Medicine firm Eli Lilly and Company (NYSE: LLY) on Wednesday reported positive topline results from ACHIEVE-3, a Phase 3, 52-week trial comparing the oral GLP-1 receptor agonist orforglipron to oral semaglutide in 1,698 adults with type 2 diabetes inadequately controlled on metformin. Orforglipron demonstrated superior efficacy in glycemic control and weight reduction across all dose comparisons.

At the highest doses, orforglipron lowered A1C by 2.2% versus 1.4% with oral semaglutide. Participants receiving orforglipron 36 mg lost an average of 19.7 lbs (9.2%) compared with 11.0 lbs (5.3%) for semaglutide 14 mg, representing a 73.6% relative improvement. A greater proportion of participants achieved A1C below 5.7% with orforglipron (37.1%) than with semaglutide (12.5%). Clinically meaningful improvements were also observed in cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure, and triglycerides.

The company said orforglipron's safety and tolerability were consistent with previous trials. Gastrointestinal events were the most common adverse effects, generally mild to moderate, with treatment discontinuation rates of 8.7% (12 mg) and 9.7% (36 mg) compared to 4.5% (7 mg) and 4.9% (14 mg) for semaglutide. No hepatic safety signals were observed.

Orforglipron, a once-daily small-molecule oral GLP-1 receptor agonist discovered by Chugai Pharmaceutical Co, Ltd and licensed by Lilly, can be taken without restrictions on food or water. The ACHIEVE global program has enrolled over 6,000 participants across multiple Phase 3 trials for type 2 diabetes, obesity and related conditions. Lilly plans regulatory submissions for orforglipron in 2026.

Eli Lilly continues to focus on advancing innovative therapies to redefine diabetes care, treat obesity, and address other major health challenges globally.