Eli Lilly’s triple glucagon agonist has achieved up to 28.7% weight loss in a Phase III trial.
In the TRIUMPH-4 trial, retatrutide, a first-in-class glucose-dependent insulinotropic polypeptide (GIP), glucagon and glucagon-like peptide-1 (GLP-1) triple hormone agonist, met all its primary and key secondary endpoints. These deliver significant weight loss and improvements in pain and physical function after 68 weeks of treatment.
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Meeting both the co-primary endpoints, once-weekly retatrutide reduced weight by up to an average of 28.7% and reduced pain by up to an average of 4.5 points, equating to 75.8%, using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score.
In the 9mg cohort, there was a 26.4% weight loss reported, which increased to 28.7% in the 12mg cohort. This was compared to a 2.1% weight loss in the placebo cohort.
WOMAC scores were reduced by 4.5 points in the 9mg cohort, 4.4 points in the 12mg cohort and 2.4 points in the placebo cohort.
Retatrutide also reduced known markers of cardiovascular risk, including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP), and at the highest dose lowered systolic blood pressure by 14.0mmHg, meeting key secondary endpoints.
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By GlobalDataIn an additional post-hoc analysis, 14.1% of patients on retatrutide 9mg and 12.0% patients on retatrutide 12mg were completely free of knee pain while this endpoint was achieved in 4.2% on placebo.
The trial evaluated the drug in adult patients with obesity or overweight and knee osteoarthritis, and without diabetes, as an adjunct to a healthy diet and physical activity.
Eli Lilly’s executive vice-president and Lilly cardiometabolic health president Dr Kenneth Custer said: “People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement.
“We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function.”
Adverse events (AEs) were consistent with other incretins, with nausea, diarrhoea, constipation, and decreased appetite being the main reported events. Discontinuation rates due to adverse events were 12.2% and 18.2% with retatrutide 9mg and 12mg, respectively, compared to 4% with placebo.
CITI analysts said the rate of discontinuations while higher than Lilly’s other weight loss candidates, was unsurprising as they “highly correlated with baseline BMI and excessive weight loss”.
TRIUMPH-4 data will be presented at a future medical meeting and published in a peer-reviewed journal.
Lilly has seven more Phase III readouts expected in 2026, which include a maintenance dose of 4mg in addition to 9mg and 12mg doses. Citi analysts added that TRIUMPH-1 specifically could hit endpoints of over 30% weight loss due to its 80-week length.
GlobalData, parent company of Clinical Trials Arena, predicts a 2027 approval for retatrutide, with a 2031 sales forecast of $15.6bn in 2031, according to the patient-based forecast.
Lilly’s weight loss dominance continues to grow
Lilly’s flagship weight loss drug, Zepbound, is a dual agonist of GIP and GLP-1. The new candidate adds receptor agonism to a third hormone, glucagon, to the mix. Lilly’s Zepbound (tirzepatide) generated sales of $3.6bn in Q3 2025 alone.
The company is also awaiting a decision from the US Food and Drug Administration (FDA) on the approval of its oral GLP-1RA orforglipron, which has succeeded in Phase III trials in both obesity and type 2 diabetes.
Lilly’s main rival, Novo Nordisk, is also hoping for approval of its oral GLP-1RA Wegovy (semaglutide) after a successful Phase III trial. The drug is already approved in its subcutaneous form in obesity, with an oral version, Rybelsus, approved in type 2 diabetes.
GlobalData predicts that the obesity market will reach $206.5bn, up from $12.3bn across the 68 markets, with $981.3m of that expected from the Asia-Pacific (APAC) region.
