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, ph

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Orforglipron, a novel non-peptide GLP-1 receptor agonist, was compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin.
The study was a 52-week, randomized, open-label, phase 3 trial involving 1698 participants from multiple countries.
Orforglipron 12 mg and 36 mg demonstrated non-inferiority and superiority to semaglutide 7 mg and 14 mg in reducing HbA1c levels.
Mean HbA1c reductions were greater with orforglipron (-1.71% for 12 mg, -1.91% for 36 mg) compared to semaglutide (-1.23% for 7 mg, -1.47% for 14 mg).
Gastrointestinal events were more frequent with orforglipron (59% for 12 mg, 58% for 36 mg) than semaglutide (37% for 7 mg, 45% for 14 mg).
Discontinuation due to adverse events and increased pulse rate were higher with orforglipron than semaglutide.
Four deaths occurred during the study, with one each in the orforglipron groups and two in the semaglutide 7 mg group.
The safety profiles of both drugs were consistent with the GLP-1 receptor agonist class, but orforglipron had higher incidences of certain adverse effects.

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