Background

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors.

Methods

In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA_1c) of 7·0–10·5%, body-mass index of at least 25 kg/m², stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA_1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA_1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA_1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA_1c and bodyweight, and the proportion of participants achieving HbA_1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA_1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete.

Findings

Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA_1c of 8·17% (SD 0·91), the reductions in HbA_1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from –0·59% to –1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA_1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%–93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (–7·5 kg to –12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from –9·8 kg to –15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12–24%), diarrhoea (15–17%), decreased appetite (6–12%), and vomiting (6–10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment.

Interpretation

In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA_1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists.

Funding

Eli Lilly and Company.

中文翻译：

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每周一次的 tirzepatide 与每天一次的德谷胰岛素作为 2 型糖尿病患者（SURPASS-3）的二甲双胍的附加治疗（SURPASS-3）：一项随机、开放标签、平行组、3 期试验

背景

Tirzepatide 是一种新型的双重葡萄糖依赖性促胰岛素多肽和 GLP-1 受体激动剂，正在开发用于治疗 2 型糖尿病。我们旨在评估替西帕肽与滴定的德谷胰岛素在二甲双胍控制不充分的 2 型糖尿病患者中的疗效和安全性，伴或不伴 SGLT2 抑制剂。

方法

在这项开放标签、平行组、多中心（122 个地点）、跨国（13 个国家）的 3 期研究中，符合条件的参与者（年龄≥18 岁）的基线糖化血红蛋白 (HbA _1c ) 为 7·0–10· 5%，体重指数至少为 25 kg/m ²，体重稳定，未使用过胰岛素，并且在筛选前接受过二甲双胍单独治疗或与 SGLT2 抑制剂联合治疗至少 3 个月。参与者被随机分配 (1:1:1:1)，使用交互式网络响应系统，每周一次皮下注射 tirzepatide（5、10 或 15 mg）或每天一次皮下注射滴定的德谷胰岛素，并按国家分层，HbA _1c，并同时使用口服降糖药。Tirzepatide 最初以 2·5 mg 给药，每 4 周增加 2·5 mg，直至达到指定剂量。Insulin degludec 最初以每天 10 U 给药，并每周滴定一次至空腹自我监测血糖低于 5·0 mmol/L (<90 mg/dL)，遵循目标治疗算法，对于52 周。主要疗效终点是第 52 周HbA _1c相对于基线的平均变化中 tirzepatide 10 mg 或 15 mg 或两者的非劣效性。 关键次要疗效终点是 tirzepatide 5 mg 与德谷胰岛素的非劣效性HbA _1c从基线的平均变化在第 52 周时，所有剂量的 tirzepatide 与德谷胰岛素相比，在 HbA _1c和体重的平均变化以及第52 周时达到 HbA _1c低于 7·0% (<53 mmol/mol)的参与者比例方面的优势。我们使用 0·3% 的边界来确定治疗之间HbA _1c差异的非劣效性。在改良的意向治疗人群（接受至少一剂研究药物的所有参与者）中评估疗效和安全性分析。该试验已在 ClinicalTrials.gov 注册，编号 NCT03882970，并且已完成。

发现

2019 年 4 月 1 日至 11 月 15 日期间，我们评估了 1947 名参与者的资格，其中 1444 人被随机分配接受治疗。改良的意向治疗人群是来自 tirzepatide 5 mg (n=358)、tirzepatide 10 mg (n=360)、tirzepatide 15 mg (n=359) 和德谷胰岛素 (n=360) 组的 1437 名参与者。从平均基线 HbA _1c为 8·17% (SD 0·91)，HbA _1c的降低在第 52 周时，tirzepatide 5 mg 为 1·93% (SE 0·05)，tirzepatide 10 mg 为 2·20% (0·05)，tirzepatide 15 mg 为 2·37% (0·05)，和 1 ·34% (0·05) 用于德谷胰岛素。满足 0·3% 的非劣效性界限。估计治疗差异 (ETD) 与德谷胰岛素相比，对于 tirzepatide 范围为 –0·59% 至 –1·04%（对于所有 tirzepatide 剂量，p<0·0001）。达到 HbA _1c的参与者比例与德谷胰岛素 (61%) 相比，在所有三个 tirzepatide 组 (82%–93%) 中，在第 52 周时小于 7·0% (<53 mmol/mol) 的比例更高 (p<0·0001)。在第 52 周时，从 94·3 kg (SD 20·1) 的基线开始，所有三种 tirzepatide 剂量均降低体重（–7·5 kg 至 –12·9 kg），而德谷胰岛素使体重增加 2·3 kg。对于tirzepatide，ETD与德谷胰岛素的范围为–9·8 kg至–15·2 kg（对于所有tirzepatide剂量，p<0·0001）。替西帕肽治疗的参与者最常见的不良事件是轻度至中度胃肠道事件，随着时间的推移而减少。据报道，与接受胰岛素治疗的参与者相比，接受替泽帕肽治疗的参与者出现恶心 (12–24%)、腹泻 (15–17%)、食欲下降 (6–12%) 和呕吐 (6–10%) 的发生率更高degludec（分别为 2%、4%、1% 和 1%）。低血糖（< 分别有五名 (1%)、四名 (1%) 和八名 (2%) 的参与者在接受 tirzepatide 5、10 和 15 mg 治疗时报告了 54 mg/dL 或重度)，而接受德谷胰岛素治疗的则有 26 名 (7%) . 与德谷胰岛素组相比，替西帕肽组因不良事件而中断治疗的情况更常见。五名参与者在研究期间死亡；研究人员认为没有一例死亡与研究治疗有关。

解释

在 2 型糖尿病患者中，tirzepatide（5、10 和 15 mg）优于滴定的德谷胰岛素，第 52 周时HbA _1c和体重降低更多，低血糖风险更低。Tirzepatide 显示出与 GLP-1 受体激动剂相似的安全性特征。

资金

礼来公司。