Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial.

While some peptide GLP-1 receptor agonists have established cardiovascular benefit, the cardiovascular safety of non-peptide GLP-1 receptor agonists has not been studied.

尽管一些肽类 GLP-1 受体激动剂已确立了心血管益处，但非肽类 GLP-1 受体激动剂的心血管安全性尚未得到研究。

This study aimed to compare the effect of orforglipron with insulin glargine on the incidenceof major adverse cardiovascular events in individuals with type 2 diabetes and obesity or overweight who are at increased risk for cardiovascular events.

本研究旨在比较 orforglipron 与胰岛素格拉珍对 2 型糖尿病和肥胖或超重个体心血管不良事件发生率的影响，这些个体具有增加的心血管事件风险。

Methods

This event-driven, phase 3, multicentre, randomised, open-label, active comparator, parallel-group study was conducted in 317 sites across 16 countries and territories.

这是一项事件驱动的、第三阶段、多中心、随机、开放标签、活性对照、平行组研究，在 16 个国家和地区的 317 个地点进行。

Adults with type 2 diabetes at increased cardiovascular risk with glycated haemoglobin (HbA1c) concentrations between 7·0% and 10·5% (53-91 mmol/mol) and a BMI of 25 kg/m2 or more, treated with up to three glucose-lowering medications (metformin, a sulfonylurea, and/or an SGLT2 inhibitor), were randomly assigned (1:1) to oral orforglipron maximum tolerated dose (up to 36 mg capsule [equivalent to 17·2 mg tablet]) or injectable titrated insulin glargine, each administered once daily.

患有 2 型糖尿病且心血管风险增加的成年人，其糖化血红蛋白（HbA1c）浓度在 7.0% 至 10.5%（53-91 mmol/mol）之间，BMI 为 25 kg/m2 或更高，并且正在接受最多三种降糖药物（二甲双胍、磺脲类药物和/或 SGLT2 抑制剂）治疗，被随机分配（1:1）接受口服 orforglipron 最大耐受剂量（最多 36 mg 胶囊[相当于 17.2 mg 片剂]）或注射用胰岛素格拉珍，每天一次。

All participants had established cardiovascular or chronic kidney disease.

所有参与者都有已确立的心血管或慢性肾脏疾病。

The primary outcome was time to occurrence of four-component major adverse cardiovascular events (MACE-4), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina.

主要结果是四组分主要不良心血管事件（MACE-4）发生的时间，包括心血管死亡、非致命性心肌梗死、非致命性中风或因不稳定性心绞痛住院。

Non-inferiority of orforglipron to insulin glargine was declared if the upper limit of the two-sided 95% CI for the hazard ratio(HR; orforglipron vs insulin glargine) was less than 1·8.

如果双侧 95% 置信区间（CI）的上限对于风险比（HR；orforglipron 对比胰岛素格拉珍）小于 1.8，则宣布 orforglipron 对胰岛素格拉珍非劣效。

The primary endpoint and other safety endpoints were assessed in all participants who took at least one dose of assigned treatment using all datapoints from baseline until withdrawal or study completion, regardless of treatment adherence.

主要终点和其他安全性终点在所有至少接受一次指定治疗的参与者中进行评估，使用从基线到退出或研究完成的所有数据点，无论治疗依从性如何。

This trial was registered on ClinicalTrials.gov (NCT05803421) and is completed.

该试验已在ClinicalTrials.gov上注册（NCT05803421），并已完成。

Results

Between May 1, 2023, and Sept 5, 2024, 2749 participants were randomly assigned (1371 to orforglipron and 1378 to insulin glargine). 1032 (38%) participants were female and 1717 (62·5%) male. 2362 (85·9%) participants had established cardiovascular disease and 1033 (37·6%) had chronic kidney disease.

在2023年5月1日至2024年9月5日期间，共有2749名参与者被随机分配（1371名分配至orforglipron，1378名分配至胰岛素glargine）。其中1032名（38%）为女性，1717名（62.5%）为男性。2362名（85.9%）参与者有已确立的心血管疾病，1033名（37.6%）有慢性肾脏疾病。

Mean baseline age, HbA1c, and BMI were 63·1 years (SD 9·9), 8·2% (1·0), and 33 kg/m2 (6·2), respectively.

平均基线年龄、HbA1c和BMI分别为63.1岁（标准差9.9）、8.2%（1.0）和33 kg/m2（6.2）。

Over a median follow-up of 2 years, the primary outcome occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants, showing non-inferiority to insulin glargine for MACE-4 (HR 0·84; 95% CI 0·59-1·20; p<0·0001 for non-inferiority).

在中位随访2年期间，主要结果在1358名orforglipron参与者中发生了57例（4.2%），在1343名胰岛素glargine参与者中发生了67例（5.0%），显示出与胰岛素glargine相比对MACE-4的非劣效性（HR 0.84；95% CI 0.59-1.20；p<0.0001表示非劣效性）。

Gastrointestinal adverse events were reported in 851 (62·1%) of 1371 orforglipron participants and 193 (14·2%) of 1355 insulin glargine participants; clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]) occurred in 93 (6·8%) of 1371 orforglipron participants and 260 (19·2%) of 1355 insulin glargine participants. 62 deaths were reported during the study: 19 (1·4%) of 1371 participants receiving orforglipron and 43 (3·2%) of 1355 participants receiving insulin glargine; all deaths except one (in the insulin glargine group) were deemed unrelated to treatment.

在1371名orforglipron参与者中有851例（62.1%）报告了胃肠道不良事件，在1355名胰岛素glargine参与者中有193例（14.2%）报告了胃肠道不良事件；临床显著或严重的低血糖（血糖<3 mmol/L [54 mg/dL]）在1371名orforglipron参与者中有93例（6.8%），在1355名胰岛素glargine参与者中有260例（19.2%）。研究期间报告了62例死亡：1371名接受orforglipron的参与者中有19例（1.4%），1355名接受胰岛素glargine的参与者中有43例（3.2%）；除了一例（在胰岛素glargine组）外，所有死亡均被认为与治疗无关。

interpretation

In people with type 2 diabetes at increased cardiovascular risk, the cardiovascular safety of orforglipron was confirmed by demonstrating non-inferiority to insulin glargine for MACE-4.

在有2型糖尿病且心血管风险增加的人群中，通过证明与胰岛素glargine相比对MACE-4的非劣效性，确认了orforglipron的心血管安全性。

Gastrointestinal adverse events were the most frequent adverse eventand most common reason for orforglipron treatment discontinuation with orforglipron, while clinically significant hypoglycaemia occurred less frequently with orforglipron than with insulin glargine.

胃肠道不良事件是orforglipron治疗中发生最频繁的不良事件，也是停止orforglipron治疗的最常见原因，而临床显著的低血糖在使用orforglipron的患者中比使用胰岛素glargine的患者发生得更少。

These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk.

这些发现支持orforglipron作为一种潜在的每日一次口服治疗选择，对于2型糖尿病患者且心血管风险增加的人群具有确立的心血管安全性。

funding

Eli Lilly and Company.

礼来公司