Eli Lilly has announced positive topline results from ACHIEVE-3, an open-label randomised Phase III clinical trial evaluating the safety and efficacy of orforglipron compared to oral semaglutide.
The trial used 1698 adults with type 2 diabetes inadequately controlled with metformin.
The 52-week trial compared orforglipron (12 mg and 36 mg) to oral semaglutide (7 mg and 14 mg) across four active treatment arms to assess glycemic control and weight loss.
At 52 weeks, orforglipron met the primary and all key secondary endpoints across each dose comparison versus oral semaglutide, delivering greater improvements in A1C and weight.
"Head-to-head trials are a gold standard for comparing potential treatments," said Kenneth Custer, Executive Vice President and President of Lilly Cardiometabolic Health.
"In this type 2 diabetes trial, orforglipron, even at the lower dose, outperformed both doses of oral semaglutide in reducing A1C."
"At the highest dose, orforglipron helped nearly three times as many participants reach near-normal blood sugar versus the highest dose of oral semaglutide."
"These results, combined with orforglipron's once-daily oral dosing and broad scalability, reinforce its potential as a foundational treatment for type 2 diabetes."
In the ACHIEVE-3 trial, orforglipron met the primary endpoint and showed superiority versus oral semaglutide, lowering A1C by an average of 1.9% (12 mg) and 2.2% (36 mg) compared with 1.1% (7 mg) and 1.4% (14 mg) with oral semaglutide at 52 weeks using the efficacy estimand.
In a secondary endpoint, 37.1% of participants taking the highest dose of orforglipron achieved an A1C <5.7% compared with 12.5% taking the highest dose of oral semaglutide.
In key secondary endpoints, orforglipron was also superior to oral semaglutide for weight loss, with participants taking orforglipron achieving a 73.6% greater relative weight loss at the highest dose compared with semaglutide.
Orforglipron also showed clinically meaningful improvements across key cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure and triglycerides.
The overall safety and tolerability profile of orforglipron in ACHIEVE-3 was consistent with previous trials.
The most commonly reported adverse events were gastrointestinal-related and generally mild-to-moderate in severity.
Treatment discontinuation rates due to adverse events were 8.7% (12 mg) and 9.7% (36 mg) for orforglipron versus 4.5% (7 mg) and 4.9% (14 mg) for oral semaglutide.
However, the study was not powered to compare the safety and tolerability of orforglipron and oral semaglutide. No hepatic safety signal was observed for orforglipron.
The detailed results of the ACHIEVE-3 trial will be presented at a future medical meeting and published in a peer-reviewed journal.
Lilly expects to submit orforglipron for the treatment of type 2 diabetes to global regulatory agencies in 2026.