三重激动剂Retatrutide治疗肥胖：2期试验

SCI

16 August 2023

Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

(The New England Journal of Medicine, IF: 158.5)

Ania M. Jastreboff, Lee M. Kaplan., Juan P. Frias, Qiwei Wu, Yu Du., Sirel Gurbuz, Tamer Coskun, Axel Haupt, Zvonko Milicevic., and Mark L. Hartman, for the Retatrutide Phase 2 Obesity Trial Investigators

CORRESPONDENCE TO: ania.jastreboff@yale.edu

BACKGROUND 背景

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.

Retatrutide（LY3437943）是葡萄糖依赖性促胰岛素多肽受体、胰高血糖素样肽-1受体和胰高血糖素受体的三重激动剂。它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。

METHODS 方法  

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.

我们进行了一项2期、双盲、随机、安慰剂对照试验，涉及体重指数（BMI，以公斤为单位的体重除以以米为单位的身高的平方）为30或更高的成年人，或者BMI为27- 30间、加上至少一种与体重相关的疾病的成年人。参与者按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【初始给药，2 mg】、8 mg【初始计量，4 mg】或12 mg【初始计量，2 mg】）或安慰剂，每周一次，持续48周。主要终点是从基线到24周体重变化的百分比。次要终点包括从基线到48周体重变化的百分比，以及体重减轻5%或更多、10%或更多、15%或更多。试验还对Retatrutide的安全性进行了评估。

RESULTS 结果  

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. 

我们招募了338名成年人，其中51.8%是男性。将各组的24周时体重的矫正均数百分比的变化进行对比，与安慰剂组的−1.6%相比， Retatrutide组中的1 mg组为−7.2%，4 mg组为−12.9%，8 mg组中为−17.3%，12 mg组合中为−17.5%。在48周时，与安慰剂组的−2.1%相比，Retatrutide组的矫正均数百分比变化在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4mg Retatrutide治疗的参与者中，体重分别减轻了5%或更多、10%或更多和15%或更多的患者比例分别为92%、75%和60%的；接受8 mg Retatrutide的患者相应体重减轻的比例分别为100%、91%和75%；接受12 mg Retatrutide治疗的患者相应体重减轻比列分别为100%、93%和83%；在接受安慰剂治疗的患者中，分别为27%、9%和2%。Retatrutide组最常见的不良事件是胃肠道反应；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 vs.4mg）可部分缓解不良事件。心率升高的剂量依赖性在24周时达到峰值，此后下降。

CONCLUSIONS 结论  

In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.)

在患有肥胖症的成年人中，Retatrutide治疗48周可显著减少体重。（由礼来公司资助；ClinicalTrials.gov编号，NCT04881760。）

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