Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes.

我们的目标是比较每周一次卡格利肽与司美格鲁肽（CagriSema）联合治疗与安慰剂作为基础胰岛素辅助治疗在2型糖尿病患者中的疗效和安全性。

Methods

This double-blind, parallel-group, randomised, controlled, phase 3a study (REIMAGINE 3) was done at 46 centres (university hospitals, health-care centres, research centres, and other clinical trial sites) in six countries (the USA, China, Japan, Serbia, Slovakia, and South Africa).

这是一项双盲、平行组、随机对照的3a期研究（REIMAGINE 3），在六个国家（美国、中国、日本、塞尔维亚、斯洛伐克和南非）的46个中心（大学医院、医疗中心、研究中心和其他临床试验地点）进行。

Adults with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0-10·5%) receiving stable once per day basal insulin with or without metformin were randomly assigned (2:2:1:1) to once per week subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (hereafter cagrilintide-semaglutide [2·4 mg each]) or cagrilintide 1·0 mg plus semaglutide 1·0 mg (hereafter cagrilintide-semaglutide [1·0 mg each]) or dose-matched placebo (2·4 mg plus 2·4 mg or 1·0 mg plus 1·0 mg) for 40 weeks.

患有2型糖尿病（糖化血红蛋白[HbA1c] 7.0-10.5%）的成年人，每天一次稳定使用基础胰岛素，无论是否使用二甲双胍，被随机分配（2:2:1:1）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]）或cagrilintide 1.0 mg加semaglutide 1.0 mg（以下简称cagrilintide-semaglutide [每种1.0 mg]）或剂量匹配的安慰剂（2.4 mg加2.4 mg或1.0 mg加1.0 mg），为期40周。

Randomisation was stratified by HbA1c of less than 8·5% at screening (yes or no) and country (Japan; yes or no).

随机分组按筛查时HbA1c小于8.5%（是或否）和国家（日本；是或否）进行分层。

Participants, care providers, investigators, and outcome assessors were masked within each dose level to treatment allocation, with active treatments visually identical to placebo.

在每个剂量水平内，参与者、护理提供者、调查员和结果评估者对治疗分配进行了盲法处理，活性治疗在视觉上与安慰剂相同。

The primary endpoint was mean HbA1c change (percentage points) from baseline to week 40 in all participants randomly assigned to treatment; secondary endpoints included change in bodyweight and safety, including hypoglycaemia.

主要终点是所有随机分配至治疗组的参与者从基线到第40周的平均糖化血红蛋白（HbA1c）变化（百分点）；次要终点包括体重变化和安全性，包括低血糖事件。

This trial was registered with ClinicalTrials.gov (NCT06323161) and is complete.

该试验已在ClinicalTrials.gov注册（NCT06323161），并已完成。

Results

Between March 26 and Nov 29, 2024, we screened 340 individuals and 274 were included and randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=90), cagrilintide-semaglutide (1·0 mg each; n=93), or placebo (pooled; n=91).

在2024年3月26日至11月29日期间，我们筛查了340名个体，其中274名被纳入并随机分配到cagrilintide-semaglutide（各2.4毫克；n=90）、cagrilintide-semaglutide（各1.0毫克；n=93）或安慰剂（合并；n=91）。

Mean baseline HbA1c was 8·8% (SD 1·0), 159 (58%) participants were male, and 115 (42%) were female.

基线平均HbA1c为8.8%（标准差1.0），159名（58%）参与者为男性，115名（42%）为女性。

Mean HbA1c reductions were significantly greater with cagrilintide-semaglutide (2·4 mg each -2·33% [SE 0·08] and 1·0 mg each -2·10% [0·08]) versus placebo (-0·66% [0·11]) at week 40, using the efficacy estimand (estimated treatment difference for cagrilintide-semaglutide [2·4 mg each] vs placebo -1·68 percentage points [95% CI -1·95 to -1·41], p<0·0001; for cagrilintide-semaglutide [1·0 mg each] vs placebo -1·44 percentage points [95% CI -1·71 to -1·17], p<0·0001).

在第40周时，使用疗效估计量（cagrilintide-semaglutide [每2·4毫克]与安慰剂相比的估计治疗差异为-1·68个百分点[95%置信区间-1·95至-1·41]，p<0·0001；cagrilintide-semaglutide [每1·0毫克]与安慰剂相比的估计治疗差异为-1·44个百分点[95%置信区间-1·71至-1·17]，p<0·0001），cagrilintide-semaglutide（每2·4毫克）和cagrilintide-semaglutide（每1·0毫克）的平均糖化血红蛋白（HbA1c）降低显著大于安慰剂（分别为-2·33% [标准误0·08]和-2·10% [0·08]，而安慰剂为-0·66% [0·11]）。

Cagrilintide-semaglutide provided bodyweight reductions of 10-12%.

Cagrilintide-semaglutide提供了10-12%的体重降低。

Adverse events were reported by 72 (80%) of 90 participants receiving cagrilintide-semaglutide (2·4 mg each), 66 (71%) of 93 receiving cagrilintide-semaglutide (1·0 mg each), and 65 (71%) of 91 receiving placebo, and were mostly mild or moderate gastrointestinal disorders.

72名（80%）接受cagrilintide-semaglutide（各2.4毫克）的90名参与者、66名（71%）接受cagrilintide-semaglutide（各1.0毫克）的93名参与者和65名（71%）接受安慰剂的91名参与者报告了不良事件，这些不良事件大多为轻度或中度的胃肠道疾病。

No severe hypoglycaemia was reported.

没有报告严重的低血糖事件。

There was one death in the cagrilintide-semaglutide (1·0 mg each) group not related to treatment (due to malignancy).

在 cagrilintide-semaglutide (每种1.0 mg)组中，有一例死亡与治疗无关（由于恶性肿瘤）。

interpretation

Cagrilintide-semaglutide at doses of 2·4 mg each and 1·0 mg each met the primary endpoint, with statistically significant and clinically relevant HbA1c reductions versus placebo when added to basal insulin-treated type 2 diabetes.

cagrilintide-semaglutide 在每种2.4 mg和1.0 mg的剂量下均达到了主要终点，与安慰剂相比，在基础胰岛素治疗的2型糖尿病中加入时，HbA1c的降低具有统计学意义和临床相关性。

These reductions were accompanied by robust bodyweight reduction and no additional risk of hypoglycaemia.

这些减少伴随着显著的体重减轻，并且没有增加低血糖的风险。

The safety profile was consistent with that of 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以往的安全性数据相符。

Findings support the use of cagrilintide-semaglutide as an add-on to once per day basal insulin to significantly improve glycaemic control.

研究结果支持将cagrilintide-semaglutide作为每日一次基础胰岛素的辅助治疗，以显著改善血糖控制。

funding

Novo Nordisk.

诺和诺德公司。