Retatrutide (development code LY3437943) is a synthetic, fatty-acid-modified, once-weekly peptide that functions as a triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Retatrutide is the first agent of its triple-incretin class to advance to late-stage clinical development. It is the subject of an active Phase 3 trial program in adult human participants, with Phase 2 results published in The New England Journal of Medicine, The Lancet, and Nature Medicine. Retatrutide has not received regulatory approval and is investigational only.
In the Phase 2 obesity trial published by Jastreboff and colleagues in the New England Journal of Medicine, adults with obesity who received once-weekly subcutaneous retatrutide demonstrated mean body-weight reductions of −17.1%, −22.8%, and −24.2% at the 4 mg, 8 mg, and 12 mg amounts respectively at week 48, compared with −2.1% in placebo [1]. In the parallel Phase 2 type 2 diabetes trial published by Rosenstock and colleagues in The Lancet, retatrutide produced concentration-dependent reductions in glycated hemoglobin and body weight in adults with T2D inadequately controlled on metformin [2]. A Phase 2a substudy in adults with metabolic dysfunction–associated steatotic liver disease (MASLD), published by Sanyal and colleagues in Nature Medicine (2024), reported relative liver-fat reductions ranging from approximately 43% (1 mg) to 82% (12 mg) at 24 weeks, with normal liver fat (<5%) achieved by 86% of participants in the 12 mg arm [3].
Retatrutide’s addition of glucagon-receptor agonism to the dual-incretin scaffold is the structural feature that distinguishes it from tirzepatide. The glucagon-receptor component is hypothesized to contribute to the magnitude of liver-fat reduction reported in the MASLD substudy, since glucagon-receptor agonism has direct hepatic effects on lipid metabolism not produced by GIP or GLP-1 agonism alone. Researchers consulting this page should treat retatrutide as an investigational compound: published efficacy data are from Phase 2 trials only, and Phase 3 trials (the TRIUMPH program) remain ongoing.
Mechanism of Action
Retatrutide produces its metabolic effects through simultaneous agonism of three peptide-hormone receptors. The pharmacological rationale is that combining receptor agonism across three complementary endocrine pathways may produce metabolic benefits beyond what dual-incretin agents can achieve.
Three-receptor engagement. Coskun and colleagues at Eli Lilly characterized retatrutide’s pharmacological profile across cell-line signaling assays and the first-in-human Phase 1b multi-escalating-amount trial in adults with type 2 diabetes [4]. On the basis of in vitro studies, retatrutide is approximately 8.9 times more potent than endogenous ligands at the human GIP receptor; at the GLP-1 receptor, retatrutide is approximately 0.4 times as active as native GLP-1; and at the glucagon receptor, retatrutide is approximately 0.3 times as active as native glucagon. The compound is a single fatty-acid-modified peptide with a circulatory half-life of approximately six days, enabling once-weekly subcutaneous administration.
GLP-1 and GIP receptor pathways. The dual-incretin component of retatrutide’s mechanism overlaps with the mechanism of tirzepatide: GLP-1 receptor agonism promotes glucose-dependent insulin secretion, suppresses inappropriate glucagon release, slows gastric emptying, and produces central appetite suppression mediated by GLP-1 receptors in brainstem and hypothalamic nuclei. GIP receptor agonism complements these effects through additional insulinotropic activity and modulation of adipose-tissue lipid metabolism.
Glucagon receptor pathway. The third receptor target is the distinguishing pharmacological feature of retatrutide. The glucagon receptor is expressed in hepatocytes, adipocytes, and cardiac tissue. Glucagon receptor agonism increases hepatic glucose output, enhances lipolysis in adipose tissue, increases energy expenditure, and exerts direct effects on hepatic lipid metabolism. In the context of a triple agonist, the glucagon-receptor component is partially offset by the simultaneous GLP-1 and GIP agonism, which counteract the hyperglycemic potential of glucagon. The net effect in the published Phase 2 trials has been substantial body-weight reduction and substantial reductions in liver fat content.
