[Meta] the mechanism rule is doing its job and people should stop complaining
Putting this to the board: the mechanism rule is doing its job and people should stop complaining.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
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.
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
Would rather be corrected in public than confident in private.
best — the order this archive was captured in
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.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
I would not read that in vitro number across to a person. The conditions are nothing like physiological.
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
Tolerance to the gastric effect develops with continued exposure while the appetite effect largely persists. That single fact explains most of the "it settles but it still works" pattern the side-effect board reports.
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
read the discussion section, that is where the honesty lives
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
the peripheral and central stories are not in competition
gastric emptying slows, it does not stop
Does the effect persist with continued dosing or does tolerance develop?
Why mechanism talk keeps misleading people, including me.
A mechanism tells you a direction. It does not tell you a magnitude, a timescale, or whether the pathway is operative at the exposures involved. "Receptor X is expressed in tissue Y" is a fact; "therefore effect Z in a person" is a hypothesis with several missing steps.
The corrective is boring and it works: ask whether the evidence is preclinical or human, ask what exposure was used, and read the limitations section before the abstract. Most of the confidently wrong posts on this board — several of them mine — skipped all three.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
Right — mechanism gives you a direction. It never gives you an effect size and people use it as though it does.
preclinical is not clinical and rodents are not small people
tolerance to the gastric effect develops, appetite effect largely persists
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what the side-effect board reports.
Same view.
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
receptor agonism is not the same as receptor activation in every tissue
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are robust regardless, which is an uncomfortable and interesting position.
the central appetite effect is doing more work than the gut effect
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
The incretin effect is the observation that oral glucose provokes a larger insulin response than intravenous glucose at matched glycaemia, and the difference is mediated by gut hormones. That is the foundation the whole class sits on.
- 1Careful — you have a plausible mechanism and no evidence that it is the…6 comments in this branch · started by u/runa_cabrera
- 2gastric emptying slows, it does not stop6 comments in this branch · started by u/rafael_ostergaard