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.

This study aimed to compare the efficacy and safety of orforglipron with oral semaglutide in individuals with type 2 diabetes inadequately controlled with metformin.

本研究旨在比较 orforglipron 与口服 semaglutide 在使用二甲双胍控制不佳的2型糖尿病患者中的疗效和安全性。

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.

在这项为期52周的随机、开放标签、活性对照、多中心、多国的III期研究中，我们招募了成年（≥18岁）2型糖尿病患者，这些患者使用二甲双胍（每天≥1500毫克）控制不佳，糖化血红蛋白（HbA1c）在7.0%至10.5%（53-91毫摩/摩尔）之间，BMI至少为25 kg/m2，来自阿根廷、中国、日本、墨西哥和美国的131个医学研究中心和医院。

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.

参与者被随机分配（1:1:1:1）到或尔格利普隆（12毫克或36毫克）或司美格鲁肽（7毫克或14毫克）；所有组别都有长达4周的导入期和52周的治疗期，药物每天口服一次。

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-treatpopulation.

该研究的主要目标是评估或非格利普隆36毫克与司美格鲁肽14毫克以及或非格利普隆12毫克与司美格鲁肽7毫克在基线至第52周的HbA1c平均变化上是否非劣效（非劣效界值为0.3%），在意向性治疗人群中进行评估。

Hierarchical analysis for superiority was prespecified after attainment of non-inferiority.

在达到非劣效性后，预先规定了按层次分析的优越性分析。

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.

基于所有随机分配参与者（不论中途事件）的数据，治疗方案的估计值是主要估计值；疗效估计值被视为支持性的。

The safety endpoints used data from all participants who received at least one dose of the study drug.

安全性终点使用了所有至少接受过一次研究药物剂量的参与者的数据。

This trial was registered on ClinicalTrials.gov (NCT06045221) and is completed.

该试验已在ClinicalTrials.gov上注册（NCT06045221），并已完成。

Results

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).

从2023年9月22日到2025年8月22日，共有1698名参与者被招募并随机分配到orforglipron组（12 mg组424人，36 mg组423人）或semaglutide组（7 mg组426人，14 mg组425人）。

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.

对于治疗方案估计值，从基线HbA1c为8.3%的平均变化在第52周，使用12毫克的orforglipron为-1.71%（标准误0.07），使用36毫克的orforglipron为-1.91%（标准误0.08），使用7毫克的semaglutide为-1.23%（标准误0.05），使用14毫克的semaglutide为-1.47%（标准误0.06）。

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.

估计的治疗差异为：对于12毫克的orforglipron与7毫克的semaglutide相比，差异为-0.48%（95%置信区间-0.65至-0.31；p<0.0001）；对于36毫克的orforglipron与14毫克的semaglutide相比，差异为-0.44%（95%置信区间-0.62至-0.26；p<0.0001）；对于12毫克的orforglipron与14毫克的semaglutide相比，差异为-0.24%（95%置信区间-0.41至-0.072；p=0.0050）；对于36毫克的orforglipron与7毫克的semaglutide相比，差异为-0.68%（95%置信区间-0.85至-0.50；p<0.0001）。

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.

非劣效性的主要目标已经达成，两种或福德利普隆剂量均显示出优于两种司美格鲁肽剂量的优势，包括或福德利普隆12毫克与司美格鲁肽14毫克的比较。

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.

最常见的不良事件是胃肠道事件（或福德利普隆：12毫克组424人中有249人[59%]，36毫克组423人中有245人[58%]；司美格鲁肽：7毫克组426人中有157人[37%]，14毫克组425人中有193人[45%]），其中大多数为轻度至中度严重。

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).

在orforglipron组中，由于不良事件而停止研究治疗的参与者更多（12 mg组37人[9%]，36 mg组41人[10%]），而在semaglutide组中则较少（7 mg组19人[4%]，14 mg组21人[5%]）。此外，orforglipron组的平均心率增加更大（12 mg组3.7次/分钟；36 mg组4.7次/分钟），而semaglutide组的平均心率增加较小（7 mg组1.0次/分钟；14 mg组1.5次/分钟）。

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.

研究期间发生了四起死亡事件：orforglipron 12 mg组中有一例，orforglipron 36 mg组中有一例，semaglutide 7 mg组中有两例。

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.

在使用二甲双胍控制不佳的2型糖尿病患者中，或forglipron 12毫克和36毫克在52周时与基线相比，糖化血红蛋白（HbA1c）的平均变化显示出非劣效性，并且优于semaglutide 7毫克和14毫克。

Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidenceof gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide.

尽管或forglipron和semaglutide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semaglutide相比，或forglipron的胃肠道事件发生率、因不良事件导致的停药率以及脉搏率的平均增加均较高。

funding

Eli Lilly.

礼来公司