Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial.

We aimed to assess the efficacy and safety of retatrutide in adults with obesity and type 2 diabetes.

我们的目标是评估 retatrutide 在肥胖症和 2 型糖尿病成年患者中的疗效和安全性。

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.

TRIUMPH-2 是一项在八个不同国家的 92 个医疗和研究中心及医院进行的双盲、平行组、随机、安慰剂对照的 3 期临床试验。

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.

我们招募了年龄≥18 岁、BMI 为 27 kg/m2 或更高、2 型糖尿病（糖化血红蛋白 [HbA1c] 6·5-10·5%）的成年人，他们在筛选前至少 90 天内对 2 型糖尿病进行了稳定的治疗（仅饮食或运动，或最多三种口服降糖药），并且至少有一次自我报告的减重饮食尝试失败的历史。

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.

参与者通过交互式网络响应系统随机分配（1:1:1:1），接受每周一次的皮下注射（自我给药）安慰剂或 retatrutide 4 mg、9 mg 或 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.

主要终点是 retatrutide 9 mg 和 12 mg 剂量与安慰剂相比，从基线到第 80 周体重的百分比变化，而 4 mg 与安慰剂相比是一个关键的次要终点。

Efficacy analyses included all randomly assigned participants, with missing data imputed with a primary multiple imputation strategy for the treatment regimen estimand.

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插补策略对治疗方案进行估算。

Safety analyses included all randomly assigned participants who received at least one dose of study drug.

安全性分析包括所有随机分配的参与者，他们至少接受了一次研究药物的剂量。

This trial is registered with ClinicalTrials.gov, NCT05929079 (completed).

该试验已在ClinicalTrials.gov注册，编号NCT05929079（已完成）。

Results

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).

在2023年7月11日至2024年11月1日期间，共有2047名参与者接受了筛选，其中1152名（平均年龄55.1岁[标准差10.8]，女性554名[48%]，男性598名[52%]，白人672名[58%]）被随机分配到retatrutide 4 mg组（n=292），9 mg组（n=284），12 mg组（n=287）或安慰剂组（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).

在基线时，平均BMI为38.2 kg/m2（标准差7.4），平均HbA1c为7.71%（1.07），肥胖的中位持续时间为21年（四分位数间距11-31），糖尿病的中位持续时间为5.6年（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.

在基线时，1152名参与者中有1055名（92%）正在使用任何口服降糖药物，包括双胍类药物、SGLT2抑制剂、磺脲类药物和其他口服降糖药物。

Of 1152 participants, 965 (84%) completed the study drug.

在1152名参与者中，有965名（84%）完成了研究药物的使用。

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.

对于治疗方案估计值，第80周时体重从基线开始的平均百分比变化为：retatrutide 4 mg组为-11.9%（标准误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）。

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).

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%置信区间-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）。

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%]).

报告的最常见不良事件是胃肠道事件，这些在retatrutide组中比安慰剂组更为常见（在4 mg组的292名参与者中有80名[27%]出现腹泻，在9 mg组的284名中有95名[34%]，在12 mg组的286名中有96名[34%]，而在安慰剂组的287名中有38名[13%]；恶心的发生率分别为40名[14%]，59名[21%]和80名[28%]，而在安慰剂组为23名[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).

与安慰剂相比，使用retatrutide的患者出现低血压和感觉异常的频率更高（4 mg组有四例[1%]，9 mg组有14例[5%]，12 mg组有18例[6%]与低血压；与安慰剂组的低血压患者少于1%；9 mg组有13例[4%]，12 mg组有16例[6%]，与安慰剂组的两例[1%]相比，感觉异常更为频繁）。

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%]).

因不良事件或死亡而永久停药的情况在使用retatrutide 9 mg（33例[12%]）和12 mg（22例[8%]）的参与者中比使用retatrutide 4 mg（11例[4%]）和安慰剂（14例[5%]）的更为频繁。

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.

在retatrutide 4 mg组中有两名参与者死亡，在9 mg组中有三名，在12 mg组中有一名，在安慰剂组中有一名；所有死亡均被调查员判定与研究干预无关。

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.

使用retatrutide治疗后，肥胖和2型糖尿病患者的体重显著改善，并且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。

These results show that retatrutide might be effective for the treatment of obesity in people with type 2 diabetes.

这些结果表明，retatrutide可能对治疗2型糖尿病患者的肥胖有效。

funding

Eli Lilly and Company.

礼来公司。