A new study has found that orforglipron, a novel, once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, leads to significant weight loss in adults with obesity or overweight and type 2 diabetes (T2D). The findings come from the phase 3 ATTAIN-2 trial.¹

Orforglipron is a non-peptide, small-molecule GLP-1 receptor agonist, distinguishing it from existing injectable peptide-based therapies in this class. This oral formulation offers a potential alternative for weight management in this patient population.

ATTAIN-2 was a 72-week, double-blind, randomised, placebo-controlled trial conducted across 136 sites in ten countries. The study enrolled 1,613 adults with a body mass index (BMI) of 27 kg/m² or higher and a glycated haemoglobin (HbA1c) level between 7% and 10%.

Participants were randomly assigned to receive once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, or a placebo, as an adjunct to lifestyle modification. The primary endpoint was the mean percentage change in bodyweight from baseline to week 72.

At baseline, the mean bodyweight was 101.4 kg, BMI was 35.6 kg/m², and HbA1c was 8.05%. At week 72, participants in the placebo group experienced a mean bodyweight reduction of -2.5%.

In contrast, all orforglipron groups achieved statistically superior weight loss. The mean percentage change in bodyweight was -5.1% for the 6 mg group, -7.0% for the 12 mg group, and -9.6% for the 36 mg group (p<0.0001 for all comparisons with placebo). All prespecified cardiometabolic measures, including HbA1c, also showed statistically significant improvements with orforglipron.

The safety profile was consistent with the GLP-1 receptor agonist class. The most common adverse events were mild-to-moderate gastrointestinal issues, which predominantly occurred during the dose-escalation period. Treatment discontinuation due to adverse events was higher for orforglipron (6.1–9.9%) compared with placebo (4.1%).

The trial demonstrates the efficacy of an oral, non-peptide GLP-1 receptor agonist for weight management in a population where obesity and T2D coexist. The study authors concluded that "in adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists."¹ These findings build on previous phase 2 data for the agent.²

This study was funded by Eli Lilly and Company.

References

1. Horn DB, Ryan DH, Giljanovic Kis S, 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. https://doi.org/10.1016/S0140-6736(25)02165-8

2. Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023;402:472-483.

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