Oral orforglipron reduced bodyweight more than placebo at 72 weeks in Japanese adults

The study

ATTAIN-J was a double-blind, randomised, placebo-controlled, parallel-group, phase 3 trial. It was published in The Lancet Diabetes & Endocrinology and ran at 16 medical research centres and hospitals in Japan. Orforglipron is a small-molecule, non-peptide, oral GLP-1 receptor agonist.

Adults aged 18 years or older were eligible if they had a BMI from 27 kg/m2 to under 35 kg/m2 with two or more obesity-related health disorders, or a BMI of 35 kg/m2 or higher with one or more such disorders. At least one of the disorders had to be hypertension, dyslipidaemia or type 2 diabetes. Type 2 diabetes was targeted at about 25% of participants. All had at least one unsuccessful dietary attempt to lose weight.

Of 291 people screened, 238 were randomly assigned 1:1:1:1 to once-daily oral orforglipron 6 mg (n=61), 12 mg (n=57) or 36 mg (n=60), or placebo (n=60). Mean age was 54.1 years. There were 144 men (61%) and 94 women (39%). The co-primary endpoints were mean percentage change in bodyweight and the percentage of participants with at least 5% bodyweight reduction, both from baseline to week 72.

What they found

A total of 214 participants (90%) completed the study. Bodyweight fell in the orforglipron groups. The mean percentage change in bodyweight at week 72 was:

• -5.9% (95% CI -7.6 to -4.2) with 6 mg
• -8.7% (-10.9 to -6.5) with 12 mg
• -7.9% (-10.0 to -5.8) with 36 mg
• -0.6% (-2.1 to 0.8) with placebo

All three orforglipron doses differed from placebo with p<0.0001.

A reduction of at least 5% was reached by 45.6% (28 of 61) with 6 mg, 60.8% (35 of 57) with 12 mg and 58.8% (35 of 60) with 36 mg. In the placebo group it was 15.2% (nine of 60).

The authors describe the adverse events as mostly mild-to-moderate gastrointestinal symptoms. Nausea most often led to stopping treatment: one participant (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, against none with placebo. Vomiting led to stopping in none of the 6 mg group, two (4%) in the 12 mg group and one (2%) in the 36 mg group, against none with placebo.

How much weight to give it

This is a randomised, double-blind, placebo-controlled phase 3 trial. That design gives good protection against bias for the question it asks. The authors call the weight loss statistically superior to placebo, and the data support this.

Several limits apply. The trial is small, with about 60 people per group, and it was done only in Japan. The comparator was placebo, so there is no head-to-head result against another obesity drug. The abstract does not report a formal comparison between the orforglipron doses. The weight changes with 12 mg and 36 mg should not be read as showing a difference between them.

The efficacy results in the abstract are bodyweight measures only. It reports no hard clinical outcomes such as cardiovascular events. It also does not report serious adverse events, or what happened to weight after treatment stopped. The main efficacy results used the treatment regimen estimand in all randomly assigned participants. The trial was funded by Eli Lilly and Company.

For your clinic

These results add to the evidence on oral GLP-1 receptor agonists for obesity. Over 72 weeks, the once-daily tablet produced statistically superior bodyweight reductions versus placebo: mean change -5.9% to -8.7% with orforglipron against -0.6% with placebo. Gastrointestinal side effects, especially nausea, are the main issue to discuss with patients. Stopping for nausea was more frequent in the 36 mg group.

Be careful before applying this to Indian patients. The trial enrolled Japanese adults using Japanese BMI and indication criteria. Read the full paper first for serious adverse events, results in participants with type 2 diabetes, and the weight-loss pattern over time. Check current national guidance before changing any practice.