Ahrén Bo
Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Front Endocrinol (Lausanne). 2019 Jun 19;10:376. doi: 10.3389/fendo.2019.00376. eCollection 2019.
In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.
20世纪90年代发现，二肽基肽酶-4（DPP-4）可使肠促胰岛素激素胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）失活。抑制DPP-4会导致这两种肠促胰岛素激素水平升高，进而通过刺激胰岛素分泌和抑制胰高血糖素分泌来降低循环葡萄糖水平。从那时起，已开发出几种具有DPP-4抑制作用的口服小分子药物。20世纪90年代的早期研究表明，DPP-4抑制剂可改善动物的血糖水平。21世纪的后续临床研究表明，DPP-4抑制剂在2型糖尿病患者中也具有降糖作用。当DPP-4抑制剂作为单一疗法以及与其他疗法（即二甲双胍、磺脲类药物、噻唑烷二酮类药物或外源性胰岛素）联合使用时，均可观察到这种作用。还发现DPP-4抑制剂发生不良事件的风险较低，包括低血糖。其中五种DPP-4抑制剂（西格列汀、维格列汀、阿格列汀、沙格列汀和利格列汀）已获得监管机构批准，并于2006年至2013年期间上市。此后，DPP-4抑制剂进行了长期心血管结局试验，结果显示在主要急性心血管终点风险方面不劣于其他药物。在这些长期研究中，其他潜在不良事件的风险也较低。目前，DPP-4抑制剂已被纳入指南，作为单一疗法和联合疗法中的一种降糖方案。本文总结了DPP-4抑制概念从20世纪90年代早期开始的发展历程。文章强调，这一发展基于对2型糖尿病病理生理学的科学研究以及针对胰岛功能障碍的重要性，通过学术科学与以研究为导向的制药行业合作得以实现，并且新概念的发展需要时间，需要专注的努力、坚持不懈和长期的毅力。
