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Friday 30 July 2021

Virta Health vs Seidelmann - of ketones and COVID-19

You would have seen this paper; senior author is Sara Seidelmann of the infamous "low carb kills" paper, the reviewers were one vegan propagandist David Jenkins (a friend of the family, so to speak) and an Iranian prof with a decent publications list in the plant-based area - neither with any infectious diseases expertise.

There were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following ‘plant-based diets’ and ‘plant-based diets or pescatarian diets’ had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following ‘plant-based diets’, those who reported following ‘low carbohydrate, high protein diets’ had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration.

you'll find good criticisms in the rapid responses attached, and my PubPeer comment here.

 The methods state 
Lastly, we combined ‘low carbohydrate’ diets and ‘high protein’ diets into another category (‘low carbohydrate, high protein diet’, n=483) to evaluate whether these dietary patterns are associated with COVID-19 severity.

Why? No reason is given for combining these 2 categories. 

There was a keto option, so why didn't they add keto + low carb?

Methods state
Before analyses, we selected dietary patterns with sufficient ‘yes’ responses (‘yes’ response of at least 100 individuals). To increase precision, we analysed three dietary patterns after combining dietary patterns that are similar in terms of dietary intake.

Perhaps keto had less that 100 responses? But there was no registered protocol, those decisions were post-hoc - even if keto had fewer than 100 responses, adding it would have still increased numerical power, which was presumably the point of combining categories as they did. And there's nowhere it says how many responses, and we also have no way of knowing how similar low carb and high protein really were (everything was pretty similar really, these were for most respondents just the virtue-signaling labels they gave to their eating habits).

Anyway, there was no association once people with a negative or no PCR test were excluded.
That's not in the abstract.

But, you know, people are using the keto and LCHF diets to treat diabetes and reduce COVID19 mortality associated with type 2 diabetes, MetSyn, or obesity, so this is a nasty thing to say if it's not true. It's a bit like trying to get people to stop taking vaccines based on your bias and some shit you didn't understand.

Fortunately Vitra Health have ridden to the rescue with a survey of their own T2D population on a ketogenic diet. We know these people are actually following the diet, or adhering closely to it.

The abstract (presented at an ADA conference) is 
COVID-19 Severity in a Geographically Diverse, U.S.-based, Ambulatory Population with Type 2 Diabetes on a Medically Supervised Ketogenic Diet

Data were obtained from medical records and from surveys sent to T2D patients who self-reported COVID-19 diagnosis; 47.8% (294/614) responses and one known COVID-related death yielded a sample of 295 (50% male, 54±9 years, across 41 US states). We observed low reported rates of hospitalization (10.9%), ventilation (2.0%), and death (0.3%) relative to national reports.
Let's compare with the Seidelmann paper - 1) we know the diet is real. 2) COVID-19 is self-reported (some will have tests some not, as in Seidelmann) but - we do have people being hospitalised, unlike Seidelmann, and we even have one death, so Virta are able to capture events that people weren't able to report directly, because their model includes liaison with primary providers likely to report deaths to them. 3) the event rates are low for a population with type 2 diabetes, as shown by the comparison with this population. The populations, though much the same age, aren't identical, but the biggest difference seems to long term inclusion in the Virta Health population (note the "baseline" HbA1c data in Virta - before treatment with the ketogenic diet - is similar to the overall HbAic data in the comparator vs standard practice, but many of the Virta Health population have put their T2D in remission. At this stage, we have to say that the EFFECTS of the keto program are protective - weightloss and euglycaemia, etc. We don't have evidence that keto per se is protective apart from those factors. But that may well be hidden in the data, once the whole set is fully written up. But once again, it looks like Harvard is a bad actor, an ill informant in the nutrition-and-health space, interfering with effective treatments to preserve its own ill-gotten (by a process of bloviation if not graft) dietary hegemony.

Wednesday 7 July 2021

The Carb-Fat Food Quality Gradient - a real metabolic advantage

This post was originally published as a subscriber-only post on Patreon. You don't have encourage the speculations of the likes of me, but if you want to try, please subscribe!

By now, we've all seen them - studies that purport to show equivalent effects of LCHF and HCLF diets once diet quality is addressed and people are Eating Whole Unprocessed Foods.
The latter is a good thing, the default to go for in terms of population health; macronutrient tweaking is next-level.
But here's a question - why were almost all the original studies that validated the efficacy of LCHF diets to a skeptical medical world comparisons of ad lib low carb vs energy-restricted low fat?
To make a really low carb high fat diet (unless you want to pretend a high-protein diet is that) you're going to be using some isolated fats (cream) or refined ones (coconut oil, olive oil). There may not be sugar in your chocolate bar, but there will be cocoa butter.
This only works if in some way those isolated fats are NOT equivalent to sugar and flour.
What is the evidence for a difference?

One of the more lasting concepts in carb nutrition is the glycemic index, the average speed at which a food appears as glucose in the system. It's not perfect because sugar is only half glucose so is lower GI, but you get the idea.
High GI is worse for you.

