Retatrutide
LY3437943 · Triple-G · TRIUMPH Program
An investigational first-in-class triple hormone receptor agonist — a single 39-amino-acid molecule that simultaneously activates GLP-1, GIP, and glucagon receptors. Phase 2 produced 24.2% weight loss at 48 weeks; in the published phase 3 TRIUMPH-1 trial (2,339 adults, 80 weeks), 12 mg gave 25.0% against 3.9% on placebo.
What is it?
Retatrutide (LY3437943, sometimes called 'Triple-G') is an investigational once-weekly peptide developed by Eli Lilly as the next-generation successor to tirzepatide. Its defining feature is triple agonism at three metabolic receptors — GLP-1, GIP, and glucagon — in a single 39-amino-acid molecule built on a GIP backbone. Non-coded amino acids (Aib at positions 2 and 20, α-methyl-leucine at 13) protect against DPP-4 degradation, and a C20 fatty diacid conjugation at Lys17 enables albumin binding and a ~6-day half-life. In vitro potency is GIP-biased (EC50 0.064 nM) with moderate GLP-1 engagement (0.775 nM) and weaker but clinically relevant glucagon agonism (5.79 nM) — a balance deliberately engineered to add glucagon's thermogenic effects without triggering hyperglycemia.
The Phase 2 obesity trial (Jastreboff et al., NEJM 2023) established retatrutide's unprecedented efficacy: 24.2% mean weight loss at 48 weeks on the 12 mg dose versus 2.1% on placebo — exceeding anything previously seen with a single-agent pharmacotherapy, and with no plateau observed through 48 weeks. A liver-fat substudy (Sanyal et al., Nature Medicine 2024) reported 82% liver fat reduction at 24 weeks, the largest pharmacological MASLD effect ever documented, driving Lilly to add MASH to the Phase 3 program. The first full Phase 3 readout — TRIUMPH-4 in obesity with knee osteoarthritis (December 2025) — produced 28.7% weight loss at 68 weeks, but also flagged a higher discontinuation rate (~18% at 12 mg) than tirzepatide's comparable trials. TRIUMPH-1 (2,339 adults without diabetes) and TRIUMPH-2 (1,152 adults with type 2 diabetes) have since been published: at 80 weeks, 12 mg gave 25.0% and 18.8% weight loss against 3.9% and 5.1% on placebo. Lilly has said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027.
Mechanism of Action
Retatrutide simultaneously activates three metabolic receptors — GLP-1, GIP, and glucagon — in a single peptide molecule. The rationale is mechanistic stacking: each receptor contributes a distinct metabolic action, and their combined effect appears to exceed what dual agonists achieve. The novelty over tirzepatide is the glucagon component, which adds direct energy expenditure on top of appetite suppression:
Weight and liver fat were measured in people. The glucagon arm's extra calorie burning is a mouse finding these trials did not measure.
Each step is tagged with where it was shown. A dashed red arrow marks a link the evidence does not establish.
The pathway in words
- Retatrutide. One peptide active at three receptors, glucagon, GIP and GLP-1; in the laboratory its GIP activity is the strongest. Shown in: lab. Source: PubMed 35985340.
- Eating less, burning more. In obese mice, lower intake from the GIP and GLP-1 arms was added to by glucagon-receptor increases in energy expenditure. Shown in: animals. Source: PubMed 35985340.
- Weekly dosing. In a single-dose phase 1 study its pharmacokinetics supported once-weekly dosing, and weight stayed lower for 43 days. Shown in: people. Source: PubMed 35985340.
- Weight loss. In 338 adults with obesity over 48 weeks, weight fell 24.2% on 12 mg against 2.1% on placebo. Shown in: people. Source: PubMed 37366315.
- Liver fat. In 98 people with fatty liver disease, liver fat fell 82.4% at 24 weeks on 12 mg, and 86% reached normal levels. Shown in: people. Source: PubMed 38858523.
- shown in mice, not measured here. Burning more, in people. The trials here report weight and liver fat, not energy expenditure; the glucagon arm's share comes from mice. Shown in: animals. Source: PubMed 35985340.
