Retatrutide Cuts Weight, Cardiovascular Disease Risk in TRIUMPH-3

Triple hormone receptor agonism continues to show cardiometabolic promise in obesity treatment, with new phase 3 data indicating retatrutide can pair substantial weight loss with meaningful reductions in cardiovascular risk factors among patients with established cardiovascular disease.

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

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

TRIUMPH-3 enrolled >1900 participants with class II or III obesity (body mass index of 35 or higher) and established cardiovascular disease, randomizing them across global sites to 9 mg, 12 mg, or placebo over 80 weeks. The 9 mg dose produced average weight loss of 22%, or 53 pounds, and the 12 mg dose produced 23%, or 56 pounds, compared with 3% among patients receiving placebo. Weight loss was somewhat less pronounced than in TRIUMPH-1, where the highest dose reached 28.3%, a difference investigators partly attributed to inclusion of some participants with type 2 diabetes in the TRIUMPH-3 population.¹

The 12 mg dose was also associated with a 37% reduction in triglycerides, a 17% reduction in non-high-density lipoprotein cholesterol, a 9.3 mmHg reduction in systolic blood pressure, a 19 cm reduction in waist circumference, and a 51% reduction in high-sensitivity C-reactive protein. 3-point and 5-point major adverse cardiovascular event outcomes trended favorably but did not reach statistical significance, a limitation the hosts attributed to the trial's relatively short 80-week duration compared with dedicated cardiovascular outcomes trials such as the 5-year REWIND study of dulaglutide. A properly designed cardiovascular outcomes trial will be needed to confirm whether the risk-factor improvements translate into fewer events.¹

Gastrointestinal effects were common, with diarrhea reported in up to 34% of participants, nausea in up to 28%, constipation in 17%, decreased appetite in 17%, and vomiting in up to 16%, a profile consistent with other incretin-based therapies. Discontinuation rates were 3.8% with the 4 mg dose, 11% with 9 mg, and 7.7% with 12 mg, compared with nearly 5% among patients receiving placebo. The hosts noted patients who discontinue 1 incretin agent because of side effects may tolerate a different 1, underscoring the value of having multiple agents available in practice.¹

The findings add to a growing body of evidence supporting triple agonist therapy as a tool for addressing weight and cardiometabolic risk together in patients with established cardiovascular disease, even as the topline data lacked continuous glucose monitoring metrics investigators hope will appear in the trial's full readout. As increasingly potent incretin-based agents advance through a crowded pipeline, the field is beginning to weigh whether older, less potent molecules will retain a lasting clinical role.¹

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