近日，美国得克萨斯大学西南医学中心Julio Rosenstock团队研究了成人2型糖尿病患者每日一次口服奥福格利朋与口服司美格鲁肽的疗效和安全性比较。相关论文于2026年2月26日发表在《柳叶刀》杂志上。

奥福格利朋是一种新型非肽类GLP-1受体激动剂，设计用于每日口服给药，且不受饮食或饮水的限制。该研究旨在比较奥福格利朋与口服司美格鲁肽在经二甲双胍治疗后血糖控制不佳的2型糖尿病患者中的疗效和安全性。

这项为期52周的随机、开放标签、活性药物对照、多中心、跨国III期研究，在阿根廷、中国、日本、墨西哥和美国的131个医学研究中心和医院进行。研究纳入的成年受试者（≥18岁）需满足以下条件：经二甲双胍（≥1500 mg/天）治疗后血糖控制不佳的2型糖尿病，糖化血红蛋白（HbA_1c）在7.0%至10.5%（53–91 mmol/mol）之间，且体重指数（BMI）至少为25 kg/m²。受试者被随机分配（1:1:1:1）至奥福格利朋（12 mg 或 36 mg）组或司美格鲁肽（7 mg 或 14 mg）组；所有组均包括最多4周的导入期和52周的治疗期，药物均为每日一次口服给药。

研究的主要目的是在意向治疗人群中，评估第52周时HbA_1c较基线的平均变化，验证奥福格利朋36 mg对比司美格鲁肽14 mg、以及奥福格利朋12 mg对比司美格鲁肽7 mg的非劣效性（非劣效性界值为0.3%）。在确认非劣效性后，预先设定了优效性的分层分析。基于所有随机分配受试者的数据（不考虑伴发事件）的治疗方案估计量是主要估计量；疗效估计量作为支持性分析。安全性终点使用了所有至少接受过一次研究药物受试者的数据。该试验已在ClinicalTrials.gov注册（NCT06045221），并已完成。

2023年9月22日至2025年8月22日，研究组共招募了1698名受试者，被随机分配至奥福格利朋组（12 mg组n=424，36 mg组n=423）或司美格鲁肽组（7 mg组n=426，14 mg组n=425）。对于治疗方案估计量，基线HbA_1c为8.3%，第52周时的平均变化为：奥福格利朋12 mg组为–1.71%（标准误0.07），奥福格利朋36 mg组为–1.91%（0.08），司美格鲁肽7 mg组为–1.23%（0.05），司美格鲁肽14 mg组为–1.47%（0.06）。估计的治疗差异分别为：奥福格利朋12 mg对比司美格鲁肽7 mg为–0.48%（95% CI –0.65至–0.31；p<0.0001）；奥福格利朋36 mg对比司美格鲁肽14 mg为–0.44%（–0.62至–0.26；p<0.0001）；奥福格利朋12 mg对比司美格鲁肽14 mg为–0.24%（95% CI –0.41至–0.072；p=0.0050）；奥福格利朋36 mg对比司美格鲁肽7 mg为–0.68%（–0.85至–0.50；p<0.0001）。达到了非劣效性的主要目标，并且两个剂量的奥福格利朋均显示出对两个剂量司美格鲁肽的优效性，包括奥福格利朋12 mg对比司美格鲁肽14 mg。

最常见的不良事件是胃肠道事件（奥福格利朋：12 mg组424例中249例[59%]，36 mg组423例中245例[58%]；司美格鲁肽：7 mg组426例中157例[37%]，14 mg组425例中193例[45%]），其中大部分为轻中度。因不良事件而停止研究治疗的受试者比例，奥福格利朋组（12 mg组37例[9%]，36 mg组41例[10%]）高于司美格鲁肽组（7 mg组19例[4%]，14 mg组21例[5%]），并且奥福格利朋组的平均脉搏增加幅度（12 mg组 3.7次/分；36 mg组 4.7次/分）也大于司美格鲁肽组（7 mg组 1.0次/分；14 mg组 1.5次/分）。研究期间发生4例死亡：奥福格利朋12 mg组1例，奥福格利朋36 mg组1例，司美格鲁肽7 mg组2例。

