Research Summary

Oral Orforglipron Shows Greater HbA1c Reduction Than Oral Semaglutide in Type 2 Diabetes

Ashton L. Stahl

Key Highlights

  • Orforglipron 12 mg and 36 mg were noninferior and superior to oral semaglutide 7 mg and 14 mg for HbA1c reduction at 52 weeks.
  • The phase 3 ACHIEVE-3 trial included 1,698 adults with type 2 diabetes inadequately controlled with metformin.
  • Gastrointestinal events, treatment discontinuations due to adverse events, and pulse rate increases were higher with orforglipron.

Once-daily oral orforglipron demonstrated noninferiority and superiority to oral semaglutide for reducing glycated hemoglobin (HbA1c) over 52 weeks in adults with type 2 diabetes, inadequately controlled with metformin, according to findings from the ACHIEVE-3 trial published in The Lancet. Orforglipron is a novel nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist designed for daily oral administration without food or water restrictions.

ACHIEVE-3 was a 52-week, randomized, open-label, active-controlled, multicenter, multinational, phase 3 trial conducted at 131 medical research centers and hospitals in Argentina, China, Japan, Mexico, and the United States. Eligible participants were adults aged 18 years or older with type 2 diabetes, inadequately controlled with metformin, at a dosage of at least 1,500 mg of metformin per day, an HbA1c between 7% and 10.5%, and a body mass index of at least 25 kg/m². Participants were randomly assigned in a 1:1:1:1 ratio to receive oral orforglipron 12 mg, orforglipron 36 mg, semaglutide 7 mg, or semaglutide 14 mg once daily. The primary objective was to assess noninferiority of orforglipron 36 mg vs semaglutide 14 mg and orforglipron 12 mg vs semaglutide 7 mg for mean change in HbA1c from baseline to week 52, using a noninferiority margin of 0.3%.

Study Findings

From September 22, 2023, to August 22, 2025, 1,698 participants were recruited and randomly assigned to orforglipron 12 mg (n = 424), orforglipron 36 mg (n = 423), semaglutide 7 mg (n = 426), or semaglutide 14 mg (n = 425).

For the treatment regimen estimand, the mean HbA1c decreased from a baseline of 8.3% by 1.71% with orforglipron 12 mg, 1.91% with orforglipron 36 mg, 1.23% with semaglutide 7 mg, and 1.47% with semaglutide 14 mg at week 52. The estimated treatment differences were –0.48% for orforglipron 12 mg vs semaglutide 7 mg (95% CI, –0.65 to –0.31; P < .0001) and –0.44% for orforglipron 36 mg vs semaglutide 14 mg (95% CI, –0.62 to –0.26; P < .0001). Orforglipron 12 mg also showed superiority to semaglutide 14 mg, with an estimated treatment difference of –0.24% (95% CI, –0.41 to –0.072; P = .0050).

Gastrointestinal events were the most frequent adverse events, occurring in 59% of participants receiving orforglipron 12 mg, 58% receiving orforglipron 36 mg, 37% receiving semaglutide 7 mg, and 45% receiving semaglutide 14 mg. Most gastrointestinal events were mild to moderate. Discontinuations due to adverse events occurred in 9% and 10% of the orforglipron 12 mg and 36 mg groups, respectively, compared with 4% and 5% of the semaglutide 7 mg and 14 mg groups. The mean pulse rate increases were also greater with orforglipron than semaglutide.

Clinical Implications

According to the study authors, the findings suggest that oral orforglipron 12 mg and 36 mg provided greater HbA1c reductions than oral semaglutide 7 mg and 14 mg in adults with type 2 diabetes, inadequately controlled with metformin. The authors also noted that although safety profiles were generally consistent with the GLP-1 receptor agonist class, gastrointestinal events, discontinuations due to adverse events, and mean pulse rate increases were higher with orforglipron than with oral semaglutide.

Expert Commentary

“In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA1c from baseline to 52 weeks,” the researchers concluded.

Reference

Rosenstock J, Yabe D, Cox D, Li J, Denning M, Wu WS, et al. 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. Lancet. Published online February 25, 2026. doi:10.1016/S0140-6736(26)00202-3