GLP-1/GIP receptor co-agonism — September 2026

Dr.ReproEndo said:

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

Pushing back on Dr.ReproEndo here. The "tirzepatide is simply better" summary irritates me. It is better on mean weight loss, and the cardiovascular outcome evidence is far thinner than semaglutide's. If the reason for treating is cardiovascular risk rather than weight, the evidence base points the other way.

One concrete data point for the thread. Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about five days for tirzepatide, steady state at four to five half-lives, subcutaneous bioavailability high enough that site choice is irrelevant.

Worth separating that from the pharmacology, which this thread keeps folding into the same question. They behave differently and the advice does not transfer.

Dr.GastroMayo said:

The "tirzepatide is simply better" summary irritates me.

Adding the part of the answer the thread has not reached. 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.

Worth separating that from the pharmacology, which this thread keeps folding into the same question. They behave differently and the advice does not transfer.

One thing that is still open after dave_SLC’s answer:

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?

Reporting back.

Reporting back after another eight months at the same dose. Still losing slowly, no new side effects, and no reason I can find to climb further.