Singh Awadhesh Kumar, Singh Ritu
Department of Endocrinology, G.D Hospital and Diabetes Institute, Kolkata, West Bengal, India.
Department of Gynecology and Obstetrics, G.D Hospital and Diabetes Institute, Kolkata, West Bengal, India.
Indian J Endocrinol Metab. 2019 Jan-Feb;23(1):128-133. doi: 10.4103/ijem.IJEM_613_18.
Heart failure hospitalization (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) remains at the center stage since the publication of Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction (SAVOR-TIMI) in 2013 showing significant increase with saxagliptin, compared to placebo. This outcome led to additional label of hHF to both saxagliptin and alogliptin in April 2016 and eventual labelling of hHF to all the four approved DPP-4Is in United States in August 2017, by US Food Drug Administration. To note, neither Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), nor Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), showed any signals of hHF with these two agents. These developments have seriously generated an uncertainty among clinicians with regards to hHF effect of DPP-4Is in type 2 diabetic patients with high risk of cardiovascular (CV) disease.
We systematically searched the database of PubMed, Embase, Cochrane Central library, ClinicalTrials.gov, and International conference presentation from the inception up to October 25, 2018 using MeSH and specific key words. We retrieved all those studies that explicitly looked for hHF as a prespecified end point and were conducted for ≥52 weeks. Subsequently, we conducted the meta-analysis using comprehensive meta-analysis software Version 3, using different sensitivity analysis to study the effect of DPP-4Is on hHF in both dedicated CV outcome trials as well as randomized controlled trials.
The meta-analysis of four exclusive dedicated CV outcome trials ( = 43,522) did not find significant increase in hHF with DPP-4 inhibitors (Fixed model Relative Risk [RR] 1.06; 95% Confidence Interval [CI], 0.96-1.17; = 0.25; I: 53.95%, tau: 0.012, = 0.089). Meta-analysis of all randomized controlled trials that explicitly looked for hHF for ≥52 weeks ( = 48,199) also did not show any significant increase in hHF (fixed model peto odds ratio 1.05; 95% CI 0.95-1.15, = 0.36; I: 43.74%, tau: 0.016, = 0.10).
This meta-analysis suggests no significant increase in hHF with DPP-4 inhibitors, although a nonsignificant heterogeneity across the trials might limit this observation.
自2013年发表《糖尿病患者血管结局评估记录-心肌梗死溶栓治疗（SAVOR-TIMI）》显示与安慰剂相比，沙格列汀导致心力衰竭住院（hHF）显著增加以来，二肽基肽酶-4抑制剂（DPP-4Is）所致的心力衰竭住院一直备受关注。这一结果导致2016年4月沙格列汀和阿格列汀的药品标签中都增加了hHF这一不良反应，最终在2017年8月，美国食品药品监督管理局要求在美国所有四种已获批的DPP-4Is药品标签中都标注hHF这一不良反应。需要注意的是，西他列汀心血管结局评估试验（TECOS）以及利格列汀心血管和肾脏微血管结局研究（CARMELINA）均未显示这两种药物有hHF的迹象。这些进展使得临床医生对于DPP-4Is在心血管（CV）疾病高危的2型糖尿病患者中对hHF的影响产生了严重的不确定性。
我们使用医学主题词（MeSH）和特定关键词，系统检索了PubMed、Embase、Cochrane中央图书馆、ClinicalTrials.gov数据库以及截至2018年10月25日的国际会议报告。我们检索了所有明确将hHF作为预设终点且研究时长≥52周的研究。随后，我们使用综合荟萃分析软件3.0版进行荟萃分析，采用不同的敏感性分析来研究DPP-4Is在专门的CV结局试验以及随机对照试验中对hHF的影响。
四项独立的专门CV结局试验（n = 43,522）的荟萃分析未发现DPP-4抑制剂使hHF显著增加（固定模型相对危险度[RR] 1.06；95%置信区间[CI]，0.96 - 1.17；P = 0.25；I²：53.95%，tau²：0.012，P = 0.089）；所有明确将hHF作为预设终点且研究时长≥52周的随机对照试验（n = 48,199）的荟萃分析也未显示hHF有任何显著增加（固定模型Peto比值比1.05；95% CI 0.95 - 1.15，P = 0.36；I²：43.74%，tau²：0.016，P = 0.10）。
本荟萃分析表明DPP-4抑制剂不会使hHF显著增加，尽管各试验间存在无统计学意义的异质性可能会限制这一观察结果。
