Saturday, February 01, 2020

Looking in to the future of Low Energy Diets

I think I picked this up from Jan Vyjidak on Faceache but it's done the rounds on twitter too.

Low-energy total diet replacement intervention in patients with type 2 diabetes mellitus and obesity treated with insulin: a randomized trial

"At randomization, participants commenced a 12-week TDR [total diet replacement] formula LED [low energy diet]... followed by 12 weeks of structured food reintroduction and then ongoing followup in combination with an energy deficit diet at 3-month intervals until 12 months. For the first 12 weeks, all meals were replaced with four formula LED products per day (800–820 kcal/day, 57%
carbohydrate, 14% fat, 26% protein and 3% fiber) in addition to at least 2.25 liters of energy-free beverages. A fiber supplement was recommended, if required, to avoid constipation, a common side effect of using a TDR".

For three months patients were starved on 800kcal per day. At 56% carbohydrate that makes carbs come out at around 100g/d. Oddly enough, restricting carbs to this level allowed a drop in insulin usage. Indeed, there was such a marked drop in insulin usage that some patients coming off insulin all together. I wonder what these starvation subjects would think if you told them that they could have had equal reductions in insulin usage just by restricting the carbohydrate content of their diets to that 100g/d, while still allowing fat and protein to satiety... I suspect  that a) no one has told them this and b) they might not be best pleased to find out retrospectively.

For a second three months a little food was added to their diet, but not much. For the final six months patients were kept a little hungry but not so much as in the first six months of the study.

Here is what the abstract says:

"Results: Mean weight loss at 12 months was 9.8 kg (SD 4.9) in the intervention and 5.6 kg (SD 6.1) in the control group (adjusted mean difference −4.3 kg, 95% CI −6.3 to 2.3, p less than 0.001)".

Here is what the results show for the intervention group:

Here is the same graph but simplified in to three red lines representing the three phases of the study:

You can argue the exact slopes of the lines but overall the pattern is correct. Something like this:

Now it is time to look into the future. Usually this is difficult but I think that in this case the general shape of the graph lets us predict the shape of things to come when related to weight gain. Plus, because it becomes obvious in the later months of the study (from HbA1c values) that insulin is going to have to be added back in, at this time the rate of weight gain might actually increase (dramatically), but we can't know that.

Using a simple maintenance of the status quo (best case scenario) we get this, looking forwards to around about the 24 month mark:

Weight gain, in the aftermath of a year of hunger, might not stop at baseline mass either.

I think it is also possible to look in to the future of glycaemia too, by extending the plot of HbA1c with time, working from the published graph in the results. Taken forwards to 16 months or so, it looks something like this:

Maybe I'm being pessimistic. Maybe sudden tolerance of chronic hunger might kick in and reverse the adverse trends in weight and glycaemia clearly present at the end of the study. Maybe subjects might suddenly become slim and euglycaemic.

Maybe not.



cavenewt said...

"Conclusions and implications to practice—This study confirms that a low-energy TDR [total diet replacement] intervention including behavior modification and physical activity can be used effectively to manage patients with type 2 diabetes and obesity receiving IT [insulin therapy]. At present there are very few effective treatments for those with long-standing type 2 diabetes apart from escalating pharmacotherapy or bariatric surgery. This study fills the current gap in knowledge not addressed by the Diabetes Remission Clinical Trial, which focused on those diagnosed with type 2 diabetes for less than 6 years who were not treated with insulin. Patients with long-standing type 2 diabetes and obesity on IT can, with sufficient weight loss achieved through a low-energy TDR intervention, reduce insulin burden and improve QoL. Maintenance strategies are required to ensure the preservation of the early beneficial effects of the TDR intervention."

It certainly is a good example of the blinkered outlook caused by the inability to climb out of one's dominant paradigm.

Passthecream said...

Insulin algebra:

a) + b) =


Frunobulax said...

Curious, where can we find the supplementary tables mentioned? I can't see anything at the given link ( I'm curious how many calories the poor guys ate after the initial 12 weeks.

cavenewt said...

@Frunobulax, They are at

Page 12 might have what you're looking for. It's just a flow chart of the protocol. In a quick scan of the data I couldn't find any table explicitly mentioning calories in a timeline.

raphi said... i've had a Twitter exchange with the first author Adrian Brown

Frunobulax said...

Thanks @cavenewt. The list of side effects is fairly impressive, would have been worth a comment in the paper, no? :)
Fatigue, Dizzyness, Diarrhoea, constipation, sensitivity to cold all more than a third of the participants. Mood changes, headaches, toothaches and sleeplessness in the 25% region. Poor lab animals, ahem, humans.

Peter said...

Had a quick scan through raphi, The man has a job to do and is doing it as well as he can!

Frunobulax, I never saw a calories count except for the period on the meal replacement either. However we know, absolutely, that the second three months was severely calorie restricted because the subjects continued to lose a little weight in the aftermath of 3 months starvation...


