Gooßen K, Gräber S
Department of Chemistry - Toxicology, Technical University Kaiserslautern, Kaiserslautern, GermanyInstitute for Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Homburg, Germany.
Diabetes Obes Metab. 2012 Dec;14(12):1061-72. doi: 10.1111/j.1463-1326.2012.01610.x. Epub 2012 May 17.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic agents that hold the potential of slowing the progress of type 2 diabetes mellitus. Their long-term safety is still a subject of debate. A systematic review of randomized, controlled trials was undertaken to comprehensively profile the safety of chronic treatment of type 2 diabetes mellitus with DPP-4 inhibitors. We searched data sources including MEDLINE, CENTRAL, publishers' and manufacturers' databases. Eligible trials were double-blind, randomized, placebo or active-controlled trials with ≥18 weeks duration in patients with type 2 diabetes reporting safety outcomes. Meta-analysis was performed separately for trials in which the control group received placebo (44 studies), another gliptin (3 studies) and any other antidiabetic drug (20 studies). Risk ratios with 95% confidence intervals were computed using a Mantel-Haenszel fixed-effect model for general safety outcomes, hypoglycaemia and adverse events by system organ class. Of 307 publications retrieved, 67 randomized, controlled trials met the eligibility criteria and were included in this review (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin trials). Adverse events with gliptin treatment were at placebo level (relative risk (RR) 1.02 [0.99, 1.04]). No increased risk of infections was detectable (RR 0.98 [0.93, 1.05] compared to placebo and 1.02 [0.97, 1.07] compared to other antidiabetic drugs). Asthenia (RR 1.57 [1.09, 2.27]) as well as cardiac (RR 1.37 [1.00, 1.89]) and vascular disorders (RR 1.74 [1.05, 2.86] for linagliptin) emerged as adverse events associated with DPP-4 inhibitor treatment. The risk of hypoglycaemia was low with DPP-4 inhibitor treatment (RR 0.92 [0.74, 1.15] compared to placebo, RR 0.20 [0.17, 0.24] compared to sulphonylureas) in the absence of sulphonylurea or insulin co-therapy, but significantly elevated for combination therapy of sulphonylurea or insulin with sitagliptin or linagliptin (RR 1.86 [1.46, 2.37] compared to placebo). A large body of data supports the long-term safety of gliptin treatment and refutes an increased risk of infections. Further research is needed to clarify a possible link to asthenia, cardiac and vascular events. For combination therapy with insulin or insulin secretagogues, a careful choice of the agent used may limit the risk of hypoglycaemia.
二肽基肽酶-4（DPP-4）抑制剂是一类口服抗糖尿病药物，具有减缓2型糖尿病病情进展的潜力。其长期安全性仍是一个有争议的话题。我们进行了一项随机对照试验的系统评价，以全面描述DPP-4抑制剂长期治疗2型糖尿病的安全性。我们检索了包括MEDLINE、CENTRAL、出版商和制造商数据库在内的数据来源。符合条件的试验为双盲、随机、安慰剂或活性对照试验，研究对象为2型糖尿病患者，试验持续时间≥18周且报告了安全性结果。对对照组接受安慰剂的试验（44项研究）、接受另一种格列汀的试验（3项研究）以及接受任何其他抗糖尿病药物的试验（20项研究）分别进行荟萃分析。使用Mantel-Haenszel固定效应模型计算一般安全性结果、低血糖和按系统器官分类的不良事件的风险比及95%置信区间。在检索到的307篇文献中，67项随机对照试验符合纳入标准并被纳入本评价（4项阿格列汀试验、8项利格列汀试验、8项沙格列汀试验、20项西格列汀试验和27项维格列汀试验）。格列汀治疗的不良事件发生率与安慰剂水平相当（相对风险（RR）为1.02[0.99，1.04]）。未检测到感染风险增加（与安慰剂相比RR为0.98[0.93，1.05]，与其他抗糖尿病药物相比RR为1.02[0.97，1.07]）。乏力（RR为1.57[1.09，2.27]）以及心脏疾病（RR为1.37[1.00，1.89]）和血管疾病（利格列汀的RR为1.74[1.05，2.86]）是与DPP-4抑制剂治疗相关的不良事件。在未联合使用磺脲类药物或胰岛素的情况下，DPP-4抑制剂治疗的低血糖风险较低（与安慰剂相比RR为0.92[0.74，1.15]，与磺脲类药物相比RR为0.20[0.17，0.24]），但磺脲类药物或胰岛素与西格列汀或利格列汀联合治疗时低血糖风险显著升高（与安慰剂相比RR为1.86[1.46，2.37]）。大量数据支持格列汀治疗具有长期安全性，并反驳了感染风险增加的说法。需要进一步研究以阐明与乏力、心脏和血管事件之间可能存在的联系。对于与胰岛素或胰岛素促泌剂的联合治疗，谨慎选择所用药物可能会降低低血糖风险。
