Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, University of Liège, Liège, Belgium.
Postgrad Med. 2013 May;125(3):7-20. doi: 10.3810/pgm.2013.05.2659.
Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are oral incretin-based glucose-lowering agents with proven efficacy and safety in the management of type 2 diabetes mellitus (T2DM). In addition, preclinical data and mechanistic studies suggest a possible additional non-glycemic beneficial action on blood vessels and the heart, via both glucagon-like peptide-1-dependent and glucagon-like peptide-1-independent effects. As a matter of fact, DPP-4 inhibitors improve several cardiovascular risk factors: they improve glucose control (mainly by reducing the risk of postprandial hyperglycemia) and are weight neutral; may lower blood pressure somewhat; improve postprandial (and even fasting) lipemia; reduce inflammatory markers; diminish oxidative stress; improve endothelial function; and reduce platelet aggregation in patients with T2DM. In addition, positive effects on the myocardium have been described in patients with ischemic heart disease. Results of post hoc analyses of phase 2/3 controlled trials suggest a possible cardioprotective effect with a trend (sometimes significant) toward lower incidence of major cardiovascular events with sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin compared with placebo or other active glucose-lowering agents. However, the definite relationship between DPP-4 inhibition and better cardiovascular outcomes remains to be proven. Major prospective clinical trials involving various DPP-4 inhibitors with predefined cardiovascular outcomes are under way in patients with T2DM and a high-risk cardiovascular profile: the Sitagliptin Cardiovascular Outcome Study (TECOS) on sitagliptin, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial on saxagliptin, the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE) trial on alogliptin, and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) on linagliptin. If these trials confirm that a DPP-4 inhibitor can reduce the cardiovascular burden of T2DM, it would be major progress that would dramatically influence the management of the disease.
二肽基肽酶-4（DPP-4）抑制剂（gliptins）是基于肠降血糖素的口服降糖药物，在 2 型糖尿病（T2DM）的治疗中已被证实具有疗效和安全性。此外，临床前数据和机制研究表明，通过胰高血糖素样肽-1 依赖性和非依赖性作用，它们可能对血管和心脏产生额外的非血糖有益作用。事实上，DPP-4 抑制剂可改善多种心血管危险因素：它们改善血糖控制（主要通过降低餐后高血糖的风险）且不增加体重；可能会降低血压；改善餐后（甚至空腹）血脂；降低炎症标志物；减少氧化应激；改善内皮功能；并减少 T2DM 患者的血小板聚集。此外，在缺血性心脏病患者中也描述了对心肌的积极作用。2/3 期对照试验的事后分析结果表明，与安慰剂或其他活性降糖药物相比，西格列汀、维格列汀、沙格列汀、利格列汀或阿格列汀可能具有降低主要心血管事件发生率的趋势（有时具有统计学意义），提示可能具有心脏保护作用。然而，DPP-4 抑制与更好的心血管结局之间的明确关系仍有待证明。几项涉及不同 DPP-4 抑制剂和已预设心血管结局的主要前瞻性临床试验正在 T2DM 患者和心血管高危人群中进行：西格列汀心血管结局研究（TECOS）评估西格列汀、沙格列汀评估血管结局在糖尿病患者中的记录-心肌梗死溶栓治疗（SAVOR-TIMI）53 试验评估沙格列汀、阿格列汀在 2 型糖尿病和急性冠脉综合征患者中的心血管结局研究（EXAMINE）试验评估阿格列汀、以及在 2 型糖尿病患者中比较利格列汀与格列美脲的心血管结局研究（CAROLINA）试验评估利格列汀。如果这些试验证实 DPP-4 抑制剂可以降低 T2DM 的心血管负担，这将是一个重大进展，将极大地影响疾病的治疗。
