OBJECTIVE Multiregional trials are designed under the assumption that treatment effect applies to the entire target population, yet several factors may introduce geographic heterogeneity in treatment effect. We explored whether such variations exist in trials assessing the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in major cardiovascular events (MACE) in type 2 diabetes. RESEARCH DESIGN AND METHODS A systematic search of Medline and the Cochrane Library was conducted from inception until 30 June 2020. We included international randomized controlled trials comparing any GLP-1RA versus placebo, with MACE as a primary end point. Individual participant data were subsequently requested from the sponsor or through data sharing platforms. For each trial, we calculated hazard ratios (HRs) and their 95% CIs for MACE, subgrouped by region. We then performed a random-effects meta-analysis and conducted meta-regressions to assess the influence of predetermined variables of interest on treatment effect. RESULTS We included six trials including 45,426 patients. Baseline risk of MACE ranged from 2.9 per 100 patient-years in Southern Asia to 7.4 per 100 patient-years in Sub-Saharan Africa. HRs for MACE ranged between 0.25 (95% CI 0.05, 1.12) in Northern Africa to 0.98 (0.79, 1.22) in Western Europe. There was no significant subgroup difference across regions (P = 0.70). Baseline risk of MACE and indexes of development status (i.e., Human Development Index, gross domestic product) were independently associated with GLP-1RA efficacy. CONCLUSIONS This study does not suggest any regional heterogeneity of GLP-1RA efficacy in MACE. However, a higher baseline risk and lower development status were associated with a greater benefit of these drugs.

中文翻译：

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2 型糖尿病胰高血糖素样肽 1 受体激动剂试验结果的区域异质性：个体参与者数据的再分析


目的 多区域试验的设计假设治疗效果适用于整个目标人群，但有几个因素可能会引入治疗效果的地理异质性。我们探讨了在评估胰高血糖素样肽 1 受体激动剂 （GLP-1RAs） 对 2 型糖尿病主要心血管事件 （MACE） 疗效的试验中是否存在此类差异。研究、设计和方法 从建库到 2020 年 6 月 30 日，对 Medline 和 Cochrane 图书馆进行了系统检索。我们纳入了以 MACE 为主要终点，比较任何 GLP-1RA 与安慰剂的国际随机对照试验。随后向申办方或通过数据共享平台请求个人参与者数据。对于每项试验，我们计算了 MACE 的风险比 （HRs） 及其 95% CIs，按地区分组。然后，我们进行了随机效应荟萃分析并进行了荟萃回归，以评估预先确定的感兴趣变量对治疗效果的影响。结果 我们纳入了 6 项试验，包括 45,426 名患者。MACE 的基线风险范围从南亚的每 100 患者年 2.9 例到撒哈拉以南非洲的每 100 患者年 7.4 例。MACE 的 HR 范围在北非的 0.25 （95% CI 0.05， 1.12） 到西欧的 0.98 （0.79， 1.22） 之间。各地区之间没有显著的亚组差异 （P = 0.70）。MACE 的基线风险和发育状况指标 （即人类发展指数、国内生产总值） 与 GLP-1RA 疗效独立相关。结论 本研究未表明 GLP-1RA 在 MACE 中的疗效存在任何区域异质性。然而，较高的基线风险和较低的发育状态与这些药物的更大益处相关。