why does nobody talk about mechanism
why does nobody talk about mechanism, and I want the answer with the reasoning attached rather than just the conclusion.
Was completely wrong about the gastric emptying story in a thread here two years ago. Someone corrected me with a citation and I have not made that mistake since.
Receptor expression in a tissue is necessary but not sufficient for an effect. You also need the agonist to reach it at relevant exposure, and that is where a lot of confident mechanism talk falls down.
Read the primary paper after arguing about the summary for a fortnight. The discussion section said almost the opposite of what the thread had concluded.
If two or three other people have done the same thing we might actually learn something. Alone it is an anecdote.
best — the order this archive was captured in
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
Is there any human data on that mechanism yet?
receptor agonism is not the same as receptor activation in every tissue
receptor agonism is not the same as receptor activation in every tissue
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
Long half-life in this class comes from structural modification that promotes albumin binding and resists enzymatic degradation. Weekly dosing is a consequence of the molecule, not a convenience decision.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
the peripheral and central stories are not in competition
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
the central appetite effect is doing more work than the gut effect
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what the side-effect board reports.
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
incretin effect first, then everything else in this board makes sense
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Went looking for human data on a mechanism everybody here asserts.
Agreed — and it is why the central and peripheral stories are complementary rather than rival.
Right — mechanism gives you a direction. It never gives you an effect size and people use it as though it does.
What does the discussion section say about the limitation you are glossing?
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
- 1Speculation is welcome here if it is labelled. This one has been relabelled…7 comments in this branch · started by u/gastric_emptying_g
- 2Same view. Tolerance developing to the gastric effect while the appetite…7 comments in this branch · started by u/elodie_grimaldi