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Randomized controlled trial

ATTAIN-2: orforglipron, a daily pill, for obesity with diabetes

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; the difference versus placebo was −7.1 percentage points with 36 mg (95% CI, −8.2 to −6.1), −4.5 with 12 mg (95% CI, −5.5 to −3.6) and −2.7 with 6 mg (95% CI, −3.7 to −1.6).

Horn DB et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. The Lancet, 2025. DOI: 10.1016/S0140-6736(25)02165-8

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Key facts

Drug
orforglipron
Design
Randomized controlled trial
Participants
1,613
Duration
72 weeks
Funding
Eli Lilly
Registry
NCT05872620
Population
1,613 adults with type 2 diabetes (HbA1c of 7 to 10%) and a BMI of 27 or more, at 136 sites in ten countries, randomized to orforglipron 6 mg (329), 12 mg (332) or 36 mg (322) or to placebo (630); 46.9% women, mean weight 101.4 kg, mean BMI 35.6 and mean HbA1c 8.05%.
Primary outcome
Mean percentage change in body weight from baseline to week 72 with oral orforglipron 6, 12 or 36 mg daily versus placebo, as an adjunct to lifestyle changes.

What it found

Mean weight loss, % of starting weight · 72 weeks
  • Orforglipron 6 mg daily (oral)−5.1%
  • Orforglipron 12 mg daily (oral)−7.0%
  • Orforglipron 36 mg daily (oral)−9.6%
  • Placebo−2.5%

Difference (Orforglipron 6 mg daily (oral)): −2.7 points vs placebo (95% CI, −3.7 to −1.6).

Difference (Orforglipron 12 mg daily (oral)): −4.5 points vs placebo (95% CI, −5.5 to −3.6).

Difference (Orforglipron 36 mg daily (oral)): −7.1 points vs placebo (95% CI, −8.2 to −6.1).

Figures from the paperSee the results in a chart

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; the difference versus placebo was −7.1 percentage points with 36 mg (95% CI, −8.2 to −6.1), −4.5 with 12 mg (95% CI, −5.5 to −3.6) and −2.7 with 6 mg (95% CI, −3.7 to −1.6). These are results for the treatment-regimen estimand, which includes everyone randomized regardless of what happened during the trial. HbA1c and all prespecified weight and cardiometabolic measures improved with orforglipron. The most common adverse effects were digestive, mild or moderate and mostly during dose escalation; between 6.1 and 9.9% stopped treatment because of adverse effects on orforglipron, compared with 4.1% on placebo.

Limitations

Funded by Eli Lilly, which is developing orforglipron. It included only people with type 2 diabetes, in whom weight loss with these drugs is usually smaller than in people without diabetes, so its figures are not directly comparable with those of ATTAIN-1. It was compared with placebo, not with other treatments. There were 10 deaths (6 on orforglipron and 4 on placebo), which the investigators did not attribute to the drug.

What it means for you

In people with type 2 diabetes and excess weight, orforglipron as a daily pill reduced weight by an average of 9.6% with the highest dose over 72 weeks, compared with 2.5% on placebo, and it also improved HbA1c. With diabetes, weight loss is usually smaller than without it. Your doctor can explain whether it makes sense for your treatment.

Further reading

Related trials

  • orforglipron52 weeks

    ATTAIN-MAINTAIN

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

  • orforglipron72 weeks

    ATTAIN-1

    Orforglipron, an oral small-molecule GLP-1 receptor agonist, reduced weight at 72 weeks by 11.2% with 36 mg, 8.4% with 12 mg and 7.5% with 6 mg, compared with 2.1% on placebo.

  • 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.

Sources

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

  1. The Lancet.Horn DB, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. Lancet. 2025;406(10522):2927-2944.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 41275875 (abstract).accessed .