Once-weekly IcoSema versus once-daily insulin glargine U100 in type 2 diabetes management (COMBINE 4): an open-label, multicentre, treat-to-target, randomised, phase 3b trial.

Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk.

指南建议将GLP-1受体激动剂与基础胰岛素联合使用，以提高血糖控制效果，同时减少体重增加和低血糖风险。

COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications.

COMBINE 4评估了IcoSema（基础胰岛素icodec与GLP-1受体激动剂semaglutide的每周一次联合疗法）与胰岛素glargine U100（glargine U100）在口服降糖药物治疗的2型糖尿病患者中的疗效和安全性。

Methods

COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries.

COMBINE 4是一项为期40周的随机、开放标签、目标治疗、3b期试验，在九个国家的97个地点进行。

Adults (aged ≥18 years) with type 2 diabetes (HbA1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100.

年龄≥18岁的2型糖尿病患者（HbA1c ≥8·0%）正在接受口服降糖药物治疗，按照1:1的比例随机分配到IcoSema组或每日一次的glargine U100组，无需分层。

The titration target was 3·9-5·0 mmol/L (70-90 mg/dL).

调整目标是3·9-5·0 mmol/L（70-90 mg/dL）。

The primary endpoint was change in HbA1c and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants.

主要终点是基线至第40周HbA1c的变化，次要确认终点是基线至第40周体重的变化，评估所有随机分配的参与者。

Adverse events were recorded during weeks 0-45.

在第0-45周记录不良事件。

This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete.

该试验已在ClinicalTrials.gov注册（NCT06269107），且已完成。

Results

Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100.

在2024年2月15日至8月6日期间筛选的653名个体中，有151人未满足筛选标准，另有17人在开始治疗前退出；243人被随机分配到IcoSema组，242人被分配到glargine U100组。

Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82).

在随机分配的485名参与者中，286人（59%）为男性，199人（41%）为女性，中位年龄为58岁（范围26-82岁）。

For HbA1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001).

对于HbA1c，从基线（IcoSema为9.57%，glargine U100为9.50%）到第40周，IcoSema组的平均变化大于glargine U100组（-3.32比-2.44个百分点；估计治疗差异[ETD]为-0.88个百分点[95% CI -1.12至-0.63]），确认了IcoSema的优越性（p<0.001）。

From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001).

从基线到第40周，IcoSema组的平均体重下降，而glargine U100组的体重增加（-0.79比3.81公斤；ETD为-4.61公斤[95% CI -5.46至-3.75]），确认了IcoSema的优越性（p<0.001）。

Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59 episodes per person-year of exposure; estimated rate ratio 0·56 [95% CI 0·32 to 0·97]; p=0·04).

与glargine U100相比，IcoSema组的临床显著（血糖<3.0 mmol/L[<54 mg/dL]，通过血糖仪确认）或严重低血糖（严重认知障碍需要外部帮助恢复）的发生率显著降低（每暴露人年0.29比0.59次；估计发生率比为0.56[95% CI 0.32至0.97]；p=0.04）。

Gastrointestinal disorders were the most frequently reported adverse events with IcoSema.

胃肠道疾病是与IcoSema相关的最常见不良事件。

interpretation

Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications.

每周一次的IcoSema显示出比glargine U100更好的HbA1c降低和体重变化，且临床显著或严重低血糖的发生率较低，这表明对于那些在口服降糖药物控制不佳的胰岛素未使用型2型糖尿病患者，IcoSema可能是一种有效的每周一次治疗选择。

funding

Novo Nordisk.

诺和诺德公司