Hepatic effects in MASLD. The Phase 2a MASLD substudy provides direct evidence that retatrutide produces substantial liver-fat reduction beyond what would be predicted from weight loss alone. The MASLD substudy reported that retatrutide may serve as an effective treatment for MASLD
, with relative liver-fat reductions of approximately 43–82% at 24 weeks across the four active-arm amount levels [3]. This hepatic effect is consistent with the hypothesized contribution of direct glucagon-receptor agonism to hepatic lipid metabolism.
Adverse-event signal — heart rate. The Phase 2 obesity trial reported concentration-dependent increases in heart rate that peaked at 24 weeks and declined thereafter, with the magnitude of the heart-rate signal somewhat greater than that observed with selective GLP-1 or dual GIP/GLP-1 agonists in their respective Phase 3 programs [1]. This signal is being monitored in the ongoing Phase 3 trial program.
Available Forms
Omnix Peptides currently supplies retatrutide in a single research format. Each lot is independently characterized by HPLC and LC–MS, with a batch-specific Certificate of Analysis available on the product page.
- Retatrutide Vial — lyophilized powder for reconstitution. Multiple strengths available per vial. The vial is the canonical research format used in the published Phase 2 clinical literature; once-weekly subcutaneous administration is the route used in the published trials.
Retatrutide is classified under the Metabolic & Weight research category. For research framed around overlapping mechanisms, see also the related compound hubs for Tirzepatide (dual GIP/GLP-1 receptor agonist, approved), Semaglutide (selective GLP-1 receptor agonist, approved), and Orforglipron (oral small-molecule GLP-1 receptor agonist in late-stage development).
Amount in the Published Research Literature
The following administration ranges describe the protocols used in the peer-reviewed retatrutide Phase 2 trial program. They are reported here for research-reference purposes only and do not constitute administration recommendations of any kind.
Phase 2 obesity trial (Jastreboff 2023). Adults with a body-mass index of 30 or higher (or 27 to less than 30 with at least one weight-related condition) were randomized to once-weekly subcutaneous retatrutide at 1 mg, 4 mg (with two starting-amount subgroups: starting at 2 mg vs. 4 mg), 8 mg (starting at 2 mg or 4 mg), or 12 mg (starting at 2 mg or 4 mg), or placebo, over a 48-week treatment period [1]. The stepwise escalating-amount schedule increased amount at 4-week intervals; the lower 2 mg starting amount was reported to partially mitigate gastrointestinal adverse events relative to the 4 mg starting amount.
Phase 2 type 2 diabetes trial (Rosenstock 2023). Adults with T2D inadequately controlled on metformin were randomized to once-weekly subcutaneous retatrutide at 0.5 mg, 4 mg, 8 mg, or 12 mg, or to placebo or active comparator (dulaglutide 1.5 mg), over a 36-week treatment period [2].
Phase 2a MASLD substudy (Sanyal 2024). Participants from the Phase 2 obesity trial who met an inclusion criterion of liver fat content of 10% or greater (assessed by MRI-PDFF) were randomized to placebo or to one of four retatrutide amounts (1 mg, 4 mg, 8 mg, 12 mg) once weekly subcutaneously over 48 weeks [3].
Phase 1b multi-escalating-amount trial (Coskun 2022). The first-in-human Phase 1b trial used multi-escalating-amount regimens up to 12 mg weekly, establishing pharmacokinetic profile, safety, and proof-of-concept efficacy signals that informed the subsequent Phase 2 program [4].
Adverse-event profile across the Phase 2 program. The most commonly reported adverse events in the retatrutide Phase 2 trials were gastrointestinal — nausea, diarrhea, vomiting, decreased appetite, and constipation — consistent with the class profile of incretin-mimetic agents and most frequent during escalating-amount. Concentration-dependent increases in heart rate (peaking at 24 weeks and declining thereafter) were also reported and are being monitored in the ongoing Phase 3 program. Researchers planning protocols are referred to the original primary literature cited in the References section for full methodological detail.
Frequently Asked Questions
Is retatrutide FDA-approved?
No. Retatrutide has not received regulatory approval from the FDA, EMA, or any other authority. It is an investigational compound with published Phase 2 data and is currently in Phase 3 clinical trials (the TRIUMPH program) for obesity and type 2 diabetes.
