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Lilly’s retatrutide delivers 20.8% weight loss in Phase III diabetes-obesity trial

Edited by Robert McTiernan··2 min read
Lilly’s retatrutide delivers 20.8% weight loss in Phase III diabetes-obesity trial

Eli Lilly and Company (NYSE: LLY) reported detailed Phase III data from TRIUMPH-2, one of the studies supporting its planned US regulatory filing for retatrutide, showing substantial weight loss and improved glycemic control in adults with obesity or overweight and type 2 diabetes.

In the 80-week TRIUMPH-2 trial, once-weekly retatrutide 12 mg produced 20.8% mean weight loss using the efficacy estimand. Results were presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes in Milan and simultaneously published in The Lancet.

Retatrutide is an investigational once-weekly subcutaneous peptide therapy that activates the GIP, GLP-1, and glucagon receptors. In Phase III studies, treatment starts at 2 mg weekly and is escalated every four weeks to target doses of up to 12 mg.

TRIUMPH-2 randomized 1,152 participants 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg, or placebo once weekly for 80 weeks. Using the efficacy estimand, mean weight change was -12.7%, -19.1%, and -20.8% with retatrutide versus -4.0% with placebo from a mean baseline weight of 106.4 kg. A1C fell by 1.4, 1.6, and 1.5 percentage points versus 0.2 points with placebo from a baseline of 7.7%, with up to 40.0% of participants reaching A1C below 5.7%.

The peer-reviewed analysis also reported a treatment-regimen estimand, which accounts for treatment discontinuation and other intercurrent events; by that measure, mean weight loss with 12 mg was approximately 18.8% versus 5.1% with placebo.

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At 12 mg, 59.5% of participants no longer met BMI criteria for obesity, while those with a baseline BMI of 35 or higher lost 23.4% on average. Retatrutide also reduced triglycerides, non-HDL cholesterol, systolic blood pressure, waist circumference, and high-sensitivity C-reactive protein. Weight loss was numerically lower than the 28.3% mean reduction reported with 12 mg in TRIUMPH-1 among participants without diabetes, consistent with the generally smaller weight reductions seen with obesity therapies in populations with type 2 diabetes.

The most common adverse events were diarrhea, nausea, constipation, decreased appetite, and vomiting, generally mild to moderate and mostly resolving during treatment. Adverse events led to discontinuation in 3.8%, 11.6%, and 7.7% of participants receiving 4 mg, 9 mg, and 12 mg, respectively, versus 4.9% with placebo. Dysesthesia occurred in 4.5%, 5.6%, and 7.3% of retatrutide-treated participants versus 0.7% with placebo.

Lilly plans to submit a Biologics License Application to the US FDA in Q1 2027. Results from the separate obstructive sleep apnea component of TRIUMPH-2 are expected to be presented and published later.

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