Glucagon Receptor Agonism (The New Lever)
The mechanistic differentiator from tirzepatide. Glucagon receptor (GCGR) activation in the liver drives lipid oxidation and increases resting energy expenditure by roughly 5–10% in clinical measurements. This adds a thermogenic component that GLP-1/GIP dual agonism cannot replicate, and is the leading hypothesis for why retatrutide produces greater weight loss than tirzepatide at similar exposures. The glucagon agonism is deliberately weaker than native glucagon — tuned to add thermogenesis without inducing hyperglycemia, which GLP-1 agonism simultaneously counteracts.
Enhanced Hepatic Fat Oxidation
Glucagon receptor activation directly drives hepatic lipolysis and β-oxidation. This is the proposed mechanism for retatrutide's remarkable liver fat reduction — up to 82% at 24 weeks in the MASLD substudy (Sanyal 2024), larger than any pharmacologic intervention ever reported. GLP-1 monoagonists reduce liver fat primarily through weight loss; retatrutide's glucagon component adds a direct hepatic action, and the two effects compound.
Central Appetite Suppression (GLP-1 + GIP)
The dominant weight-loss mechanism — inherited from the tirzepatide template. GLP-1 receptor activation in the arcuate nucleus reduces hunger through POMC/CART pathways; GIP receptor activation engages overlapping but non-identical hypothalamic and brainstem regions. In retatrutide the central appetite suppression appears more profound than tirzepatide's, partly because the GIP engagement is stronger (EC50 0.064 vs 0.135 nM) and partly because glucagon receptors are also expressed centrally and may contribute.
Glucose-Dependent Insulin Secretion
Both GIP and GLP-1 receptors on pancreatic β-cells drive glucose-dependent insulin release. In Phase 2 T2DM data (Rosenstock 2023), retatrutide 12 mg produced 2.02% HbA1c reduction at 24 weeks versus 0.01% placebo — comparable to tirzepatide at its maximum dose. The glucagon component's hyperglycemic tendency is fully offset by the stronger incretin drive, demonstrated by net HbA1c reductions and no signal of worsening glycemic control even at the highest doses.
Gastric Emptying & Systemic Effects
Like other incretin agonists, retatrutide slows gastric emptying and contributes to early satiety. Phase 2 data also showed notable reductions in systolic blood pressure (−7 to −10 mmHg at higher doses), triglycerides, and non-HDL cholesterol — exceeding what weight loss alone predicts. These extra-metabolic effects suggest the triple mechanism reaches into cardiovascular risk factors directly, not just through weight reduction.
Published Research
Retatrutide has rapidly-accumulating clinical data across obesity, type 2 diabetes, MASLD, and osteoarthritis. As of September 2026, TRIUMPH-1 and TRIUMPH-2 have been published in full, and TRIUMPH-3 and TRIUMPH-4 have reported topline results. The list below covers the pivotal Phase 2 trials and the phase 3 results so far. Filter by study type below.
TRIUMPH-1: Phase 3 in Obesity Without Diabetes
Jastreboff et al. (N Engl J Med 2026). 2,339 adults with obesity and no diabetes took retatrutide 4, 9 or 12 mg or placebo weekly for 80 weeks. Weight fell 17.6%, 23.7% and 25.0% against 3.9% on placebo. In the 574 with knee osteoarthritis, pain scores fell more than on placebo, and in the 243 with sleep apnoea the apnoea-hypopnoea index fell by 23 to 34 events an hour against about 10. The most common adverse events were gastrointestinal.
TRIUMPH-2: Phase 3 in Obesity With Type 2 Diabetes
Bellido et al. (Lancet 2026). 1,152 adults with type 2 diabetes and a BMI of 27 or more took retatrutide 4, 9 or 12 mg or placebo weekly for 80 weeks. Weight fell 11.9%, 16.8% and 18.8% against 5.1% on placebo. Diarrhoea (27 to 34% against 13%) and nausea (14 to 28% against 8%) were more common on retatrutide, as were low blood pressure and dysaesthesia, and stopping for adverse events was highest at 9 mg (12%).
TRANSCEND-T2D-1: First Phase 3 in Type 2 Diabetes (Topline)
Lilly topline, March 2026. Phase 3 in T2DM patients on diet and exercise. Retatrutide met primary endpoint with superior A1C reduction and weight loss vs placebo at 40 weeks. No plateau observed. Detailed results pending peer-reviewed publication. Primary Phase 3 evidence for the T2DM indication.
