Phase III trial shows up to 28.7% weight loss, but tolerability remains a key concern for Eli Lilly’s triple-agonist therapy.
Major American global pharmaceutical company Eli Lilly’s experimental obesity therapy, retatrutide, has surpassed expectations in its Phase 3 TRIUMPH-4 trial, producing an average weight loss of 28.7% among participants who completed 68 weeks of treatment. The results suggest retatrutide could redefine standards for metabolic and obesity care, though higher discontinuation rates compared with existing therapies remain a concern [1].
Retatrutide is a first-in-class triple hormone receptor agonist, simultaneously activating GLP-1, GIP and glucagon receptors. This builds on the dual-agonist mechanism found in Lilly’s marketed drug, tirzepatide.
TRIUMPH-4 enrolled 445 adults with obesity or overweight, comparing once-weekly 9-mg and 12-mg doses against placebo.
Participants taking the higher 12-mg dose of retatrutide lost about 32 kg (71 lbs) on average, while those on the 9-mg dose lost around 29 kg (64 lbs). Including people who stopped the treatment early, the 12-mg group still saw an average weight loss of nearly 24% after 68 weeks.
TRIUMPH-4 also evaluated participants with knee osteoarthritis. Retatrutide significantly improved pain and physical function.
Patients reported a reduction of up to 4.5 points in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, representing a 75.8% improvement, and over one in eight treated patients were completely free from knee pain by the end of the trial.
“People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement,” said Dr Kenneth Custer, executive vice president and president of Lilly Cardiometabolic Health.
“We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide… on body weight, pain and physical function,” he added.
While retatrutide’s results surpassed experts’ expectations, the trial also highlighted some side-effect challenges.
About 18% of patients on the higher 12-mg dose and 12% on the 9-mg dose stopped treatment due to side effects, compared with just 4% on a placebo. Some patients – around one in five on the 12-mg dose – experienced a mild tingling or uncomfortable skin sensation, but it rarely caused them to quit the trial.
Lilly said that people with higher starting body weight were more likely to stop the treatment, and some participants felt they were losing weight too quickly. When looking only at participants with a BMI of 35 or higher, fewer people discontinued the therapy, 12.1% on 12 mg and 8.8% on 9 mg, compared with 4.8% in the placebo group.
Retatrutide enters a competitive and fast-growing obesity-drug market dominated by incretin-based therapies. Tirzepatide has produced 22.5% weight loss at 72 weeks, while semaglutide typically achieves 15–17% reductions.
Retatrutide’s higher efficacy may appeal to patients needing deeper weight loss or additional metabolic benefits, but tolerability and adherence will be crucial for commercial success.
Retatrutide’s record-breaking efficacy positions it as a potential category-defining therapy, but real-world outcomes will depend on managing side effects and sustaining patient adherence.
Lilly plans seven additional Phase 3 readouts in 2025, including studies of a 4-mg maintenance dose that may offer a different balance of efficacy and tolerability.
Across the TRIUMPH program, which began in 2023, over 5,800 participants are being studied for obesity, type 2 diabetes, knee osteoarthritis, cardiovascular and renal outcomes, sleep apnea, chronic back pain and metabolic dysfunction-associated steatotic liver disease.
Detailed TRIUMPH-4 results are expected to be presented at a future medical meeting and published in a peer-reviewed journal.
With ongoing studies, retatrutide could soon become a transformative option for patients seeking substantial weight loss along with improvements in pain and metabolic health.
