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Evidence-based GLP-1 & peptide discussion since 2023
ForumsPharmacology & MechanismsGLP-1/GIP receptor co-agonism — what worked for you?

GLP-1/GIP receptor co-agonism — what worked for you?

zoe_NC Fri, May 16, 2025 at 4:25 AM 13 replies 1,641 viewsPage 1 of 3
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zoe_NC
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May 16, 2025 at 4:25 AM#1

I moved from semaglutide to tirzepatide after a long stall and the first eight weeks looked like starting over — which I gather is the usual pattern rather than a lucky one.

What I am after is 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.

Practical detail welcome, however dull — the duller the better.

44 14Dr.BariatricHTX, LindaRN_retired, tommy_boulder and 41 others
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MikeFit_NJ
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May 16, 2025 at 6:25 AM#2

Taking the question as asked, rather than the general version of it. The GIP arm is doing real work rather than padding the label. GIP receptor agonism appears to improve adipose insulin sensitivity and lipid handling, and — counter-intuitively — GIP signalling in the CNS reduces nausea rather than adding to it, which is why tolerability at high total agonism is better than the GLP-1-only comparison would predict. SURPASS-2 is the cleanest head-to-head: tirzepatide beat semaglutide 1mg at every dose tier.

Last edited: May 16, 2025 at 9:25 AM
43 13marcus_mpls, DeniseRN_TPA, SandraNC_45 and 40 others
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SurmountFan_IN
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May 16, 2025 at 8:25 AM#3
MikeFit_NJ said:
The GIP arm is doing real work rather than padding the label.

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.

Last edited: May 16, 2025 at 9:25 AM
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pam_stl
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May 16, 2025 at 10:25 AM#4
zoe_NC said:
I moved from semaglutide to tirzepatide after a long stall and the first eight weeks looked like starting over — which I gather is the usual pattern…

This matches mine closely enough to be worth saying so. Steady state is faster than people expect: half-life about five days, so you are at plateau in roughly three to four weeks rather than five. That matters when you are deciding whether a dose step has finished expressing itself.

Last edited: May 16, 2025 at 3:25 PM
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Dr.Martinez
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May 16, 2025 at 10:17 PM#5

Clinical perspective, offered as context rather than as advice.

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.

40 10adam_van, Dr.SurgeonPGH, rachel_ABQ and 37 others
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