Lilly says oral orforglipron met its goal in a third phase 3 obesity trial

Eli Lilly said Aug. 26, 2025 that its experimental once-daily pill orforglipron helped adults with obesity or overweight and type 2 diabetes lose weight and lower blood sugar in the Phase 3 ATTAIN-2 trial, completing the data package the company says it needs to begin global regulatory submissions for obesity ^[1].

Orforglipron is an investigational oral GLP-1 receptor agonist, the same drug class as Ozempic, Wegovy and Rybelsus (semaglutide) and Mounjaro and Zepbound (tirzepatide), which are given by injection or, in Rybelsus's case, as a pill. Lilly says orforglipron is designed to be taken once a day at any time, without restrictions on food or water ^[1].

In the 72-week trial, the highest dose, 36 milligrams, produced average weight loss of 10.5%, or 22.9 pounds, compared with 2.2%, or 5.1 pounds, on placebo using the efficacy estimand — a measure that assumes participants stayed on their assigned treatment ^[1]. Average A1C fell by 1.3% to 1.8% across the three doses from a starting average of 8.1%, compared with 0.1% on placebo. On the 36 mg dose, 85.1% of participants reached an A1C below 7%, versus 23.0% on placebo, and 75.0% reached 6.5% or lower, the American Diabetes Association's threshold for diabetes, versus 10.6% on placebo ^[1].

The trial also reported weight-loss thresholds. Half of participants on 36 mg (50.1%) lost at least 10% of body weight, compared with 7.0% on placebo, and 28.4% lost at least 15%, compared with 1.9% ^[1]. Under the stricter treatment-regimen estimand, which counts everyone regardless of whether they stayed on the drug, the 36 mg dose produced 9.6% weight loss, compared with 2.5% for placebo ^[1]. Lilly said the highest dose cut high-sensitivity C-reactive protein, a marker of inflammation, by 50.6% in a pre-specified exploratory analysis ^[1].

Gastrointestinal side effects were the most common. On 36 mg, nausea was reported by 36.4% of participants versus 8.4% on placebo, vomiting by 23.1% versus 3.8%, diarrhea by 27.4% versus 15.0%, and constipation by 22.4% versus 7.8% ^[1]. Lilly said these events were generally mild to moderate and that no liver safety signal was seen. Discontinuation because of side effects was 6.1% on 6 mg, 10.6% on 12 mg and 10.6% on 36 mg, versus 4.6% on placebo; overall discontinuation was about 20% in every group, including placebo ^[1].

ATTAIN-2 randomized more than 1,600 adults with a BMI of at least 27 and type 2 diabetes across the United States, Argentina, Australia, Brazil, China, Czechia, Germany, Greece, India, South Korea and Puerto Rico ^[1].

Why it matters for patients

Every GLP-1 medicine approved in the U.S. for obesity is injected; Rybelsus, the oral semaglutide, is approved for type 2 diabetes, not weight loss. An effective once-daily pill with no food or water timing rules could be an alternative for people who do not want injections, though orforglipron is not approved by the FDA or any other regulator, and no decision date has been disclosed ^[1].

The population studied matters. ATTAIN-2 enrolled people with type 2 diabetes, a group Lilly describes as having more difficulty losing weight, so these results may not match what is seen in people without diabetes ^[1]. Results were also averaged over 72 weeks, meaning weight loss accumulated over more than a year, not weeks. About one in ten participants on the two higher doses stopped treatment because of side effects, and nausea, vomiting, diarrhea and constipation were common ^[1]. Lilly has not disclosed what the drug would cost if approved.

What happens next

Lilly says it will begin global regulatory submissions for obesity this year. Kenneth Custer, president of Lilly Cardiometabolic Health, said the company is "moving with urgency toward global regulatory submissions" ^[1]. Detailed ATTAIN-2 results will be presented at a future medical meeting and published in a peer-reviewed journal; no dates have been disclosed ^[1]. Orforglipron is also being studied for type 2 diabetes, and for obstructive sleep apnea and hypertension in adults with obesity ^[1]. The ATTAIN program has enrolled more than 4,500 people across two global registration trials ^[1].