Retatrutide用于肥胖和2型糖尿病成人（TRIUMPH-2）：一项双盲、平行组、随机、安慰剂对照的3期试验。
完整摘要 · 中文译文
背景：瑞他鲁肽（retatrutide）是GIP（葡萄糖依赖性促胰岛素多肽）、GLP-1（胰高血糖素样肽-1）和胰高血糖素受体的激动剂，目前正在研究用于治疗肥胖、2型糖尿病以及其他合并症，包括膝骨关节炎和阻塞性睡眠呼吸暂停。我们旨在评估瑞他鲁肽在患有肥胖症和2型糖尿病的成人中的疗效和安全性。 方法：TRIUMPH-2是一项双盲、平行组、随机、安慰剂对照的3期试验，在8个国家的92个医疗和研究中心及医院进行。我们纳入了BMI为27 kg/m2或更高、患有2型糖尿病（糖化血红蛋白[HbA1c] 6·5-10·5%）、在筛选前接受稳定治疗至少90天（单独饮食或运动，或最多三种口服降糖药物）的成人（年龄≥18岁），并且至少有一次自我报告的减重饮食失败史。参与者使用交互式网络应答系统按1:1:1:1随机分配，接受每周一次皮下注射（自行给药）安慰剂或retatrutide 4 mg、9 mg或12 mg。主要终点是retatrutide 9 mg和12 mg剂量组与安慰剂组相比，从基线到第80周体重变化的百分比，4 mg与安慰剂比较是关键次要终点。疗效分析包括所有随机分配的参与者，缺失数据采用主要多重填补策略对治疗方案的估计目标进行填补。安全性分析包括所有随机分配且至少接受一剂研究药物的参与者。本试验已在ClinicalTrials.gov注册，编号NCT05929079（已完成）。 结果：在2023年7月11日至2024年11月1日期间，筛选了2047名参与者，1152名（平均年龄55·1岁[SD 10·8]，554名[48%]女性和598名[52%]男性，以及672名[58%]白人）被随机分配至retatrutide 4 mg（n=292）、9 mg（n=284）或12 mg（n=287），或安慰剂组（n=289）。基线时，平均BMI为38·2 kg/m2（SD 7·4），平均HbA1c为7·71%（1·07），肥胖中位持续时间为21年（IQR 11-31），糖尿病中位持续时间为5·6年（2·6-10·4）。基线时，1152名参与者中有1055名（92%）正在服用任何口服降糖药物，包括双胍类、SGLT2抑制剂、磺脲类和其他口服降糖药物。1152名参与者中，965名（84%）完成了研究药物。就治疗方案估计目标而言，第80周体重相对于基线的平均百分比变化为：retatrutide 4 mg组为-11·9%（SE 0·6），retatrutide 9 mg组为-16·8%（0·7），retatrutide 12 mg组为-18·8%（0·7），安慰剂组为-5·1%（0·7）。与安慰剂相比，体重百分比变化的估计治疗差异为：retatrutide 4 mg组为-6·9%（95% CI -8·7至-5·1），retatrutide 9 mg组为-11·8%（-13·7至-9·8），retatrutide 12 mg组为-13·8%（-15·8至-11·8）（所有p<0·0001）。最常报告的不良事件为胃肠道事件，在retatrutide组中比安慰剂组更常见（腹泻发生在4 mg组292名参与者中的80名[27%]，9 mg组284名中的95名[34%]，12 mg组286名中的96名[34%]，而安慰剂组287名中的38名[13%]；恶心发生 在40例[14%]、59例[21%]和80例[28%]对比23例[8%]中）。低血压和感觉迟钝在retatrutide组较安慰剂组更常见（4 mg组4例[1%]，9 mg组14例[5%]，12 mg组18例(6%)，而安慰剂组低血压1例[<1%]；感觉迟钝分别为13例[4%]、16例[6%]和21例[7%]，而安慰剂组2例[1%]）。与retatrutide 4 mg组（11例[4%]）和安慰剂组（14例[5%]）相比，retatrutide 9 mg组（33例[12%]）和12 mg组（22例[8%]）参与者因不良事件或死亡而永久停止治疗更常见。retatrutide 4 mg组有2名参与者死亡，9 mg组3名，12 mg组1名，安慰剂组1名；所有死亡均被研究者认为与研究干预无关。 解读：使用retatrutide治疗导致肥胖和2型糖尿病参与者的体重显著改善，并与血糖控制的改善相关，其安全性特征通常与其他具有GLP-1受体激动作用的分子一致。这些结果表明，retatrutide可能有效治疗2型糖尿病患者的肥胖。 资助：礼来公司。
完整摘要 · 英文原文
BACKGROUND: Retatrutide is an agonist of GIP, GLP-1, and glucagon receptors, and is currently under investigation for the treatment of obesity, type 2 diabetes, and other comorbidities, including knee osteoarthritis and obstructive sleep apnoea. We aimed to assess the efficacy and safety of retatrutide in adults with obesity and type 2 diabetes. METHODS: TRIUMPH-2 was a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial conducted at 92 medical and research centres and hospitals across eight countries. We enrolled adults (aged ≥18 years) with a BMI of 27 kg/m2 or higher and type 2 diabetes (glycated haemoglobin [HbA1c] 6·5-10·5%) on stable treatment for type 2 diabetes for at least 90 days before screening (diet or exercise alone, or up to three oral glucose-lowering medications), and a history of at least one self-reported unsuccessful dietary effort to reduce bodyweight. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to receive once-weekly subcutaneous injections (self-administered) of placebo or retatrutide 4 mg, 9 mg, or 12 mg. The primary endpoint was the percentage change from baseline to week 80 in bodyweight for the retatrutide 9 mg and 12 mg doses versus placebo, with 4 mg versus placebo a key secondary endpoint. Efficacy analyses included all randomly assigned participants, with missing data imputed with a primary multiple imputation strategy for the treatment regimen estimand. Safety analyses included all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05929079 (completed). FINDINGS: Between July 11, 2023, and Nov 1, 2024, 2047 participants were screened, and 1152 (mean age 55·1 years [SD 10·8], 554 [48%] females and 598 [52%] males, and 672 [58%] of White ethnicity) were randomly assigned to retatrutide 4 mg (n=292), 9 mg (n=284), or 12 mg (n=287), or placebo (n=289). At baseline, the mean BMI was 38·2 kg/m2 (SD 7·4), mean HbA1c was 7·71% (1·07), median duration of obesity was 21 years (IQR 11-31), and median duration of diabetes was 5·6 years (2·6-10·4). At baseline, 1055 (92%) of 1152 participants were on any oral glucose-lowering medication, including biguanides, SGLT2 inhibitors, sulfonylureas, and other oral glucose-lowering medications. Of 1152 participants, 965 (84%) completed the study drug. For the treatment regimen estimand, the mean percentage change from baseline in bodyweight at week 80 was -11·9% (SE 0·6) with retatrutide 4 mg, -16·8% (0·7) with retatrutide 9 mg, -18·8% (0·7) with retatrutide 12 mg, and -5·1% (0·7) with placebo. Estimated treatment differences compared with placebo for percentage change in bodyweight were -6·9% (95% CI -8·7 to -5·1) with retatrutide 4 mg, -11·8% (-13·7 to -9·8) with retatrutide 9 mg, and -13·8% (-15·8 to -11·8) with retatrutide 12 mg (p<0·0001 for all). The most frequently reported adverse events were gastrointestinal, which were more common in the retatrutide groups than in the placebo group (diarrhoea occurred in 80 [27%] of 292 participants in the 4 mg group, 95 [34%] of 284 in the 9 mg group, and 96 [34%] of 286 in the 12 mg group vs 38 [13%] of 287 in the placebo group, and nausea occurred in 40 [14%], 59 [21%], and 80 [28%] vs 23 [8%]). Hypotension and dysesthesia were more frequent with retatrutide than with placebo (four [1%] in the 4 mg group, 14 [5%] in the 9 mg group, and 18 (6%) in the 12 mg group vs one [<1%] in the placebo group with hypotension; 13 [4%], 16 [6%], and 21 [7%] vs two [1%] in the placebo group with dysesthesia). Permanent treatment discontinuation due to adverse events or death was more frequent in participants treated with retatrutide 9 mg (33 [12%]) and 12 mg (22 [8%]) compared with retatrutide 4 mg (11 [4%]) and placebo (14 [5%]). Two participants died in the retatrutide 4 mg group, three in the 9 mg group, one in the 12 mg group, and one in the placebo group; all deaths were deemed to be unrelated to the study intervention by the investigator. INTERPRETATION: Treatment with retatrutide resulted in substantial improvements in bodyweight and was associated with improvements in glycaemic control in participants with obesity and type 2 diabetes, with a safety profile generally consistent with other molecules with GLP-1 receptor agonism. These results show that retatrutide might be effective for the treatment of obesity in people with type 2 diabetes. FUNDING: Eli Lilly and Company.