Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial.

Summary

In a 52-week, multinational, open-label, randomized phase 3 trial (n=1698), once-daily oral orforglipron (12 mg and 36 mg) achieved noninferiority and superiority versus oral semaglutide (7 mg and 14 mg) for change in HbA1c in adults with type 2 diabetes inadequately controlled on metformin. Orforglipron is an oral, non-peptide GLP-1 receptor agonist administered without food or water restrictions.

Key Findings

• Orforglipron 12 mg and 36 mg achieved noninferiority and superiority to oral semaglutide 7 mg and 14 mg for HbA1c change at week 52.
• The trial enrolled 1,698 adults with type 2 diabetes inadequately controlled on metformin in a 52-week, multinational, open-label, randomized, active-controlled design.
• Orforglipron is a once-daily, oral, non-peptide GLP-1 receptor agonist administered without food or water restrictions.

Clinical Implications

Orforglipron may become a preferred oral incretin option for patients averse to injectables or constrained by food/water administration requirements, supporting tighter glycemic control alongside metformin.

Limitations

• Open-label design may introduce performance and detection bias
• Abstract provides limited detail on secondary endpoints and safety profile

Future Directions

Evaluate long-term cardiovascular and renal outcomes, durability of glycemic and weight effects, and comparative effectiveness against injectable GLP-1RAs and dual agonists in diverse populations.