Retatrutide

What It Is

Retatrutide (LY3437943) is an investigational triple incretin agonist targeting GIP, GLP-1, and glucagon receptors simultaneously, developed by Eli Lilly. It is the first triple agonist to reach Phase 3 development and has produced the highest weight loss of any GLP-1-class therapy tested to date. In the Phase 3 TRIUMPH-4 trial (December 2025), retatrutide achieved 28.7% mean body weight loss at 68 weeks on the 12 mg dose — participants lost an average of 71.2 lbs (32.3 kg) from a baseline of 248.5 lbs, with 58.6% achieving ≥25% total body weight loss. Beyond weight, retatrutide reduced WOMAC knee pain scores by 75.8%, with more than 1 in 8 patients becoming completely pain-free — the first successful Phase 3 demonstrating weight-loss-mediated joint pain improvement. In March 2026, the TRANSCEND-T2D-1 trial reported A1C reductions of up to 2.0% and weight loss of up to 36.6 lbs (16.8%) at 40 weeks in type 2 diabetes patients. The TRIUMPH Phase 3 program includes eight clinical trials evaluating retatrutide in general obesity, type 2 diabetes, obstructive sleep apnea, and knee osteoarthritis. On May 21, 2026, Eli Lilly announced positive topline data from TRIUMPH-1, the pivotal 80-week general obesity trial: participants on the 12 mg dose lost an average of 28.3% of their body weight at 80 weeks, with all three doses (4 mg, 9 mg, and 12 mg) meeting primary and key secondary endpoints. Among participants with a starting BMI of 35 or higher who continued on the drug, weight loss reached up to 30.3% at 104 weeks. These results form the primary basis for the planned NDA submission. A notable safety signal is dysesthesia (abnormal skin sensation), reported in 8.8% (9 mg) and 20.9% (12 mg) of patients vs 0.7% on placebo, and higher discontinuation rates (18.2%) compared to competitors. Eli Lilly plans to file the NDA in Q4 2026, with a potential FDA decision by mid-to-late 2027. The pivotal TRIUMPH-1 trial — the largest in the program at 80 weeks in adults with obesity/overweight without T2D — is the registration study for the weight-management NDA. The TRIUMPH-1 results confirm retatrutide as the highest-efficacy weight-loss compound in clinical development, with additional Phase 3 readouts for type 2 diabetes, cardiovascular disease, and other indications expected through Q3–Q4 2026. Seven additional Phase III readouts are expected throughout 2026, and the overall TRIUMPH program encompasses eight pivotal trials enrolling more than 5,800 participants plus a separate roughly 10,000-patient cardiovascular outcomes trial (TRANSCEND-CV). TRIUMPH-1 secondary biomarker endpoints showed statistically significant improvements across waist circumference, non-HDL cholesterol, triglycerides, systolic blood pressure, and high-sensitivity C-reactive protein at 80 weeks across all dose groups, though the trial was not powered for cardiovascular event outcomes. At the ADA 2026 Scientific Sessions (June 5–8, New Orleans), Eli Lilly is presenting full TRIUMPH-1 data with complete secondary biomarker endpoints, and TRANSCEND-T2D-1 full data for type 2 diabetes. These presentations represent the first comprehensive peer-reviewed disclosure of the pivotal registration data underpinning the planned Q4 2026 NDA submission. At the ADA 2026 Scientific Sessions (June 7, New Orleans), Eli Lilly presented full data from TRIUMPH-4, the first Phase 3 trial evaluating a pharmacotherapy in adults with both obesity/overweight and knee osteoarthritis. TRIUMPH-4 met all primary and key secondary endpoints at 68 weeks. Participants receiving retatrutide 12 mg achieved 28.7% mean body weight loss (vs 3.3% placebo) — the highest weight loss figure across all retatrutide Phase 3 trials to date — alongside a 75.8% reduction in WOMAC knee pain scores (4.5-point reduction vs 0.5-point placebo). At 68 weeks, 12.0% of the 12 mg group were completely free of knee pain compared with 4.2% in the placebo group. Participants also experienced a 14 mmHg reduction in systolic blood pressure and significant improvements in physical function. The average weight loss of 71.2 lbs in the TRIUMPH-4 12 mg arm represents the highest absolute weight reduction reported in any retatrutide trial to date. These data support a potential sNDA or supplemental indication for musculoskeletal comorbidities alongside the obesity NDA filing planned for Q4 2026.

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Citations

1. [1] Jastreboff AM. et al. — Triple-hormone-receptor agonist retatrutide for obesity. N Engl J Med. 2023 PubMed
2. [2] Eli Lilly — TRIUMPH-4 Phase 3 results, December 2025 PubMed
3. [3] Eli Lilly — TRANSCEND-T2D-1 Phase 3 topline results, March 2026 PubMed
4. [4] Giblin MJ. et al. — TRIUMPH registrational clinical trials design: obesity, OSA, and knee OA. Diabetes Obes Metab. 2026 PubMed
5. [5] Eli Lilly — TRIUMPH-1 Phase 3 topline results (28.3% weight loss at 80 weeks), May 21, 2026 PubMed
6. [6] Eli Lilly — Retatrutide TRIUMPH-1 and TRANSCEND-T2D-1 full data at ADA 2026 Scientific Sessions. June 2026 PubMed
7. [7] Lilly — TRIUMPH-4: Retatrutide Delivers Weight Loss and Osteoarthritis Pain Relief, ADA 2026 PubMed
8. [8] TRIUMPH-4: Retatrutide Achieves 28.7% Weight Loss and Marked Knee Pain Reduction — Patient Care Online PubMed

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