Erythritol - Reason For Concern? by Dr. Adrian Soto-Mota MD PhD
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Erythritol - Reason For Concern?
Not mutually exclusive, but most people said they'd prefer seeing rather than joining a discussion to analyze THAT erythritol paper, and I have some airport hours ahead... Here go . In case you've been living under a rock, this is the paper.
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Relevant disclosures for interpreting my interpretation?
I'll speak more as a clinician who sees many CVDrisk patients following a low-carb diet than as a healthy adult who follows a low-carb diet and occasionally consumes erythritol.
Things I liked about the paper = ✅.
Things I didn't like (and matter) = .
Things I didn't like (and are nitpicking) = 🧐 .
🩸 [] = blood concentration.
CVD = Cardiovascular Disease.
MACE = Major Adverse Cardiovascular Events.
Erythritol is an increasingly present (especially in "keto-friendly" products) sweetener. Also, some studies showed some appealing effects.
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Since it doesn't raise insulin or glucose, #CIM people like it.
Since it doesn't "have calories" (because it's poorly metabolized and excreted almost entirely 🚽), #CICO people like it too.
You don't get to see that every day 🤣
NHANES 2013-2018 (arguably, before it was "cool") showed the daily intake of erythritol could reach ~30g (this will be important later).
Thus, 🩸 [erythritol] = endogenous production ➕ intake (also important later).
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Now, this is one of those papers with many "nested" papers/studies/experiments. They likely were aggregated to aim at a more prestigious journal (which clearly worked).
In my opinion, its strongest point is the convergence/consistency of all studies, not their separate results.
"Shotgun approach" (untargeted metabolomics) in people with CVDrisk. Result: Those with the
est 🩸 [erythritol] had
CVDrisk.
Note it's 🩸 [erythritol] not erythritol intake so... ✅
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Small ().
✅ their MACE definition (death, MI, stroke). Mixed outcomes often put together hardly comparable things (i.e. hospitalizations and death).
Sergio Iván Valdés, MD, PhD, Isaac Núñez and I published an editorial about why this was problematic in COVID RCTs.
Not so fast. There are other plausible explanations:
Confounding (maybe those with CVD consume more erythritol)
Reverse causation (maybe the CVD mileu with inflammation + insulin resistance
the endogenous production of erythritol).
Confounding first. Does the HR of
🩸[erythritol] goes
(or away) AFTER accounting for other things that also
CVDrisk (age, 🚻, diabetes, blood pressure, BMI, LDL, HDL, trigs & 🚬)?
No, not really.
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But 👆 this doesn't rule out something being intrinsically wrong with that cohort/dataset.
Would you observe the same in other populations ?
Yes. And note in all cohorts the HR's magnitude is comparable and "resilient" to the adjustments.
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But HEY! The most important (statistically speaking) risk factor for MACE is already having some CVD history.
They adjusted for that, too.
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Nitpicking parenthesis 🧐. I would've liked to see 95%CI bands in these time-to-event lines.
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But HEY!
It's often a bad idea to break into quartiles a continuous variable like 🩸 [erythritol] https://t.co/RHvWRKmWnS.
PLUS, it actually looks like risk goes only for Q4.
They used 🩸 [erythritol] as a continuous variable as well.
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Ok, so far, it definitely looks like there is an association between 🩸[erythritol] and
CVDrisk that is resilient to all the relevant adjustments.
But, you know... correlation ≠ causation.
You need to show a plausible pathophysiology link between these two.
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How can erythritol cause
🧠 🫀infarctions?
How can we address the possibility of the CVDrisk mileu raising
🩸[erythritol] instead?
Platelet studies.
Does erythritol make your platelets "stickier"?
Yeah, it looks like it does.
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But, you know, this is really "just" a functional observation.
What if they messed up their experiments or there is something wrong with the equipment they used?
Anyone who has worked in a "wet-lab" knows this is more than a possibility.
Would you observe other platelet aggregation related phenomena supporting "platelets are stickier when exposed to the same 🩸 [erythritol]" with different methods, equipment?
In other words, with independent sources of error?
Ca, IIb/IIIa & p-selectin.
Yup.
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Hold on 👆... Maybe this is just an interaction between erythritol and platelets from people with CVDrisk.
Nope, they used platelets from healthy volunteers, so... ✅
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This is my biggest concern about his paper. I think it is necessary to actually show healthy=healthy.
You know... there are famous examples of "classic" RCTs with controversial definitions for "healthy."
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Now, coagulation is way more than platelets. It involves whole blood and a vessel.
Did they observe phenomena supporting "stickier" 🩸 when exposed to erythritol?
In vivo platelet adhesion in human physiological conditions.
Vessel injury 🐁 model. Yeah.
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How "easy" it is to get that 🩸 [erythritol]?
They used a drink with 30gr (because of NHANES 2013-2018).
Since very few products disclose their erythritol content, it could not be intuitive to all how 30gr compares to an average "keto-snack".
Check it. It's comparable so...✅
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Erythritol drinks for healthy volunteers.
🩸[erythritol] 1000x for many hours and stayed above the levels they saw in their coagulation studies induced platelet responses.
Maybe you don't have a 30gr snack daily, but what about one with ~10gr?
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Their fasting levels were comparable to the cohort low risk quartiles, and postprandial levels were like the Q4 ones. ✅
Isn't n=8 too small? Their response is consistent, 8M wouldn't change this result.
Shouldn't they randomize them? Not for this research question.
Far from it (there's no such thing).
Are their pre-registration inconsistencies criticizable? Sure.
However, I really don't think all the points of criticism I've found or read from others invalidate their conclusions.
Many said they were surprised and/or criticized my conclusion of "these data being enough to recommend against it".
Let me elaborate (and remember the white-coat disclosure).
Do I believe after reading this paper that erythritol should be banned from food and you'll get a stroke if indulge a keto snack? Of course not.
Will I generally avoid erythritol even with my (so far) CVDrisk? Yeah, probably.
As mentioned, what I find convincing is the convergence of all their experiments (not their individual results).
What are the costs of avoiding erythritol? None, zero, zilch, nada.
I already focused on encouraging real-food anyway.
What are the benefits? For someone with high inflammation and/or insulin resistance... This COULD mean less risk of having to face a pretty bad scenario.
Lowering (even if just mildly or potentially) CVDrisk for free?
Yeah I'll take that deal.
Thank you if you made it all the way down to here. I hope you enjoyed this 🧵 interesting. Let me know if you'd join a more in-depth discussion.
I am sure not everyone will agree with that (which is, of course, fine). Let's just at least try to keep a constructive debate.
Find an depth-discussion with Doctor Tro, MD, Brian Lenzkes, MD, Nick Norwitz PhD, Adrian Soto-Mota MD PhD on LowCarb MD Podcast.
Written by Dr. Adrian Soto-Mota MD PhD
Published April 15th, 2023
Twitter: @AdrianSotoMota
Original thread on Twitter by Adrian Soto-Mota MD Phd
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