Semaglutide fatty acid sidechain — acylation and albumin binding kinetics

Dr.LipidDallas said:

PeptideChemSF said: ...but the FDA says semaglutide...

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were relying on physical fullness feel the effect fade while the appetite effect is still working.

Dr.PathRoch said:

Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about…

Coming at Dr.PathRoch’s question from a different direction. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.

Adding the numbers, since they settle part of this. If you are going to change something, change one thing and give it long enough to express itself. Four weeks is the usual minimum for anything pharmacological on this board, and two weeks of data has told you almost nothing.

Following on from Dr.PathRoch — and this may be the naive question:

Whether anyone has held at a sub-maximal dose long term and kept the result, or whether the maintenance data only exists at 2.4mg?

Moderator note: leaving this open. It is being argued well and the disagreement is the useful part. Carry on.