{"id":"retatrutide","name":"Retatrutide","aliases":["LY3437943","triple agonist","GIP/GLP-1/glucagon agonist"],"url":"https://lyoresearch.com/compounds/retatrutide","class":{"id":"glp-1-agonists","name":"GLP-1 and incretin agonists","url":"https://lyoresearch.com/classes/glp-1-agonists"},"summary":"Retatrutide is an investigational once-weekly peptide that activates three receptors at once: GIP, GLP-1 and glucagon. In TRIUMPH-1, a 2,339-person phase 3 trial published in September 2026, adults with obesity lost 25.0% of body weight at 80 weeks on the top dose against 3.9% on placebo; in adults who also have type 2 diabetes the figure was 18.8% (TRIUMPH-2). A separate published trial cut HbA1c by up to 1.9 percentage points. It is not approved anywhere, and no legitimate supply exists outside clinical trials.","overall_grade":"B","overall_grade_meaning":"probable, not settled","human_trials":"3 phase 3 RCTs published (n=2,339; n=1,152; n=537); 2 phase 3 topline","regulatory_status":"Investigational","molecule":{"formula":null,"molecular_weight":null,"cas":null,"pubchem_cid":null,"note":"No PubChem Compound record at review (investigational; LY3437943)"},"pharmacokinetics":{"basis":"human","route":"Subcutaneous, once weekly","half_life":"About 6 days (phase 1b)","licensed_regimen":null,"product":null,"source":{"title":"Urva S, et al. LY3437943, a novel triple GIP, GLP-1 and glucagon receptor agonist in people with type 2 diabetes: a phase 1b multiple-ascending-dose trial. Lancet 2022","url":"https://pubmed.ncbi.nlm.nih.gov/36354040/"}},"outcomes":[{"outcome":"Body weight","grade":"A","grade_meaning":"established in humans","effect_size":"large","adverse":false,"human_studies":"2 phase 3 + 1 phase 2 RCT published; 2 phase 3 topline","evidence":"TRIUMPH-1, published in the New England Journal of Medicine on 29 September 2026 (2,339 adults with obesity and no diabetes, 80 weeks): −17.6% on 4 mg, −23.7% on 9 mg and −25.0% on 12 mg versus −3.9% on placebo. TRIUMPH-2, published in The Lancet the same day (1,152 adults with obesity and type 2 diabetes, 80 weeks): −11.9%, −16.8% and −18.8% versus −5.1%. Both papers count every participant randomised; the figures first announced by press release, 28.3% and 20.8% on 12 mg, were higher. Phase 2: −24.2% at 48 weeks on 12 mg. Still press releases only: TRIUMPH-4 (−28.7% at 68 weeks vs −2.1% placebo), TRIUMPH-3 (1,949 adults with severe obesity and cardiovascular disease: −22.6% vs −3.2%) and the 104-week TRIUMPH-1 extension in people with a BMI of 35 or more (−30.3%).","references":[{"citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","where":"N Engl J Med, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"},{"citation":"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.","where":"Lancet, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/"},{"citation":"Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.","where":"N Engl J Med, 2023;389:514–526","url":"https://pubmed.ncbi.nlm.nih.gov/37366315/"},{"citation":"Eli Lilly. Retatrutide delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial (TRIUMPH-4).","where":"Press release, 11 Dec 2025","url":"https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average"},{"citation":"Eli Lilly. Retatrutide TRIUMPH-1 topline results (NCT05929066).","where":"Press release, May 2026","url":"https://www.ajmc.com/view/retatrutide-achieves-up-to-30-3-average-weight-loss-in-phase-3-triumph-1-trial"},{"citation":"Eli Lilly. Lilly's triple agonist retatrutide successful in two additional phase 3 obesity trials (TRIUMPH-2, TRIUMPH-3).","where":"Press release, 23 Jul 2026","url":"https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-successful-in-two-additional-phase-3-obesity-trials-delivering-significant-improvements-in-weight-and-a1c-302832674.html"}],"verbatim":{"text":"The mean percent change in body weight in the retatrutide groups was -17.6% (4-mg dose), -23.7% (9-mg dose), and -25.0% (12-mg dose) versus -3.9% in the placebo group (differences, -19.8 and -21.0 percentage points, respectively; P<0.001 for both comparisons).","citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"}},{"outcome":"Blood glucose (HbA1c)","grade":"A","grade_meaning":"established in humans","effect_size":"large","adverse":false,"human_studies":"1 phase 3 + 1 phase 2 RCT","evidence":"TRANSCEND-T2D-1, a published 40-week phase 3 trial in 537 adults with type 2 diabetes uncontrolled by diet and exercise: HbA1c fell 1.69–1.94 percentage points across doses versus 0.81 on placebo. The earlier phase 2 trial agreed.","references":[{"citation":"Bajaj