A new study has found that the novel oral GLP-1 receptor agonist, orforglipron, demonstrated superior glycaemic control compared to oral semaglutide in adults with type 2 diabetes (T2D). The findings come from the ACHIEVE-3 trial, a phase 3 study published in The Lancet.¹

Mechanism of Action

Orforglipron is a non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist designed for once-daily oral administration, notably without the food or water restrictions associated with oral semaglutide. Its efficacy was previously demonstrated in a phase 2 study.²

Methodology

ACHIEVE-3 was a 52-week, randomised, open-label, active-controlled, non-inferiority trial conducted across 131 centres. The study enrolled 1698 adults with T2D inadequately controlled with metformin, a glycated haemoglobin (HbA1c) between 7.0% and 10.5%, and a BMI of at least 25 kg/m². Participants were randomly assigned (1:1:1:1) to receive once-daily oral orforglipron (12 mg or 36 mg) or oral semaglutide (7 mg or 14 mg). The primary endpoint was the mean change in HbA1c from baseline at week 52, with a non-inferiority margin of 0.3%.¹

Results

At 52 weeks, both doses of orforglipron resulted in greater reductions in HbA1c compared to semaglutide. The mean change from a baseline of 8.3% was -1.71% for orforglipron 12 mg and -1.91% for orforglipron 36 mg. This compared to reductions of -1.23% for semaglutide 7 mg and -1.47% for semaglutide 14 mg. The primary objective of non-inferiority was met, and a hierarchical analysis confirmed the superiority of both orforglipron doses over both semaglutide doses (p<0.005 for all comparisons). Gastrointestinal events were the most common adverse events, occurring more frequently in the orforglipron groups (59% and 58%) than in the semaglutide groups (37% and 45%). Discontinuations due to adverse events were also higher with orforglipron (9–10%) versus semaglutide (4–5%), as was the mean increase in pulse rate.¹

Interpretation

The ACHIEVE-3 investigators concluded: "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. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide."¹

This study was funded by Eli Lilly.

References

1. Rosenstock J, Yabe D, Cox D, 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. 2026. https://doi.org/10.1016/S0140-6736(26)00202-3

2. Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023;402:472-483.

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