Follow-up: Why appetite effects are mostly central posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Pharmacological class effects: all GLP-1 agonists slow gastric emptying and suppress appetite. Those are class effects, not unique to one compound. Effects that differ between compounds are usually about potency or receptor selectivity.
Narrowing post #60, because the general version has more than one answer.
Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.
Worth reading the earlier posts in this thread before acting on mine.
Everything in post #62 holds. The case it does not cover is the one I have.
Where I would push back on the appetite effects consensus is the confidence, not the direction. The direction looks right. The confidence is borrowed.
Small methodological point on appetite effects: repeating a measurement is cheap and resolves most of what is being argued about here at no cost to anyone.
Post #64 answers the question as asked. The question underneath it is different.
The area postrema sits outside the blood-brain barrier and is where a great deal of the nausea signalling in this class originates. That is why the effect is central and not gastric irritation.
I would put the burden of proof on the interesting explanation, not the dull one.
Confirming post #68 from a second method, which matters more than confirming it from a second person.
Appetite effects came up in a thread eighteen months ago and was answered well. I cannot find it, which is itself the problem, so here is the reconstruction.
Species differences: rodent studies show the same compounds produce effects in rodents that predict human effects reasonably well for semaglutide and tirzepatide. The track record is less clear for novel compounds with less human data.
Collapsed as off-topic by two members at trust level 3 or above
Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.
Noted, and I have changed what I was going to do on the strength of it.
Half-life extension by albumin binding through a fatty acid chain trades free fraction for duration. It is an engineering solution with a cost, and the cost is that the bound fraction is not active.
It cost nothing to check and would have cost something not to.
Where a mechanism is proposed to explain an effect, the useful follow-up is what observation would distinguish it from the alternative. Most mechanistic threads here never get asked that.
Post #74 is right about the mechanism and I think understates the practical bit.
Two things can be true about appetite effects at once: the mechanism is plausible and the evidence for the size of the effect is thin. Most of the argument here is people defending the first against attacks on the second.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
Adding the boring version of appetite effects, because the interesting version keeps getting posted and the boring one is usually right.
Check the ordinary explanations, in order, and stop when one of them accounts for what you are seeing. Most of the time the second one does.
Post #77 put the caveat in the right place and I want to underline it.
If you are new and reading this thread for the answer to appetite effects: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.
Endogenous versus pharmacological receptor engagement differ in magnitude and in duration by orders of magnitude. Arguments from "it is a natural hormone" do not survive that.
I would not lead a decision with this, but I would not ignore it either.
Adding the measurement that post #78 says would settle it.
Receptor occupancy required for a clinical effect is not the same as full occupancy, and dose-response curves flattening at the top is what you would expect from that.
I would put this at better than even and not much better.
I would be cautious about generalising from the appetite effects example above. It is a good example. It is one example.
What I would check first on appetite effects is whether the thing being measured moved or whether the way of measuring it moved. Those look identical in a graph.
Answering the question post #84 raises rather than the one it answers.
Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.
The uncertainty is in the assumption, not in the calculation.
The reason appetite effects is hard to answer is that the obvious measurement and the relevant quantity are not the same thing, and substituting one for the other is silent.
Two sentences on appetite effects and then I will stop, because the rest is speculation and the thread is better without mine.
What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.
The area postrema sits outside the blood-brain barrier and is where a great deal of the nausea signalling in this class originates. That is why the effect is central and not gastric irritation.
The rule of thumb is fine; the edge cases are where it earns its keep.
Whatever the answer on appetite effects turns out to be, the method for getting there is the same: state the assumption, do the arithmetic in public, invite the correction.