美国华盛顿大学Steven E Kahn团队联合意大利比萨大学Stefano Del Prato团队比较了tirzepatide与甘精胰岛素治疗2型糖尿病和心血管风险增加患者的疗效和安全性。2021年10月18日，《柳叶刀》杂志发表了这一成果。

该研究旨在评估新型双GIP和GLP-1受体激动剂tirzepatide与甘精胰岛素在口服降糖药物控制不佳的2型糖尿病和高心血管风险成人中的有效性和安全性。

这项开放标签、平行组3期临床研究在五大洲14个国家的187个地点进行。符合条件的参与者年龄在18岁或以上，患有2型糖尿病，接受过二甲双胍、磺酰脲或钠-葡萄糖协同转运蛋白2抑制剂的任何组合治疗，基线糖化血红蛋白（HbA1c）为7.5-10.5%，体重指数为25 kg/m²或更高，心血管疾病或心血管事件风险较高。

将参与者按1:1:1:3随机分配，每周一次皮下注射tirzepatide（5 mg, 10 mg，或15 mg）或甘精胰岛素(100 U/mL)，剂量递增至空腹血糖低于100 mg/dL。主要终点是从基线检查到52周的HbA1c变化中，与甘精胰岛素相比，10 mg或15 mg（或两者）的tirzepatide的非劣效性（0.3%非劣效边界）。所有参与者接受至少52周的治疗，治疗最多持续104周或直到研究完成，以收集和判定重大心血管不良事件（MACE）。

患者招募时间为2018年11月20日至2019年12月30日。共筛选了3045名受试者，其中2002名受试者随机分为tirzepatide组或甘精胰岛素组。1995例患者至少接受了一剂治疗，其中tirzepatide 5 mg组329例（17%）、10 mg组328例（16%）、15 mg组338例（17%），甘精氨酸组1000例（50%），并被纳入改良意向治疗人群。

在52周时，tirzepatide 10 mg组的HbA1c平均变化为−2.43%，15 mg组为−2.58%，甘精胰岛素组为-1.44%。与甘精胰岛素组相比，tirzepatide 10 mg组估计的治疗差异为−0.99%，15 mg组为−1.14%，两种剂量均满足0.3%的非劣效边界。与甘精胰岛素组（恶心2%、腹泻4%、食欲下降<1%和呕吐2%）相比，tirzepatide组更容易出现恶心（12-23%）、腹泻（13-22%）、食欲下降（9-11%）和呕吐（5-9%）；大多数病例为轻度至中度，发生在剂量递增阶段。

Tirzepatide组中患有低血糖（血糖<54 mg/dL）的受试者占6-9%，显著低于甘精胰岛素组（19%），尤其是未服用磺脲类药物的受试者（tirzepatide组中1-3%低于甘精胰岛素组的16%）。共109名受试者发生了判定的MACE-4事件（心血管死亡、心肌梗死、中风、不稳定型心绞痛住院），与甘精胰岛素组相比，tirzepatide组并未显著增加。研究期间发生了60例死亡，其中tirzepatide组25例，甘精胰岛素组35例。

研究结果表明，对于患有2型糖尿病和心血管风险升高的人群，与甘精胰岛素相比，tirzepatide在第52周时表现出更大且具有临床意义的HbA1c降低，低血糖发生率更低。Tirzepatide治疗与过度心血管风险无关。

附：英文原文

Title: Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

Author: Stefano Del Prato, Steven E Kahn, Imre Pavo, Govinda J Weerakkody, Zhengyu Yang, John Doupis, Diego Aizenberg, Alan G Wynne, Jeffrey S Riesmeyer, Robert J Heine, Russell J Wiese, Andrew J Ahmann, Samir Arora, Eric M Ball, Rafael B Calderon, David J Butuk, Leila Chaychi, Michael C Chen, Brian M Curtis, Ronald Chochinov, Christopher Chow, Clancy L Cone, Lisa Connery, Gregorio A Cortes-Maisonet, Jose de Souza, Kathleen Dungan, David Bradley, Juan P Frias, Nashwa Gabra, Linda Gaudiani, Luis Herandez-Vazquez, Stanley H Hsia, Michael R Jardula, Eric J Klein, Mark E Kutner, Juan Loy, Francisco G Miranda, Lazaro D Nunez, Miguel Mujica-Baella, Alexander V Murray, Michael J Oliver, Ramon Oritz-Carrasquillo, Betsy Palal, Michael T Parke, Athena Philis-Tsimikas, Raman S Purighalla, Julio Rosenstock, Airani Sathananthan, Courtney Shelton, Kanagaratnam Sivalingam, Ehab Sorial, Joseph Soufer, Helen L Stacey, Larry D Stonesifer, Stanley Stringam, Joanna T Van, Jose B Vazquez-Tanus, Ramon Reyes, Michelle Welch, Najmuddin Karimjee, Earl E Martin, Ahmed Arif, Timothy W Jennings, Neil J Fraser, Anuj Bhargava, Alan G Wynne, Evelyne Davidson, Liana Billings, Elizabeth A Barranco-Santana, Michael E Dever, Patrick Walsh, Austina Cho, James W Chu, Jay Shubrook, Albert B Knouse, Venkatesh Nadar, Lorena Lewy-Alterbaum, Michael J Lillestol, Daniel J Humiston, Alexander J White, Ronald K Mayfield, Fahed G Bitar, Fernando Cereto, Carmen de la Cuesta, Luis De Teresa Parreno, Esteban Jodar Gimeno, Pedro Mezquita-Raya, Cristobal J Morales Portillo, Miguel Quesada Charneco, Francisco J Tinahones Madueno, Santiago Tofe Povedano, Luis Vazquez, Carmen Fajardo Montaana, Alfonso Soto Gonzalez, Cristina Mistodie, Iosif Szilagyi, Adriana Filimon, Nicoleta M Mindrescu, Lavinia Pop, Marlena Pascu, Gabriela D Negrisanu, Daniela Ciomos, Valentina Neacsu, Amalia Thury-Burileanu, Idit Liberty, Naftali Stern, Yael Sofer, Jessica Sack, Ilan Shimon, Amir Tirosh, Avraham Ishay, Ofri Mosenzon Ninio, Naim Shehadeh, Julio Wainstein, Mahmud Darawsha, Dasa Skripova, Eva Pavleova, Viera Donicova, Ludmila Kubincova, Dalibor Sosovec, Martina Merciakova, Fadia El Boreky, Eric St-Amour, Zeina Yared, Francois Blouin, Buki Ajala, Naresh K Aggarwal, Harpreet Bajaj, Chetna Tailor, Alan Egan, John OMahony, Natasha St.Onge, James R Conway, Gustavo Akerman Augusto, Joao L C Borges, Maria José A Gomes Cerqueira, Denise R Franco

Issue&Volume: 2021-10-18

Abstract:

Background

We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications.

Methods

This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662.

Findings

Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were 2·43% (SD 0·05) with 10 mg and 2·58% (0·05) with 15 mg, versus 1·44% (0·03) with glargine. The estimated treatment difference versus glargine was 0·99% (multiplicity adjusted 97·5% CI 1·13 to 0·86) for tirzepatide 10 mg and 1·14% (1·28 to 1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study.

Interpretation

In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk.

DOI: 10.1016/S0140-6736(21)02188-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02188-7/fulltext