Investigational Oral GLP-1 RA, Orforglipron, Yields Dose-Dependent Weight Loss in Phase 3 Trial

Sean Wharton, MD, PharmD
Courtesy of Wharton Medical Clinic

An investigational once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, orforglipron, produced significant weight loss and improvements in cardiometabolic risk factors among adults with obesity or overweight, according to complete results from the phase 3 ATTAIN-1 clinical trial.¹

The findings were presented at the European Association for the Study of Diabetes 2025 Annual Meeting and published simultaneously in The New England Journal of Medicine.

"Obesity is a complex, global health challenge — and patients need treatment options that are both effective and easy to integrate into everyday life," lead author Sean Wharton, MD, director at Wharton Medical Clinic, said in a press release.¹ "In this Phase 3 study, orforglipron demonstrated strong efficacy results and safety consistent with the GLP-1 class, reinforcing its potential as a first-line treatment in primary care. Additionally, orforglipron could help reduce known markers of cardiovascular risk associated with obesity and support meaningful improvements in public health."

At 72 weeks, participants receiving the highest dose of orforglipron lost an average of 27.3 lbs (12.4%) from baseline, compared with 2.2 lbs (0.9%) with placebo. All 3 doses of orforglipron (6 mg, 12 mg, and 36 mg) met the primary endpoint of superior body weight reduction versus placebo. Across secondary endpoints, 59.6% of participants on the highest dose lost at least 10% of body weight and 39.6% lost at least 15%, compared with 8.6% and 3.6% on placebo, respectively.¹

Among 1127 participants with prediabetes at baseline, up to 91% of those treated with orforglipron achieved near-normal blood glucose levels at 72 weeks versus 42% on placebo. The agent was also associated with reductions in waist circumference, non-HDL cholesterol, triglycerides, and systolic blood pressure. In an exploratory analysis, the highest dose reduced high-sensitivity C-reactive protein levels by 47.7%.¹

The safety profile of orforglipron was consistent with other GLP-1 receptor agonists. The most common adverse events were gastrointestinal in nature, including nausea, constipation, diarrhea, and vomiting, which were generally mild to moderate in severity. Treatment discontinuation rates ranged from 5.3% to 10.3% across orforglipron doses compared with 2.7% for placebo.¹

"Small molecules may bind to off-target receptors, which raises the potential for additional adverse effects," researchers pointed out in the study. "No such effects have been detected in the orforglipron development program to date, and the orforglipron safety profile has been consistent with peptide GLP-1 receptor agonists in phase III clinical trials."²

Orforglipron is designed to be taken once daily by mouth, but doesn't carry the same restrictions on food or liquid intake as the oral formulation of semaglutide (Rybelsus), which is only approved for type 2 diabetes. Lilly is advancing global regulatory submissions for orforglipron for obesity, with potential regulatory action as early as 2026. Development for type 2 diabetes and other obesity-related conditions is also ongoing.¹

References:

1. Lilly's oral GLP-1, orforglipron, demonstrated meaningful weight loss and cardiometabolic improvements in complete ATTAIN-1 results published in The New England Journal of Medicine. News release. Eli Lilly. September 16, 2025. Accessed September 17, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-meaningful-weight
2. Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med. Published online September 16, 2025. doi:10.1056/NEJMoa2511774