HS, et al. Efficacy and safety of retatrutide in people with type 2 diabetes inadequately controlled with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.","where":"Lancet, 2026;407:2402–2413","url":"https://pubmed.ncbi.nlm.nih.gov/42250575/"},{"citation":"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, phase 2 trial.","where":"Lancet, 2023;402:529–544","url":"https://pubmed.ncbi.nlm.nih.gov/37385280/"}],"verbatim":{"text":"For the treatment regimen estimand, the mean change from baseline in HbA1c concentration was -1·69% (SE 0·11) with retatrutide 4 mg, -1·86% (0·10) with 9 mg, and -1·94% (0·08) with 12 mg, versus -0·81% (0·12) with placebo, resulting in estimated treatment differences versus placebo of -0·88% (95% CI -1·18 to -0·59) with retatrutide 4 mg, -1·04% (-1·32 to -0·76) with 9 mg, and -1·12% (-1·39 to -0·85) with 12 mg (all p<0·0001).","citation":"Bajaj HS, et al. Efficacy and safety of retatrutide in people with type 2 diabetes inadequately controlled with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.","url":"https://pubmed.ncbi.nlm.nih.gov/42250575/"}},{"outcome":"Knee osteoarthritis pain","grade":"B","grade_meaning":"probable, not settled","effect_size":"moderate","adverse":false,"human_studies":"1 phase 3 RCT published (subgroup n=574); 1 phase 3 topline","evidence":"TRIUMPH-1, now published, included 574 participants with knee osteoarthritis: WOMAC pain fell 3.9 points on 9 mg and 4.1 on 12 mg versus 2.5 on placebo, counting everyone randomised (differences −1.4 and −1.6; both P<0.001). TRIUMPH-4, still a press release, enrolled only adults with obesity and knee osteoarthritis: up to 4.5 points (75.8%) vs 2.4 (40.3%) on placebo. Weight loss likely explains much of it.","references":[{"citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","where":"N Engl J Med, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"},{"citation":"Eli Lilly. Retatrutide delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial (TRIUMPH-4).","where":"Press release, 11 Dec 2025","url":"https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average"}],"verbatim":{"text":"Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were -3.2, -3.5, and -3.6 versus -1.9 with placebo (differences, -1.6 and -1.8 points; both P<0.001); the corresponding changes for the ITT estimand were -3.4, -3.9, and -4.1 versus -2.5 with placebo (differences, -1.4 and -1.6 points; both P<0.001).","citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"}},{"outcome":"Obstructive sleep apnoea","grade":"B","grade_meaning":"probable, not settled","effect_size":"moderate","adverse":false,"human_studies":"1 phase 3 RCT (subgroup n=243)","evidence":"In the 243 TRIUMPH-1 participants with obstructive sleep apnoea, the apnoea–hypopnoea index fell by 34.3 events per hour on 9 mg and 32.1 on 12 mg versus 9.6 on placebo at 80 weeks, counting everyone randomised (differences −24.7 and −22.5; both P<0.001). One subgroup of one trial, so B. The sleep-apnoea results from TRIUMPH-2 have not been reported yet.","references":[{"citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","where":"N Engl J Med, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"}]},{"outcome":"GI side effects","grade":"A","grade_meaning":"established in humans","effect_size":"large","adverse":true,"human_studies":"2 phase 3 + 1 phase 2 RCT published; phase 3 topline","evidence":"TRIUMPH-2, published: diarrhoea in 27–34% vs 13% on placebo and nausea in 14–28% vs 8%; 12% on 9 mg and 8% on 12 mg stopped treatment because of adverse events or death, against 5% on placebo. TRIUMPH-1, published, also names gastrointestinal events as the most common. Press releases: TRIUMPH-4, nausea 38–43% vs 11%, vomiting 20–21% vs 0%, discontinuation for adverse events 12–18% vs 4%; TRIUMPH-1, 11.3% stopped on 12 mg vs 4.9% placebo; TRIUMPH-3, 13.5% vs 4.8%.","references":[{"citation":"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.","where":"Lancet, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/"},{"citation":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","where":"N Engl J Med, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/"},{"citation":"Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.","where":"N Engl J Med, 2023;389:514–526","url":"https://pubmed.ncbi.nlm.nih.gov/37366315/"},{"citation":"Eli Lilly. Retatrutide delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial (TRIUMPH-4).","where":"Press release, 11 Dec 2025","url":"https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average"},{"citation":"Eli