美国礼来公司Manige Konig团队研究了每日口服GLP-1受体激动剂Orforglipron治疗肥胖成年人的疗效与安全性。2023年6月23日，《新英格兰医学杂志》发表了这一成果。

肥胖是全球许多重大疾病和死亡原因的主要风险因素。目前亟需关于非肽胰高血糖素样肽-1（GLP-1）受体激动剂Orforglipron作为成人肥胖患者每日一次口服减肥疗法的疗效和安全性的数据。

在这项2期随机双盲试验中，研究招募了患有肥胖或超重加上至少一种与体重相关的共病且没有糖尿病的成年人。参与者被随机分配接受四种剂量Orforglipron（12、24、36或45mg）中的一种或安慰剂，每天一次，持续36周。在第26周（主要终点）和第36周（次要终点）评估体重与基线的百分比变化。

共有272名参与者接受了随机分组。基线时，平均体重为108.7公斤，平均体重指数（BMI）为37.9。在第26周，Orforglipron剂量组的体重与基线相比的平均变化范围为−8.6%至−12.6%，安慰剂组为−2.0%。在第36周，Orforglipron组的平均变化范围为-9.4%至-14.7%，安慰剂组的平均变化为-2.3%。到第36周，46%至75%接受Orforglipron治疗的参与者体重减轻了至少10%，而接受安慰剂治疗的参与者为9%。Orforglipron的使用改善了所有预先指定的体重相关和心脏代谢指标。Orforglipron报告的最常见不良事件是胃肠道事件，为轻度至中度，主要发生在剂量增加期间，并导致整个剂量组中10%至17%的参与者停用Orforglipron。Orforglipron的安全性与GLP-1受体激动剂类的安全性一致。

研究结果表明，每日口服Orforglipron（一种非肽GLP-1受体激动剂）与体重减轻有关。Orforglipron报告的不良事件与注射用GLP-1受体激动剂的不良事件相似。

附：英文原文

Title: Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity | NEJM

Author: Sean Wharton, M.D.,, Thomas Blevins, M.D.,, Lisa Connery, M.D.,, Julio Rosenstock, M.D.,, Sohini Raha, Ph.D.,, Rong Liu, Ph.D.,, Xiaosu Ma, Ph.D.,, Kieren J. Mather, M.D.,, Axel Haupt, M.D.,, Deborah Robins, M.S.,, Edward Pratt, M.D.,, Christof Kazda, M.D.,, and Manige Konig, M.D., Ph.D.

Issue&Volume: 2023-06-23

Abstract:

Background

Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.

Methods

In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).

Results

A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from 8.6% to 12.6% across the orforglipron dose cohorts and was 2.0% in the placebo group. At week 36, the mean change ranged from 9.4% to 14.7% with orforglipron and was 2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.

Conclusions

Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists.

DOI: 10.1056/NEJMoa2302392

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2302392