How does retatrutide differ from tirzepatide and semaglutide?
Semaglutide is a selective GLP-1 receptor agonist. Tirzepatide is a dual GIP and GLP-1 receptor agonist. Retatrutide adds glucagon receptor agonism to the dual-incretin scaffold, producing a triple agonist of the GIP, GLP-1, and glucagon receptors. The glucagon-receptor component is hypothesized to contribute to the substantial liver-fat reductions reported in the Phase 2a MASLD substudy, since glucagon receptor agonism produces direct hepatic effects on lipid metabolism not produced by GIP or GLP-1 agonism alone.
What does the Phase 2 obesity trial show about body weight?
The Phase 2 obesity trial (Jastreboff 2023, NEJM) was a 48-week, double-blind, randomized, placebo-controlled trial in 338 adults with obesity. Mean percentage changes in body weight at week 48 were −8.7%, −17.1%, −22.8%, and −24.2% for the 1 mg, 4 mg, 8 mg, and 12 mg retatrutide amounts respectively, compared with −2.1% in placebo [1]. At the 12 mg amount, 83% of participants achieved at least 15% weight reduction.
What does the Phase 2a MASLD substudy show about liver fat?
The Phase 2a MASLD substudy (Sanyal 2024, Nature Medicine) enrolled 98 participants from the Phase 2 obesity trial who had liver fat content of 10% or greater (assessed by MRI-PDFF). Mean relative change in liver fat at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), and −82.4% (12 mg), versus +0.3% in placebo [3]. Normal liver fat (<5%) was achieved by 86% of participants in the 12 mg arm at 24 weeks.
What mechanism of action does retatrutide use?
Retatrutide is a triple agonist of the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon receptor. The GLP-1 component promotes glucose-dependent insulin secretion, slows gastric emptying, and suppresses appetite centrally. The GIP component adds insulinotropic activity and modulates adipose-tissue lipid metabolism. The glucagon component increases hepatic lipid oxidation, increases energy expenditure, and produces the direct hepatic effects hypothesized to underlie retatrutide’s liver-fat reduction in MASLD.
What administration schedule is used in published retatrutide trials?
The Phase 2 obesity trial used once-weekly subcutaneous administration with a stepwise escalating-amount schedule, increasing amount at 4-week intervals until the target maintenance amount (1 mg, 4 mg, 8 mg, or 12 mg) was reached. The trial used two different starting-amount subgroups (starting at 2 mg vs. 4 mg) for the higher-amount arms; the lower 2 mg starting amount partially mitigated gastrointestinal adverse events relative to the 4 mg starting amount.
What is the heart-rate signal reported in retatrutide trials?
The Phase 2 obesity trial reported concentration-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. The magnitude was somewhat greater than reported with selective GLP-1 or dual GIP/GLP-1 receptor agonists in their respective Phase 3 programs. The mechanism is hypothesized to involve the glucagon-receptor component of retatrutide’s activity. This signal is being monitored in the ongoing Phase 3 trial program.
References
- Jastreboff AM, Kaplan LM, Frías JP, et al; Retatrutide Phase 2 Obesity Trial Investigators. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972 · PubMed: 37366315
- Rosenstock J, Frias J, Jastreboff AM, 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. doi:10.1016/S0140-6736(23)01053-X
- 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. Nat Med. 2024;30(7):2037-2048. doi:10.1038/s41591-024-03018-2
- Coskun T, Urva S, Roell WC, 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, multi-escalating-amount trial. Lancet. 2022;400(10366):1869-1881. doi:10.1016/S0140-6736(22)02033-5 · PubMed: 36354040
For Research Use Only. The product described on this page is sold strictly for in vitro laboratory research and is not intended for human or animal consumption, diagnostic use, or therapeutic use. The published research summarized above is provided as scientific reference material; retatrutide is investigational only and not approved for any therapeutic use. Nothing on this page constitutes medical advice, a therapeutic claim, or a recommendation for any use outside of a properly resourced and ethically reviewed research setting.
