Retatrutide delivers up to 71.2 pounds of average weight loss in its first successful Phase 3 trial

Eli Lilly reported positive topline results on Dec. 11, 2025, from TRIUMPH-4, the first Phase 3 trial to read out for retatrutide, an investigational once-weekly injection that activates three hormone receptors at once ^[1]. In adults with obesity or overweight plus knee osteoarthritis and no diabetes, the highest dose tested cut body weight by an average of 28.7%, or 71.2 pounds, at 68 weeks ^[1].

Retatrutide is described by Lilly as a first-in-class GIP, GLP-1 and glucagon triple hormone receptor agonist ^[1]. That is a step beyond currently marketed drugs: semaglutide (Ozempic, Wegovy, Rybelsus) targets GLP-1, and tirzepatide (Mounjaro, Zepbound) targets GIP and GLP-1. Retatrutide adds glucagon receptor activity and is not approved by any regulator ^[1].

What the trial found

TRIUMPH-4 randomized 445 participants 1:1:1 to retatrutide 9 mg, retatrutide 12 mg or placebo for 68 weeks ^[1]. Participants had a BMI of at least 27 and met American College of Rheumatology criteria for knee osteoarthritis; average starting weight was 112.7 kg (248.5 pounds) with an average BMI of 40.4, and 84.0% started with a BMI of 35 or higher ^[1]. Everyone started at 2 mg weekly and stepped up every four weeks to their target dose ^[1].

Using the efficacy estimand — which measures people who stayed on treatment and did not add other weight-loss drugs — weight fell 26.4% (64.2 pounds) on 9 mg and 28.7% (71.2 pounds) on 12 mg, versus 2.1% (4.6 pounds) on placebo ^[1]. Under the stricter treatment-regimen estimand, which counts everyone regardless of whether they stayed on the drug, losses were 20.0% (50.5 pounds) and 23.7% (60.0 pounds) versus 4.6% (11.7 pounds) ^[1].

On the pain co-primary endpoint, WOMAC pain scores dropped 4.5 points on 9 mg and 4.4 points on 12 mg from an average baseline of 6.0 points, compared with 2.4 points on placebo ^[1]. WOMAC is a patient-reported questionnaire scored 0 to 10, where higher means worse symptoms ^[1]. Physical function scores improved similarly ^[1]. In a post-hoc analysis, 14.1% of patients on 9 mg and 12.0% on 12 mg were completely free of knee pain at week 68, versus 4.2% on placebo ^[1]. Lilly notes the percentage-change figures for WOMAC were not pre-specified and come from post-hoc analysis ^[1].

Other secondary results: 58.6% of the 12 mg group lost at least 25% of body weight, 39.4% lost at least 30% and 23.7% lost at least 35%, compared with 1.3%, 0.8% and 0.0% on placebo ^[1]. The highest dose lowered systolic blood pressure by 14.0 mmHg, and the drug reduced non-HDL cholesterol, triglycerides and hsCRP ^[1]. Those measures were not controlled for multiplicity ^[1].

Side effects

The most common adverse events on 9 mg and 12 mg were nausea (38.1% and 43.2% vs. 10.7% on placebo), diarrhea (34.7% and 33.1% vs. 13.4%), constipation (21.8% and 25.0% vs. 8.7%), vomiting (20.4% and 20.9% vs. 0.0%) and decreased appetite (19.0% and 18.2% vs. 9.4%) ^[1]. Dysesthesia — abnormal or uncomfortable skin sensations — occurred in 8.8% and 20.9% of retatrutide patients versus 0.7% on placebo, and Lilly said these events were generally mild and rarely led to stopping treatment ^[1].

Discontinuations due to adverse events were 12.2% on 9 mg and 18.2% on 12 mg, versus 4.0% on placebo ^[1]. Lilly said those rates tracked with starting BMI and included people who stopped because of perceived excessive weight loss; among participants starting with a BMI of 35 or higher, the rates were 8.8% and 12.1% versus 4.8% ^[1].

Why it matters for patients

Knee osteoarthritis is common among people with obesity, and the trial pairs weight loss with a measured effect on joint pain and mobility — outcomes that matter to daily life and that can lead to joint replacement ^[1]. But this is topline data from one 445-person trial; detailed results have not been presented or peer-reviewed yet ^[1].

Retatrutide is investigational. It is not available by prescription, and the sources say nothing about pricing, insurance coverage, or when Lilly might file for approval. The gap between the two estimands also shows that real-world results depend heavily on whether people can stay on the drug ^[1].

What happens next

Seven additional Phase 3 trials in obesity and type 2 diabetes are expected to complete in 2026 ^[1]. Those will include a 4 mg maintenance dose not tested in TRIUMPH-4 ^[1]. The broader TRIUMPH program began in 2023 and has enrolled more than 5,800 participants ^[1]. Full TRIUMPH-4 results are slated for a future medical meeting and journal publication ^[1].