TRIUMPH-4: Phase 3 Obesity + Knee Osteoarthritis
First Phase 3 readout (Lilly, December 2025 topline). 445 adults with obesity and knee OA, no diabetes. Retatrutide 12 mg produced 28.7% body weight loss at 68 weeks (mean -32.3 kg / -71.2 lbs), with 75.8% WOMAC pain score reduction. 18.2% of 12 mg patients discontinued for adverse events — higher than tirzepatide's comparable trials. Publication pending.
Phase 2 Body Composition Substudy (T2DM)
Coskun et al. (Lancet Diab Endo). Body composition analysis of the Rosenstock T2DM cohort. Retatrutide produced approximately 3:1 fat-to-lean mass loss ratio at 36 weeks — more favorable than GLP-1 monotherapy, consistent with glucagon's direct lipolytic action on adipose tissue.
Phase 2a MASLD Substudy: Liver Fat Reduction
Sanyal et al. (Nature Medicine). 98 adults with ≥10% liver fat and obesity; retatrutide 12 mg produced 82.4% relative liver fat reduction at 24 weeks (vs +0.3% placebo). 86% achieved normal liver fat (<5%). Largest pharmacological liver-fat effect ever reported — drove addition of MASH as a Phase 3 indication.
Phase 2 Obesity: 48-Week Dose-Ranging
Landmark Phase 2 trial (Jastreboff et al., NEJM). 338 adults with obesity, no diabetes. Mean weight loss of 24.2% at 48 weeks on 12 mg (vs 2.1% placebo), with no plateau observed. 100% of 12 mg participants lost ≥5%, 93% ≥10%, 83% ≥15%. Basis for the TRIUMPH Phase 3 program.
Phase 2 Type 2 Diabetes
Rosenstock et al. (Lancet). 281 adults with T2DM, HbA1c 7.0–10.5%. Retatrutide 12 mg produced 2.02% HbA1c reduction and 16.9% weight loss at 24 weeks, exceeding dulaglutide 1.5 mg across all endpoints. Established efficacy in the diabetic population where weight loss is historically blunted.
Phase 1b Multiple-Ascending-Dose: Safety & PK
Urva & Coskun et al. (Lancet). First-in-human multiple-dose study in 72 T2DM adults. Established the 12-week dose-dependent weight-loss signal that justified Phase 2 (up to ~9% at 12 weeks on highest dose) and characterized the ~6-day half-life enabling weekly dosing. Supports the Phase 2/3 dose-range selection.
Discovery to Clinical Proof of Concept
Coskun et al. (Cell Metab). Foundational preclinical and Phase 1 paper. Characterizes receptor potency (GIPR EC50 0.064 nM, GLP-1R 0.775 nM, GCGR 5.79 nM — GIP-biased design), demonstrates weight-loss and glycemic effects in obese mice, and reports first-in-human single-dose safety and pharmacokinetics. The mechanistic reference for every later retatrutide paper.
What people say, and what was measured
Retatrutide is the rare case where the headline claims are broadly true and the problem lies elsewhere: it is approved nowhere, so nothing sold under the name has been through the process that makes those trial numbers mean anything about the vial in front of you.
It takes off about a quarter of your body weight, more than any other drug.
Heard in: BBC Science Focus, which calls retatrutide "otherwise known as 'triple-G', 'GLP-3' or 'reta'" in its coverage of the most powerful weight-loss drug tested (read October 1, 2026). Source
This one holds up, in the trials. In the phase 3 TRIUMPH-1 trial, mean weight change over 80 weeks was −17.6% at 4 mg, −23.7% at 9 mg and −25.0% at 12 mg, against −3.9% on placebo. The earlier phase 2 trial in 338 adults found −17.5% at 12 mg by 24 weeks against −1.6% on placebo. PMID: 42814954, 37366315
Tested in people; supportedIt is the same molecule Lilly is testing, so buying it early is just getting ahead of the queue.
Heard in: Grey Peptides listing review, October 1, 2026: listings sell vials under the names retatrutide, reta, GLP-3 and triple-G. Sellers are not named.
The trials tested a manufactured product at defined doses, given weekly under supervision, with its identity and purity assured. Nothing sold as a research chemical has been through that. The published work describes retatrutide as an agonist at the GIP, GLP-1 and glucagon receptors and nothing about what is in an unregulated vial. PMID: 36354040, 35985340
Never tested in peopleSide effects are mild, mostly a bit of nausea at the start.
