Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies.
Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies.
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DOI：
10.1136/bmj.g2366
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发表时间：
2014-04-15
期刊：
影响因子：
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通讯作者：
Sun X
中科院分区：
文献类型：
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作者：
Li L;Shen J;Bala MM;Busse JW;Ebrahim S;Vandvik PO;Rios LP;Malaga G;Wong E;Sohani Z;Guyatt GH;Sun X
目的探讨以肠促胰岛素为基础的治疗方法对2型糖尿病患者胰腺炎发病的影响。设计系统回顾和荟萃分析。数据来源：Medline， Embase, Cochrane Central Register of Controlled Trials （Central）和ClinicalTrials.gov。与安慰剂、生活方式改变或活性降糖药相比，胰高血糖素样肽-1 （GLP-1）受体激动剂或二肽基肽酶-4 （DPP-4）抑制剂治疗2型糖尿病成人患者的随机和非随机对照临床试验、前瞻性或回顾性队列研究和病例对照研究。数据收集和分析训练有素的审稿人对符合条件的研究进行独立筛选，评估偏倚风险，并提取数据。随机对照试验采用改良的Cochrane工具，观察性研究采用改良的Newcastle-Ottawa量表来评估偏倚。我们使用Peto优势比汇集了来自随机对照试验的数据，并进行了四个预先指定的亚组分析和一个事后亚组分析。由于结果测量和数据形式的差异，我们在没有汇总分析的情况下描述了观察性研究的结果。结果纳入60项研究（n=353 639），包括55项随机对照试验（n=33 350）和5项观察性研究（3项回顾性队列研究和2项病例对照研究，n=320 289）。55项随机对照试验（低或中等偏倚风险，涉及37例胰腺炎事件，原始事件率0.11%）的汇总估计未显示肠促胰岛素组与对照组相比胰腺炎风险增加（优势比1.11,95%置信区间0.57至2.17）。GLP-1激动剂与对照的肠促胰岛素类型估计值相似(1.05 (0.37 - 2.94)；DPP-4抑制剂为1.06（0.46 - 2.45）。根据对照类型、模式、治疗持续时间和个体肠促胰岛素药物进行的分析表明，亚组之间没有差异效应，通过替代统计模型和效果测量进行的敏感性分析没有显示出效果估计的重要差异。三项回顾性队列研究（中至高风险偏倚，涉及1466例胰腺炎事件，原始事件率0.47%）也未显示艾塞那肽(一项研究校正优势比0.93（0.63至1.36)，另一项研究校正优势比0.9(0.6至1.5)）或西格列汀（校正风险比1.0,0.7至1.3）与胰腺炎风险增加相关；一项中等偏倚风险的病例对照研究（1003例，4012例对照）也显示无显著相关性（校正优势比0.98,0.69 ~ 1.38）。然而，另一项中等偏倚风险的病例对照研究（1269例，1269例对照）表明，使用艾塞那肽或西格列汀与急性胰腺炎的发生率显著增加相关（两年内使用vs未使用，校正优势比2.07,1.36至3.13）。结论现有证据表明，使用肠促胰岛素的患者发生胰腺炎的几率较低，且该药不会增加胰腺炎的风险。然而，目前的证据并不确定，需要更仔细设计和实施观察性研究，以确定风险增加的程度（如果有的话）。
Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.