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Randomized controlled trial

ACHIEVE-3: orforglipron vs oral semaglutide in type 2 diabetes

HbA1c fell by 1.71 and 1.91 points with orforglipron 12 and 36 mg, and by 1.23 and 1.47 points with oral semaglutide 7 and 14 mg.

Rosenstock J 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. The Lancet, 2026. DOI: 10.1016/S0140-6736(26)00202-3

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Key facts

Drugs
orforglipron and semaglutide
Design
Randomized controlled trial
Participants
1,698
Duration
52 weeks
Funding
Eli Lilly
Registry
NCT06045221
Population
1,698 adults with type 2 diabetes inadequately controlled on metformin (HbA1c of 7.0 to 10.5%, mean 8.3%) and a BMI of 25 or more, in Argentina, China, Japan, Mexico and the United States.
Primary outcome
Noninferiority in HbA1c change at 52 weeks of orforglipron 36 mg versus oral semaglutide 14 mg and of orforglipron 12 mg versus oral semaglutide 7 mg (margin of 0.3 points).

What it found

HbA1c fell by 1.71 and 1.91 points with orforglipron 12 and 36 mg, and by 1.23 and 1.47 points with oral semaglutide 7 and 14 mg. The difference for orforglipron 36 mg versus semaglutide 14 mg was −0.44 points (95% CI, −0.62 to −0.26), and both orforglipron doses were superior to both semaglutide doses. Digestive adverse effects (58-59% versus 37-45%) and discontinuations because of adverse effects (9-10% versus 4-5%) were more frequent with orforglipron, and pulse rate rose more (3.7 to 4.7 versus 1.0 to 1.5 beats per minute).

Limitations

Funded by Eli Lilly, the maker of orforglipron. Open-label design (participants knew which drug they were taking). It only included people with type 2 diabetes treated with metformin, and oral semaglutide was used at 7 and 14 mg, not at higher doses. It says nothing about people without diabetes.

What it means for you

In type 2 diabetes treated with metformin, orforglipron lowered HbA1c more than oral semaglutide (Rybelsus) at the doses compared, with more digestive side effects and more dropouts. It was an open-label trial funded by the maker of orforglipron. Which option is better in each case depends on many factors the doctor weighs.

Further reading

Related trials

  • orforglipron40 weeks

    ACHIEVE-2

    At 40 weeks, HbA1c fell by 1.23, 1.50 and 1.56 points with orforglipron 3, 12 and 36 mg, compared with 0.81 on dapagliflozin.

  • orforglipron40 weeks

    ACHIEVE-1

    HbA1c fell by 1.24, 1.47 and 1.48 percentage points with orforglipron 3, 12 and 36 mg, compared with 0.41 points on placebo.

  • orforglipron72 weeks

    ATTAIN-2

    At 72 weeks, weight changed by −9.6% with orforglipron 36 mg, −7.0% with 12 mg and −5.1% with 6 mg, compared with −2.5% on placebo.

  • orforglipron52 weeks

    ATTAIN-MAINTAIN

    On orforglipron, 74.7% of the weight lost on tirzepatide was maintained, versus 49.2% on placebo.

Sources

The original paper and the records consulted for this summary, with the date they were accessed.

  1. The Lancet.Rosenstock J, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3). Lancet. 2026;407(10534):1147-1160.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 41765029 (abstract).accessed .