Retatrutide，一种三重激素受体激动剂，用于治疗肥胖。

文献信息

中文摘要

背景： Retatrutide 是葡萄糖依赖性促胰岛素多肽、胰高血糖素样肽-1 和胰高血糖素受体的三重受体激动剂。
方法： 在这项 3 期、随机、双盲试验中，我们将无糖尿病的肥胖成人分配接受每周一次皮下注射 retatrutide（剂量为 4 mg、9 mg 或 12 mg）或安慰剂，持续 80 周。主要结局（在 9 mg 和 12 mg 组分别与安慰剂比较中评估）为体重百分比变化、574 名膝骨关节炎参与者亚组中 WOMAC 疼痛评分（范围 1 至 10，评分越高表示疼痛越严重）的变化，以及 243 名阻塞性睡眠呼吸暂停参与者中呼吸暂停-低通气指数的变化。对于体重相关终点，间发事件通过治疗方案估计目标（意向性治疗 [ITT]）处理。对于膝骨关节炎或阻塞性睡眠呼吸暂停参与者的终点，应用混合治疗估计目标，对提示治疗失败的间发事件采用假设策略；同时也报告 ITT 结果。
结果： 共有 2339 名参与者接受了随机化。retatrutide 组体重平均百分比变化为 -17.6%（4 mg 剂量）、-23.7%（9 mg 剂量）和 -25.0%（12 mg 剂量），而安慰剂组为 -3.9%（差异分别为 -19.8 和 -21.0 个百分点；两项比较 P<0.001）。在膝骨关节炎参与者中，retatrutide 组混合估计目标的相应疼痛评分变化为 -3.2、-3.5 和 -3.6，而安慰剂组为 -1.9（差异为 -1.6 和 -1.8 分；两项均 P<0.001）；ITT 估计目标的相应变化为 -3.4、-3.9 和 -4.1，而安慰剂组为 -2.5（差异为 -1.4 和 -1.6 分；两项均 P<0.001）。在阻塞性睡眠呼吸暂停参与者中，retatrutide 组混合治疗估计目标的相应每小时事件变化为 -22.9、-34.3 和 31.7，而安慰剂组为 -9.9（差异为 -24.4 和 -21.9；两项均 P<0.001）；ITT 估计目标的相应变化为 -22.8、-34.3 和 -32.1，而安慰剂组为 -9.6（差异为 -24.7 和 -22.5；两项均 P<0.001）。最常见的不良事件为胃肠道事件。
结论： 在肥胖成人中，retatrutide 带来了显著的体重减轻，减轻了膝骨关节炎参与者的疼痛，并减少了阻塞性睡眠呼吸暂停参与者的呼吸暂停-低通气事件。（由 Eli Lilly 资助；TRIUMPH-1 ClinicalTrials.gov 编号，NCT05929066。）

英文摘要

BACKGROUND: Retatrutide is a triple-receptor agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors.
METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks. Primary outcomes (evaluated in the 9-mg and 12-mg groups each vs. placebo) were the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10, with higher scores indicating worse pain) in the subgroup of 574 participants with knee osteoarthritis and the change in the apnea-hypopnea index in the 243 participants with obstructive sleep apnea. For weight-related end points, intercurrent events were handled by a treatment-regimen estimand (intention-to-treat [ITT]). For end points in participants with knee osteoarthritis or obstructive sleep apnea, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events suggesting treatment failure; ITT results are also reported.
RESULTS: A total of 2339 participants underwent randomization. The mean percent change in body weight in the retatrutide groups was -17.6% (4-mg dose), -23.7% (9-mg dose), and -25.0% (12-mg dose) versus -3.9% in the placebo group (differences, -19.8 and -21.0 percentage points, respectively; P<0.001 for both comparisons). Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were -3.2, -3.5, and -3.6 versus -1.9 with placebo (differences, -1.6 and -1.8 points; both P<0.001); the corresponding changes for the ITT estimand were -3.4, -3.9, and -4.1 versus -2.5 with placebo (differences, -1.4 and -1.6 points; both P<0.001). Among the participants with obstructive sleep apnea, the corresponding changes in events per hour in the retatrutide groups for the hybrid-treatment estimand were -22.9, -34.3, and 31.7 versus -9.9 (differences, -24.4 and -21.9; both P<0.001); the corresponding changes for the ITT estimand were -22.8, -34.3, and -32.1 versus -9.6 (differences, -24.7 and -22.5; both P<0.001). The most common adverse events were gastrointestinal.
CONCLUSIONS: In adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea-hypopnea events in participants with obstructive sleep apnea. (Funded by Eli Lilly; TRIUMPH-1 ClinicalTrials.gov number, NCT05929066.).