Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing, China.
Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Front Endocrinol (Lausanne). 2022 May 26;13:893971. doi: 10.3389/fendo.2022.893971. eCollection 2022.
Our study aimed to evaluate the exposure-response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log C, log AUC, and log AUC are negatively correlated with MACE HR (R = 0.8494, R = 0.8728, and R = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log C, log AUC and log AUC) and MACE HR strongly corresponded with the log (inhibitor) . response curve (R = 0.8383, R = 0.8430, and R = 0.8229, respectively). The cutoff values in the ROC curves for log C, log AUC, and log AUC, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher's exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure-response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure.
我们的研究旨在通过心血管结局试验（CVOT）评估基于肠促胰岛素的药物与主要不良心血管事件（MACE）风险之间的暴露-反应关系。纳入了 11 项基于肠促胰岛素的药物 CVOT。从每个 CVOT 中获得 MACE 的中位随访时间、暴露时间百分比和风险比（HR）。从已发表的研究中获得胰高血糖素样肽-1 受体激动剂（GLP-1RA）和二肽基肽酶-4 抑制剂（DPP-4）的药代动力学参数。回归分析用于评估药物暴露与 MACE HR 之间的关系。从 ROC 曲线确定临界值。线性回归结果表明，log C、log AUC 和 log AUC 与 MACE HR 呈负相关（R = 0.8494、R = 0.8728 和 R = 0.8372，均 p < 0.0001）。药物暴露（log C、log AUC 和 log AUC）与 MACE HR 之间的关系与 log（抑制剂）反应曲线强烈对应（R = 0.8383、R = 0.8430 和 R = 0.8229，分别）。ROC 曲线中 log C、log AUC 和 log AUC 的临界值分别为 2.556、3.868 和 6.947（均 p = 0.007）。Fisher 精确检验显示这些临界值与心血管益处显著相关（均 p < 0.05）。我们的研究揭示了药物暴露与 MACE HR 之间的线性暴露-反应关系。我们得出结论，基于肠促胰岛素的治疗的心血管益处可能发生在更高剂量的 GLP-1RA 和更高的暴露量。
