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 am after 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.
NauseaFreeNow 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…
Semaglutide structural biology relevant to the pharmacology: semaglutide is a 31-amino acid peptide with 94% homology to native GLP-1(7-36). Three key modifications enable its pharmacokinetic profile:
- Aib8 substitution: DPP-4 resistance (prevents enzymatic degradation)
- Arg34 substitution: improved chemical stability
- C18 fatty diacid at Lys26: albumin binding → long half-life
These three modifications transform a peptide with a 2-minute half-life (native GLP-1) into one with a 168-hour half-life (semaglutide). A masterclass in peptide engineering.
COA_Karl said:Semaglutide structural biology relevant to the pharmacology: semaglutide is a 31-amino acid peptide with 94% homology to native GLP-1(7-36).
That is correct as far as it goes, and here is where it stops going. 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 ResultsNauseaFreeNow 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. Nothing to add that would improve it.
Adding the clinical framing, because it changes how the question reads.
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.