Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study.

We aimed to assess the efficacy and safety of cagrilintide-semaglutide for people with type 2 diabetes inadequately controlled with diet and exercise.

我们的目标是评估cagrilintide-司美格鲁肽对于那些通过饮食和运动控制不佳的2型糖尿病患者的疗效和安全性。

Methods

REIMAGINE 1 was a randomised, double-blind, parallel-group, phase 3a study carried out at 42 sites (study sites included university hospitals, health-care centres, research centres, and other centres) in six countries.

REIMAGINE 1 是一项在六个国家的42个研究地点（包括大学医院、医疗中心、研究中心和其他中心）进行的随机、双盲、平行组、3a期研究。

Adults aged 18 years or older with type 2 diabetes inadequately controlled with diet and exercise were randomly assigned (2:1:2:1) to receive once-weekly subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (cagrilintide-semaglutide [2·4 mg each]), placebo 2·4 mg plus 2·4 mg, cagrilintide 1·0 mg plus semaglutide 1·0 mg (cagrilintide-semaglutide [1·0 mg each]), or placebo 1·0 mg plus 1·0 mg for 40 weeks.

年龄在18岁或以上的2型糖尿病患者，通过饮食和运动控制不佳，被随机分配（2:1:2:1）接受每周一次皮下注射cagrilintide 2.4 mg加semaglutide 2.4 mg（cagrilintide-semaglutide [各2.4 mg]）、安慰剂2.4 mg加2.4 mg、cagrilintide 1.0 mg加semaglutide 1.0 mg（cagrilintide-semaglutide [各1.0 mg]）或安慰剂1.0 mg加1.0 mg，为期40周。

Randomisation was done using a web-based system with a block size of six and stratified according to HbA1c less than 8·5% at screening and participation in the MRI substudy.

随机分组使用了一个基于网络的系统，块大小为六，并根据筛查时的糖化血红蛋白（HbA1c）小于8.5%和参与MRI子研究的情况进行了分层。

Participants, care providers, investigators, and outcome assessors were masked within dose level and all participants received visually identical injections to maintain masking throughout the study.

参与者、护理提供者、研究人员和结果评估者在剂量水平内被蒙蔽，并且所有参与者都接受了外观相同的注射，以在整个研究期间保持蒙蔽。

The primary endpoint was change in HbA1c from baseline to week 40 in the full analysis set; safety was assessed in all participants who received at least one dose of the trial product.

主要终点是基线至第40周时全分析集中糖化血红蛋白（HbA1c）的变化；安全性评估针对所有至少接受一次试验产品剂量的参与者。

Change in bodyweight from baseline to week 40 was a prespecified secondary endpoint.

从基线至第40周体重变化是预先设定的次要终点。

This study is registered with ClinicalTrials.gov, NCT06323174, and is complete.

该研究已在ClinicalTrials.gov注册，编号为NCT06323174，研究已完成。

Results

Between March 19 and Dec 5, 2024, 294 people were screened for eligibility, 189 of whom were enrolled and randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=62), cagrilintide-semaglutide (1·0 mg each; n=63), or placebo (n=64). 103 (54%) of 189 were male, 86 (46%) were female, 147 (78%) were White, and 26 (14%) were Asian.

在2024年3月19日至12月5日期间，共有294人接受了资格筛查，其中189人符合入选标准并被随机分配接受cagrilintide-semaglutide（各2.4毫克；n=62），cagrilintide-semaglutide（各1.0毫克；n=63）或安慰剂（n=64）。在189人中，有103人（54%）为男性，86人（46%）为女性，147人（78%）为白人，26人（14%）为亚洲人。

Baseline mean HbA1c was 7·8% (SD 0·7) and BMI was 35·2 kg/m2 (7·4).

基线平均糖化血红蛋白（HbA1c）为7.8%（标准差0.7），体重指数（BMI）为35.2 kg/m²（标准差7.4）。

Using the efficacy estimand, the estimated mean change in HbA1c after 40 weeks was -1·8 percentage points (SE 0·1) with cagrilintide-semaglutide (2·4 mg each), -1·5 percentage points (0·1) with cagrilintide-semaglutide (1·0 mg each), and -0·1 percentage points (0·2) with placebo.

