Efficacy and safety of oral orforglipron in Japanese participants with obesity disease (ATTAIN-J): a double-blind, randomised, placebo-controlled, parallel-group, phase 3 trial.

Orforglipron resulted in statistically significant weight loss in Japanese adults with obesity compared to placebo, but the clinical implications of this weight loss need further investigation.

Summary and findings

This study assessed the efficacy and safety of oral orforglipron in Japanese adults with obesity disease. Participants received either orforglipron at doses of 6 mg, 12 mg, or 36 mg, or a placebo. At week 72, orforglipron demonstrated statistically significant reductions in bodyweight compared to placebo.

Abstract

<h4>Background</h4>Orforglipron, a small-molecule, non-peptide, oral GLP-1 receptor agonist, has shown bodyweight reduction and cardiometabolic benefits in adults with obesity across phase 3 trials globally. We aimed to assess the efficacy and safety of orforglipron versus placebo for treating obesity disease in Japanese adults.<h4>Methods</h4>ATTAIN-J was a double-blind, randomised, placebo-controlled, parallel-group, phase 3 trial conducted across 16 medical research centres and hospitals in Japan and included adults aged 18 years or older with a BMI between 27 kg/m² and less than 35 kg/m² and two or more obesity-related health disorders, or a BMI of 35 kg/m² or higher and one or more obesity-related health disorder, with one or more of the obesity-related health disorders being hypertension, dyslipidaemia, or type 2 diabetes (targeted at about 25% of participants), consistent with Japanese indications for tirzepatide and semaglutide for obesity disease; and at least one unsuccessful dietary attempt to lose weight. Participants were randomly assigned (1:1:1:1) via a computer-generated sequence to once-daily oral orforglipron (6 mg, 12 mg, or 36 mg) or placebo. Co-primary endpoints were mean percentage change in bodyweight and percentage of participants with at least 5% bodyweight reduction from baseline to week 72. Efficacy endpoints were primarily evaluated by the treatment regimen estimand in all randomly assigned participants. Safety was assessed in participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT05931380 (completed).<h4>Findings</h4>Between July 31, 2023, and June 19, 2025, 291 participants were screened, of whom 238 (144 [61%] males and 94 [39%] females; mean age 54·1 years [SD 11·2]) were randomly assigned to receive orforglipron 6 mg (n=61), 12 mg (n=57), or 36 mg (n=60), or placebo (n=60); 214 (90%) participants completed the study. At week 72, mean percentage change in bodyweight was -5·9% (95% CI -7·6 to -4·2) with orforglipron 6 mg, -8·7% (-10·9 to -6·5) with 12 mg, and -7·9% (-10·0 to -5·8) with 36 mg, compared with -0·6% (-2·1 to 0·8) with placebo (all p<0·0001 vs placebo). At week 72, a bodyweight reduction of at least 5% was seen in 15·2% (SE 4·8; nine of 60) of participants in the placebo group compared with 45·6% (6·1; 28 of 61; p=0·0001) of participants in the orforglipron 6 mg group, 60·8% (6·4; 35 of 57; p<0·0001) of participants in the orforglipron 12 mg group, and 58·8% (6·5; 35 of 60; p<0·0001) of participants in the orforglipron 36 mg group. Adverse events with orforglipron were mostly mild-to-moderate gastrointestinal symptoms. Across all orforglipron groups, treatment-emergent adverse events that most frequently led to study treatment discontinuation were nausea (one [2%] of 61 in the 6 mg group, one [2%] of 57 in the 12 mg group, and five [8%] of 60 in the 36 mg group vs none with placebo) and vomiting (none in the 6 mg group, two [4%] in the 12 mg group, and one [2%] in the 36 mg group vs none in the placebo group).<h4>Interpretation</h4>In Japanese adults with obesity disease, once-daily orforglipron resulted in statistically superior reductions in bodyweight versus placebo, with a safety profile consistent with that of other GLP-1 receptor agonists.<h4>Funding</h4>Eli Lilly and Company.<h4>Translation</h4>For the Japanese translation of the abstract see Supplementary Materials section.

Limitations

Not reported in abstract.

Elsewhere in the Orforglipron (LY-3502970) corpus