Lilly. Retatrutide TRIUMPH-1 topline results (NCT05929066).","where":"Press release, May 2026","url":"https://www.ajmc.com/view/retatrutide-achieves-up-to-30-3-average-weight-loss-in-phase-3-triumph-1-trial"},{"citation":"Eli Lilly. Lilly's triple agonist retatrutide successful in two additional phase 3 obesity trials (TRIUMPH-2, TRIUMPH-3).","where":"Press release, 23 Jul 2026","url":"https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-successful-in-two-additional-phase-3-obesity-trials-delivering-significant-improvements-in-weight-and-a1c-302832674.html"}],"verbatim":{"text":"The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg).","citation":"Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.","url":"https://pubmed.ncbi.nlm.nih.gov/37366315/"}},{"outcome":"Dysesthesia (skin sensation changes)","grade":"B","grade_meaning":"probable, not settled","effect_size":"small","adverse":true,"human_studies":"1 phase 3 RCT published; phase 3 topline","evidence":"TRIUMPH-2, published: dysesthesia in 4%, 6% and 7% on 4, 9 and 12 mg versus 1% on placebo; hypotension was also more frequent (1%, 5% and 6% vs under 1%). Press releases: 9–21% of treated participants vs 0.7% on placebo in TRIUMPH-4, and 4.5–7.3% vs 0.7–1.3% in TRIUMPH-2 and -3 — an effect not prominent with older GLP-1 drugs.","references":[{"citation":"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.","where":"Lancet, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/"},{"citation":"Eli Lilly. Retatrutide delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial (TRIUMPH-4).","where":"Press release, 11 Dec 2025","url":"https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average"},{"citation":"Eli Lilly. Lilly's triple agonist retatrutide successful in two additional phase 3 obesity trials (TRIUMPH-2, TRIUMPH-3).","where":"Press release, 23 Jul 2026","url":"https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-successful-in-two-additional-phase-3-obesity-trials-delivering-significant-improvements-in-weight-and-a1c-302832674.html"}],"verbatim":{"text":"Hypotension and dysesthesia were more frequent with retatrutide than with placebo (four [1%] in the 4 mg group, 14 [5%] in the 9 mg group, and 18 (6%) in the 12 mg group vs one [<1%] in the placebo group with hypotension; 13 [4%], 16 [6%], and 21 [7%] vs two [1%] in the placebo group with dysesthesia).","citation":"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.","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/"}}],"regions":[{"region":"European Union","status":"Investigational; not authorised","note":"No marketing authorisation anywhere; supply outside clinical trials is unlawful. Unlicensed pens were among the seizures in Europol's 2025 operation."},{"region":"United States","status":"Investigational; cannot be compounded","note":"FDA: retatrutide 'cannot be used in compounding under federal law' and has not been found safe and effective for any condition. Lilly has said it plans to file for approval in the first quarter of 2027."},{"region":"United Kingdom","status":"Unlicensed; illegal to sell","note":"MHRA, July 2026: 'it has not been authorised for use in the UK, meaning anyone selling this product is doing so illegally.' Thousands of doses seized in raids in October 2025, February and May 2026."},{"region":"Australia","status":"Unapproved","note":"Not registered anywhere. Named in the TGA's April 2026 advisory on unapproved peptide products."},{"region":"Canada","status":"Not authorised","note":"Investigational. Among the products Health Canada seized from a domestic vendor in August 2025."},{"region":"Sport (WADA)","status":"Prohibited at all times","note":"Unapproved anywhere, so it falls under S0 (non-approved substances)."}],"faq":[{"q":"How much weight do people lose on retatrutide?","a":"In TRIUMPH-1, published in September 2026, adults with obesity and no diabetes lost 25.0% of body weight on average over 80 weeks on the 12 mg dose, against 3.9% on placebo. Adults who also have type 2 diabetes lost 18.8% in TRIUMPH-2. In phase 2 the figure was 24.2% at 48 weeks. These are averages across everyone randomised; individual results vary widely."},{"q":"Is retatrutide better than tirzepatide?","a":"Probably more weight loss, on the numbers so far — but no trial has compared them head-to-head, and cross-trial comparisons are unreliable. The side-effect burden also appears higher. Treat “better” as unsettled until a direct comparison exists."