USA: In the ACHIEVE-3 trial published in The Lancet, once-daily orforglipron demonstrated greater reductions in HbA1c and body weight compared with once-daily oral semaglutide in adults with type 2 diabetes. More than 50% of participants receiving orforglipron achieved an HbA1c below 6.5% at 1 year, highlighting its strong glycemic efficacy. However, gastrointestinal adverse events were more frequent with orforglipron than with semaglutide, indicating a higher rate of tolerability-related side effects.The multinational, multicentre, phase 3 trial was led by Julio Rosenstock from the University of Texas Southwestern Medical Center, Dallas, and colleagues. The study evaluated the efficacy and safety of orforglipron, a novel non-peptide GLP-1 receptor agonist designed for oral use without food or water restrictions, in comparison with oral semaglutide in adults whose type 2 diabetes was inadequately controlled on metformin.A total of 1,698 participants from 131 centres across Argentina, China, Japan, Mexico, and the USA were enrolled between September 2023 and August 2025. Eligible adults had HbA1c levels between 7.0% and 10.5%, a body mass index of at least 25 kg/m², and were receiving stable metformin therapy. Participants were randomly assigned to receive orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg) once daily for 52 weeks.The primary objective was to determine whether orforglipron was non-inferior to semaglutide in reducing HbA1c at 52 weeks, with a non-inferiority margin of 0.3%. Both doses of orforglipron not only met non-inferiority criteria but also demonstrated statistical superiority over both semaglutide doses. The trial revealed the following findings:Baseline mean HbA1c was 8.3%.HbA1c reduction at week 52 was −1.71% with orforglipron 12 mg.HbA1c reduction at week 52 was −1.91% with orforglipron 36 mg.HbA1c reduction was −1.23% with semaglutide 7 mg.HbA1c reduction was −1.47% with semaglutide 14 mg.Estimated treatment differences consistently favored orforglipron over semaglutide, including comparisons of lower-dose orforglipron with higher-dose semaglutide.Gastrointestinal events were the most common adverse effects.GI events occurred in 58–59% of participants receiving orforglipron.GI events occurred in 37–45% of participants receiving semaglutide.Most adverse events were mild to moderate in severity.Treatment discontinuation due to adverse events occurred in 9–10% of the orforglipron groups.Treatment discontinuation due to adverse events occurred in 4–5% of the semaglutide groups.Increases in pulse rate were greater with orforglipron than with semaglutide.Four deaths were reported during the trial across both treatment arms.The investigators concluded that in adults with type 2 diabetes insufficiently controlled on metformin, orforglipron provided superior glycemic reductions compared with oral semaglutide over 52 weeks. While its efficacy profile appears robust, the higher incidence of gastrointestinal events and treatment discontinuations highlights the need to balance glycemic benefits with tolerability when selecting therapy.Reference: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00202-3/abstract