This gets cited here weekly, usually second-hand, so it is worth setting out what it does and does not establish.
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.
Where I think it is weakest: the population was selected and supported in ways a real cohort is not, so I would read the effect size as a ceiling rather than an expectation.
The question I want answered is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working. I have searched first, so if this is covered somewhere point me at it and I will read it.
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
PeptideChemSF said:The mechanism is more central than most summaries suggest.
Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest trajectory ever seen for an anti-obesity agent[1].
Amylin receptor agonism enhances satiety signaling through the area postrema and reduces glucagon secretion. Combined with GLP-1R agonism, this dual mechanism may produce even greater efficacy than current agents.
Early-stage data — interpret with caution. But the trajectory is extraordinary.
[1] Novo Nordisk investor presentation, September 2023.
PeptideChemSF said:The mechanism is more central than most summaries suggest.
Pushing back on PeptideChemSF here. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.
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View ResultsDr.RaviCardio said:The pharmacokinetics explain nearly every practical question asked here.
Pharmacist here. I want to add the drug interaction perspective on the pharmacology.
Key points from a pharmacokinetic standpoint:
- GLP-1 agonists delay gastric emptying, which can affect Tmax of co-administered oral medications
- Monitor patients on warfarin (INR), levothyroxine (TSH), and oral contraceptives during dose titration
- The albumin-binding mechanism of semaglutide (C-18 fatty acid linker) gives it the ~168-hour half-life that enables weekly dosing
- Steady state is reached at approximately 4-5 weeks after dose initiation or adjustment
Re: the pharmacology specifically — the pharmacology here is well-characterized and the clinical implications are straightforward.
Dr.PainCLE said:Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest…
Adding a me-too, because a thread of one person's experience is not much use. Posting only so the count is not one.