近日，加拿大约克大学Sean Wharton团队研究了口服小分子GLP-1受体激动剂Orforglipron治疗肥胖的疗效与安全性。这一研究成果发表在2025年9月16日出版的《新英格兰医学杂志》上。

Orforglipron是一种小分子、非肽口服胰高血糖素样肽-1 （GLP-1）受体激动剂，目前正被研究用于治疗肥胖。

在这项3期、多国、随机、双盲试验中，研究组检查了每日一次、剂量为6mg、12mg或36mg的Orforglipron与安慰剂（按3:3:3:4的比例分配）作为健康饮食和体育活动辅助治疗的安全性和有效性，为期72周。所有患者均为肥胖，无糖尿病。主要终点是体重从基线到第72周的变化百分比，根据治疗方案估计值和意向治疗人群进行评估。

共有3127名患者接受随机分组。从基线到第72周，体重的平均变化为：6 mg Orforglipron组为- 7.5%(95%可信区间，- 8.2至- 6.8)，12 mg Orforglipron组为- 8.4%(95%可信区间，- 9.1至- 7.7)，36 mg Orforglipron组为- 11.2%(95%可信区间，- 12.0至- 10.4)，而安慰剂组为- 2.1%(95%可信区间，- 2.8至- 1.4)（所有与安慰剂比较的P<为0.001）。在Orforglipron 36毫克组的患者中，54.6%的患者减少了10%或更多，36.0%的患者减少了15%或更多，18.4%的患者减少了20%或更多，而安慰剂组的患者分别为12.9%，5.9%和2.8%。腰围、收缩压、甘油三酯水平和非高密度脂蛋白胆固醇水平与安慰剂相比显著改善。不良事件导致orforglipron组5.3 - 10.3%的患者和安慰剂组2.7%的患者停止治疗。Orforglipron最常见的不良事件是胃肠道反应，大多为轻度至中度。

研究结果表明，在成人肥胖患者中，使用Orforglipron治疗72周后，体重的下降明显大于安慰剂；不良事件概况与其他GLP-1受体激动剂一致。

附：英文原文

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

Author: Sean Wharton, Louis J. Aronne, Adam Stefanski, Nasreen F. Alfaris, Andreea Ciudin, Koutaro Yokote, Bruno Halpern, Alpana P. Shukla, Chunmei Zhou, Lisa Macpherson, Sheryl E. Allen, Nadia N. Ahmad, Suzanne R. Klise

Issue&Volume: 2025-09-16

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.

DOI: 10.1056/NEJMoa2511774

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2511774