美国亚拉巴马大学伯明翰分校W Timothy Garvey团队研究了Tirzepatide每周一次治疗2型糖尿病患者肥胖的疗效与安全性。2023年6月26日出版的《柳叶刀》杂志发表了这项成果。

减肥对于改善肥胖和2型糖尿病患者的健康状况至关重要。研究组评估了Tirzepatide（一种葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体激动剂）与安慰剂相比，治疗肥胖和2型糖尿病患者体重管理的有效性和安全性。

这项临床3期、双盲、随机、安慰剂对照试验在7个国家进行。身体质量指数（BMI）为27 kg/m²或更高、糖化血红蛋白（HbA_1c）为7-10%（53-86 mmol/mol）的成年人（年龄≥18岁）接受随机分配（1:1:1），通过经验证的交互式网络响应系统使用计算机生成的随机序列，接受每周一次的皮下Tirzepatide（10 mg或15 mg）或安慰剂治疗72周。所有参与者、研究者和申办者都双盲接受治疗分配。共同主要终点是体重与基线相比的百分比变化和体重减少5%或更高。无论是否停止治疗或开始抗高血糖抢救治疗，治疗方案都会评估疗效。使用所有随机分配的参与者（意向治疗人群）的数据分析疗效和安全性终点。

2021年3月29日至2023年4月10日，在1514名接受资格评估的成年人中，938人（平均年龄54.2岁，476名[51%]为女性，710名[76%]为白人，561名[60%]为西班牙裔或拉丁裔）被随机分配并接受至少一剂10 mg Tirzepatide（n=312）、15 mg Tirzepatide（n=311）或安慰剂（n=315）。基线平均体重为100.7 kg，BMI为36.1 kg/m²，HbA_1c为8.02%（64.1 mmol/mol）。第72周时，Tirzepatide 10 mg和15 mg的体重最小二乘平均变化分别为-12.8%和-14.7%，安慰剂组为-3.2%，与安慰剂相比，10 mg Tirzepatide的估计治疗差异为-9.6%，15 mg Tirzepatide的估计治疗差异为-11.6%（均p＜0.0001）。

与安慰剂相比，更多接受Tirzepatide治疗的参与者达到了5%或更高的体重减轻阈值（79-83%对32%）。Tirzepatide最常见的不良事件与胃肠道相关，包括恶心、腹泻和呕吐，严重程度大多为轻度至中度，很少有事件导致治疗中断（<5%）。总共有68名（7%）参与者报告了严重不良事件，10 mg Tirzepatide组发生了两例死亡，但研究人员认为死亡与研究治疗无关。

研究结果表明，在这项针对肥胖和2型糖尿病成年人的为期72周的试验中，每周一次的10 mg和15 mg Tirzepatide显著降低了体重，具有临床意义，其安全性与其他基于肠促胰岛素的体重管理疗法相似。

附：英文原文

Title: Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

Author: W Timothy Garvey, Juan P Frias, Ania M Jastreboff, Carel W le Roux, Naveed Sattar, Diego Aizenberg, Huzhang Mao, Shuyu Zhang, Nadia N Ahmad, Mathijs C Bunck, Imane Benabbad, Xiaotian M Zhang, Franklin H. Abalos, Federico C.P. Manghi, Cesar J. Zaidman, Marisa L. Vico, Diego Aizenberg, Pablo R. Costanzo, Leonardo P. Serra, Ignacio J. MacKinnon, Miguel N. Hissa, Maria H. Vidotti, Jose F. Kerr Saraiva, Breno B. Alves, Denise R. Franco, Otavio Moratto, Sreenivasa Murthy, Ghanshyam Goyal, Yoshimitsu Yamasaki, Nobuyuki Sato, Satoshi Inoue, Taro Asakura, Marina Shestakova, Elena Khaykina, Ekaterina Troshina, Natalia Vorokhobina, Alexander Ametov, Shih-Te Tu, Chwen-Yi Yang, I-Te Lee, Chien-Ning Huang, Horng-Yih Ou, George Freeman, Sriram Machineni, Klara Klein, Senan Sultan, Alan Parsa, Juan Otero-Martinez, Alex Gonzalez, Anuj Bhargava, Susan Brian, Carlos Ince, Stephen Plantholt, Jeremy Cole, Audrey Lacour, Damaris Vega, Jose de Souza, Jane L. Rohlf, Roy C. St. John, Barry Horowitz, Hanid Audish, Rodolfo Galindo, Guillermo Umpiperrez, Jamy Ard, Brian Curtis, William T. Garvey, Neil J. Fraser, Jose Mandry, Rizwana Mohseni, Ronald Mayfield, Talessa Powell, Carl Vance, Stephen Ong, Ana L. Lewy-Alterbaum, Alexander Murray, Amer Al-Karadsheh, Tamer Yacoub, Kevin Roberts, David L. Fried, Julio Rosenstock, Bharathi Pulla, Bruce Bode, Juan Frias, Leslie Klaff, Ronald Brazg, Joanna Van, Anjanette Tan, Toby Briskin, Margaret Rhee, Tira Chaicha-Brom, Paul A. Hartley, Lazaro Nunez, Gregorio Cortes-Maisonet, Gary Soucie, Stanley Hsia, Thomas Jones

Issue&Volume: 2023-06-26

Abstract:

Background

Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes.

Methods

This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003.

Findings

Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79–83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator.

Interpretation

In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management.

DOI: 10.1016/S0140-6736(23)01200-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext