Retatrutide，一种三激素受体激动剂，用于肥胖治疗
完整摘要 · 中文译文
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至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（分别在 9 mg 组和 12 mg 组与安慰剂组比较）为体重百分比变化，以及 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，并发事件采用治疗方案估计目标（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，采用混合治疗估计目标，并对提示治疗失败的并发事件采用假设策略；同时报告 ITT 结果。 结果：共有2339名参与者接受了随机分组。retatrutide组的平均体重变化百分比分别为-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；两项比较均P<0.001）。在膝骨关节炎参与者中，retatrutide组混合估计目标的疼痛评分相应变化分别为-3.2、-3.5和-3.6，而安慰剂组为-1.9（差异为-1.6和-1.8分；均P<0.001）；ITT估计目标的相应变化分别为-3.4、-3.9和-4.1，而安慰剂组为-2.5（差异为-1.4和-1.6分；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每小时事件数相应变化分别为-22.9、-34.3和-31.7，而安慰剂组为-9.9（差异为-24.4和-21.9；均P<0.001）；ITT估计目标的相应变化分别为-22.8、-34.3和-32.1，而安慰剂组为-9.6（差异为-24.7和-22.5；均P<0.001）。最常见的不良事件为胃肠道不良事件。 结论：在肥胖成人中，retatrutide带来了显著的体重下降，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注册号，NCT05929066。）
完整摘要 · 英文原文
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.).