Orforglipron, a small-molecule, nonpeptide oral GLP-1 receptor agonist, at multiple doses produced significant weight loss and improved cardiometabolic risk factors compared with placebo, according to the phase 3 ATTAIN-1 trial, presented at the European Association for the Study of Diabetes General Assembly 2025 and simultaneously published Sept. 16 in NEJM.

Sean Wharton, MD, et al., randomly assigned 3,127 patients (64% women; 57% White, 29% Asian; mean age, 45 years) with obesity and without diabetes in nine countries to orforglipron once daily at doses of 6 mg (n=723), 12 mg (n=725) or 36 mg (n=730) compared with placebo (n=949), in addition to healthy diet and physical activity.

Results showed that at 72 weeks, the mean change in body weight for patients taking orforglipron was −7.5% with 6 mg, −8.4% with 12 mg and −11.2% with 36 mg compared with −2.1% with placebo (p<0.001 for all comparisons).

Significantly more participants in all orforglipron groups met weight reduction thresholds compared with the placebo group. Notably, among those taking the highest dose of orforglipron, 55% lost ≥10%, 36% lost ≥15% and 19% lost ≥20% vs. 13%, 6% and 3%, respectively, with placebo.

Findings also revealed that orforglipron significantly improved all measured cardiometabolic risk factors, including waist circumference, systolic blood pressure, lipid and glycemic levels, compared with placebo.

The safety profile was consistent with other GLP-1 RAs, with the gastrointestinal adverse events most frequent, and typically mild to moderate. Adverse events leading to discontinuation occurred in 5-10% of participants in the orforglipron groups and in 3% of the placebo group.

Wharton and colleagues write that "cardiometabolic improvements were similar to those reported with oral and injectable semaglutide in obesity trials, despite the modestly lower weight loss in the current trial, a finding that reinforces the clinical significance of a weight reduction of 10% or more."