Zhong Jixin, Maiseyeu Andrei, Davis Stephen N, Rajagopalan Sanjay
From the Divisions of Cardiovascular Medicine and Endocrinology, University of Maryland, Baltimore.
Circ Res. 2015 Apr 10;116(8):1491-504. doi: 10.1161/CIRCRESAHA.116.305665.
The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.
基于肠促胰岛素的药物的发现代表了2型糖尿病（T2DM）药物治疗方面的一项重大进展，因为这些药物可避免低血糖、体重增加，并简化了T2DM的管理。二肽基肽酶-4（CD26，DPP4）抑制剂是全球治疗T2DM最广泛使用的基于肠促胰岛素的疗法。DPP4抑制剂在降低糖化血红蛋白（HbA1c）方面有一定效果（约0.5%），虽然这些药物是在了解DPP4在延长胰高血糖素样肽-1和胃抑制肽等肠促胰岛素半衰期方面的作用的基础上合成的，但现在人们认识到肠促胰岛素只是DPP4众多靶点之一。DPP4在血管、心肌和髓样细胞上广泛表达，且CD26作为一种信号和结合蛋白在多种物种中具有非酶功能，这表明其在心血管调节和炎症中具有目的论作用。事实上，在包括肥胖、T2DM和动脉粥样硬化在内的促炎状态下，DPP4会上调。与这种适应不良的作用一致，至少在临床前动物模型中，DPP4抑制的作用似乎在心血管疾病中发挥着保护作用。尽管两项大型临床试验表明对心血管终点无影响，但在基于最大药物治疗的有限时间范围内对T2DM进行试验存在当前局限性，在对这些药物的心血管疗效做出判断之前必须予以承认。本综述将批判性地回顾DPP4的科学以及DPP4抑制剂对心血管系统的影响。