},{"q":"Is retatrutide available?","a":"Not legally, anywhere. It is an investigational medicine available only in clinical trials. Products sold online under the name are unlicensed and, in enforcement seizures, frequently not what the label says."},{"q":"Why is the overall grade B and not A?","a":"Body weight moved to A on 7 October 2026, once two phase 3 obesity trials had been published in peer-reviewed journals. The overall grade stays B because retatrutide is not approved anywhere, two further phase 3 trials exist only as press releases, and no cardiovascular outcomes trial has reported."}],"references":[{"cite":"Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.","where":"N Engl J Med, 2023;389:514–526","url":"https://pubmed.ncbi.nlm.nih.gov/37366315/","note":"338 adults; −24.2% at 48 weeks on 12 mg."},{"cite":"Eli Lilly. Retatrutide delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful phase 3 trial (TRIUMPH-4).","where":"Press release, 11 Dec 2025","url":"https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average","note":"445 adults, 68 weeks. Topline; not peer-reviewed."},{"cite":"Eli Lilly. Retatrutide TRIUMPH-1 topline results (NCT05929066).","where":"Press release, May 2026","url":"https://www.ajmc.com/view/retatrutide-achieves-up-to-30-3-average-weight-loss-in-phase-3-triumph-1-trial","note":"2,339 adults, 80 weeks plus 104-week extension. Detailed data promised for the ADA Scientific Sessions; not peer-reviewed at time of review."},{"cite":"Bajaj HS, et al. Efficacy and safety of retatrutide in people with type 2 diabetes inadequately controlled with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.","where":"Lancet, 2026;407:2402–2413","url":"https://pubmed.ncbi.nlm.nih.gov/42250575/","note":"537 randomised, 40 weeks. The first published phase 3 trial of retatrutide."},{"cite":"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, phase 2 trial.","where":"Lancet, 2023;402:529–544","url":"https://pubmed.ncbi.nlm.nih.gov/37385280/","note":"Phase 2 in type 2 diabetes; agrees with the phase 3 on glycaemic effect."},{"cite":"Eli Lilly. Lilly's triple agonist retatrutide successful in two additional phase 3 obesity trials (TRIUMPH-2, TRIUMPH-3).","where":"Press release, 23 Jul 2026","url":"https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-successful-in-two-additional-phase-3-obesity-trials-delivering-significant-improvements-in-weight-and-a1c-302832674.html","note":"TRIUMPH-2: 1,152 adults with obesity and type 2 diabetes, 80 weeks. TRIUMPH-3: 1,949 adults with severe obesity and cardiovascular disease, 80 weeks. Topline; not peer-reviewed. Lilly intends to file with the FDA in Q1 2027."},{"cite":"Jastreboff AM, et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1).","where":"N Engl J Med, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42814954/","note":"2,339 randomised, 80 weeks; −25.0% on 12 mg vs −3.9% placebo by intention to treat. Subgroups with knee osteoarthritis (n=574) and obstructive sleep apnoea (n=243). NCT05929066."},{"cite":"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.","where":"Lancet, 2026 (online 29 Sep)","url":"https://pubmed.ncbi.nlm.nih.gov/42810372/","note":"1,152 randomised, 92 sites, 80 weeks; −18.8% on 12 mg vs −5.1% placebo (treatment-regimen estimand). NCT05929079."}],"last_reviewed":"2026-10-07","literature_searched_to":"2026-10-07","changelog":[{"date":"2026-10-07","note":"TRIUMPH-1 (N Engl J Med) and TRIUMPH-2 (Lancet) were published on 29 Sep 2026. Body weight and GI side effects move from B to A on the published papers, with the intention-to-treat figures (25.0% and 18.8%) replacing the press-release ones; knee-pain and dysesthesia rows now cite the papers; new sleep-apnoea row at B. Overall grade held at B: unapproved, TRIUMPH-3 and -4 unpublished."},{"date":"2026-09-23","note":"TRIUMPH-2 and TRIUMPH-3 topline results (23 Jul 2026) added to the weight, side-effect and dysesthesia rows. Still press releases, so body weight stays at B."},{"date":"2026-09-03","note":"TRANSCEND-T2D-1, the first published phase 3 trial of retatrutide (Lancet, 537 adults with type 2 diabetes), added with a verbatim primary result; new blood-glucose row graded A. The obesity phase 3 results remain unpublished press releases, so body weight stays at B."},{"date":"2026-09-02","note":"Full page: mechanism, regulatory status and FAQ added. Phase 3 topline results (TRIUMPH-4, TRIUMPH-1) with osteoarthritis-pain and dysesthesia rows. Grade held at B pending peer-reviewed publication."},{"date":"2026-09-01","note":"Initial publication."}],"license":"CC BY 4.0 — cite as “LYO Research” with a link.","methodology":"https://lyoresearch.com/methodology"}