Orforglipron与甘精胰岛素在心血管风险增加的2型糖尿病成人患者中的心血管安全性（ACHIEVE-4）：一项3期、事件驱动、随机、开放标签、非劣效性、活性对照试验。
完整摘要 · 中文译文
背景：Orforglipron 是一种口服非肽类 GLP-1 受体激动剂。虽然某些肽类 GLP-1 受体激动剂已证实具有心血管获益，但非肽类 GLP-1 受体激动剂的心血管安全性尚未被研究。本研究旨在比较 orforglipron 与甘精胰岛素对伴有肥胖或超重且心血管事件风险增高的 2 型糖尿病患者主要不良心血管事件发生率的影响。 方法：本项事件驱动、3 期、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 个研究中心进行。患有 2 型糖尿病、心血管风险增高、糖化血红蛋白（HbA1c）浓度为 7.0% 至 10.5%（53-91 mmol/mol）、BMI 为 25 kg/m² 或以上、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）治疗的成人，按 1:1 随机分配接受口服 orforglipron 最大耐受剂量（最高 36 mg 胶囊 [相当于 17.2 mg 片剂]）或可注射的逐步滴定甘精胰岛素，均每日一次给药。所有参与者均患有确诊的心血管疾病或慢性肾脏病。主要结局为四组分主要不良心血管事件（MACE-4）发生时间，包括心血管死亡、非致死性心肌梗死、非致死性卒中或因不稳定型心绞痛住院。如果风险比（HR；orforglipron 与甘精胰岛素相比）的双侧 95% 置信区间上限低于预设的非劣效性界值，则宣告 orforglipron 相对于甘精胰岛素的非劣效性。 奥福格列普隆组与甘精胰岛素组之间的差异小于1·8。主要终点和其他安全性终点在所有至少接受过一剂指定治疗方案的参与者中进行了评估，使用了从基线到退出或研究完成期间的所有数据点，无论其治疗依从性如何。本试验已在ClinicalTrials.gov注册（NCT05803421），且已完成。 结果：在2023年5月1日至2024年9月5日期间，2749名参与者被随机分配（1371名接受奥福格列普隆，1378名接受甘精胰岛素）。1032名（38%）参与者为女性，1717名（62·5%）为男性。2362名（85·9%）参与者患有确诊心血管疾病，1033名（37·6%）患有慢性肾脏病。基线平均年龄、HbA1c和BMI分别为63·1岁（标准差9·9）、8·2%（1·0）和33 kg/m²（6·2）。在中位随访2年期间，奥福格列普隆组1358名参与者中有57名（4·2%）发生主要结局事件，甘精胰岛素组1343名参与者中有67名（5·0%）发生，显示其在MACE-4方面不劣于甘精胰岛素（HR 0·84；95% CI 0·59–1·20；非劣效性p<0·0001）。胃肠道不良事件在奥福格列普隆组1371名参与者中有851名（62·1%）报告，在甘精胰岛素组1355名参与者中有193名（14·2%）报告；临床显著性或严重低血糖（血糖<3 mmol/L [54 mg/dL]）在奥福格列普隆组1371名参与者中有93名（6·8%）发生，在甘精胰岛素组1355名参与者中有260名（19·2%）发生。研究期间报告了62例死亡：奥福格列普隆组1371名参与者中有19例（1·4%），甘精胰岛素组1355名参与者中有43例（3·2%）；除1例（在胰岛素组）外，所有死亡均…… （甘精胰岛素组中）均被认为与治疗无关。 结论：在心血管风险增加的2型糖尿病患者中，奥福格利普龙的心血管安全性通过证明其对于主要不良心血管事件-4（MACE-4）不劣于甘精胰岛素而得到确认。胃肠道不良事件是最常见的不良事件，也是奥福格利普龙治疗中止的最常见原因，而具有临床意义的低血糖在奥福格利普龙组的发生频率低于甘精胰岛素组。这些发现支持奥福格利普龙作为一种每日一次、口服治疗选择，在心血管风险增加的2型糖尿病患者中具有已确认的心血管安全性。 资助：礼来公司。
完整摘要 · 英文原文
BACKGROUND: Orforglipron is an oral, non-peptide GLP-1 receptor agonist. 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. This study aimed to compare the effect of orforglipron with insulin glargine on the incidence of major adverse cardiovascular events in individuals with type 2 diabetes and obesity or overweight who are at increased risk for cardiovascular events. 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. 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. All participants had established cardiovascular or chronic kidney disease. 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. 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. 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. This trial was registered on ClinicalTrials.gov (NCT05803421) and is completed. FINDINGS: 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. Mean baseline age, HbA1c, and BMI were 63·1 years (SD 9·9), 8·2% (1·0), and 33 kg/m2 (6·2), respectively. 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). 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. 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. Gastrointestinal adverse events were the most frequent adverse event and most common reason for orforglipron treatment discontinuation with orforglipron, while clinically significant hypoglycaemia occurred less frequently with orforglipron than with insulin glargine. 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. FUNDING: Eli Lilly and Company.