Compound research
Retatrutide: research overview
Retatrutide (LY3437943) is a single peptide designed to act as an agonist at three hormone receptors: the GIP receptor, the GLP-1 receptor and the glucagon receptor. It has been studied in cell-based assays, in obese mouse models and in clinical trials that examined body weight, glycaemic measures and liver fat.1–6
Mechanism at a glance
- GIP receptorIncretin receptor. In vitro, retatrutide's activity was reported to be greatest at this receptor.1
- GLP-1 receptorIncretin receptor. In vitro activity was broadly similar to glucagon-receptor activity. In mice, it was linked with reduced food intake.1
- Glucagon receptorIn mouse studies, this part of the profile was linked to increased energy expenditure.1
In mouse studies, the glucagon-receptor component was linked to energy expenditure and the incretin components to reduced food intake. How much each receptor contributes in humans is still being studied.1
What it is
Retatrutide, development code LY3437943, is a single peptide designed to activate three hormone receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor. Its discovery and early characterisation were published in 2022. Its clinical development is sponsored by Eli Lilly and Company. A 2026 publication describes it as under clinical development for type 2 diabetes, obesity and related complications.1–3, 6
How it acts
Retatrutide combines activity at the two incretin receptors, GIP and GLP-1, with activity at the glucagon receptor in one molecule. Most of what is known about how each receptor contributes comes from in-vitro and rodent work.1
Receptor profile in vitro
In cell-based assays, LY3437943 activated the glucagon and GLP-1 receptors to a broadly similar degree. Its activity at the GIP receptor was reported to be greater than at either of the other two receptors.1
Findings in animal models
In obese mice, reductions in body weight and changes in glycaemic control were reported. The authors linked the glucagon-receptor component to increased energy expenditure, on top of the reduced food intake associated with GIP and GLP-1 receptor activity. The relative contribution of each receptor is still being investigated.1
Research status
Retatrutide has been evaluated in phase 1, phase 2 and phase 3 clinical trials sponsored by Eli Lilly and Company. It is an investigational compound.1–3, 5, 6
Early clinical studies
A phase 1 study, reported in the 2022 discovery paper, examined safety, tolerability and pharmacokinetics. A phase 1b trial in people with type 2 diabetes examined safety and tolerability as its primary endpoints, with pharmacokinetic and pharmacodynamic measures as secondary endpoints.1, 2
Phase 2 trials
A randomised, double-blind, placebo-controlled phase 2 trial in adults with obesity, or with overweight and at least one weight-related condition, examined body-weight change as its primary endpoint. A phase 2a substudy of this trial, in participants with metabolic dysfunction-associated steatotic liver disease (MASLD), examined change in liver fat as its primary endpoint. It also examined how changes in liver fat related to body weight, abdominal fat and markers of insulin sensitivity and lipid metabolism.3, 4
Phase 3 programme
Results from the phase 3 TRIUMPH-1 trial in adults with obesity without diabetes were published in 2026. It examined body-weight change and, in subgroups, knee pain in knee osteoarthritis and the apnoea-hypopnoea index in obstructive sleep apnoea. The phase 3 TRANSCEND-T2D-1 trial in adults with type 2 diabetes examined change in HbA1c as its primary endpoint.5, 6
Published research at a glance
- In vitro
Activity at the GIP, GLP-1 and glucagon receptors in cell-based assays
- Animal model
Body weight, food intake, energy expenditure and glycaemic control in obese mice
- Clinical trial
Phase 1b: safety, tolerability and pharmacokinetics in people with type 2 diabetes
- Clinical trial
Phase 2: body-weight change in adults with obesity or overweight
- Clinical trial
Phase 2a substudy: liver fat in metabolic dysfunction-associated steatotic liver disease
- Clinical trial
Phase 3 TRIUMPH-1: body weight, with knee osteoarthritis and sleep apnoea subgroups
Research status: Retatrutide (LY3437943) is an investigational compound that a 2026 phase 3 publication describes as under clinical development, in trials sponsored by Eli Lilly and Company.5, 6
Technical specifications
- Molecular weight
- 4731 Da
- CAS number
- 2381089-83-2
References
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism (2022). doi:10.1016/j.cmet.2022.07.013
- Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet (2022). doi:10.1016/S0140-6736(22)02033-5
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. New England Journal of Medicine (2023). doi:10.1056/NEJMoa2301972
- Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine (2024). doi:10.1038/s41591-024-03018-2
- Jastreboff AM, Kaplan LM, Davies MJ, et al.; TRIUMPH-1 Investigators. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. New England Journal of Medicine (2026). doi:10.1056/NEJMoa2604169
- Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. The Lancet (2026). doi:10.1016/S0140-6736(26)00967-0
Literature summary compiled on 15 October 2026.