SurmountFan_IN said:

The GIP arm is doing real work rather than padding the label.

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 Dr.ObesityLA — and this may be the naive question:

How much of the tirzepatide advantage is the GIP component and how much is simply that the dose ladder goes higher in receptor-occupancy terms?

NicoleRaleigh said:

Dose-response modeling for tirzepatide: Emax model fitting to the STEP/SURMOUNT dose-finding data shows: Semaglutide: ED50 ≈ 0.6mg, Emax ≈ -18%, Hill…

Coming at NicoleRaleigh’s question from a different direction. Take it one variable at a time. Almost every unanswerable question in these threads is unanswerable because three things changed in the same fortnight, and no amount of subsequent argument can untangle them after the fact.

Closing the loop on my own question.

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

Dr.PeteFamMed said:

Almost every unanswerable question in these threads is unanswerable because three things changed in the same fortnight, and no amount of subsequent…

Agreed on the mechanism, with the caveat that the head-to-head used semaglutide 1mg, not 2.4mg. It is still the best direct evidence available, but it is not the comparison most people think they are citing.