GIP is the half of tirzepatide nobody explains. It is the other incretin — the second gut hormone, alongside GLP-1, that tells the pancreas to release more insulin after a meal. Tirzepatide switches its receptor on. An Amgen drug now in phase 3 switches the same receptor off. Both produce substantial weight loss. The scientists developing each call that a paradox, in print.
This page covers GIP and its relationship with GLP-1 as of 25 September 2026. For what GLP-1 itself does, see how GLP-1 works; for which drugs belong to which class, the register of GLP-1 drugs.
Two incretins
| GLP-1 | GIP | |
|---|---|---|
| Full name | glucagon-like peptide-1 | glucose-dependent insulinotropic polypeptide |
| What it does after a meal | raises insulin when glucose is high; lowers glucagon; slows stomach emptying; reduces appetite | raises insulin when glucose is high; acts on fat tissue |
| Approved drugs that activate it | semaglutide, liraglutide, dulaglutide, exenatide, orforglipron, tirzepatide | tirzepatide only |
| Drugs in trials that block it | — | maridebart cafraglutide |
Tirzepatide's label describes it as "a GIP receptor and GLP-1 receptor agonist" and says it "is based on the GIP sequence" — a GIP molecule modified to hit the GLP-1 receptor too, with a fatty acid that lets it last a week. That is why a drug grouped with the GLP-1s has a GIP backbone. The chemistry is on our is GLP-1 a peptide page.
The paradox, in the words of the people working on it
For years the case for adding GIP to a GLP-1 drug was that GIP activation helped. Tirzepatide's results — larger average weight loss than semaglutide in the one head-to-head trial, set out in our tirzepatide versus semaglutide comparison — seemed to confirm it.
Then Amgen built a drug on the opposite idea. Maridebart cafraglutide (MariTide) is a fully human antibody that blocks the GIP receptor, chemically joined to two GLP-1 agonist peptides. Its phase 2 results (New England Journal of Medicine, 2025, 592 people, 52 weeks):
| Group | Weight change, everyone randomised |
|---|---|
| Obesity, maridebart cafraglutide (range across doses) | −12.3% to −16.2% |
| Obesity, placebo | −2.5% |
| Obesity with type 2 diabetes, maridebart cafraglutide | −8.4% to −12.3% |
| Obesity with type 2 diabetes, placebo | −1.7% |
Doses were given every four or eight weeks — monthly, not weekly. Gastrointestinal side effects were common, and less frequent with a lower starting dose and escalation.
A 2025 review in Diabetes sets out the problem plainly: beneficial effects "are seen with both GIP receptor antagonism and GIP receptor agonism, although the mechanisms underlying this apparent paradox remain unknown". A 2026 review in the Annual Review of Nutrition is titled, simply, "The Paradox and Future of GLP-1/GIP Combination Therapies".
The evidence for blocking
The antagonist case rests on three kinds of evidence, as summarised in that Diabetes review:
- Mice. Knocking out the GIP receptor, globally or in the brain alone, protects mice on a high-fat diet from obesity.
- Human genetics. Three GIP receptor variants that reduce its function — Arg190Gln, Glu288Gly and Glu354Gln — are associated with lower body-mass index.
- Early trials. In phase 1, maridebart cafraglutide produced dose-dependent weight loss that was maintained for up to 150 days after the last dose (Nature Metabolism, 2024).
Read the review with its authorship in view. Two of its four authors are Amgen employees and stockholders; two co-founded, and hold shares in, a company developing GIP receptor antagonists; the figures were funded by Amgen. The genetic and mouse findings it cites are published separately and can be checked on their own, but the framing is that of people with a stake in the answer.
Two ways the paradox might resolve
The literature offers hypotheses, not conclusions:
- Constant activation may end up acting like blocking. Receptors of this kind are pulled inside the cell and switched off for a while after activation. The Diabetes review cites a study of 47 GIP receptor variants in which this switching-off machinery mattered to the variants' link with adiposity. That is why the field asks whether a week-long agonist, which never lets the receptor rest, leaves it partly silenced — a question, not a finding.
- GIP may not be doing much in tirzepatide. Another hypothesis is that tirzepatide's advantage comes mainly through the GLP-1 receptor, where it signals differently from native GLP-1.
Neither is settled. What can be said is that the "GIP is why tirzepatide works better" explanation, repeated widely, is a hypothesis its own field is now testing against its opposite.
Where each drug stands
- Tirzepatide — approved as Mounjaro (type 2 diabetes) and Zepbound (weight management, sleep apnoea). How the two labels differ is on our Mounjaro versus Zepbound page.
- Maridebart cafraglutide — investigational. On 25 September 2026 ClinicalTrials.gov listed 26 studies, 10 of them phase 3, including MARITIME-1 (3,853 people) and MARITIME-2 (1,105), both listing primary completion in January 2027, and cardiovascular and heart-failure outcome trials running to 2028.
- Retatrutide — investigational, and activates GIP, GLP-1 and glucagon receptors. See our retatrutide page.
What this page cannot tell you
- Which approach is better. No trial has compared a GIP agonist with a GIP antagonist.
- Whether maridebart cafraglutide will be approved, or when.
- Which drug suits anyone. That is a prescribing decision.
Sources
- MOUNJARO (tirzepatide) prescribing information, Eli Lilly, effective 2026-08-27 — DailyMed, sections 11 and 12.1.
- Jastreboff AM et al. Once-monthly maridebart cafraglutide for the treatment of obesity — a phase 2 trial. N Engl J Med 2025;393(9):843–857. doi:10.1056/NEJMoa2504214, abstract (PubMed 40549887). Funded by Amgen.
- Rosenkilde MM, George JT, Véniant MM, Holst JJ. GIP receptor antagonists in the pharmacotherapy of obesity: physiologic, genetic, and clinical rationale. Diabetes 2025;74(8):1334–1338. doi:10.2337/dbi24-0027, full text via PMC12278783, including its duality-of-interest statement.
- Véniant MM et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab 2024;6(2):290–303. doi:10.1038/s42255-023-00966-w.
- Davies I, Holst JJ, Rosenkilde MM, Tan TMM. The paradox and future of GLP-1/GIP combination therapies: efficacy and mechanisms. Annu Rev Nutr 2026;46(1):387–414. doi:10.1146/annurev-nutr-061824-043740.
- ClinicalTrials.gov API v2, intervention "maridebart", queried 25 September 2026: 26 records; MARITIME-1 NCT06858839, MARITIME-2 NCT06858878.