A novel, once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, orforglipron, has demonstrated superior weight loss compared to placebo in adults with obesity or overweight and type 2 diabetes, according to results from the ATTAIN-2 trial.¹
Orforglipron is an oral, non-peptide, small-molecule GLP-1 receptor agonist, offering a potential alternative to injectable therapies for weight management in this patient population.
The 72-week, phase 3, double-blind, randomised, placebo-controlled ATTAIN-2 trial was conducted across 136 sites in ten countries. The study enrolled 1,613 participants with a body mass index (BMI) of 27 kg/m² or higher and glycated haemoglobin (HbA1c) between 7–10%. 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 72 weeks, participants receiving orforglipron showed a statistically significant, dose-dependent reduction in bodyweight. The mean percentage change from baseline was -5.1% with 6 mg, -7.0% with 12 mg, and -9.6% with 36 mg of orforglipron, compared to -2.5% with placebo (p<0.0001 for all comparisons). All prespecified secondary endpoints, including cardiometabolic measures and HbA1c, also showed statistically significant improvements with orforglipron versus placebo.
The safety profile of orforglipron was consistent with other GLP-1 receptor agonists. 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 in the orforglipron groups (6.1–9.9%) compared to the placebo group (4.1%).
The study investigators 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
This study was funded by Eli Lilly and Company.
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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. Published online November 20, 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. https://doi.org/10.1016/S0140-6736(23)01302-8