The PURE study is good for producing null results, which makes whatever it does throw up seem a bit more reliable than most nutritional epidemiology.[1]

"In the study population, 8780 deaths and 8252 major cardiovascular events occurred during the follow-up period. After performing extensive adjustments comparing the lowest and highest glycemic-index quintiles, we found that a diet with a high glycemic index was associated with an increased risk of a major cardiovascular event or death, both among participants with preexisting cardiovascular disease (hazard ratio, 1.51; 95% confidence interval [CI], 1.25 to 1.82) and among those without such disease (hazard ratio, 1.21; 95% CI, 1.11 to 1.34). Among the components of the primary outcome, a high glycemic index was also associated with an increased risk of death from cardiovascular causes. The results with respect to glycemic load were similar to the findings regarding the glycemic index among the participants with cardiovascular disease at baseline, but the association was not significant among those without preexisting cardiovascular disease."

As I've said before, everything in plants that is supposed to be good for you but isn't actually a real nutrient is probably lowering GI in some way. It's the glucose (glycemic load above) but the way it arrives in your bloodstream (GI) is more pointed.

Is there equivalency for fats? Do fats that are rapidly absorbed correlate with disease?
That would be the medium chain fatty acids, MCFA.

"In comparison to triglycerides containing LCFAs, those containing MCFAs are more rapidly hydrolyzed in the intestinal tract and do not become incorporated into chylomicrons. SCFAs and MCFAs are transported by portal bloodstream to the liver, where they are readily metabolized."[2]

And perhaps also the unsaturated fatty acids, UFA.

"Although pancreatic lipase hydrolyzes fat only in the 1 and 3 positions of the molecule, it is nevertheless possible for fatty acids in the 2 position of the triacylglycerol to be hydrolyzed. This apparent violation of the specificity of pancreatic lipase occurs because of the relative instability of both the 2-monoacylglycerol and the 1,2-diacylglycerol (Crossley et al., 1959). These molecules rearrange by migration of the fatty acid in the 2 position to the 1 or 3 position, which is readily hydrolyzed by lipase (Figure 18–3). This rearrangement is more rapid when the fatty acid is either a short-chain one or an unsaturated one, and a portion of the 2-position fatty acids may be absorbed as fatty acids rather than as monoacylglycerols (Benzonana et al., 1964)."[3]

We'll call this the fat index, FI.
Are fatty acids with a high FI worse than low-FI fats?
In epidemiological studies of individual fatty acids and their associations with disease risk, the MCFAs, which are SFAs, are always more benign than the longer-chain SFAs (see table 2).[4]

"Two recent studies from the Netherlands reported largely diverging findings. In the European Prospective Investigation into Cancer and Nutrition study, intakes of 4:0-10:0 and 12:0 were inversely associated with ischemic heart disease risk, but no associations were found for 14:0, 16:0, and 18:0. However, in the Rotterdam study, only 16:0 intake was associated with higher risk of coronary heart disease." [see also table 2]

In an overfeeding experiment, the benefits of MCFA were obvious.[5]

"In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess."

This is because high-FI fatty acids are metabolized more rapidly, and, in the case of MCFAs, oxidized with less metabolic and hormonal effort than LCFA.[2,6]

In conclusion - if you eat carbs in bulk you will need to pay some attention to the speed at which your body absorbs them; this rules out eating purified carbohydrates.

If you eat fats in bulk, you need pay little attention to the speed your body absorbs them; you may want more fast-absorbing fatty acids in your food, but this does not rule out eating purified fats.

[1] Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, Rangarajan S, Srichaikul K, Mohan V, Avezum A, Díaz R, Rosengren A, Lanas F, Lopez-Jaramillo P, Li W, Oguz A, Khatib R, Poirier P, Mohammadifard N, Pepe A, Alhabib KF, Chifamba J, Yusufali AH, Iqbal R, Yeates K, Yusoff K, Ismail N, Teo K, Swaminathan S, Liu X, Zatońska K, Yusuf R, Yusuf S; PURE Study Investigators. Glycemic Index, Glycemic Load, and Cardiovascular Disease and Mortality. N Engl J Med. 2021 Apr 8;384(14):1312-1322. doi: 10.1056/NEJMoa2007123. Epub 2021 Feb 24. PMID: 33626252.

[2] Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016;57(6):943-954. doi:10.1194/jlr.R067629

[3] Institute of Medicine (US) Committee on Military Nutrition Research; Marriott BM, editor. Food Components to Enhance Performance: An Evaluation of Potential Performance-Enhancing Food Components for Operational Rations. Washington (DC): National Academies Press (US); 1994. 18, Structured Lipids: An Overview and Comments on Performance Enhancement Potential. Available from:

[4] Zong G, Li Y, Wanders A J, Alssema M, Zock P L, Willett W 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 doi:10.1136/bmj.i5796

[5] Anne-Marie Lundsgaard, Andreas M. Fritzen, Kim A. Sjøberg, Maximilian Kleinert, Erik A. Richter, Bente Kiens. Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans.
Diabetes Jan 2021, 70 (1) 91-98; DOI: 10.2337/db20-0582

[6] James P DeLany, Marlene M Windhauser, Catherine M Champagne, George A Bray, Differential oxidation of individual dietary fatty acids in humans, The American Journal of Clinical Nutrition, Volume 72, Issue 4, October 2000, Pages 905–911,