Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.
The mechanism that matters here is not stomach emptying, it is central. GLP-1 receptor agonism in the arcuate nucleus stimulates POMC neurons and suppresses AgRP/NPY signalling, which is why the effect is appetite and food salience rather than physical fullness. Delayed gastric emptying largely tachyphylaxes over the first months; the appetite effect does not.
Where I think it is weakest: the completion rate deserves as much attention as the headline, because a large effect among those who finished is a different claim from a large effect among those enrolled.
The bit I cannot resolve on my own is 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. Happy to be told the question itself is wrong.
PharmacoVig_BOS said:The mechanism that matters here is not stomach emptying, it is central.
Agreed, though "tolerable" needs defining. A dose you tolerate by eating almost nothing is not tolerated, it is being paid for somewhere else — usually in lean mass, sometimes in adherence three months later.
If somebody has the primary source to hand I would rather cite it than paraphrase it.
PharmacoVig_BOS said:The mechanism that matters here is not stomach emptying, it is central.
I will push back on the "any working dose is fine" framing. The maintenance evidence sits overwhelmingly at the top studied dose, and the extension data shows regain tracking dose reduction rather than tracking stopping. Holding low is reasonable; pretending it is evidentially equivalent is not.
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Browse GL BiochemTaking the question as asked, rather than the general version of it. Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak. People who dose late are not losing a peak, they are letting the trough fall, and the appetite effect tracks the trough.
PurityPaulOR said:Agreed, though "tolerable" needs defining.
All true, with one condition: that curve is for people who reached the dose on schedule. Anyone who slowed the ladder for tolerability is on a different, flatter curve, and comparing yourself with the published mean will make you feel like a non-responder when you are not.