小柯机器人

礼来西班牙分公司Ángel Rodríguez团队比较了对服用二甲双胍加或不加SGLT2抑制剂的2型糖尿病患者，每周一次tirzepatide与每天一次德谷胰岛素的疗效。该项研究成果发表在2021年8月6日出版的《柳叶刀》杂志上。

Tirzepatide是一种新型双糖依赖性促胰岛素多肽和GLP-1受体激动剂，正研发用于治疗2型糖尿病。该研究旨在比较评估tirzepatide与滴定德谷胰岛素治疗二甲双胍联合或不联合SGLT2抑制剂控制不佳的2型糖尿病患者的疗效和安全性。

在这项开放标签、平行组、多中心（122个地点）、多国（13个国家）、临床3期研究中，研究组招募年龄≥18岁、基线糖化血红蛋白（HbA1c）为7.0-10.5%、体重指数至少为25 kg/m²、体重稳定、筛查前未接受胰岛素治疗、单独使用二甲双胍或联合SGLT2抑制剂至少治疗3个月的参与者。将其按1:1:1:1随机分配，每周皮下注射一次tirzepatide（5、10或15 mg）或每日皮下注射一次滴定德谷胰岛素，并按国家、糖化血红蛋白和同时使用口服降糖药进行分层。

主要疗效终点为第52周时，10 mg或15 mg（或两者）tirzepatide组与基线检查时HbA1c的平均变化相比，与德谷胰岛素组的非劣效性。关键次要疗效终点为第52周时，5 mg tirzepatide组与德谷胰岛素组在HbA1c基线平均变化方面的非劣效性；所有剂量tirzepatide组与德谷胰岛素组在HbA1c和体重基线平均变化方面的非劣效性；第52周时各组参与者HbA1c低于7.0%的比例。各组间HbA1c差异的非劣效性边缘为0.3%。

研究组评估了1947名参与者的资格，其中1444人被随机分配到治疗组。改良意向治疗人群为1437名参与者，其中tirzepatide 5 mg组358例，tirzepatide 10 mg组360例，tirzepatide 15 mg组359例，德谷胰岛素组360例。参与者的平均基线HbA1c为8.17%，第52周时，tirzepatide 5 mg组HbA1c降低1.93%，tirzepatide 10 mg组降低2.20%，tirzepatide 15 mg组降低2.37%，德谷胰岛素组降低1.34%。满足0.3%的非劣效性界限。Tirzepatide各组与德谷胰岛素组的估计治疗差异（ETD）范围为-0.59%至-1.04%，差异均显著。

第52周时，3个tirzepatide组的HbA1c低于7.0%的参与者比例（82%–93%）均显著高于德谷胰岛素组（61%）。在第52周，3个tirzepatide组参与者的体重均从基线水平的94.3 kg减轻了7.5 kg至12.9 kg不等，而德谷胰岛素组参与者的体重平均增加了2.3 kg。Tirzepatide各组与德谷胰岛素组的ETD范围为-9.8 kg至-15.2 kg。Tirzepatide治疗的受试者最常见的不良事件为轻度至中度胃肠道事件，随时间推移而减少。

Tirzepatide治疗的受试者中恶心（12-24%）、腹泻（15-17%）、食欲下降（6-12%）和呕吐（6-10%）的发生率分别显著高于德谷胰岛素组（2%、4%、1%和1%）。分别有5名（1%）、4名（1%）和8名（2%）受试者在服用5、10和15 mg tirzepatide后出现低血糖（<54 mg/dL或严重低血糖），而德谷胰岛素组中有26名（7%）。Tirzepatide组中由于不良事件而中断治疗的情况比德谷胰岛素组更为常见。共5名参与者在研究期间死亡，均与该研究治疗无关。

研究结果表明，对于2型糖尿病患者，采用tirzepatide（5、10和15 mg）治疗优于滴定德谷胰岛素，在第52周时HbA1c和体重降低更大，低血糖风险更低。

附：英文原文

Title: Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial

Author: Bernhard Ludvik, Francesco Giorgino, Esteban Jódar, Juan P Frias, Laura Fernández Landó, Katelyn Brown, Ross Bray, ángel Rodríguez

Issue&Volume: 2021-08-06

Abstract:

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 (HbA1c) 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, HbA1c, 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 HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c 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 HbA1c of 8·17% (SD 0·91), the reductions in HbA1c 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 HbA1c 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 HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists.

DOI: 10.1016/S0140-6736(21)01443-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01443-4/fulltext

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