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Abstract：
The US Food and Drug Administration in 2008 required new type 2 diabetes (T2D) medications to be subject to cardiovascular outcomes safety requirements. Accordingly, the global LEADER trial investigated cardiovascular outcomes of T2D treatment with liraglutide, a glucagon-like peptide-1 receptor agonist. LEADER (NCT01179048) was a multiregional clinical trial (MRCT) conducted from 2010 to 2016, thus completed before publication of the International Council for Harmonization (ICH) E17 guideline on MRCTs in 2017. Novo Nordisk pre-specified analysis of regional cardiovascular outcomes of LEADER participants. This paper assesses the pre-specified regional outcomes based on the ICH E17 guidelines on consistency evaluation. Regional LEADER participant numbers were broadly aligned with ICH E17 guidance and equally balanced across Europe, Asia, North America, and rest of the world. Overall primary major adverse cardiovascular events (MACE) composite outcome for the trial: hazard ratio (HR) (95% CI) 0.87 (0.78; 0.97); regional results varied, ranging from HR (95% CI) 0.62 (0.37; 1.04) (Asia) to 1.01 (0.84; 1.22) (North America). However, pre-specified Cox proportional-hazard regression analyses did not show clear evidence of interaction between regions and primary outcome (p = 0.20). Furthermore, post hoc analysis of the US population in the North American region found that adjusting for extrinsic or intrinsic factors did not account for this difference [HR (95% CI) 1.03 (0.84; 1.25)]. LEADER data evaluation demonstrated general consistency in cardiovascular safety across regions, except for US participants. Discrepancies in the North American region may relate to drug exposure or chance, but, as these were post hoc findings, the overall primary result is valid, aligned with ICH E17 guidelines.
摘要：
2008年，美国食品和药物管理局要求新的2型糖尿病（T2D）药物必须符合心血管结局安全要求。因此，全球LEADER试验调查了利拉鲁肽治疗T2D的心血管结局，胰高血糖素样肽-1受体激动剂。LEADER（NCT01179048）是一项从2010年至2016年进行的多区域临床试验（MRCT），在2017年国际协调理事会（ICH）关于MRCT的E17指南发布之前完成。诺和诺德预先指定的LEADER参与者区域心血管结局分析。本文根据ICHE17一致性评价指南对预先指定的区域结果进行评估。区域LEADER参与者人数与ICHE17指南大致一致，在整个欧洲同样平衡，亚洲,北美,和世界其他地方。试验的总体主要不良心血管事件（MACE）复合结局：风险比（HR）（95％CI）0.87（0.78;0.97）；区域结果各不相同，范围从HR（95%CI）0.62（0.37；1.04）（亚洲）到1.01（0.84；1.22）（北美）。然而,预先指定的Cox比例风险回归分析未显示区域与主要结局之间相互作用的明确证据(p=0.20).此外，对北美地区美国人口的事后分析发现,调整外在或内在因素并不能解释这一差异[HR(95%CI)1.03(0.84;1.25)].LEADER数据评估表明，不同地区的心血管安全总体上是一致的，除了美国的参与者。北美地区的差异可能与药物暴露或机会有关，但是,因为这些是事后调查结果，总体主要结果是有效的，符合ICHE17指南。
