October 21, 2026 · 2 min read

Tirzepatide: a research overview of the GIP and GLP-1 dual agonist

How tirzepatide acts on two incretin receptors, and what the SURMOUNT-1 phase 3 trial and later reviews report about it.

Tirzepatide is a synthetic peptide that activates both the GIP and GLP-1 receptors. It was the first dual agonist of this kind to finish large phase 3 programs, and regulators have approved it for specific indications. Here is what the published research says, with the main trial in some detail.

How it works

Incretins are gut hormones released after a meal. They help coordinate insulin secretion and appetite. Earlier drugs targeted GLP-1 alone. Tirzepatide adds GIP receptor activity to the same molecule. How much each half contributes is still an open question in the literature, particularly for GIP.

What tirzepatide acts on

1
After a meal
The gut releases incretin hormones.
2
GIP and GLP-1
Two incretins that help coordinate insulin secretion and appetite.
3
Tirzepatide
A single peptide that activates both receptors.
4
Open question
How much each receptor contributes is still studied.

A simplified view of incretin signaling, based on the descriptions in the cited reviews. Illustrative only.

SURMOUNT-1

SURMOUNT-1 was a phase 3, double-blind, randomized trial of 2,539 adults with obesity, or overweight plus a weight-related complication, and no diabetes. Participants took tirzepatide at 5, 10 or 15 mg once a week, or placebo, for 72 weeks. The first 20 weeks were dose escalation.

Mean weight change at week 72 was -15.0% on 5 mg, -19.5% on 10 mg and -20.9% on 15 mg, compared with -3.1% on placebo. On the two higher doses, 50% and 57% of participants lost 20% or more of body weight, against 3% on placebo. The common adverse events were gastrointestinal, mostly mild to moderate, and clustered in the escalation period.

Mean body-weight change at week 72

Placebo-3.1%
5 mg-15%
10 mg-19.5%
15 mg-20.9%

Treatment-regimen estimand from SURMOUNT-1, 2,539 adults without diabetes (Jastreboff et al., N Engl J Med 2022). Doses are once weekly.

Later work

The SURMOUNT program went on to trials in type 2 diabetes and to longer follow-up, including a 2025 NEJM paper on diabetes prevention. For the overall picture, systematic reviews and meta-analyses are more reliable than any single trial.

Check the estimand. Results regardless of treatment discontinuation differ from results among people who stayed on drug.
Check the population. Trials in people with and without diabetes report different average effects.
Look at when adverse events occurred, because many cluster during dose escalation.

Trial findings describe the manufactured drug used in those trials. They say nothing about the identity, purity or stability of any other material, which is why laboratory work should rest on batch-specific HPLC and mass spectrometry data.