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美国达拉斯医学城糖尿病研究中心Julio Rosenstock团队研究了新型双GIP和GLP-1受体激动剂tirzepatide治疗2型糖尿病的疗效和安全性。2021年6月26日出版的《柳叶刀》杂志发表了这项成果。

尽管在治疗方面取得了一定进步，但许多2型糖尿病患者未能达到治疗目标；因此，尚需要开发新的疗法。该研究旨在评估新型双葡萄糖依赖促胰岛素多肽和GLP-1受体激动剂tirzepatide单药治疗与安慰剂治疗仅通过饮食和运动控制不足的2型糖尿病患者的有效性、安全性和耐受性。

研究组在印度、日本、墨西哥和美国的52个医学研究中心和医院进行了一项为期40周、双盲、随机、安慰剂对照的3期临床试验，招募仅通过饮食和运动控制不足且未接受糖尿病注射治疗的2型糖尿病成年（≥18岁）患者。将其按1：1：1：1随机分组，分别接受每周一次5、10、15 mg tirzepatide或安慰剂治疗。主要终点是40周时糖化血红蛋白（HbA1c）较基线的平均变化。

2019年6月3日至2020年10月28日，在705名评估为合格的个体中有478名接受随机分组，平均基线HbA1c为7.9%，平均年龄为54.1岁，48%为女性，平均糖尿病病程4.7年，平均体重指数为31.9 kg/m²。其中5、10、15 mg tirzepatide组每组121例，安慰剂组115例。有66（14%）名参与者中止了药物研究，50（10%）名参与者过早中止了研究。

在40周时，tirzepatide所有剂量组在HbA1c、空腹血糖、体重较基线的变化，以及HbA1c目标低于7.0%和低于5.7%方面均显著优于安慰剂。 5 mg tirzepatide组的平均糖化血红蛋白（HbA1c）较基线下降1.87%，10 mg组下降1.89%，15 mg组下降2.07%，而安慰剂组却增加0.04%；与安慰剂组相比，5 mg tirzepatide组降低1.91%，10 mg组降低1.93%，15 mg组降低2.11%，差异均显著。

Tirzepatide各组中有87–92%的患者HbA1c低于7.0%，显著高于安慰剂组（20%）；81-86%的患者HbA1c低于6.5%，显著高于安慰剂组（10%）；31-52%的患者HbA1c低于5.7%，亦显著高于安慰剂组（1%）。Tirzepatide可使体重减轻7.0-9.5 kg，且呈剂量依赖性。最常见的不良事件是轻中度和短暂的胃肠道事件，包括恶心、腹泻和呕吐。没有临床显著或严重低血糖的报道。安慰剂组有1例患者死亡。

研究结果表明，Tirzepatide治疗2型糖尿病患者在血糖控制和体重方面有显著改善，且未增加低血糖风险。

附：英文原文

Title: Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial

Author: Julio Rosenstock, Carol Wysham, Juan P Frías, Shizuka Kaneko, Clare J Lee, Laura Fernández Landó, Huzhang Mao, Xuewei Cui, Chrisanthi A Karanikas, Vivian T Thieu

Issue&Volume: 2021-06-26

Abstract: Background

Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone.

Methods

We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834.

Findings

From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of 1·91% (21 mmol/mol) with tirzepatide 5 mg, 1·93% (21 mmol/mol) with tirzepatide 10 mg, and 2·11% (23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87–92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81–86% vs 10%) and 31–52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12–18% vs 6%), diarrhoea (12–14% vs 8%), and vomiting (2–6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group.

Interpretation

Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment.

DOI: 10.1016/S0140-6736(21)01324-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01324-6/fulltext

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