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Evidence-based GLP-1 & peptide discussion since 2023
ForumsPharmacology & MechanismsStructure-function of tirzepatide — unimolecular dual agonist design Page 2

Structure-function of tirzepatide — unimolecular dual agonist design

PeptideChemSF Thu, May 21, 2026 at 12:31 AM 14 replies 437 viewsPage 2 of 3
Dr.PathRoch
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May 22, 2026 at 6:47 AM#6
PeptideChemSF said:
SURMOUNT-1 landed around 20.9% mean weight loss at 15mg over 72 weeks, against roughly 15% for semaglutide 2.4mg in STEP 1.

Dose-response modeling for tirzepatide: Emax model fitting to the STEP/SURMOUNT dose-finding data shows:

Semaglutide: ED50 ≈ 0.6mg, Emax ≈ -18%, Hill coefficient ≈ 1.3
Tirzepatide: ED50 ≈ 6mg, Emax ≈ -25%, Hill coefficient ≈ 1.5

Clinical implication: most patients achieve >80% of maximal response by the mid-range dose (1.7mg sema, 10mg tirz). Going to the maximum dose provides diminishing returns — possibly not worth the additional side effect burden for some patients. Individualize dosing based on response vs tolerability.

Last edited: May 22, 2026 at 12:47 PM
46 16MikeFit_NJ, InsuranceTom, WendyG_ATL and 43 others
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denise_HTX
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May 22, 2026 at 6:51 PM#7

A narrower follow-up, since the general answer is now clear:

Whether anyone has held 10mg long term rather than climbing, and what happened over the following year?

Last edited: May 22, 2026 at 8:51 PM
45 15NeuroNate, JessicaH_TX, KevinCompounds and 42 others
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Dr.ObesityMed
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May 23, 2026 at 6:55 AM#8
Dr.PathRoch said:
Dose-response modeling for tirzepatide: Emax model fitting to the STEP/SURMOUNT dose-finding data shows: Semaglutide: ED50 ≈ 0.6mg, Emax ≈ -18%, Hill…

Adding the part of the answer the thread has not reached. If two explanations both fit, the useful question is which one predicts something the other does not. That is answerable; arguing about which sounds more plausible is not.

44 14SurmountFan_IN, PeptideChemSF, A1cHero_PHX and 41 others
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PeptideChemSF
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May 23, 2026 at 6:59 PM#9

OP back with an update, since a thread like this is useless without one.

Update: the eight-week restart pattern people described is exactly what happened. I nearly abandoned it at week five.

Last edited: May 23, 2026 at 10:59 PM
43 13ricardo_MIA, BrianDallas92, labquiet_amy and 40 others
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mike_mod
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May 26, 2026 at 4:52 AM#10
Dr.ObesityMed said:
If two explanations both fit, the useful question is which one predicts something the other does not.

True, though the ladder is longer and that is not a neutral detail — six dose steps means six opportunities to stall on the way up, and plenty of people never reach the dose the headline number came from.

31 6PurityPaulOR, MaxMetOK, MounjBrad and 28 others
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