Structure-function of tirzepatide — unimolecular dual agonist design

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.

Following on from JenPlateau — and this may be the naive question:

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

dave_SLC 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. There is a difference between no evidence and evidence of no effect, and this subject is one where the two get swapped freely in both directions.

Reporting back.

I stayed at 10mg. Another six months, another 7kg, no new side effects, and my reading of the dose-response says the last two steps were never going to be worth what they cost me.

Dr.ObesityLA said:

There is a difference between no evidence and evidence of no effect, and this subject is one where the two get swapped freely in both directions.

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.

Correct me if the detail matters more than I have assumed.