Background

Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies.

Methods

This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbA_1c ≥7·0% to <11·0%) type 2 diabetes and were receiving oral antihyperglycaemic monotherapy (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors) for at least 3 months (stable dose for ≥8 weeks before screening), had a BMI of 23 kg/m² or higher, and stable bodyweight (±5%) for at least 3 months before screening. After a 2-week screening and 2-week lead-in period, all participants were randomly assigned (1:1:1) to receive 5, 10, or 15 mg of tirzepatide, administered once per week subcutaneously for 52 weeks followed by a 4 week safety follow-up period, using a computer-generated random sequence and interactive web response system, stratified by oral antihyperglycaemic medication group. All participants started receiving 2·5 mg tirzepatide and doses were escalated by 2·5 mg every 4 weeks until the assigned dose was reached. The primary endpoint was safety and tolerability during 52 weeks of treatment, assessed as incidence of treatment-emergent adverse events in the modified intention-to-treat (mITT) population. This trial is registered with ClinicalTrials.gov, NCT03861039.

Findings

Between March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were –3·8 kg (SE 0·5; –5·1% reduction) in the 5 mg group, –7·5 kg (0·5; –10·1% reduction) in the 10 mg group, and –10·2 kg (0·5; –13·2% reduction) in the 15 mg group. Least squares mean HbA_1c at baseline reduced from 8·5% (SE 0·1) to 6·0% (0·1) in the 5 mg tirzepatide group, from 8·6% (0·1) to 5·6% (0·1) in the 10 mg group, and from 8·6% (0·1) to 5·6% (0·1) in the 15 mg group at week 52. No adjudication-confirmed deaths were reported.

Interpretation

Tirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication.

Funding

Eli Lilly and Company.

Translation

For the Japanese translation of the abstract see Supplementary Materials section.

中文翻译：

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替西帕肽作为日本 2 型糖尿病患者单次口服抗高血糖药物附加药物的安全性和有效性（SURPASS J-combo）：一项多中心、随机、开放标签、平行组、3 期试验

背景

由于 2 型糖尿病的病理生理学存在潜在的种族差异，因此需要在日本患者中评估新的治疗方法。我们的目的是评估替西帕肽作为一种附加治疗在使用稳定剂量的各种口服抗高血糖单药治疗时血糖控制不足的日本 2 型糖尿病患者的安全性和血糖疗效。

方法

这项多中心、开放标签、平行组、随机的 3 期试验在日本的 34 个医学研究中心和医院进行。符合条件的参与者年龄在 20 岁或以上，患有控制不佳（HbA _1c ≥7·0% 至 <11·0%）的 2 型糖尿病，并且正在接受口服抗高血糖单药治疗（磺脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类、格列奈类或SGLT2 抑制剂）至少 3 个月（筛选前 ≥8 周的稳定剂量），BMI 为 23 kg/m ²或更高，并且在筛选前至少3个月稳定体重（±5％）。经过 2 周筛选和 2 周导入期后，所有参与者被随机分配 (1:1:1) 接受 5、10 或 15 mg 替西帕肽，每周一次皮下给药，持续 52 周，随后为期 4 周的安全随访期，使用计算机生成的随机序列和交互式网络响应系统，按口服抗高血糖药物组分层。所有参与者开始接受 2·5 mg tirzepatide，剂量每 4 周增加 2·5 mg，直至达到指定剂量。主要终点是治疗 52 周期间的安全性和耐受性，评估为改良意向治疗 (mITT) 人群中治疗出现的不良事件的发生率。该试验已在 ClinicalTrials.gov 注册，NCT03861039。

发现

在 2019 年 3 月 30 日至 2021 年 2 月 16 日期间，招募和登记将持续到 2020 年 2 月 4 日，484 名参与者接受了资格评估，443 名参与者被随机分配接受至少一剂替西帕肽（148 名 [33%] 在5 mg 组、10 mg 组 147 [33%] 和 15 mg 组 148 [33%]）。398 名 (90%) 参与者完成了研究和治疗。大多数参与者（443 名中的 343 名 [77%]）至少有一次治疗中出现的不良事件。tirzepatide 15 mg 组（148 人中的 125 [84%]）治疗中出现的不良事件比 5 mg（148 人中的 109 [74%]）和 10 mg 组（147 人中的 109 [74%]）更常见。替西帕肽治疗最常见的不良事件是轻度或中度鼻咽炎 (75 [17%])、恶心 (74 [17%])、便秘 (54 [12%])、腹泻 (51 [12%])、和食欲下降（44 [10%]）。在第 52 周，5 mg 组的体重相对于基线的平均变化为 –3·8 kg（SE 0·5；–5·1% 减少），–7·5 kg（0·5；–10·1%在 10 mg 组中减少），在 15 mg 组中减少 –10·2 kg（0·5；–13·2% 减少）。最小二乘均值 HbA_{在 5 mg 替西帕肽组中，基线1c}从 8·5% (SE 0·1) 降至 6·0% (0·1)，从 8·6% (0·1) 降至 5·6% (0· 1) 在 10 mg 组中，在第 52 周时从 8·6% (0·1) 到 15 mg 组中的 5·6% (0·1)。没有经裁定确认的死亡报告。

解释

在日本患有 2 型糖尿病的参与者中，替西帕肽作为口服抗高血糖单药治疗的附加药物具有良好的耐受性，并且无论背景口服抗高血糖药物如何，都显示出血糖控制和体重的改善。Tirzepatide 是日本 2 型糖尿病患者的一种潜在的新治疗选择，单次口服抗高血糖药物控制不佳。

资金

礼来公司。

翻译

对于摘要的日文翻译，请参阅补充材料部分。