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Randomized controlled trial

ACHIEVE-1: the orforglipron pill in early type 2 diabetes

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; the differences were −0.83 (95% CI, −1.10 to −0.56), −1.06 (95% CI, −1.33 to −0.79) and −1.07 points (95% CI, −1.33 to −0.81).

Rosenstock J et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. New England Journal of Medicine, 2025. DOI: 10.1056/NEJMoa2505669

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Key facts

Drug
orforglipron
Design
Randomized controlled trial
Participants
559
Duration
40 weeks
Funding
Eli Lilly
Registry
NCT05971940
Population
559 adults with recently diagnosed type 2 diabetes treated with diet and exercise alone; baseline HbA1c of 8.0%.
Primary outcome
Change in HbA1c at 40 weeks with orforglipron 3, 12 or 36 mg daily versus placebo.

What it found

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; the differences were −0.83 (95% CI, −1.10 to −0.56), −1.06 (95% CI, −1.33 to −0.79) and −1.07 points (95% CI, −1.33 to −0.81). Weight fell by 4.5%, 5.8% and 7.6%, compared with 1.7% on placebo. The most common adverse effects were digestive, mild to moderate in severity.

Limitations

Funded by Eli Lilly. The population had recent diabetes and took no other diabetes drugs, so it says nothing about use in combination with metformin or other drugs. As of the review date, the type 2 diabetes indication was under FDA review.

What it means for you

In recently diagnosed type 2 diabetes, orforglipron tablets lowered HbA1c by more than one point versus placebo over 40 weeks. This is a result on blood sugar control, not on weight in people without diabetes. Your doctor can explain whether it makes sense in your treatment.

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.

  • orforglipron and semaglutide52 weeks

    ACHIEVE-3

    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.

  • 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. New England Journal of Medicine.Rosenstock J, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. N Engl J Med. 2025;393(11):1065-1076.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 40544435 (abstract).accessed .