近日，美国得克萨斯大学麦戈文医学院Deborah B Horn团队研究了口服小分子GLP-1受体激动剂Orforglipron治疗2型糖尿病患者肥胖的疗效与安全性。2025年11月20日出版的《柳叶刀》杂志发表了这项成果。

肥胖是一种慢性疾病，是2型糖尿病及其并发症的重要诱因。该研究旨在评估口服小分子（非肽）GLP-1受体激动剂orforglipron治疗成人2型糖尿病的肥胖效果。

这项为期72周的三期、双盲、安慰剂对照试验在10个国家的136个地点进行。BMI为27 kg/m²或更高，糖化血红蛋白（HbA1c）为7-10% （53-86 mmol/mol）的参与者被随机分配（1:1:1:2），每天一次接受6 mg、12 mg、36 mg或安慰剂治疗。主要终点是体重从基线到第72周的平均变化百分比。治疗方案估计（使用来自所有随机分配的参与者的数据，不考虑并发事件）是主要估计，疗效估计被认为是支持性的。对所有接受至少一剂研究药物的患者进行安全性评估。

从2023年6月5日至2024年2月15日，筛选了2859名参与者，其中1613名（757名[46.9%]女性）被随机分配，在剂量递增阶段后，接受orforglipron 6mg（n=329）、12mg（n=332）、36mg（n=322）或安慰剂（n=630），作为生活方式改变的辅助治疗；1444例（89.5%）完成了研究。基线体重为101.4 kg (SD 22.5)， BMI为35.6 kg/m² (SD 6.6)， HbA1c为8.05%（SD 0.75; 64.4 mmol/mol [SD 8.2]）。对于治疗方案估计，体重从基线到第72周的平均百分比变化为6 mg组（估计治疗差异[ETD] -2·7；p< 0.0001）为- 5.1% (95% CI为-6·0至- 4.2)，12 mg组（ETD - 4.5[-5·5至-3·6]；p< 0.0001）为- 7.0%(- 7.8至- 6.2)，36 mg组（ETD - 7.1[-8·2至-6·1]；p< 0.0001）为- 9.6%(- 10.5至- 8.7)，安慰剂组为- 5.5%(-3·0至-1·9)（与安慰剂相比，所有p< 0.0001）。

所有预先设定的体重和心脏代谢指标，包括HbA1c，在orforglipron治疗后均有统计学上的显著改善。因不良事件（主要是胃肠道相关）而中断治疗的orforglipron（6.1% ~ 9.5%）高于安慰剂（4.1%）。最常见的不良事件是轻至中度胃肠道事件，主要发生在剂量增加期间。在研究期间报告了10例死亡：6例使用orforglipron， 4例使用安慰剂。研究者认为所有的死亡都与研究治疗无关，除了安慰剂组的1例和12mg orforglipron组的1例。对于orforglipron组的病例，没有治疗相关的关联报道。

研究结果表明，在患有肥胖或超重和2型糖尿病的成年人中，每天一次的orforglipron作为生活方式改变的辅助治疗，与安慰剂相比，在统计学上有更好的体重减轻效果，其安全性与其他GLP-1受体激动剂相似。

附：英文原文

Title: Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial

Author: Deborah B Horn, Donna H Ryan, Sanja Giljanovic Kis, Breno Alves, Yiming Mu, Sin Gon Kim, Jens Aberle, Stephen C Bain, Sheryl Allen, Elizabeth Sarker, Qiwei Wu, Adam Stefanski, Irina Jouravskaya

Issue&Volume: 2025-11-20

Abstract:

Background

Obesity is a chronic disease that significantly contributes to type 2 diabetes and its complications. We aimed to evaluate orforglipron, an oral small-molecule (non-peptide) GLP-1 receptor agonist, for obesity treatment in adults with type 2 diabetes.

Methods

This 72-week, phase 3, double-blind, placebo-controlled trial was conducted across 136 sites in ten countries. Participants with a BMI of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1:2) to once-daily orforglipron 6 mg, 12 mg, 36 mg, or placebo. The primary endpoint was the mean percent change in bodyweight from baseline to week 72. The treatment regimen estimand (using data from all randomly assigned participants, regardless of intercurrent events) was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT05872620) and is completed.

Findings

From June 5, 2023, to Feb 15, 2024, 2859 participants were screened, and 1613 (757 [46·9%] female) were randomly assigned, following a dose-escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification; 1444 (89·5%) completed the study. Baseline bodyweight was 101·4 kg (SD 22·5), BMI 35·6 kg/m2 (SD 6·6), and HbA1c 8·05% (SD 0·75; 64·4 mmol/mol [SD 8·2]). For the treatment regimen estimand, the mean percent change in bodyweight from baseline to week 72 was –5·1% (95% CI –6·0 to –4·2) with 6 mg (estimated treatment difference [ETD] –2·7 [95% CI –3·7 to –1·6]; p<0·0001), –7·0% (–7·8 to –6·2) with 12 mg (ETD –4·5 [–5·5 to –3·6]; p<0·0001), and –9·6% (–10·5 to –8·7) with 36 mg orforglipron (ETD –7·1 [–8·2 to –6·1]; p<0·0001), versus –2·5% (–3·0 to –1·9) with placebo (all p<0·0001 compared with placebo). All prespecified weight and cardiometabolic measures including HbA1c statistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6·1–9·9%) versus placebo (4·1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation. Ten deaths were reported during the study: six with orforglipron and four with placebo. Investigators deemed all deaths unrelated to the study treatment, except for one case in the placebo group and one case in the 12 mg orforglipron group. For the case in the orforglipron group, no treatment-related association was reported.

Interpretation

In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.

DOI: 10.1016/S0140-6736(25)02165-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)02165-8/abstract