Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial.

We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population.

我们评估了固定剂量组合cagrilintide 2·4 mg和semaglutide 2·4 mg与单独semaglutide 2·4 mg在东亚人群中用于体重管理的疗效和安全性。

Methods

This double-blind, parallel-group, phase 3a trial (REDEFINE 5) was conducted across 21 sites (community, hospital) in Japan and one site in Taiwan.

这是一项双盲、平行组、3a期试验（REDEFINE 5），在日本的21个地点（社区、医院）和台湾的一个地点进行。

We included participants aged at least 18 years with a BMI of at least 27 kg/m2 and at least two obesity-related complications, or with a BMI of at least 35 kg/m2 and at least one obesity-related complication (per the Japan Society for the Study of Obesity guidelines), with or without type 2 diabetes.

我们纳入了年龄至少18岁的参与者，其体质指数（BMI）至少为27 kg/m2且至少有两项与肥胖相关的并发症，或者BMI至少为35 kg/m2且至少有一项与肥胖相关的并发症（根据日本肥胖研究学会指南），无论是否伴有2型糖尿病。

Participants were randomly assigned (1:1) to once-weekly subcutaneous injections of cagrilintide-semaglutide or semaglutide (both escalated to 2·4 mg), plus lifestyle intervention, for 68 weeks.

参与者被随机分配（1:1）至每周一次皮下注射cagrilintide-semaglutide或semaglutide（均增至2.4毫克），加上生活方式干预，为期68周。

Randomisation was done centrally using an interactive web response system and stratified according to planned CT scan, BMI of at least 35 kg/m2, and type 2 diabetes status.

随机分组是通过交互式网络响应系统在中心进行的，并根据计划的CT扫描、BMI至少为35 kg/m2和2型糖尿病状态进行分层。

Participants, site staff, investigators, and study funder were all masked to active study treatments.

参与者、现场工作人员、研究人员和研究资助者均对活性研究治疗措施进行了盲法处理。

The primary endpoint was relative change in bodyweight from baseline to week 68.

主要终点是基线至第68周体重的相对变化。

Efficacy analyses were done in all participants who underwent randomisation, using the trial product estimand (ie, assuming the treatment was taken as intended, regardless of dose) as the primary estimand.

在所有接受随机分组的参与者中进行了疗效分析，使用试验产品估计量（即，假设治疗按照预期进行，无论剂量如何）作为主要估计量。

Missing data at week 68 were imputed.

在第68周时缺失的数据进行了估算。

Safety analyses were done in all participants who underwent randomisation and received at least one dose of trial product.

安全性分析在所有接受随机化并至少接受一次试验产品剂量的参与者中进行。

This trial is registered with ClinicalTrials.gov (NCT05813925) and is complete.

该试验已在ClinicalTrials.gov注册（NCT05813925），并已完成。

Results

Between April 3, 2023, and Sept 15, 2023, we screened 355 individuals; 331 were randomly assigned to cagrilintide-semaglutide (n=164) or semaglutide (n=167). 226 (68%) participants were male and 105 (32%) were female; 80 (24%) had type 2 diabetes. 17 (10%) participants discontinued cagrilintide-semaglutide and ten (6%) discontinued semaglutide.

2023年4月3日至2023年9月15日期间，我们筛查了355名个体；331人被随机分配到cagrilintide-semaglutide组（n=164）或semaglutide组（n=167）。226名（68%）参与者为男性，105名（32%）为女性；80名（24%）患有2型糖尿病。有17名（10%）参与者停止使用cagrilintide-semaglutide，而有十名（6%）停止使用semaglutide。

The estimated mean change in bodyweight from baseline to week 68 was -18·4% (SE 0·7) in the cagrilintide-semaglutide group versus -11·9% (0·7) in the semaglutide group (estimated treatment difference [ETD] -6·5 percentage points [95% CI -8·4 to -4·6]; p<0·0001).

从基线到第68周，cagrilintide-semaglutide组的体重平均变化估计为-18·4%（标准误0·7），而semaglutide组为-11·9%（标准误0·7）（估计的治疗差异[ETD]为-6·5个百分点[95%置信区间-8·4至-4·6]；p<0·0001）。

Adverse events were reported by 143 (87%) of 164 participants in the cagrilintide-semaglutide group and 141 (84%) of 167 in the semaglutide group, the most common of which were gastrointestinal disorders (87 [53%] of 164 participants in the cagrilintide-semaglutide group vs 85 [51%] of 167 in the semaglutide group).

在接受cagrilintide-semaglutide治疗的164名参与者中，有143人（87%）报告了不良事件，而在接受semaglutide治疗的167名参与者中，有141人（84%）报告了不良事件，其中最常见的不良事件是胃肠道疾病（cagrilintide-semaglutide组的164名参与者中有87人[53%]，semaglutide组的167名参与者中有85人[51%]）。

One death was reported in the semaglutide 2·4 mg group, which was not judged to be treatment related by the investigator.

在semaglutide 2·4 mg组中报告了一例死亡，但调查员未判断该死亡与治疗相关。

interpretation

These findings support the efficacy and safety of cagrilintide-semaglutide for weight management in individuals from east Asia with overweight or obesity, with or without type 2 diabetes.

这些发现支持了cagrilintide-semaglutide在东亚地区超重或肥胖个体（无论是否伴有2型糖尿病）中用于体重管理的有效性和安全性。

funding

Novo Nordisk.

诺和诺德公司。

translations

For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.

摘要的日文和中文翻译请参见补充材料部分。