Retatrutide
Triple agonist — GIP, GLP-1 and, uniquely, the glucagon receptor.
Metabolic · 9 min read · updated 13 Aug 2026
Research use only. The ranges below are what published studies and community protocols report. They are reference material for laboratory research, not medical advice or a recommendation for human or veterinary use.
The compound
Retatrutide
View- Type
- Triple Receptor Agonist
- CAS
- 2381089-83-2
- Formula
- C₂₂₁H₃₄₂N₄₆O₆₈
- Mass
- ~4731.33 Da
At a glance
- Class
- Triple GIP / GLP-1 / glucagon receptor agonist
- Also known as
- LY3437943
- Length
- 39 amino acids
- Molecular weight
- ~4731.33 Da
- CAS
- 2381089-83-2
- Half-life
- ~6 days
- Development stage
- Phase 3 — not an approved medicine anywhere
- Vial sizes stocked
- 5, 10, 20, 30, 50, 60 mg
Retatrutide adds a third receptor to the tirzepatide template. Alongside GIP and GLP-1 agonism it activates the glucagon receptor — the same receptor whose suppression is part of how conventional incretin agonists work. That apparent contradiction is the whole point of the molecule.
Glucagon receptor agonism raises energy expenditure. It drives hepatic lipolysis and fatty-acid oxidation, increases resting metabolic rate, and mobilises hepatic fat stores. On its own it would also raise blood glucose, which is why glucagon agonists failed as standalone metabolic agents. Paired with strong GLP-1 and GIP signalling, the glycaemic penalty is neutralised by the insulinotropic arms while the expenditure effect is retained.
This is what separates retatrutide mechanistically from everything before it: the incretin agonists reduce energy intake, while retatrutide reduces intake and raises expenditure at the same time. The phase 2 data reflect that — mean weight reduction around 24% at 48 weeks on 12 mg weekly, a magnitude no single- or dual-agonist has matched.
It is an investigational compound. There is no approved product, no established long-term safety record, and the phase 3 programme is still reading out.
The three arms, separately
- GLP-1 receptor: reduced energy intake through hypothalamic and hindbrain signalling, glucose-dependent insulin secretion, delayed gastric emptying. The familiar arm.
- GIP receptor: adipose lipid buffering, insulin secretion, and the hindbrain nausea-blunting effect that lets the total incretin load run higher.
- Glucagon receptor: hepatic fatty-acid oxidation, increased resting energy expenditure, and mobilisation of hepatic triglyceride. This arm is the reason hepatic-steatosis endpoints appear in the retatrutide literature and not in the semaglutide literature.
What the research literature covers
The evidence base is thinner than for the approved incretins because the compound is newer.
- Jastreboff AM et al., NEJM 2023 — the phase 2 obesity trial. 48 weeks, doses of 1, 4, 8 and 12 mg weekly, with the 12 mg arm reaching roughly 24% mean weight reduction. This is the source of essentially every dose figure in circulation.
- Rosenstock J et al., Lancet 2023 — phase 2 in type 2 diabetes, glycaemic endpoints.
- Sanyal AJ et al., Nat Med 2024 — hepatic steatosis (MASLD) endpoints, the readout most specific to the glucagon arm.
- TRIUMPH — the phase 3 programme. TRIUMPH-1 (2,339 adults, 80 weeks) read out in 2026 with mean weight reduction of 19.0% / 25.9% / 28.3% at the 4 / 9 / 12 mg maintenance doses versus 2.2% on placebo; the rest of the programme is still reading out.
Why the escalation is slower than it looks
Retatrutide is titrated, not started at the target dose. The phase 2 trial (NEJM 2023) stepped up 2 → 4 → 8 → 12 mg — reaching the 12 mg arm by about week 13, and it compared 2 mg and 4 mg starting doses for tolerability. The ongoing phase 3 TRIUMPH programme steps 2 → 4 → 6 → 9 → 12 mg (the ladder above). Either way, reported protocols that jump straight to 8 or 12 mg are skipping the steps that make the dose tolerable.
The glucagon arm also introduces effects the pure incretins do not have: heart rate rises more, and the metabolic-rate increase is real rather than theoretical. Both argue for the slow approach rather than against it.
Storage
- Lyophilised: 2–8 °C, or −20 °C for long-term storage. Protect from light.
- Reconstituted: 2–8 °C, used within about 28–30 days, never frozen.
- Large vials reconstituted at maintenance concentrations will outlast the 30-day window. Splitting a 60 mg vial across two reconstitutions is not possible once opened — plan the fill volume accordingly.
Cautions
- Investigational compound. No regulatory approval in any jurisdiction, and no long-term human safety data.
- Heart rate rises more than with GLP-1-only agonists — a direct consequence of glucagon receptor agonism.
- The glycaemic effect of the glucagon arm is offset by the incretin arms, but that balance depends on both arms being active at the intended ratio. It is not a compound to under-dose one arm of.
- Gastrointestinal effects follow the class pattern and scale with escalation speed.
- All the class-level signals from the incretin family apply, and none of them have been excluded for retatrutide.
References & credit
- 1Jastreboff AM et al., NEJM 2023 — Phase 2 obesity trial — the source of the dose ladder above.
- 2Rosenstock J et al., Lancet 2023 — Phase 2 in type 2 diabetes.
- 3Coskun T et al., Cell Metab 2022 — Preclinical characterisation of LY3437943 triple agonism.
This article was written in-house. Where a dose range reflects community practice rather than a published trial, the community references we consulted are credited above and the article says which is which.