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
Authors' conclusion
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.
Study context
- Population
- Adults (≥18 years) with T2D inadequately controlled with metformin (≥1500 mg/day), HbA1c 7.0%–10.5% (53–91 mmol/mol), BMI ≥25 kg/m²; 131 centres in Argentina, China, Japan, Mexico and the USArandomized 1:1:1:1
- Participants
- 1,698 adults
- Comparison
- Once-daily oral orforglipron vs oral semaglutide
- Orforglipron 12 mgn = 424
- Orforglipron 36 mgn = 423
- Semaglutide 7 mgn = 426reference
- Semaglutide 14 mgn = 425reference
- Primary endpoint
- Non-inferiority of orforglipron 36 mg vs semaglutide 14 mg and orforglipron 12 mg vs semaglutide 7 mg for mean change from baseline in HbA1c (non-inferiority margin 0.3%)
- Follow-up
- Week 52
Methodological detailsmultinational, multicentre, non-inferiority, open-label, active-controlled, phase 3, 52-week, Enrolment Sept 22, 2023, to Aug 22, 2025, Safety analysed in all participants receiving ≥1 dose
- Multinational
- Multicentre
- Non-inferiority
- Open-label
- Active-controlled
- Phase 3
- 52-week
- Enrolment Sept 22, 2023, to Aug 22, 2025
- Safety analysed in all participants receiving ≥1 dose
Primary result
As reported in the abstract
Orforglipron 12 mg
−1.71
mean · SE 0.07 · %
Orforglipron 36 mg
−1.91
mean · SE 0.08 · %
Semaglutide 7 mg
−1.23
mean · SE 0.05 · %
Semaglutide 14 mg
−1.47
mean · SE 0.06 · %
Non-inferiority margin 0.3 as printed, not drawn
Further findings
Events
| Outcome | Orforglipron 12 mg | Orforglipron 36 mg | Semaglutide 7 mg |
|---|---|---|---|
| Deaths | 1 | 1 | 2 |
- Deaths — Deaths during the study
- 4
Safety
Gastrointestinal adverse events (most frequent AEs) · mostly mild to moderate
Discontinuation of study treatment due to adverse events
Mean, bpm
| Outcome | Orforglipron 12 mg | Orforglipron 36 mg | Semaglutide 7 mg | Semaglutide 14 mg |
|---|---|---|---|---|
| Mean increase in pulse rate | 3.7 | 4.7 | 1.0 | 1.5 |
Original publication
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