Heard in: Grey Peptides listing review, October 1, 2026: listings describe gastrointestinal effects as the main drawback, easing with time. Sellers are not named.
Gut effects were indeed the most common adverse events in both trials, but the phase 2 trial also recorded dose-dependent increases in heart rate, peaking at 24 weeks before declining. Dose escalation in the trials was structured and supervised, which is part of why tolerability looked as it did. PMID: 37366315, 42814954
Tested in people; mixedIt fixes the conditions that come with obesity too, so it is a metabolic cure-all.
Heard in: The Lancet, Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2), the trial programme the broader claims draw on (read October 1, 2026). Source
Several related conditions have been measured, with real but specific results: in TRIUMPH-1, knee osteoarthritis pain and sleep-apnoea events both improved in the relevant subgroups, 574 and 243 participants; a separate trial measured fatty liver disease. These are individual endpoints in defined populations, not a general claim about metabolic health. PMID: 42814954, 38858523, 42810372
Tested in people; supportedEach claim is quoted from where it is said, never from a seller, and checked as of October 1, 2026 against the studies listed below.
Dosing Data
Retatrutide is INVESTIGATIONAL and not FDA-approved as of September 2026. The protocols below reflect Phase 2/3 trial regimens and are presented for educational reference only. There is no approved dosing label; there is no lawful clinical-care prescription.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
Based on Phase 2 Jastreboff (NEJM 2023) and Rosenstock (Lancet 2023) data, plus Phase 3 TRIUMPH-4 topline (December 2025). The side-effect profile mostly parallels other incretin agonists but with one distinctive addition (dysesthesia) and a higher discontinuation rate at maximum dose:
Contraindications & Cautions
Retatrutide is investigational — formal contraindications have not been finalized. The list below reflects exclusion criteria from the Phase 2/3 trials and the expected class-level cautions for incretin/glucagon agonists:
Legal Status
Retatrutide is INVESTIGATIONAL in every jurisdiction worldwide. It has no marketing authorization anywhere as of September 2026. Lilly has said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027. Any retatrutide for sale outside a clinical trial is not regulator-approved and not lawful for human use.
Frequently Asked Questions
?What is retatrutide?
Retatrutide (LY3437943) is an investigational once-weekly injectable developed by Eli Lilly. It's a first-in-class triple hormone receptor agonist — a single peptide that activates GLP-1, GIP, and glucagon receptors simultaneously. In Phase 2 trials it produced 24.2% weight loss at 48 weeks, and in the first Phase 3 readout (TRIUMPH-4, December 2025) 28.7% at 68 weeks — the largest weight loss ever reported for a single-agent pharmacotherapy. It is not FDA-approved; Lilly has said it plans to submit it to the FDA in the first quarter of 2027.
?When will retatrutide be FDA approved?
Lilly has said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027, after four phase 3 obesity trials (TRIUMPH-1 to TRIUMPH-4) reported between December 2025 and July 2026. An FDA decision can only follow review of that application. Until then, retatrutide is available only through clinical trials.
?Retatrutide vs tirzepatide — how different are they?
Both are made by Lilly and share a similar molecular framework, but retatrutide adds a third receptor target: glucagon. That glucagon component drives direct hepatic fat oxidation and increases resting energy expenditure, adding a thermogenic effect on top of tirzepatide's appetite suppression. In head-to-head context (cross-trial comparison, not direct), retatrutide 12 mg produced 28.7% weight loss at 68 weeks vs tirzepatide's ~20.9% at 72 weeks — roughly 40% greater relative effect. The tradeoff is a higher discontinuation rate and a retatrutide-specific side effect (dysesthesia) not seen with tirzepatide.
?What is the dosing for retatrutide?
Phase 2 trials used weekly subcutaneous doses from 0.5 mg to 12 mg; the phase 3 TRIUMPH trials used 4, 9 or 12 mg once weekly for 80 weeks. There is no FDA-approved dosing label because retatrutide is not approved — the protocols here are research regimens, not prescription guidance.
?What are the side effects of retatrutide?
The main side effects mirror other incretin agonists: nausea (most common during titration), diarrhea, constipation, vomiting, and fatigue. Two distinctive features: (1) a retatrutide-specific side effect called dysesthesia — unusual skin sensations — occurring in roughly 20% of patients at the 12 mg dose, not seen with tirzepatide or semaglutide; (2) a small heart rate increase (3–5 bpm) attributed to the glucagon component. Discontinuation rates in Phase 2/3 were 16–18% at 12 mg, higher than tirzepatide's ~2–3% at comparable efficacy.
