From Diabetes Center Bochum-Hattingen, St Josef-Hospital, Ruhr-University Bochum, Germany (M.A.N., J.J.M., M.A.E.A.); Department of Medicine, University of North Carolina, Chapel Hill (M.A.C.); and Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt Sinai Hospital, University of Toronto, Ontario, Canada (D.J.D.).
Circulation. 2017 Aug 29;136(9):849-870. doi: 10.1161/CIRCULATIONAHA.117.028136.
Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.
通过选择性 GLP-1 受体 (GLP-1R) 激动剂或通过抑制二肽基肽酶-4 (DPP-4) 来防止酶促降解来增强胰高血糖素样肽-1 (GLP-1) 的作用，通过葡萄糖依赖性控制胰岛素和胰高血糖素的分泌来促进 2 型糖尿病的血糖降低。GLP-1R 激动剂还可减缓胃排空，通过减少食物摄入和降低循环脂蛋白、炎症和收缩压来减轻体重。临床前研究表明，GLP-1R 激动剂和 DPP-4 抑制剂在心肌缺血和心室功能障碍的动物模型中通过尚未完全明确的机制表现出心脏保护作用。在伴有心血管风险增加的 2 型糖尿病患者的心血管结局试验中，结果表明 GLP-1R 激动剂利拉鲁肽（LEADER 试验[利拉鲁肽对糖尿病的作用和作用：评估心血管结局结果]，-13%）和司美格鲁肽（SUSTAIN-6 试验[评估司美格鲁肽的心血管和其他长期结局]，-24%）具有心血管益处（首次主要不良心血管事件时间的显著减少）。相比之下，检查短期作用 GLP-1R 激动剂利西那肽（ELIXA 试验[评价利西那肽在急性冠状动脉综合征中的作用]）和 DPP-4 抑制剂西格列汀（SAVOR-TIMI 53 试验[西格列汀评估糖尿病患者的血管结局-心肌梗死 53 溶栓]）、阿格列汀（EXAMINE 试验[评估阿格列汀与 2 型糖尿病和急性冠状动脉综合征患者标准护理的心血管结局]）和沙格列汀（TECOS[评价沙格列汀治疗的心血管结局]）安全性的心血管结局试验发现，这些药物既没有增加也没有减少心血管事件。在这里，我们回顾了 GLP-1R 激动剂和 DPP-4 抑制剂的心血管作用，重点是将来自临床前研究的机制转化为临床研究中的补充发现。我们强调了需要在正在进行的基础科学和临床研究中更仔细地研究的不确定领域。随着用于治疗 2 型糖尿病、肥胖症和非酒精性脂肪性肝炎的新型更有效的 GLP-1R 激动剂和共激动剂的开发，这些药物的心血管获益和安全性的潜在机制的明确对于心血管疾病的预防和治疗具有直接意义。
