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

作者：Sean Wharton, Louis J. Aronne, Adam Stefański, Nasreen Alfaris, Andreea Ciudin, Koutaro Yokote, Bruno Halpern, Alpana P. Shukla, Chunmei Zhou, Lisa Macpherson, Sheryl Allen, Nadia N. Ahmad, Suzanne Klise · 发表于：New England Journal of Medicine · 年份：2025 · DOI：10.1056/nejmoa2511774 · 被引用次数：141 · 研究领域：Diabetes Treatment and Management、Bariatric Surgery and Outcomes、Pharmacology and Obesity Treatment

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 orf...