使用效能估计量，40周后，糖化血红蛋白（HbA1c）的平均变化估计值为：cagrilintide-semaglutide（每次2.4毫克）组为-1.8个百分点（标准误0.1），cagrilintide-semaglutide（每次1.0毫克）组为-1.5个百分点（标准误0.1），安慰剂组为-0.1个百分点（标准误0.2）。

This corresponded to an estimated treatment difference of -1·7 percentage points (95% CI -2·0 to -1·3; p<0·0001) for cagrilintide-semaglutide (2·4 mg each) versus placebo and -1·3 percentage points (-1·8 to -0·9; p<0·0001) for cagrilintide-semaglutide (1·0 mg each) versus placebo.

这相当于cagrilintide-semaglutide（每种2·4毫克）与安慰剂相比的估计治疗差异为-1·7个百分点（95%置信区间-2·0至-1·3；p<0·0001），以及cagrilintide-semaglutide（每种1·0毫克）与安慰剂相比的估计治疗差异为-1·3个百分点（95%置信区间-1·8至-0·9；p<0·0001）。

Cagrilintide-semaglutide was superior to placebo with respect to estimated mean relative change in bodyweight from baseline to week 40 for cagrilintide-semaglutide (2·4 mg each; -13·8% [SE 1·0]) versus placebo (-1·4% [0·7]; estimated treatment difference -12·4 percentage points [95% CI -14·7 to -10·1]; p<0·0001) and cagrilintide-semaglutide (1·0 mg each; -11·8% [1·0]) versus placebo (-1·4% [0·7]; estimated treatment difference -10·4 percentage points [-12·9 to -8·0]; p<0·0001).

在从基线到第40周的体重平均相对变化估计值方面，cagrilintide-semaglutide（每种2·4毫克；-13·8% [标准误1·0]）与安慰剂（-1·4% [0·7]；估计治疗差异-12·4个百分点 [95%置信区间-14·7至-10·1]；p<0·0001）相比具有优越性，以及cagrilintide-semaglutide（每种1·0毫克；-11·8% [1·0]）与安慰剂（-1·4% [0·7]；估计治疗差异-10·4个百分点 [-12·9至-8·0]；p<0·0001）相比也具有优越性。

Adverse events were reported by 49 (79%) of 62 participants in the cagrilintide-semaglutide (2·4 mg each) group, 47 (75%) of 63 in the cagrilintide-semaglutide (1·0 mg each) group, and 42 (66%) of 64 in the placebo group.

在cagrilintide-semaglutide（各2.4毫克）组的62名参与者中有49名（79%）报告了不良事件，在cagrilintide-semaglutide（各1.0毫克）组的63名中有47名（75%）报告了不良事件，以及在安慰剂组的64名中有42名（66%）报告了不良事件。

Most adverse events were mild or moderate and gastrointestinal related.

大多数不良事件为轻度或中度，并且与胃肠道相关。

interpretation

In a population of people with early-stage type 2 diabetes inadequately controlled with diet and exercise, cagrilintide-semaglutide (2·4 mg each and 1·0 mg each) was superior to placebo in reducing HbA1c.

在那些通过饮食和运动控制不佳的早期2型糖尿病患者中，cagrilintide-semaglutide（每次2.4毫克和每次1.0毫克）在降低糖化血红蛋白（HbA1c）方面优于安慰剂。

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

安全性特征与GLP-1受体激动剂类药物一致，并且与cagrilintide的先前安全数据相符。

These findings support cagrilintide-semaglutide as a potential novel and effective therapeutic intervention for people with early-stage type 2 diabetes.

这些发现支持cagrilintide-semaglutide作为早期2型糖尿病患者的一种潜在的新颖且有效的治疗干预手段。

funding

Novo Nordisk.

诺和诺德。