Background

As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes.

Methods

This multicentre, randomised, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-naïve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0·75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA_1c (≤8·5% or >8·5%), baseline BMI (<25 or ≥25 kg/m²), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2·5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2·5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA_1c from baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052.

Findings

Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0·75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56·6 years (SD 10·3) and were mostly male (481 [76%]). At week 52, HbA_1c decreased from baseline by a least squares mean of −2·4 (SE 0·1) for tirzepatide 5 mg, −2·6 (0·1) for tirzepatide 10 mg, −2·8 (0·1) for tirzepatide 15 mg, and −1·3 (0·1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were −1·1 (95% CI −1·3 to −0·9) for tirzepatide 5 mg, −1·3 (−1·5 to −1·1) for tirzepatide 10 mg, and −1·5 (−1·71 to −1·4) for tirzepatide 15 mg (all p<0·0001). Tirzepatide was associated with dose-dependent reductions in bodyweight with a least square mean difference of −5·8 kg (SE 0·4; −7·8% reduction) for 5 mg, −8·5 kg (0·4; −11·0% reduction) for 10 mg, and −10·7 kg (0·4; −13·9% reduction) for 15 mg of tirzepatide compared with −0·5 kg (0·4; –0·7% reduction) for dulaglutide. The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636).

Interpretation

Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes.

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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在日本 2 型糖尿病患者（SURPASS J-mono）中，tirzepatide 单药治疗与度拉鲁肽的疗效和安全性比较：一项双盲、多中心、随机、3 期试验

背景

随着疾病的进展，许多 2 型糖尿病患者难以达到治疗目标。我们旨在评估新型 GIP 和 GLP-1 受体激动剂 tirzepatide 与度拉鲁肽在日本 2 型糖尿病患者中的疗效和安全性。

方法

这项多中心、随机、双盲、平行、主动控制的 3 期试验在日本的 46 个医学研究中心和医院进行。年龄在 20 岁或以上且已停止口服抗高血糖单药治疗或未接受过治疗的 2 型糖尿病成人被纳入研究。参与者被随机分配（1:1:1:1）每周一次接受替西帕肽（5、10 或 15 mg）或度拉鲁肽（0·75 mg），使用计算机生成的随机序列和交互式网络响应系统。参与者根据基线 HbA _1c（≤8·5% 或 >8·5%）、基线 BMI（<25 或 ≥25 kg/m ²)，以及清除抗糖尿病药物。参与者、研究者和申办者对治疗分配不知情。替西帕肽的起始剂量为每周一次 2·5 mg，持续 4 周，然后在替西帕肽 5 mg 治疗组中增加到 5 mg。对于 tirzepatide 10 和 15 mg 治疗组，每 4 周一次增加 2·5 mg，直到达到指定剂量。主要终点是在改良意向治疗人群中测量的第 52 周时 HbA _1c从基线的平均变化。该试验已在 ClinicalTrials.gov 注册，NCT03861052。

发现

在 2019 年 5 月 7 日至 2021 年 3 月 31 日期间，821 名参与者接受了研究资格评估，636 名参与者被随机分配接受至少一剂 5 mg (n=159)、10 mg (n=158) 或 15 mg (n=160)，或度拉鲁肽 0·75 mg (n=159)。615 名 (97%) 参与者完成了研究，21 名 (3%) 停止了研究。参与者的平均年龄为 56·6 岁 (SD 10·3)，大多数为男性 (481 [76%])。在第 52 周，HbA _1ctirzepatide 5 mg 与基线相比最小二乘均值为 -2·4 (SE 0·1)，tirzepatide 10 mg 为 -2·6 (0·1)，tirzepatide 15 为 -2·8 (0·1) mg，度拉鲁肽为 -1·3 (0·1)。tirzepatide 5 mg 与度拉鲁肽的估计平均治疗差异为 -1·1 (95% CI -1·3 至 -0·9)，tirzepatide 10 mg 为 -1·3 (-1·5 至 -1·1)，对于 tirzepatide 15 mg，为 -1·5（-1·71 至 -1·4）（所有 p<0·0001）。Tirzepatide 与体重的剂量依赖性降低相关，对于 5 mg、-8·5 kg (0·4; -与 -0·5 kg (0·4; –0·7%) 相比，10 mg 和 -10·7 kg (0·4; -13·9%) 15 mg tirzepatide 减少 11·0%)减少）用于度拉鲁肽。最常见的治疗中出现的不良事件是恶心（5 mg 组的 19 名 [12%] 参与者vs10 mg 组 31 [20%] vs 15 mg 组 32 [20%] 全部接受替西帕肽vs度拉鲁肽组12 (8%)，便秘 (24 [15%] vs 28 [18%] 22 [14%] vs 17 [11%]）和鼻咽炎（29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]）。最常见的不良事件是胃肠道（636 例中的 23 例 [4%]）。

解释

与度拉鲁肽相比，Tirzepatide 在血糖控制和体重减轻方面具有优势。tirzepatide 的安全性与 GLP-1 受体激动剂的安全性一致，表明在日本 2 型糖尿病患者中具有潜在的治疗用途。

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。