Lancet

Investigational oral GLP‑1 agonist outperforms oral semaglutide in diabetes trial

February 27, 2026

In a 52‑week, multinational phase 3 trial (NCT06045221) of 1,698 adults with T2DM inadequately controlled on metformin, once‑daily orforglipron (12 mg or 36 mg) led to greater HbA1c reductions than oral semaglutide (7 mg or 14 mg), meeting non‑inferiority and achieving superiority across all dose comparisons. Mean HbA1c reductions were –1.71% to –1.91% with orforglipron vs. -1.23% to -1.47% with semaglutide. Gastrointestinal adverse events and treatment discontinuations were more common with orforglipron, though typically mild to moderate. Increases in pulse rate were also higher with orforglipron (3.7 to 4.7 bpm) compared with semaglutide (1.0 to 1.5 bpm).

Clinical takeaway: Orforglipron may offer stronger glycemic efficacy than existing oral GLP‑1 options, but clinicians should balance these benefits against higher rates of GI intolerance, treatment discontinuation, and pulse‑rate increases.

Source:

Rosenstock J, et al. (2026, February 26). The Lancet. 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. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00202-3/abstract