Diabetes Dialogue: Reacting to Retatrutide and TRIUMPH-4 Topline Data

Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!

In this episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and co-director of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, share early impressions of topline phase 3 results from the TRIUMPH-4 trial of retatrutide, a once-weekly triple agonist targeting GIP, GLP-1, and glucagon receptors. Recorded from the ADCES Technology Conference, the conversation frames retatrutide as a potential next step beyond current GLP-1 and dual incretin options, while emphasizing that detailed trial data remain pending.

TRIUMPH-4 was a phase 3 study enrolling patients with obesity and osteoarthritis. Topline data suggests participants receiving retatrutide 12 mg achieved a mean weight loss of 28.7% at 68 weeks. Among this population, the trial also reported a 75.8% reduction in WOMAC pain scores from baseline, with approximately 1 in 8 participants reporting complete pain freedom at week 68. Isaacs highlights how striking these figures are in light of the already high bar set by semaglutide and tirzepatide, noting that confirmation in phase 3 heightens anticipation for full publications and future readouts.

The hosts connect these findings to evolving clinical priorities reflected in the American Diabetes Association’s expanding attention to obesity-related comorbidities, including osteoarthritis, MASLD/MASH, sleep apnea, and kidney disease. They note the broader retatrutide phase 3 program includes studies in type 2 diabetes, moderate-to-severe obstructive sleep apnea, chronic low back pain, MASLD/MASH, and planned cardiovascular and renal outcomes trials. Isaacs underscores the ongoing question of whether benefits across these conditions will be primarily molecule-specific or largely driven by the magnitude of weight loss, particularly given the inclusion of glucagon receptor activity.

Safety is discussed cautiously, given the limited nature of top-line disclosures. The hosts note that discontinuation due to adverse events appeared higher with retatrutide than placebo, and they emphasize the need for full reporting on gastrointestinal tolerability and other adverse events. Bellini also points to an intriguing subgroup signal suggesting lower discontinuation rates among participants with higher baseline BMI, while acknowledging this could reflect chance in a modestly sized trial population.

Overall, Isaacs and Bellini characterize retatrutide’s TRIUMPH-4 update as an important milestone, while stressing that interpretation should remain measured until complete efficacy and safety data are available.

Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others.

References:

1. Eli Lilly and Company. Lilly's triple agonist, 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. December 11, 2025. Accessed December 11, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average

2. American Diabetes Association. The American Diabetes Association Launches a New Obesity Division | ADA. diabetes.org. Published June 21, 2024. Accessed December 16, 2025. https://diabetes.org/newsroom/press-releases/american-diabetes-association-launches-new-obesity-division