每周一次瑞他鲁肽治疗阻塞性睡眠呼吸暂停

文献信息

中文摘要

背景： 瑞他鲁肽是一种在研的葡萄糖依赖性促胰岛素多肽、胰高血糖素样肽1和胰高血糖素受体三重激动剂，可能对治疗阻塞性睡眠呼吸暂停（OSA）有用。
方法： 在两项嵌套于更大篮式试验中的3期、双盲、随机、安慰剂对照试验中，我们分配患有中重度OSA且体重指数（体重千克数除以身高米数的平方）至少为27的成人，无（TRIUMPH-1-OSA）或伴有（TRIUMPH-2-OSA）2型糖尿病，接受瑞他鲁肽（4、9或12 mg）或安慰剂，每周皮下注射一次。主要终点是80周时9 mg和12 mg瑞他鲁肽组呼吸暂停低通气指数（AHI，即每小时睡眠中呼吸暂停和低通气的平均次数）的变化。对于OSA相关终点，采用混合治疗估计目标，对出现提示治疗失败的伴发事件的参与者使用假设策略，其他情况使用治疗策略。我们还报告意向性治疗（ITT）结果。
结果： TRIUMPH-1-OSA共有243名参与者随机分组，TRIUMPH-2-OSA有448名。基线平均AHI分别为每小时58.6和55.9次事件，平均体重分别为119.6和115.9 kg。在80周时，TRIUMPH-1-OSA中瑞他鲁肽组AHI的平均变化（混合治疗估计目标）为-22.9（4 mg）、-34.3（9 mg）和-31.7（12 mg）次事件/小时，而安慰剂组为-9.9（与安慰剂的差异分别为-13.0[95%置信区间{CI}，-23.0至-3.0]、-24.4[95% CI，-34.1至-14.7]和-21.9[95% CI，-32.2至-11.5]）。TRIUMPH-2-OSA中瑞他鲁肽组的变化为-19.2（4 mg）、-24.7（9 mg）和-25.4（12 mg）次事件/小时，而安慰剂组为-10.3（与安慰剂的差异分别为-8.9[95% CI，-15.9至-2.0]、-14.4[95% CI，-21.6至-7.2]和-15.1[95% CI，-22.5至-7.7]）。对于ITT估计目标，TRIUMPH-1-OSA中与安慰剂的相应差异为-13.2（95% CI，-22.6至-3.9）、-24.7（95% CI，-34.1至-15.3）和-22.5（95% CI，-31.9至-13.1），TRIUMPH-2-OSA中为-8.8（95% CI，-15.8至-1.7）、-13.9（95% CI，-21.3至-6.6）和-15.0（95% CI，-22.5至-7.4）。瑞他鲁肽组体重的平均百分比变化（关键次要终点）在TRIUMPH-1-OSA中为-12.5%至-22.2%，在TRIUMPH-2-OSA中为-12.1%至-18.5%，而安慰剂组分别为-4.8%和-5.6%（治疗方案估计目标）。最常见的不良事件为胃肠道事件。
结论： 在患有OSA且伴肥胖或超重、伴或不伴2型糖尿病的成人中，瑞他鲁肽使AHI的下降显著大于安慰剂。（由Eli Lilly资助；TRIUMPH-1和-2的ClinicalTrials.gov编号分别为NCT05929066和NCT05929079。）

英文摘要

BACKGROUND: Retatrutide, an investigational triple agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, may be useful for treating obstructive sleep apnea (OSA).
METHODS: In two phase 3, double-blind, randomized, placebo-controlled trials nested within larger basket trials of once-weekly subcutaneous retatrutide, we assigned adults with moderate-to-severe OSA and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 27, without (TRIUMPH-1-OSA) or with (TRIUMPH-2-OSA) type 2 diabetes, to receive retatrutide (4, 9, or 12 mg) or placebo. The primary end point was the change in the apnea-hypopnea index (AHI, the average number of apneas and hypopneas per hour of sleep) at 80 weeks with 9 mg and 12 mg of retatrutide. For OSA-related end points, a hybrid-treatment estimand was applied, with a hypothetical strategy used for participants who had intercurrent events suggesting treatment failure and a treatment-policy strategy used elsewhere. We also report intention-to-treat (ITT) results.
RESULTS: A total of 243 participants underwent randomization in TRIUMPH-1-OSA and 448 in TRIUMPH-2-OSA. The baseline mean AHI was 58.6 and 55.9 events per hour, respectively, and the mean body weight was 119.6 and 115.9 kg. At 80 weeks, the mean changes in the AHI (hybrid-treatment estimand) with retatrutide in TRIUMPH-1-OSA were -22.9 (4 mg), -34.3 (9 mg), and -31.7 (12 mg) events per hour, versus -9.9 with placebo (difference vs. placebo, -13.0 [95% confidence interval {CI}, -23.0 to -3.0], -24.4 [95% CI, -34.1 to -14.7], and -21.9 [95% CI, -32.2 to -11.5], respectively). The changes with retatrutide in TRIUMPH-2-OSA were -19.2 (4 mg), -24.7 (9 mg), and -25.4 (12 mg) events per hour, versus -10.3 with placebo (difference vs. placebo, -8.9 [95% CI, -15.9 to -2.0], -14.4 [95% CI, -21.6 to -7.2], and -15.1 [95% CI, -22.5 to -7.7]). For the ITT estimand, the corresponding differences from placebo were -13.2 (95% CI, -22.6 to -3.9), -24.7 (95% CI, -34.1 to -15.3), and -22.5 (95% CI, -31.9 to -13.1) in TRIUMPH-1-OSA and -8.8 (95% CI, -15.8 to -1.7), -13.9 (95% CI, -21.3 to -6.6), and -15.0 (95% CI, -22.5 to -7.4) in TRIUMPH-2-OSA. The mean percent change in body weight with retatrutide (key secondary end point) was -12.5 to -22.2% in TRIUMPH-1-OSA and -12.1 to -18.5% in TRIUMPH-2-OSA, versus -4.8% and -5.6% with placebo (treatment-regimen estimand). The most common adverse events were gastrointestinal.
CONCLUSIONS: In adults with OSA and obesity or overweight with or without type 2 diabetes, retatrutide resulted in significantly greater decreases in the AHI than placebo. (Funded by Eli Lilly; TRIUMPH-1 and -2 ClinicalTrials.gov numbers, NCT05929066 and NCT05929079.).