Saturday, October 16, 2021

Modelling energy intake (3): empagliflozin

In the aftermath of the of canfliglozin post I picked up this paper via Tucker:

Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition

It's the group including Hall again, with a different drug but still looking at glycosuria as an "insensible" caloric loss. If you feed the daily glucose loss in to their sophisticated CICO derived formula the weight loss over 90 weeks should be 11.3kg whereas the actual weight loss was 3.2kg.

This was correctly attributed to increased calorie intake, reverse modelled to an increase of calories in the region of 270kcal/day. What to do about this?

The best section of the abstract is the conclusion, which sums up the paper:

"Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss."

Translation, "starve the buggers". Starvation ALWAYS facilitates "major weight loss".

That was 2015. But even then Hall was well aware of the stupidity of this approach, as he detailed in his 2016 publication:

If caloric restriction where a feasible option I guess no one would ever get fat and, if they did, anyone could easily lose weight by caloric restriction, without the risk of fungal necrotising fasciitis (necessitating emergency removal of significant parts of a person's genitalia and possibly surrounding tissues) which comes as a real risk with the canagliflozin or empagliflozin deal. Sadly caloric restriction is generally associated with intolerable hunger and rapidly failing ability to maintain any large caloric restriction. An insight superbly documented Hall et al.

Ultimately in the real world of the CIM, the urinary loss of "x" glucose calories drops insulin. It appears that this drop in insulin releases a certain amount of FFAs from adipocytes, say "y" kcal, but y is never quite enough to fully compensate for the urinary loss x (no reason it should be). So a small amount of food is needed to make up the deficit as perceived by the brain stem. Back in 2015 I guess diabetics were being advised to eat low fat, high carbohydrate diets. So each patient eats a few extra calories, roughly x minus y extra. That food will be around 55% carbohydrate. Which will directly offset the urinary loss per se but more importantly, will increment the level of insulin in the bloodstream.

As insulin is incremented upwards by the extra food, so FFA release from adipocytes will increment downwards and so a spiral of rising food intake, rising insulin and falling FFAs (limiting weight loss) will ensue.

There is some sustained weight loss. I would guess that this is related to the residual fat content of the extra food eaten, which won't raise insulin the way the carbohydrate component will.

Which leaves you wondering if by providing the small food increment needed to off set the x - y deficit in the form of fat, perhaps a much more significant weight loss might have occurred. Not sure 11.3kg would be possible, but it might be.

And of course starvation would not be needed... But perhaps that smacks of LC eating and the CIM too much.



cavenewt said...

Who thinks up drug names? I always feel like I'm trying to read Klingon.

Peter said...

Any drug with a simple name, especially if it does not include an x, y or z, will bomb. Those with execrable names including one of the above letter are probably equally useless but are much less likely to bomb immediately... Marketing. Makes you wonder how simple drugs like morphine or atropine ever came in to general usage.


LA_Bob said...

cavenewt, I love that question! I've wondered myself. Here's my long layman 2 cents worth answer.

First, I suspect morphine and atropine (along with epinephrine, aspirin, penicillin, and others), lacking "x", "y", or "z" in their names, made it into general usage because they...worked. Once upon a time this was surely a plus.

Second, I became curious about drug names when clinical trials held the fates of the CETP inhibitors -- the HDL cholesterol boosters -- in their testy little hands. At the time, torceptrapib had already failed, and three similar drugs were lined up to fail as well. How on earth, I wondered, had Pfizer given such a horrid name to a drug? Torcetrapib! Sounds like cussing in Klingon.

I noticed the other CETP inhibitors all had "cetrapib" in their names (dalcetrapib, anacetrapib, etc) as well. I figured there was some sort of clearinghouse for drug names, a governing body or something that assigned the names or least the suffixes. Turns out that's the case.

It finally occurred to my weak little mind that "cetrapib" was short for (C)holesteryl (E)ster (TRA)nsfer (P)rotein inh(IB)itor, which is the full name for "CETP inhibitor". I felt triumphant in this epiphany, which shows how low I set the bar for personal achievement.

So, "cetrapib" makes sense. But, for the life of me, I can't figure how one gets "afil" from "blood flow" for a PDE 5 inhibitor -- sildenafil (Viagra) or tadalafil (Cialis). Or how "3-Hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor" becomes "statin". Or how SGLT 2 inhibitor becomes "gliflozin" (never mind what I can imagine).

Our friends at Pfizer explain it all -- or most of it. Appropriate as Pfizer knows a thing or two about bad drug names. And maybe bad drugs.

If you read the piece, you'll note "y" is not used. We're down to "x" and "z" for Cool Names.

Finally, as for reading Klingon, I note that William Shatner boldly went Where No Fat Old Man Has Gone Before. We'll surely all be reading and speaking Klingon long after Mr Shatner has left for the Final Frontier for good.

Steve said...

You actually have to apply for drug names and you can give suggestions but ultimately they can be rejected. The generic names are often awful (I've been involved in this discussion before and it's much less scientific than some would imagine). The idea behind it is the INN (international nonproprietary name) has to be distinguishable from all others. As there are literally thousands of drugs this obviously lends itself to some craziness. Some things are common though, example monoclonal antibodies end in "mab".

Eric said...

The empire strikes back:

The comments (only 35 so far) are surprisingly diverse, with only 20>% in the lower LDL camp. Seems the to be medicated public is well informed these days and does not buy any old story.

Justin said...

Here you go Peter. Derek has been gaining a lot of momentum in this very interesting (to me) subculture. Would love it if you could check out this and some other other clips in this series and give your opinion.

Justin said...

These guys abviously do a lot of hormone testing. Lol

Justin said...

Like we often say at work, it's always good to bookend things and then get that third data point to see if there is a linear or nonlinear relationship. Lol!!!

Gyan said...

Sorry for being off-topic but I recently found out that UK is still having 52000 cases daily of covid. How come?
Today saw a paper through DR Eades newsletter that incidence of new covid cases is unrelated to vaccination level in 68 countries and USA counties.

Peter said...

Hi Justin, just had time to listen to the first few minutes, I'll get back to it later but I agree, these people are thinking about stuff beyond the practicalities of the end result....

Gyan, I suspect we have no more covid than anywhere else in Europe but we are testing, testing, testing and then testing some more. Mostly school kids who either have a mild sniffle or are asymptomatic. Parents are advised to test twice a week and any positives trigger an avalanche of more testing. Our overall death rate is low because it has been summer until a month ago and many who were susceptible died in the first two waves. Life is normal if you don't listen to the BBC and don't test your children (it's not a legal requirement).


Peter said...

Hi Justin,

Wow, really fun clip. These people really do have some insight about what they are doing. Of course they lack any ROS concept but that's not their fault. What ultimately hit me was how they are looking to do the exact opposite of what I would like to achieve. I stay specifically ketogenic to stop IGF-1 production in response to the GH response to protein. They are specifically using exogenous insulin to maximise IGF-1 production from the spike in GH which occurs during fasting. So they can get anabolic fasting.

That's fine if you are just a kid in your 30s or 40s. If you are an adult in your 60s you might not want all that IGF-1 hitting any neoplastic cells which might stay quiescent without it. Especially as you consider entering middle age in your 70s, 80s and 90s. Once you consider actually getting really old this might matter even more, if you live that long.

Of course my trade off is I might well miss out on muscle hyperplasia (confession, I didn't know muscle hyperplasia was a Thing. Hypertrophy yes, but increased muscle cell numbers is not something I've considered, are there data on this?) but that's fine by me, not marching to that particular drum myself.