Eli Lilly and Company has announced positive topline results from its Phase 3 ACHIEVE-3 clinical trial, which evaluated the safety and efficacy of orforglipron versus oral semaglutide in 1,698 adults with Type 2 Diabetes inadequately controlled on metformin. The 52-week, open-label randomized study compared orforglipron (12 mg and 36 mg) with oral semaglutide (7 mg and 14 mg) to assess glycemic control and weight loss outcomes.
At 52 weeks, orforglipron met the primary and all key secondary endpoints, demonstrating superior reductions in A1C and weight at both doses compared to oral semaglutide.
“Head-to-head trials are a gold standard for comparing potential treatments,” said Kenneth Custer, Ph.D., 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.”
Key efficacy findings:
A1C reduction: -1.9% (12 mg) and -2.2% (36 mg) with orforglipron vs. -1.1% (7 mg) and -1.4% (14 mg) with oral semaglutide
Weight loss: -6.7% (14.6 lbs; 12 mg) and -9.2% (19.7 lbs; 36 mg) vs. -3.7% (7.9 lbs; 7 mg) and -5.3% (11.0 lbs; 14 mg)
A1C <5.7% achievement: 25.4% (12 mg) and 37.1% (36 mg) vs. 7.8% (7 mg) and 12.5% (14 mg)
Participants on orforglipron also showed improvements in non-HDL cholesterol, systolic blood pressure, and triglycerides. The safety profile was consistent with earlier trials, with gastrointestinal events being the most common and generally mild-to-moderate. Discontinuation rates due to adverse events were slightly higher for orforglipron (8.7%–9.7%) versus oral semaglutide (4.5%–4.9%). No hepatic safety concerns emerged.
Eli Lilly and Company plans to submit orforglipron for regulatory approval for the treatment of type 2 diabetes in 2026, with full ACHIEVE-3 data to be presented at an upcoming medical meeting and published in a peer-reviewed journal.