), whereas only half the subjects consuming the LFD had a decrease in saturates. Taking into account the change in absolute fasting TAG levels, the absolute concentration of total saturates in plasma TAG was reduced by 57% in response to the CRD, compared to 24% in response to the LFD.

Thus we see that, as we would expect, myristic acid in the blood is decreased by carbohydrate restriction faster than longer-chain saturated fats. HDL of course increased in the low-carb arm; which is consistent with this study showing that higher myristic acid in the blood (not diet) of a Mediterranean population is associated with lower HDL.[15] This paper also cites Mensink et al “a large meta-analysis including 60 dietary intervention studies concluded that the increase of HDL-C due to SFA progressively decreases with the elongation of the acyl chain, being maximal for C12:0 (lauric acid) and not relevant for C18:0” – so the faster beta-oxidation of myristic acid (and lauric acid, not isolated in the CLEAR study) correlates with the greater rise in HDL.

And if myristic acid isn’t oxidised, because the carbohydrate content of the diet is too high for the insulin sensitivity of the individual – carbohydrate intolerance – HDL can go down instead.

The following human study also shows that myristic acid modulates omega 3 status;[16]

In addition, in humans, compared with a diet containing 0.6% of myristic acid mainly in the sn-2 position in the TAG [i.e. dairy fat], a diet containing 1.2% of myristic acid during a 5-week consumption period significantly enhanced EPA and DHA levels in the plasma PL and DHA level in the plasma cholesteryl esters [60]. When the intake of myristic acid increased from 1.2 to 1.8% energy in the same population, EPA, DPA and DHA decreased significantly in plasma PL and EPA also decreased in cholesteryl esters [61]. This result suggest that, in humans, the effect of myristic acid on circulating (n-3) PUFA follows a U-shaped curve with a favorable turning point at around 1.2% of total daily energy.

1.2% of dietary energy would be equal to 10-12% of energy from dairy fat. But note that this was in the context of a high carb diet, and that it’s likely this threshold would increase as the rate of myristic acid oxidation increased at lower carbohydrate intakes.

In low-fat diets, it looks like there’s an optimal amount of myristic acid, which you’d get by including full fat dairy foods, as shown by the DASH diet study of Chiu et al (increasing saturated fat from animal foods over baseline improves biomarkers in people eating a supposedly “healthy” diet pattern).[17] The omega-3 study we cited above, and the Med diet serum HDL study, show that in low-fat diets or in carbohydrate intolerant individuals there’s a limit to benefit – a U shaped curve. Putting lots of butter on white bread with jam, or in sweet cakes, as Kiwis did in the 1960’s, you can maybe come off that curve and prang badly. But once you look at lower carb diets, it looks as if myristic acid is a fat that’s well tolerated, doesn’t hang around, and is easy to benefit from (remember, at around 16% of coconut oil, 10% of dairy fat, much lower amounts in other animal fats, and almost none in olive oil and nuts, it’s unlikely to be a major type of fat in the average low carb diet).

The PURE study
And, to turn to the famous PURE study, also a case-control study but a very large one with dietary intakes and lipids stratified into quintiles,
“higher carbohydrates intake has the most adverse effect on lipid profiles and replacing it with saturated fat improved HDL and TG and replacing it with MUFA improved TC/HDL-C and ApoA/ApoB.”[18]

ApoB/ApoA was the lipid marker chosen as the best risk predictor in PURE and the INTERHEART study. Animal fats are predominantly mixtures of saturated fat and MUFA.
We discussed the reasons why using ApoB/ApoA1 predicts that there will be cardiovascular benefits of carbohydrate restriction in this post.

Looking at the evidence around myristic acid shows us, once again, that carbohydrate drives the pathologies fat gets blamed for.
And it shows us, once again, that judging foods based on their effects on cholesterol and LDL as if this was the only game in town has been a huge blunder in terms of public health.

If you erroneously think that replacing fat with carbohydrate, because this will lower cholesterol, is the key to health, and find out this doesn’t work, then restricting certain kinds of fat becomes a logical, but largely ineffective,  and sometimes counterproductive, follow-up part of your strategy.

You can even end up thinking that it’s okay that palm oil is overtaking butter in the NZ diet. Not that there’s much evidence that it’s harmful yet, except to orangutans, but surely, it’s just unnecessary, and takes us further away from eating real foods that could be produced at home, and deeper into the hands of a global food industry that hasn’t really looked after our interests so far.

References

[1] Kim et al. “Effects of dietary components on high-density lipoprotein measures in a cohort of 1,566 participants.” Nutrition & Metabolism 2014, 11:44.

[2] Kim DS, Burt AA, Rosenthal EA, et al. HDL‐3 is a Superior Predictor of Carotid Artery Disease in a Case‐Control Cohort of 1725 Participants. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease. 2014;3(3):e000902. doi:10.1161/JAHA.114.000902.

[3] Zong Geng, Li Yanping, Wanders Anne J, Alssema Marjan, Zock Peter L, Willett Walter C et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies BMJ 2016; 355 :i5796.
http://www.bmj.com/content/355/bmj.i5796

[4] Ericson, U, Hellstrand, S, Brunkwall, L, Schulz, C-A, Sonestedt, E, Wallström, P, et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. AJCN 2015;114.103010v1
http://ajcn.nutrition.org/content/101/5/1065.full.pdf

[5] Praagman J, Beulens JW, Alssema M, et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Am J Clin Nutr2016;103:356-65.

http://dss.mef-cakovec.hr/wp-content/uploads/2015/12/MARTAN-ANAMARIJA.pdf

[6] Praagman J, de Jonge EA, Kiefte-de Jong JC, Beulens JW, Sluijs I, Schoufour JD, et al. Dietary Saturated Fatty Acids and Coronary Heart Disease Risk in a Dutch Middle-Aged and Elderly Population. Arterioscler Thromb Vasc Biol. 2016; 36(9): 2011-8.

[7] Lossow WJ, Chaikoff IL. Carbohydrate sparing of fatty acid oxidation. I. The relation of fatty acid chain length to the degree of sparing. II. The mechanism by which carbohydrate spares the oxidation of palmitic acid. Arch Biochem Biophys. 1955; 57(1):23-40.

[8] Volk BM, Kunces LJ, Freidenreich DJ, et al. Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome. PLoS ONE. 2014;9(11):e113605. doi:10.1371/journal.pone.0113605.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240601/

[9] DeLany, JP, Windhauser, MW, Champagne, CM, Bray, GA. Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr October 2000;72(4):  905-911

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