Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.

We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity.

我们旨在研究固定剂量组合的cagrilintide和semaglutide（cagrilintide-semaglutide，也称为CagriSema）与semaglutide或cagrilintide相比，在2型糖尿病和超重或肥胖患者中控制血糖的疗效和安全性。

Methods

REIMAGINE 2 was a randomised, double-blind, placebo-controlledand active-controlled, parallel-group study conducted in 30 countries (trial sites included university hospitals, health-care centres, research centres, and other centres).

REIMAGINE 2 是一项在30个国家开展的随机、双盲、安慰剂对照和活性对照、平行组研究（试验地点包括大学医院、医疗中心、研究中心和其他中心）。

Participants aged 18 years or older with inadequately controlled type 2 diabetes (HbA1c 7·0-10·5% [53-91 mmol/mol]) receiving metformin with or without an SGLT2 inhibitor, and a BMI of 25 kg/m2 or more, were randomly assigned (8:8:2:8:8:1:1) to receive once-weekly subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (hereafter cagrilintide-semaglutide [2·4 mg each]), semaglutide 2·4 mg, cagrilintide 2·4 mg, cagrilintide 1·0 mg plus semaglutide 1·0 mg (hereafter cagrilintide-semaglutide [1·0 mg each]), semaglutide 1·0 mg, or corresponding placebo for 68 weeks.

年龄在18岁或以上的2型糖尿病患者（HbA1c 7·0-10·5% [53-91 mmol/mol]），正在接受二甲双胍治疗，有或没有SGLT2抑制剂，且BMI为25 kg/m2或更高，被随机分配（8:8:2:8:8:1:1）接受每周一次皮下注射cagrilintide 2·4 mg加semaglutide 2·4 mg（以下简称cagrilintide-semaglutide [每种2·4 mg]），semaglutide 2·4 mg，cagrilintide 2·4 mg，cagrilintide 1·0 mg加semaglutide 1·0 mg（以下简称cagrilintide-semaglutide [每种1·0 mg]），semaglutide 1·0 mg，或相应的安慰剂，为期68周。

Randomisation was done using a web-based system with blocked randomisation (block size 36) and stratification according to inclusion in the continuous glucose monitoring subgroup, HbA1c less than 8·5% at screening (yes or no), and country of participation (Japan; yes or no).

随机化是通过基于网络的系统完成的，使用了阻塞随机化（阻塞大小为36），并根据是否纳入连续血糖监测亚组、筛查时HbA1c是否低于8.5%以及参与国家（日本；是或否）进行了分层。

The study participants, investigators, and study sponsor staff were masked to treatment allocation within dose level throughout the study.

在整个研究期间，研究参与者、研究人员和研究赞助方的工作人员对剂量水平内的治疗分配进行了盲法处理。

The primary endpoint was change in HbA1c from baseline to week 68 with cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg in the full analysis set; safety was assessed in all participants who received at least one dose of study product.

主要终点是从基线到第68周HbA1c的变化，比较cagrilintide-semaglutide（各2.4 mg）与semaglutide 2.4 mg在完整分析集中的效果；所有至少接受一次研究产品剂量的参与者均进行了安全性评估。

This study is registered with ClinicalTrials.gov (NCT06065540) and is complete.

该研究已在ClinicalTrials.gov注册（NCT06065540），研究已完成。

Results

From Oct 10, 2023, to July 29, 2024, 3593 people were screened for eligibility, 2713 of whom were randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=603), semaglutide 2·4 mg (n=605), cagrilintide 2·4 mg (n=152), cagrilintide-semaglutide (1·0 mg each; n=595), semaglutide 1·0 mg (n=609), or placebo (pooled 2·4 mg and 1·0 mg; n=149). 1164 (42·9%) of 2713 were female, 1549 (57·1%) were male, and 2207 (81·3%) were White.

从2023年10月10日至2024年7月29日，共有3593人被筛查以确定是否符合资格，其中2713人被随机分配到cagrilintide-semaglutide组（各2.4毫克；n=603）、semaglutide 2.4毫克组（n=605）、cagrilintide 2.4毫克组（n=152）、cagrilintide-semaglutide组（各1.0毫克；n=595）、semaglutide 1.0毫克组（n=609）或安慰剂组（2.4毫克和1.0毫克合并；n=149）。2713人中有1164人（42.9%）为女性，1549人（57.1%）为男性，2207人（81.3%）为白人。

Of the randomly assigned participants, 2595 (95·7%) completed the study and 2376 (87·6%) were on treatment at week 68.

在随机分配的参与者中，有2595人（95.7%）完成了研究，2376人（87.6%）在第68周仍在接受治疗。

Mean baseline HbA1c was 8·2% (SD 0·9).

基线平均糖化血红蛋白（HbA1c）为8.2%（标准差0.9）。

For the primary endpoint using the efficacy estimand, mean HbA1c change was significantly greater with cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg (-1·91 percentage points [SE 0·04] vs -1·75 percentage points [0·04]; estimated treatment difference -0·16 percentage points [95% CI -0·27 to -0·05]; p=0·0035).

在主要终点使用疗效估计值时，cagrilintide-semaglutide（各2.4毫克）与semaglutide 2.4毫克相比，平均HbA1c变化显著更大（-1.91个百分点[标准误0.04]对比-1.75个百分点[0.04]；估计治疗差异为-0.16个百分点[95%置信区间-0.27至-0.05]；p=0.0035）。

Adverse events were reported in 524 (86·9%) of 603 participants in the cagrilintide-semaglutide (2·4 mg each) group, 491 (81·2%) of 605 in the semaglutide 2·4 mg group, 125 (82·2%) of 152 in the cagrilintide 2·4 mg group, 485 (81·6%) of 594 in the cagrilintide-semaglutide (1·0 mg each) group, 477 (78·5%) of 608 in the semaglutide 1·0 mg group, and 105 (70·5%) of 149 in the placebo group.

在接受cagrilintide-semaglutide（各2.4毫克）治疗的603名参与者中，有524人（86.9%）报告了不良事件，在接受semaglutide 2.4毫克治疗的605名参与者中，有491人（81.2%）报告了不良事件，在接受cagrilintide 2.4毫克治疗的152名参与者中，有125人（82.2%）报告了不良事件，在接受cagrilintide-semaglutide（各1.0毫克）治疗的594名参与者中，有485人（81.6%）报告了不良事件，在接受semaglutide 1.0毫克治疗的608名参与者中，有477人（78.5%）报告了不良事件，而在接受安慰剂治疗的149名参与者中，有105人（70.5%）报告了不良事件。

The most common adverse events in the active treatment groups were gastrointestinal disorders.

活性治疗组中最常见的不良事件是胃肠道疾病。

interpretation

Cagrilintide-semaglutide (2·4 mg each) was superior to semaglutide 2·4 mg in reducing HbA1c in participants with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor.

在使用二甲双胍，无论是否联合SGLT2抑制剂的2型糖尿病患者中，Cagrilintide-semaglutide (每种2·4 mg)在降低HbA1c方面优于semaglutide 2·4 mg。

The safety profile of cagrilintide-semaglutide was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide.

Cagrilintide-semaglutide的安全性与其所属的GLP-1受体激动剂类别一致，并与cagrilintide以往的安全数据相符。

These findings support the added benefit of cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg for glycaemic control.

这些发现支持了cagrilintide-semaglutide（各2.4 mg）相比semaglutide 2.4 mg在血糖控制上的附加益处。

funding

Novo Nordisk.

诺和诺德。