Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment

  • N Engl J Med. 2025 Nov 6;393(18):1796-1806. doi: 10.1056/NEJMoa2511774.
Sean Wharton  1  2  3 ,  Louis J Aronne  4 ,  Adam Stefanski  5 ,  Nasreen F Alfaris  6 ,  Andreea Ciudin  7  8  9  10  11 ,  Koutaro Yokote  12 ,  Bruno Halpern  13 ,  Alpana P Shukla  4 ,  Chunmei Zhou  5 ,  Lisa Macpherson  5 ,  Sheryl E Allen  5 ,  Nadia N Ahmad  5 ,  Suzanne R Klise  5 ,  ATTAIN-1 Trial Investigators
Affiliations
  • 1. McMaster University, Hamilton, ON, Canada.
  • 2. York University, Toronto.
  • 3. Wharton Weight Management Clinic, Burlington, ON, Canada.
  • 4. Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York.
  • 5. Eli Lilly, Indianapolis.
  • 6. Obesity, Endocrine, and Metabolism Center, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 7. Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Barcelona.
  • 8. Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca, Barcelona.
  • 9. Department of Human Physiology, Universitat Autònoma de Barcelona, Barcelona.
  • 10. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid.
  • 11. Instituto de Salud Carlos III, Madrid.
  • 12. Chiba University, Chiba, Japan.
  • 13. Obesity Center, Nove de Julho Hospital, São Paulo.
PMID: 40960239 DOI: 10.1056/NEJMoa2511774
Abstract

Background: Orforglipron, a small-molecule, nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, is being investigated as a treatment for Obesity.

Methods: In this phase 3, multinational, randomized, double-blind trial, we examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks. All the patients had Obesity without diabetes mellitus. The primary end point was the percent change in body weight from baseline to week 72, as assessed according to the treatment-regimen estimand in the intention-to-treat population.

Results: A total of 3127 patients underwent randomization. The mean change in body weight from baseline to week 72 was -7.5% (95% confidence interval [CI], -8.2 to -6.8) with 6 mg of orforglipron, -8.4% (95% CI, -9.1 to -7.7) with 12 mg of orforglipron, and -11.2% (95% CI, -12.0 to -10.4) with 36 mg of orforglipron, as compared with -2.1% (95% CI, -2.8 to -1.4) with placebo (P<0.001 for all comparisons with placebo). Among the patients in the orforglipron 36-mg group, 54.6% had a reduction of 10% or more, 36.0% had a reduction of 15% or more, and 18.4% had a reduction of 20% or more, as compared with 12.9%, 5.9%, and 2.8% of the patients, respectively, in the placebo group. Waist circumference, systolic blood pressure, triglyceride levels, and non-HDL Cholesterol levels significantly improved with orforglipron treatment as compared with placebo. Adverse events resulted in treatment discontinuation in 5.3 to 10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate.

Conclusions: In adults with Obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo; the adverse-event profile was consistent with that of other GLP-1 Receptor agonists. (Funded by Eli Lilly; ATTAIN-1 ClinicalTrials.gov number, NCT05869903.).