TRIUMPH-4: Topline Data Highlights Retatrutide's Significant Weight Loss Effects

On December 11, 2025, Eli Lilly announced positive topline results from the phase 3 TRIUMPH-4 trial, evaluating retatrutide in patients with overweight or obesity and osteoarthritis. The investigational once-weekly triple hormone receptor agonist, delivered at the 2 highest doses approved for investigation, provided substantial weight loss while reducing WOMAC pain subscale score and various markers for cardiovascular risk. Full data from the trial will be presented at an upcoming medical conference.1

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss TRIUMPH-4 and its results, highlighting the promising efficacy data surrounding retatrutide in weight loss.

Check out the full episode on recent GLP-1 trials and results here.

In this segment, Isaacs and Bellini discuss emerging topline findings from the TRIUMPH-4 phase 3 trial evaluating retatrutide, a novel triple-agonist therapy targeting GLP-1, GIP, and glucagon receptors, in individuals with obesity and osteoarthritis. Over 68 weeks, participants receiving the highest dose (12 mg) achieved an average weight loss of 71.2 pounds, representing 28.7% of body weight, while the 9 mg dose produced 26.4% weight loss, compared with 2.1% in the placebo group despite concurrent lifestyle counseling. With a baseline average BMI of 40 and mean starting weight of 248 pounds, the magnitude of weight reduction was described as unprecedented in clinical trials.

Beyond weight outcomes, investigators evaluated osteoarthritis symptoms using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), a validated patient-reported measure of pain, stiffness, and physical function. The results demonstrated substantial improvements in osteoarthritis-related symptoms, including a striking finding that one in eight participants treated with retatrutide reported complete resolution of knee pain by the end of the trial. Improvements in WOMAC scores were observed across dosing groups, with similar symptom benefits between the 9 mg and 12 mg doses despite the incremental difference in weight loss.

Secondary endpoints further underscored the drug’s efficacy: 47% of participants on the 9 mg dose and 58% on the 12 mg dose achieved at least 25% weight loss, while 30–39% achieved 30% weight loss, and 18–23.7% achieved 35% weight loss depending on dose. These results suggest that clinically meaningful outcomes may be attainable even at lower doses, which may have implications for tolerability and treatment adherence.

The hosts also review the emerging safety profile. Gastrointestinal events were the most common adverse effects, including nausea (38.1% with 9 mg; 43% with 12 mg vs 10% with placebo), along with diarrhea and constipation. Treatment discontinuation occurred in 12% of participants receiving 9 mg and 18% receiving 12 mg, compared with 4% in the placebo group, highlighting the importance of managing side effects in clinical practice.

Finally, the discussion highlights the broader development program for retatrutide, with seven additional phase 3 trials underway evaluating the once-weekly therapy in obesity and type 2 diabetes, all expected to conclude in 2026. Isaacs and Bellini emphasize the medication’s novelty as a triple-agonist metabolic therapy, which may explain its exceptional weight-loss efficacy. They conclude by underscoring the importance of multidisciplinary care, including dietitians and diabetes education specialists, to help patients optimize nutrition, mitigate gastrointestinal side effects, and sustain treatment adherence as this new class of therapies continues to evolve.

Editor’s 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, 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 March 6, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average

2. Eli Lilly and Company. A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee (TRIUMPH-4). ClinicalTrials.gov Identifier: NCT05931367. Updated January 21, 2026. Accessed March 6, 2026. https://clinicaltrials.gov/study/NCT05931367