This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Receptor desensitisation and internalisation are real phenomena in vitro and their clinical relevance to these compounds is not established. That distinction gets lost in discussions about tolerance.
I am confident about the direction and much less about the magnitude.
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.
If that is already documented somewhere, ignore me and link it.
A note on scope: what I am saying about biased agonism applies to the case in the first post and I would not extend it further without checking.
Post #60 put the caveat in the right place and I want to underline it.
Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.
The arithmetic in post #62 is right; the assumption feeding it is the part to check.
The most useful thing anyone has posted about biased agonism in this category was a table of what had been measured and by whom. That is what I would want again.
I would rather this thread reach "we do not know" about biased agonism than reach a confident answer that nobody can support when asked.
GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.
Second-hand, so weight it accordingly.
Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.
That is all I can say without guessing.
Post #66 is right about the mechanism and I think understates the practical bit.
What I can speak to on biased agonism is narrow, so I will keep it narrow rather than generalising from it. Beyond that boundary I do not know.
Coming back to post #68, because the follow-up matters more than the original answer.
Since biased agonism keeps coming up, it should probably be a maintained page rather than a recurring thread. I am happy to draft it if someone with more direct experience will review it.
Mechanistic plausibility has a poor record of predicting clinical outcomes across this whole field. It is a good reason to run the trial and a bad reason to skip it.
The general answer and the answer for your case may diverge here.
Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
Where I part company with post #71, and it is a narrow parting.
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 have deliberately not rounded that, because the rounding is where the argument starts.
Reading rather than contributing, but this is the most useful thread I have found on it.
GLP-1 receptor agonism produces its metabolic effects through more than one route: central satiety signalling, delayed gastric emptying, and glucose-dependent insulin secretion. Attributing everything to one of them is where most simplified accounts go wrong.
I have separated what I observed from what I concluded, which does not always happen.
Picking up post #75: that is the part I would want checked first.
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.
That is the version I would defend. It is not the version I started with.
I had written a reply contradicting post #75 and deleted it. Here is what survived.
Biased agonism was covered in the wiki last year and the page has a review date on it, which is a better starting point than my memory of a thread.
Everything in post #75 holds. The case it does not cover is the one I have.
Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.
Narrowing post #79, because the general version has more than one answer.
My understanding of biased agonism is a few years old and may have been superseded. If it has been, I would genuinely like to know rather than keep repeating it.
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low.
The strength of my opinion here exceeds the strength of my evidence.
Building on post #80 rather than restating it.
Adding a null result on biased agonism. I looked, carefully, and found nothing, and null results deserve posting precisely because they never are.
Ghrelin receptor agonism drives growth hormone release in pulses and also increases appetite, which is the effect people most reliably report and least often want.
Genuinely open to being wrong about this one.
Post #82 describes the usual case. This is about the unusual one.
GIP receptor biology is genuinely contested. Both agonism and antagonism have been argued to produce weight reduction, and the fact that the field can hold both positions tells you how open it is.
Not the answer, but possibly the question that gets there.
On biased agonism, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit.
If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the conclusion.
Picking up post #88: that is the part I would want checked first.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
I would rather be precise about what I do not know than vague about what I do.
On post #86 — agreed on the reasoning, with one qualification.
Glucagon receptor agonism raises energy expenditure and promotes hepatic fat oxidation. In a triple agonist the incretin limbs offset the glycaemic consequence, which is why the combination is not self-defeating.
Small point, but it is the one that usually catches people.