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.

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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

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