?What is dysesthesia and should I be worried about it?
Dysesthesia is an unusual skin sensation — participants in retatrutide trials describe it as tingling, prickling, or mild burning, typically in the extremities. It occurred in about 20% of patients at the 12 mg dose in Phase 2 and was typically mild and self-limited. The mechanism is not fully understood. It has not been reported with tirzepatide or semaglutide, suggesting it's related to the glucagon or GIP component specifically. If retatrutide is approved, dosing and titration guidance will be designed partly around managing this effect.
?How much weight can you lose on retatrutide?
Across the 12 mg dose: 24.2% at 48 weeks in Phase 2 (Jastreboff 2023, no diabetes), and 28.7% at 68 weeks in the first Phase 3 trial (TRIUMPH-4, December 2025, obesity + knee osteoarthritis). A distinctive feature is that no weight loss plateau was observed at 48 weeks — participants were still losing weight when the Phase 2 endpoint was reached. In the published TRIUMPH-1 trial (80 weeks, adults without diabetes), 12 mg gave 25.0% against 3.9% on placebo.
?Can retatrutide treat fatty liver disease?
Phase 2 data are extraordinarily positive. A MASLD substudy (Sanyal et al., Nature Medicine 2024) found that retatrutide 12 mg reduced liver fat by 82.4% at 24 weeks, with 86% of participants achieving normal liver fat levels — the largest pharmacological liver fat reduction ever reported. This prompted Lilly to add MASH (the inflammatory form of MASLD) as a Phase 3 target. The Phase 3 MASLD trial had not reported as of September 2026; it assesses not just liver fat but also histological resolution of steatohepatitis and fibrosis — the regulatory bar for a liver-disease indication.
?Can I buy retatrutide now?
Not lawfully for human use. Retatrutide is investigational and available only through Eli Lilly's clinical trials. Many peptide vendors sell 'research use only' retatrutide, but these products are not FDA-regulated, have variable purity and potency, and are not legal to administer to humans. Compounding pharmacies cannot compound retatrutide because it is not on the FDA's Drug Shortage list and has no reference listed drug. Waiting for approval is the only safe path.
?Why does retatrutide work better than tirzepatide?
The leading hypothesis is the glucagon receptor component. GLP-1 and GIP both suppress appetite and improve insulin response, but glucagon receptor agonism adds a distinct action: direct hepatic lipid oxidation and a modest increase in resting energy expenditure (roughly 5–10% in clinical measurements). This stacks with appetite suppression rather than overlapping it. The liver fat data — 82% reduction vs ~30% with tirzepatide — is the clearest mechanistic evidence that the third receptor is doing distinct work, not just amplifying what the other two do.
References
- [clinical-trial] Jastreboff AM, et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial." N Engl J Med, 2023;389:514-526. PMID: 37366315.
- [clinical-trial] Rosenstock J, 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. PMID: 37385280.
- [clinical-trial] ClinicalTrials.gov NCT05929066 (TRIUMPH-1, Phase 3 obesity trial).
- [pubmed] Coskun T, et al. "Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial." Lancet Diabetes Endocrinol, 2025;13(8):674-684. PMID: 40609566.
- [pubmed] Sanyal AJ, 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. PMID: 38858523.
- [pubmed] Urva 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. PMID: 36354040.
- [pubmed] Coskun T, 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. PMID: 35985340.
- [pubmed] Jastreboff AM, et al. "Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity." N Engl J Med, 2026;. PMID: 42814954.
- [pubmed] Bellido V, et al. "Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial." Lancet, 2026;. PMID: 42810372.
- [other] Eli Lilly and Company. "Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C." Investor news release, July 23, 2026 (read September 30, 2026).
Sources & Citations
Molecular data from PubChem (CID 171390338) and Eli Lilly technical disclosures. Clinical trial data from peer-reviewed publications (NEJM, Lancet, Nature Medicine) and Lilly press releases for Phase 3 topline results. Legal status current as of September 2026 — retatrutide is INVESTIGATIONAL in every jurisdiction worldwide. This page is reviewed and updated monthly to track the rapidly-evolving Phase 3 readout schedule. Educational content only; not medical advice.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.