Frunobulax said...
This comment has been removed by the author.
Frunobulax said...

@Peter It's in the supplement. In months 4 to 6 they got 1000 calories, for the remaining 6 months 600 calories below baseline (just as the control group). So your wording appears to be quite correct, they were starving for half a year and then kept just a bit hungry for 6 more months.

As the study is ITT and they didn't make any attempt to verify compliance, I wonder what the participants really ate. Keys starvation experiments reported significant problems with cheating, and the guys in Minnesota were (a) in a controlled environment and (b) got twice as much calories.

Also this comment from the supplement makes you think: "The impact of non-response and missing data at 12 months follow-up were examined in a sensitivity analyses. In order to avoid a loss in efficiency, missing values were imputed using multiple imputation by chained equations.1 In this, 20 imputed datasets were created by
replacing missing values with simulated values from a set of imputation models built from all potential prognostic and the outcome variable (weight loss)." Watch the mathematicians turning in their graves.

The good thing: We can question the results, but it doesn't make much of a difference because the diet does obviously not work. Either it's impossible to comply or the base metabolic rate changes so much that weight is gained back. But which one of the two is dominant does matter a lot if you want to know how much the bmr changes in starvation.

ctviggen said...

Hmm..."sensitivity to cold". This implies to me a reduction in their basal metabolic rate. That's not what they want. This is The Biggest Loser conundrum, where they lose weight only to have a (seemingly) permanent decrease in their basal metabolic rate.

Do you think if one made the researchers follow their own diet, they might not think so well of it? ;-) Seriously, who can eat a diet of 800 calories for 3 months? I'm surprised they got anyone to do this.

cavenewt said...

"The impact of non-response and missing data at 12 months follow-up were examined in a sensitivity analyses. In order to avoid a loss in efficiency, missing values were imputed using multiple imputation by chained equations.1 In this, 20 imputed datasets were created by replacing missing values with simulated values from a set of imputation models built from all potential prognostic and the outcome variable (weight loss)."

Yes that should make mathematicians spin in their graves. But among the living, it should be a clear warning that there are meaningless conclusions ahead—better known as GIGO or garbage in, garbage out.

Why am I reminded of the bit in Jurassic Park where they used frog DNA to fill in the missing gaps in the dinosaur DNA?

Hap said...

"Why am I reminded of the bit in Jurassic Park where they used frog DNA to fill in the missing gaps in the dinosaur DNA?" gotta use something to fill out. I would have used alligator.

Hap said...

Haven't we seen enough of pictures of Roy Walford emerging from biosphere, not to find the idea repugnant?

Hap said...

A much happier thought....butter croissants.

Peter said...

"to fill in the missing gaps in the dinosaur DNA"...chickens, I'd have used chickens. Alligator would have been cool, but not as cool as chicken... I still have twenty-odd very tame feathered dinosaur derivatives


cavenewt said...

Yes, a much better choice.

I'm sure the frog DNA was simply a plot device because of frogs' ability to change genders, which was important to the plot of the movie.

Peter said...

Oh! I didn't realise there was a plot...


cavenewt said...

Peter—I was about to explain, till I detected that dry British sarcasm.

Peter said...

Smiley face! Many years ago I read Terry Pratchett's book Bags of Time and as a result decided that I really should watch Alien. Initially I was very, very impressed. The spaceship was a freighter and everything looked rough and tatty, much like a tramp steamer in Somerset Maugham's novels. Then the script turned out to be equally untidy and rough around the edges. I gave up at "organic acid!!!!". Never have watched Jurassic Park. Maybe I should try... Heeeheee


cavenewt said...

I recommend Jurassic Park. It's pretty well done for its time, has some genuinely funny moments, and the science was a notch above the average science-fiction movie. Amber and frogs.

I never got the attraction of the Alien movies (and SF is my genre of choice.)

Douglas Adams is my personal deity. Terry Pratchett is a close second—I own every single Discworld book and reread them regularly, but I can't remember Bags of Time. Google no help. Was it an essay?

Peter said...

Mea culpa cave, it was Only You Can Save Mankind where Kirsty chooses the handle Sigourney to battle space invaders that gave me the link to Alien. I'm guessing that Bags of Time was part of the plot-line or a chapter title from Johnny And The Bomb, not quite sure, I read them a very long time ago!


cavenewt said...

That was a great trilogy!

Passthecream said...

Hap, a snip from wikip. about Walford which seems very relevant in this context:

"Walford's death from amyotrophic lateral sclerosis has provoked consideration about whether his practice of caloric restriction (CR) may have contributed to, or accelerated, his development of the disease. Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh et al. therefore concluded, "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated."[13]Hamadeh et al. also note two human studies[14] that show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state, "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They conclude, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake."[14]

Previously, Pedersen and Mattson found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.[15]Suggesting that a calorically dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow the progress of disease.[16]"

karl said...