研究结果表明，在经二甲双胍治疗后血糖控制不佳的2型糖尿病患者中，从基线至52周的HbA_1c平均变化而言，奥福格利朋12 mg和36 mg不劣于且优于司美格鲁肽7 mg和14 mg。尽管奥福格利朋和司美格鲁肽的安全性特征总体上与GLP-1受体激动剂类药物一致，但与口服司美格鲁肽相比，奥福格利朋的胃肠道事件发生率、因不良事件停药率和平均脉搏增加幅度更高。

附：英文原文

Title: Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial

Author: Julio Rosenstock, Daisuke Yabe, David Cox, Jianghao Li, Max Denning, Wen-Shuo Wu, Rong Liu, Youna Zhao, Federico Perez Manghi, Franklin Abalos, Pablo Costanzo, Ana Chiesa, Natacha Maldonado, Susana Salzberg, Claudia Goycoa, Horacio Sessa, Diego Aizenberg, Marisa Vico, Fernando Guerlloy, María Schiavoni, Mariano Chahin, Adriana Villarino, Ines Bartolacci, Adrian Hernandez Gauna, Marcos Mayer, Shunbin Li, Zhenmei An, Jianhua Ma, Shu Li, Jian Zhou, Guoyue Yuan, Yibing Lu, Hongman Wang, Qingju Li, Xinyu Li, Tian Feng Wu, Xiaozhen Jiang, Yawei Zhang, Yufeng Li, Hong Zhu, Yihua Wang, Hongwei Jiang, Jie Shen, Xiaolin Dong, ZhiFeng Cheng, Tetsuji Niiya, Shinya Nakamoto, Nobuyuki Sato, Masahiko Takai, Takehiro Kato, Toshihiko Shiraiwa, Hidenori Bando, Akira Ohishi, Takeshi Osonoi, Melchor Alpizar Salazar, Pedro García Hernández, Elías Alberto García Cantú, Manuel de los Rios Ibarra, Emilia Pelayo Orozco, Maria Arechavaleta Granell, José Lazcano Soto, Luis Virgen Carrillo, Laura Castro Castrezana, Silvia Jimenez Ramos, Arnulfo Gonzalez, Carlos Alejandro Stobschinski de Alba, Ramiro Banda Elizondo, Raymundo García Reza, Guillermo Gonzalez Galvez, Jose Gerardo Gonzalez Gonzalez, Yshay Shlesinger, Jawad Sarwar, Sumana Gangi, Bram Wieskopf, Thaidra Gaufin, Rachel Anderson, Eric Garcia-Torres, Eduardo Luna, Peter Philander, Christopher Chow, Sridhar Guduri, Alex Gonzalez-Bossolo, Brock McConnehey, Lisa Usdan, Donald Brautigam, Martha Gomez-Cuellar, Michael Adams, Alison Schneider, Dennis Tsang, Peter Mattar, Talessa Powell, Paola Mansilla-Letelier, Lisa Connery, Reynaldo Lopez, Robert Buynak, Damaris Vega, Juan Loy, Herbert Conaway, James Schultz, John Kim, Jon Finley, James Beach, Bob Hutchins, Susan Brian, Lon Lynn, Anjanette Tan, Jose Vazquez-Tanus, Joseph Moran, Chad Crystal, Nicole Pant, Bryce Palchick, Flint Packer, Frances Broyles, Brandon Alleman, Jose Mandry, Hanid Audish, Evelyne Davidson, Jamy Ard, Barry Horowitz, Kathryn Lucas, Orlando Puente, Julio Rosenstock, Jorge Serje, Patrick Dennis, Tonita Washington, Alexander Murray, Michael Oliver, Robert Busch, Samuel Harrison Ross, Jeffrey London, Charles Montano, Michael Zimmerman, Abdulhassan Saad, Amer Al-Karadsheh, Leonard Dunn, Shannon Hopson, Bradley Freilich

Issue&Volume: 2026-02-26

Abstract:

Background

Orforglipron is a novel non-peptide (GLP-1) receptor agonist designed for daily oral administration without food or water restrictions. This study aimed to compare the efficacy and safety of orforglipron with oral semaglutide in individuals with type 2 diabetes inadequately controlled with metformin.

