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ForumsOther Peptides & Research CompoundsPeptide half-lives comparison chart — May 2025

Peptide half-lives comparison chart — May 2025

LarryQC_SD Tue, Jul 9, 2024 at 4:41 AM 24 replies 1,958 viewsPage 1 of 5
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LarryQC_SD
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Jul 9, 2024 at 4:41 AM#1

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 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 question I want answered is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working. If the honest answer is that nobody knows, that is a useful answer and I would rather have it.

Note on sourcing:
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.
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Dr.ObesityMed
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Jul 9, 2024 at 5:53 AM#2
LarryQC_SD 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.

References:
[1] Novo Nordisk investor presentation, September 2023.
Last edited: Jul 9, 2024 at 11:53 AM
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Dr.AddMedPHL
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Jul 9, 2024 at 7:05 AM#3
LarryQC_SD said:
The mechanism is more central than most summaries suggest.

Filing a mild objection. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit. 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.

Ask again with the specifics and you will get a better answer than this one.

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Dr.ObesityLA
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Jul 9, 2024 at 8:17 AM#4
Dr.AddMedPHL said:
The pharmacokinetics explain nearly every practical question asked here.

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.

References:
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.
Last edited: Jul 9, 2024 at 9:17 AM
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AttorneyGrant
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Jul 9, 2024 at 3:15 PM#5
Dr.ObesityMed 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…

Same pattern here, and in the same order. Posting only so the count is not one.

Last edited: Jul 9, 2024 at 4:15 PM
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