Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience both.
What I actually want to know is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
I would rather have one careful answer than five confident ones.
SkepticalSean said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%), creating a depot effect with a ~168-hour half-life enabling weekly dosing[1].
Tirzepatide is a dual GIP/GLP-1R agonist with higher GIP affinity (5:1 GIP:GLP-1 potency ratio). The GIP component may enhance beta-cell function and adipocyte lipid metabolism beyond what GLP-1 alone achieves.
For the pharmacology, the pharmacology explains the clinical differences between these agents.
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.
TrialTracker_MD said:Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%),…
No disagreement with TrialTracker_MD. One condition attached. 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.
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Shop Reference StandardsSkepticalSean said:Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…
Same experience, arrived at from the opposite direction.
Adding the clinical framing, because it changes how the question reads.
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.