Methods

In this 52-week, randomised, open-label, active-controlled, multicentre, multinational, phase 3 study, we enrolled adults (≥18 years) with type 2 diabetes inadequately controlled with metformin (≥1500 mg per day), glycated haemoglobin (HbA1c) between 7·0% and 10·5% (53–91 mmol/mol), and BMI at least 25 kg/m2 from 131 medical research centres and hospitals in Argentina, China, Japan, Mexico, and the USA. Participants were randomly assigned (1:1:1:1) to orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg); all groups had an up to 4-week lead-in period and 52-week treatment period, with the drugs administered orally once per day. The primary objective of the study was to assess non-inferiority of orforglipron 36 mg versus semaglutide 14 mg and orforglipron 12 mg versus semaglutide 7 mg for mean change at week 52 from baseline in HbA1c (with a non-inferiority margin of 0·3%) in the intention-to-treat population. Hierarchical analysis for superiority was prespecified after attainment of non-inferiority. The treatment regimen estimand, based on data from all randomly assigned participants regardless of intercurrent events, was the primary estimand; the efficacy estimand was considered supportive. The safety endpoints used data from all participants who received at least one dose of the study drug. This trial was registered on ClinicalTrials.gov (NCT06045221) and is completed.

Findings

From Sept 22, 2023, to Aug 22, 2025, 1698 participants were recruited and randomly assigned to orforglipron (n=424 on 12 mg and n=423 on 36 mg) or semaglutide (n=426 on 7 mg and n=425 on 14 mg). For the treatment regimen estimand, mean changes at week 52 from a baseline HbA1c of 8·3% were –1·71% (SE 0·07) with orforglipron 12 mg, –1·91% (0·08) with orforglipron 36 mg, –1·23% (0·05) with semaglutide 7 mg, and –1·47% (0·06) with semaglutide 14 mg. Estimated treatment differences were –0·48% (95% CI –0·65 to –0·31; p<0·0001) for orforglipron 12 mg versus semaglutide 7 mg; –0·44% (–0·62 to –0·26; p<0·0001) for orforglipron 36 mg versus semaglutide 14 mg; –0·24% (95% CI –0·41 to –0·072; p=0·0050) for orforglipron 12 mg versus semaglutide 14 mg; and –0·68% (–0·85 to –0·50; p<0·0001) for orforglipron 36 mg versus semaglutide 7 mg. The primary objective of non-inferiority was met and both orforglipron doses showed superiority to both semaglutide doses, including orforglipron 12 mg versus semaglutide 14 mg. The most frequent adverse events were gastrointestinal events (orforglipron: 249 [59%] of 424 on 12 mg and 245 [58%] of 423 on 36 mg; semaglutide: 157 [37%] of 426 on 7 mg and 193 [45%] of 425 on 14 mg), most of which were mild to moderate in severity. More participants in the orforglipron groups (37 [9%] on 12 mg and 41 [10%] on 36 mg) discontinued study treatment due to adverse events than in the semaglutide groups (19 (4%) on 7 mg and 21 (5%) on 14 mg), and mean increase in pulse rate was greater in the orforglipron groups (12 mg 3·7 bpm; 36 mg 4·7 bpm) than in the semaglutide groups (7 mg 1·0 bpm; 14 mg 1·5 bpm). Four deaths occurred during the study: one in the orforglipron 12 mg group, one in the orforglipron 36 mg group, and two in the semaglutide 7 mg group.

Interpretation

In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA1c from baseline to 52 weeks. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide.

DOI: 10.1016/S0140-6736(26)00202-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00202-3/abstract