Retatrutideresearch overview.

Overview

Retatrutide, development code LY3437943, is a single synthetic peptide with agonist activity at three receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) ¹. Coskun et al. (2022) described its discovery and early pharmacology ¹.

Almost all published data come from the developer’s clinical programme, funded by Eli Lilly: a phase 1b study ², phase 2 trials in three populations ^3,4,5, and a phase 3 trial ⁶.

Retatrutide is an investigational drug and is not approved as a medicine. The TGA has stated that it is not approved in Australia and is still being tested in clinical trials, and has issued a safety alert about a counterfeit product sold as retatrutide ⁷. OzPept’s retatrutide is a research chemical, not a medicine, and is not for human use.

Structure and chemistry

A 39-residue peptide with α-⁠aminoisobutyric acid (Aib) at position 2, α-⁠methyl-leucine at position 13, a lipidated lysine at position 17 and a C-terminal amide. The lysine carries a C20 fatty diacid attached through a γ-⁠glutamate and two OEG (8-amino-3,6-dioxaoctanoic acid) linker units. Molecular formula C221H342N46O68, molecular weight 4731.3 g/mol, CAS 2381089-83-2.

These features follow common design patterns in incretin analogues. Aib at position 2 is not a substrate for dipeptidyl peptidase-4, which cleaves native GIP and GLP-1 after their second residue. The fatty diacid side chain binds serum albumin, a strategy used to extend circulating half-life. α-⁠Methyl amino acids restrict backbone flexibility and resist proteolysis.

In vitro, Coskun et al. reported balanced activity at GCGR and GLP-1R and greater activity at GIPR ¹.

Mechanisms investigated

Trials are described below by design, population and prespecified primary endpoint. They studied a defined investigational product under regulatory conditions.

• Discovery and mice. Coskun et al. (2022) characterised receptor activity in vitro, and measured body weight, glycaemic measures and energy expenditure in mouse models. They also reported a phase 1 study of safety, tolerability and pharmacokinetics ¹.
• Phase 1b. Urva et al. (2022) ran a 12-week, double-blind, placebo-controlled trial in 72 adults with type 2 diabetes. The primary outcome was safety and tolerability, and gastrointestinal events were the most frequently reported adverse events ².
• Phase 2, type 2 diabetes. Rosenstock et al. (2023) randomised 281 adults with type 2 diabetes to retatrutide, placebo or the active comparator dulaglutide. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to 24 weeks ³.
• Phase 2, obesity. Jastreboff et al. (2023) randomised 338 adults with obesity, or overweight with at least one related condition, to retatrutide or placebo for 48 weeks. The primary endpoint was the percentage change in body weight from baseline to 24 weeks ⁴.
• Phase 2a, liver substudy. Sanyal et al. (2024) studied 98 participants from that trial who had metabolic dysfunction-associated steatotic liver disease. The primary endpoint was the relative change in liver lipid content from baseline at 24 weeks ⁵.
• Phase 3. In the TRIUMPH-1 trial, Jastreboff et al. (2026) randomised 2339 adults with obesity without diabetes for 80 weeks. Primary outcomes were the percentage change in body weight, a knee pain score in participants with knee osteoarthritis, and the apnoea-hypopnoea index in participants with obstructive sleep apnoea. The authors reported statistically significant differences from placebo for these outcomes, with gastrointestinal events the most common adverse events ⁶.

Research areas

• Receptor pharmacology and mouse models (in vitro and animal) ¹
• Safety and pharmacokinetics in type 2 diabetes (human, phase 1b) ²
• HbA1c endpoint with an active comparator (human, phase 2) ³
• Body weight endpoint over 48 weeks (human, phase 2) ⁴
• Liver lipid content substudy (human, phase 2a) ⁵
• Multi-endpoint phase 3 trial (human) ⁶

Limits of the evidence

All of the clinical studies cited here were designed and funded by the developer, with overlapping investigators ^1,2,3,4,5,6. Independent trials are not yet published.

The trials studied a defined investigational product, in defined populations, under regulatory conditions. Their findings describe that product in that setting, not research-grade material. Endpoints were measured over weeks to months, and longer-term outcomes have not been reported.

Products sold as retatrutide outside clinical trials may not contain it. The TGA found undeclared semaglutide and no retatrutide in one such product ⁷.

OzPept’s retatrutide is a research chemical, not a medicine, and is not for human use.

Key studies

1. 2022Animal

   Discovery, receptor activity and mouse models ¹

2. 2022Human

   Phase 1b trial, 72 participants with type 2 diabetes ²

3. 2023Human

   Phase 2 trial, HbA1c endpoint, 281 participants ³

4. 2023Human

   Phase 2 trial, body weight endpoint, 338 participants ⁴

5. 2024Human

   Phase 2a liver lipid content substudy ⁵

6. 2026Human

   Phase 3 TRIUMPH-1 trial, 2339 participants ⁶

Questions

References

1. Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, 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 Metab. 2022;34(9):1234-1247.e9. Source
2. Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, 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. Lancet. 2022;400(10366):1869-1881. Source
3. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. Source
4. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389(6):514-526. Source
5. Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037-2048. Source
6. Jastreboff AM, Kaplan LM, Davies MJ, Wilding JPH, Ahmad NN, Murray M, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity. N Engl J Med. 2026. doi:10.1056/NEJMoa2604169. Source
7. Therapeutic Goods Administration. TGA tests counterfeit retatrutide product following serious adverse event report. Safety alert. 14 September 2026. Accessed October 2026. Source