I've tried the starvation diet - for most of a year - not pleasant. One of the tricks I used was to go to bed hungry.. Didn't work. I craved food - got cold - back-pain problems. Never got to my target weight - just got harder and harder to do.

T2D appears to be easily cured with a combination of a low-carb diet and strength training (not to be confused with exercise).

There appears to a popularization of irrational virtue signaling by eating carbs. (Reminds me of the joke: What should you ask to find out if someone is a vegan? There is no need to ask - they will tell you). I just wonder how much virtue they feel when they force this IQ lowering fad on their children?

There is some idea that they are saving the planet - sustainability bits. Some bit of truth - there just isn't enough high quality food to go around - thus the selling of PUFA and sugar (empty calories) to feed the world. The problem is even if the birth rate drops - I don't see how we avoid a Malthusian bottle neck - even if half the world is forced to eat a brain destroying diet - and of course history is full of examples of people thinking they are creating utopias only to actually create horrible distopias. - but back to my point - I think these contorted papers that get published are the result of the politics of the irresolvable quality food shortage. Hard to see a happy ending.

Frunobulax said...

@karl The dividing line is not between vegetarian and meat. I'd say you can eat a fairly healthy vegetarian diet with butter, coconut oil, olive oil, eggs and dairy. O believe the fat composition of butter specifically is fairly similar to animal fat, and eggs have all the proteins that we need. Omega-3 is an issue of course, but maybe butter (from grass-fed cows) and linseed oil are sufficient, I don't know.

I fail to see how a vegan can be healthy, though. The big issue is that ethics must *not* be confused with health. If someone believes that we shouldn't kill animals (which is basically religion IMO, and everybody is free to choose her/his religion) that's fine, but this has zero implications on whether a meat-free diet is healthy or not. Also the health of meat in context of mass production of meat is a concern independent of ethics, because meat will be less healthy if animals are fed with corn and soy.

@Peter As Pratchett says: It's time to do some solid science. Which is to find and kill the butterflies in Australia that cause all those damn hurricanes over here. :)
I have all of his books, and the Johnny books and the bromeliad trilogy have a special place in my heart :)

Galina L. said...

It strangely reminds me another experiment conducted by Dr.J.Proietto in order to investigate the reason why people can't hold a weight-loss result

Passthecream said...

Frunobulax, what you write does remind me of the old saw - 'if we weren't meant to eat animals they wouldn't be made of meat'. But vegetables seem increasingly tricky for me as I age less graciously than I'd like to. I am juggling complete avoidance of anything with oxalate, histamine, sirbital, salicylate etc with my fondness for consuming the damn things. There is definitely something screwy about the modern dietary advice to eat luscious servings of the so-called healthy fruit and veg versus the problems they end up causing. Vegetarianism - been there seen there done that. Veganism - just plain stoopid, I think, but evolution in action also.

Peter said...

Thanks Galina,

Amazing that semi starved people are hungry and stay hungry! I think a year might set the stage for the rest of their lives, unless they go LC of course. Doesn't seem to stop the studies being done using very low energy diets.



Galina L. said...

Peter, the history of calories-restricted-for-a-weight-loss-diets is the history of human stupidity. Recently I have decided to collect what I could find on the subject. The first study proved that restriction in calories leads to a weight gain above initial weight because metabolism was changed by starvation. That first study was conducted at 1918 by Francis Gano Benedict who invented the way to measure human metabolism. Since than study after study consistently demonstrates the same result. Including the famous Minnesota study when people were starving on almost 1600 calories a day. Yes, going rtnj makes big difference because people are less hungry due to а different hormones signalling. People in Virta group discovered how it worked , but still cutting calories is a very bad idea. We rarely think how body changes to accommodate our changes in lifestyles. In response to starvation it slows down metabolism probably forever and changes how we think and feel about food. I have not find it in a literature? but I am sure in response to a prolong starvation body should decrease the amount of mitochondria

Frunobulax said...

@passthecream I'm agnostic on the carnivore/vegetarian front. I would love to eat mostly grass fed meat, but frankly I can't afford that on a daily basis. Now, I can choose between pest and cholera: Industrial meat with unnatural fatty acids (high n-6 PUFA), antibiotics and such vs. some vegetables. Currently I'm eating some keto veggies and am doing better than when I was nearly carnivore, but I still eat a lot of meat compared to most other people.

IMO the jury is out there *if* a vegetarian (or nearly vegetarian) diet *can* be healthy if it contains plenty of eggs and dairy fat and is low on grains, soy and all the other crap. But I certainly won't be the n=1 experiment here, it's up to the people who are in love with vegetarianism to prove that such a diet exists.

So I think basically we're on the same page, with opinions differing in some nuances :)