appetite — 15 things I got wrong before I got it right
Thinking out loud about this: appetite — 15 things I got wrong before I got it right.
The GIP question, which is the most interesting unsettled thing in this field.
Dual agonism at GIP and GLP-1 receptors produces clinical results that are robust and well replicated. What is not settled is the mechanism by which the GIP arm contributes — there is a genuine scientific argument about agonism versus antagonism at that receptor, with reasonable people and real data on both sides.
It is worth sitting with that. The clinical effect is not in doubt; the explanation is. That is an ordinary state of affairs in pharmacology and it is a good corrective to the confident mechanistic stories that circulate here.
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.
GLP-1 receptor agonism acts both peripherally — insulin secretion in a glucose-dependent way, slowed gastric emptying — and centrally, on appetite regulation. The central component is the better explanation for sustained intake reduction.
I will update this if the picture changes rather than quietly leaving it up.
best — the order this archive was captured in
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.
the central appetite effect is doing more work than the gut effect
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.
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.