TRIUMPH-2: Retatrutide Reduces Weight, A1C in Patients With Obesity

Triple hormone receptor agonism continues to advance obesity and diabetes care, with new phase 3 data suggesting retatrutide can drive substantial glycemic improvement alongside major weight loss in people with type 2 diabetes.

On a recent episode of Diabetes Dialogue, cohosts Natalie Bellini, DNP, and Diana Isaacs, PharmD, reviewed topline results from the phase 3 TRIUMPH-2 trial evaluating retatrutide, a glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor triple agonist, in patients with type 2 diabetes.

Watch the full episode on the TRIUMPH-2 and TRIUMPH-3 data here.

The trial enrolled roughly 1000 participants across 98 centers worldwide beginning in 2023, testing 4 mg, 9 mg, and 12 mg doses against placebo over 80 weeks. Weight loss proved dose-dependent, reaching up to 21% of body weight, with participants on the 12 mg dose losing an average of 23 kg from a baseline of 106 kg. Glycemic control improved in parallel, with A1C reductions of 1.4% to 1.6% compared with 0.2% in the placebo group.

The trial population entered with a mean A1C of 7.7%, a starting point closer to target than many incretin trials, which typically enroll patients nearer 9%. This finding echoes early data from the SURPASS program, where tirzepatide likewise produced pronounced A1C lowering in populations without markedly elevated baseline values, hinting the profile may extend to earlier-stage disease.

Discontinuation at the highest dose reached 14%, translating to 86% treatment continuation, a rate considered favorable given the magnitude of weight loss achieved. Investigators noted flexible titration strategies, including slower dose escalation and antiemetic support, can mitigate gastrointestinal tolerability issues seen across incretin-based therapies. Mandatory forced titration used in trial protocols contrasts with real-world practice, where clinicians often individualize dosing pace.

Collectively, the findings position retatrutide among the most potent agents yet studied for type 2 diabetes and obesity, with real-world dosing flexibility likely to shape adoption. The prospect of pairing dramatic weight loss with near-normalization of glycemic control has fueled interest in introducing triple agonist therapy earlier in the disease course, potentially blunting long-term complications.

Editors’ Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

References

1. Eli Lilly. Lilly’s triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. July 23, 2026. Accessed August 4, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional