美国耶鲁大学医学院Ania M. Jastreboff团队研究了三重激素受体激动剂Retatutide治疗肥胖的疗效与安全性。该研究于2023年6月26日发表在《新英格兰医学杂志》上。

Retatrutide（LY3437943）是葡萄糖依赖性促胰岛素多肽、胰高血糖素样肽1和胰高血糖肽受体的激动剂，其在治疗肥胖的副作用、安全性和疗效方面的剂量-反应关系尚不清楚。

研究组进行了一项临床2期、双盲、随机、安慰剂对照试验，招募体重指数（BMI）为30或以上的成年人，或BMI为27至30以下的成年人，合并至少一种与体重相关的疾病。参与者以2:1:1:1:2:2的比例被随机分配接受皮下Retatrutide（1 mg，4 mg [初始剂量，2 mg]，4 mg [初始剂量，4 mg]，8 mg [初始剂量，2 mg]，8mg [初始剂量，4 mg]或12 mg [初始剂量，2 mg]）或安慰剂，每周一次，持续48周。主要终点是从基线到24周体重的百分比变化。次要终点包括从基线到48周体重的百分比变化，以及体重减轻5%或更多、10%或更多或15%或更多。还对安全性进行了评估。

研究组招募了338名成年人，其中51.8%为男性。与安慰剂组的−1.6%相比，Retatrutide组在24周时体重的最小二乘平均百分比变化在1 mg组为−7.2%，在4 mg组合组为−12.9%，在8 mg组合组中为−17.3%，在12 mg组合中为−17.5%。在48周时，与安慰剂组的−2.1%相比，Retatrutide组的最小二乘平均百分比变化在1 mg组为−8.7%，在4 mg组合组为−17.1%，在8 mg组合组中为−22.8%，在12 mg组合中为−24.2%。

在48周时，接受4 mg Retatrutide治疗的参与者中，分别有92%、75%和60%的人体重减轻了5%或更多、10%或更多和15%或更多；接受8 mg的患者分别为100%、91%和75%；接受12 mg的患者分别为100%、93%和83%；接受安慰剂治疗的患者分别为27%、9%和2%。Retatrutide组最常见的不良事件是胃肠道；这些事件与剂量有关，严重程度大多为轻度至中度，较低的起始剂量（2mg对4mg）可部分缓解。心率的剂量依赖性增加在24周达到峰值，此后下降。

研究结果表明，在患有肥胖症的成年人中，Retatrutide治疗48周可显著减轻体重。

附：英文原文

Title: Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial | NEJM

Author: Ania M. Jastreboff, M.D., Ph.D.,, Lee M. Kaplan, M.D., Ph.D.,, Juan P. Frías, M.D.,, Qiwei Wu, Ph.D.,, Yu Du, Ph.D.,, Sirel Gurbuz, M.D.,, Tamer Coskun, M.D., Ph.D.,, Axel Haupt, M.D., Ph.D.,, Zvonko Milicevic, M.D.,, and Mark L. Hartman, M.D.

Issue&Volume: 2023-06-26

Abstract:

Background

Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose–response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known.

Methods

We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.

Results

We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was 7.2% in the 1-mg group, 12.9% in the combined 4-mg group, 17.3% in the combined 8-mg group, and 17.5% in the 12-mg group, as compared with 1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was 8.7% in the 1-mg group, 17.1% in the combined 4-mg group, 22.8% in the combined 8-mg group, and 24.2% in the 12-mg group, as compared with 2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.

Conclusions

In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight.

DOI: 10.1056/NEJMoa2301972

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2301972