Glucagon-like peptide 1 receptor agonists (GLP-1RAs) injected periodically have been shown to not increase and, for some members of this class, decrease the risk of cardiovascular events. The cardiovascular safety of delivering a continuous subcutaneous infusion of the GLP-1RA exenatide (ITCA 650) is unknown. Here, we randomly assigned patients with type 2 diabetes with, or at risk for, atherosclerotic cardiovascular disease (ASCVD) to receive ITCA 650 or placebo to assess cardiovascular safety in a pre-approval trial (NCT01455896). The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. On the basis of 2008 guidance from the US Food and Drug Administration, a non-inferiority margin of 1.8 for the upper bound of the 95% confidence interval (CI) of the hazard ratio (HR) was used. We randomized 4,156 patients (2,075 assigned to receive ITCA 650 and 2,081 assigned to receive placebo) who were followed for a median of 16 months. The primary outcome occurred in 4.6% (95/2,075) of patients in the ITCA 650 group and 3.8% (79/2,081) of patients in the placebo group, meeting the pre-specified non-inferiority criterion (HR = 1.21, 95% CI, 0.90–1.63, P_{non-inferiority} = 0.004). Serious adverse events were similar between the two groups. Adverse events were more frequent in the ITCA 650 group (72%, 1,491/2,074) than in the placebo group (63.9%, 1,325/2,070), mainly due to an increase in gastrointestinal events and disorders while on ITCA 650. In patients with type 2 diabetes with, or at risk for, ASCVD, ITCA 650 was non-inferior to placebo. A larger and longer-duration cardiovascular outcomes trial is needed to define more precisely the cardiovascular effects of ITCA 650 in this population.

定期注射的胰高血糖素样肽 1 受体激动剂 (GLP-1RAs) 已显示不会增加，并且对于此类的一些成员，降低心血管事件的风险。持续皮下输注 GLP-1RA 艾塞那肽 (ITCA 650) 的心血管安全性尚不清楚。在这里，我们将患有动脉粥样硬化性心血管疾病 (ASCVD) 或有患动脉粥样硬化性心血管疾病 (ASCVD) 风险的 2 型糖尿病患者随机分配接受 ITCA 650 或安慰剂，以在一项预批准试验 (NCT01455896) 中评估心血管安全性。主要结局是心血管死亡、非致死性心肌梗死、非致死性中风或因不稳定型心绞痛住院的复合结局。根据美国食品和药物管理局 2008 年的指南，非劣效性差值为 1。8 用于风险比 (HR) 的 95% 置信区间 (CI) 的上限。我们随机分配了 4,156 名患者（2,075 名分配接受 ITCA 650，2,081 名分配接受安慰剂），中位随访时间为 16 个月。主要结局发生在 ITCA 650 组 4.6% (95/2,075) 的患者和安慰剂组 3.8% (79/2,081) 的患者中，符合预先指定的非劣效性标准 (HR = 1.21, 95%置信区间，0.90–1.63，P_非劣效性 = 0.004）。两组之间的严重不良事件相似。ITCA 650 组的不良事件（72%，1,491/2,074）比安慰剂组（63.9%，1,325/2,070）更频繁，主要是由于在使用 ITCA 650 时胃肠道事件和疾病的增加。患有 ASCVD 或有患 ASCVD 风险的 2 型糖尿病，ITCA 650 不劣于安慰剂。需要进行更大规模、持续时间更长的心血管结局试验，以更准确地定义 ITCA 650 在该人群中的心血管效应。