质子泵抑制剂的使用与胰腺癌发生有关:系统综述和meta分析

Usage of proton pump inhibitors is associated with pancreatic cancer:a systematic review and meta-analysis

目的评估质子泵抑制剂(proton pump inhibitor,PPI)的使用与胰腺癌发生风险之间的关系。方法系统地检索了PubMed、Embase、Web of Science、Cochrane图书馆、ClinicalTrials.gov、中国知网、万方及维普数据库中的观察性研究,根据异质性检索结果采用相应的效应模型估计胰腺癌发病风险的合并比值比(odds ratio,OR)和95%可信区间(confidence interval,CI),并且进行亚组分析、meta回归和敏感性分析。此外,使用限制性立方样条研究了PPI使用剂量和使用时间与胰腺癌发生之间的风险关系。结果总共纳入14项研究共1601430例受试者。meta分析结果显示,PPI使用增加胰腺癌发生风险[OR(95%CI)=1.60(1.21,2.11),P<0.001]。亚组分析结果显示,在2018年前发表的研究[OR(95%CI)=1.88(1.05,3.38),P=0.034]、非亚洲地区的研究[OR(95%CI)=1.37(1.04,1.82:),P=0.028]、病例对照研究[OR(95%CI)=1.59(1.16,2.18),P=0.004]、队列研究[OR(95%CI)=1.65(1.13,2.39),P=0.009]和高质量研究[OR(95%CI)=1.62(1.19,2.20),P=0.002]中也发现PPI使用会增加胰腺癌发生风险。剂量-反应曲线显示,PPI使用剂量与胰腺癌风险之间存在非线性关系(χ^(2)线性=2.27,P=0.132;P非线性=0.039),PPI使用限定日剂量(defined daily dose,DDD)在800以内时会增加胰腺癌的风险,但超过800 DDD时未发现PPI使用与胰腺癌发生有关;时间-效应曲线提示,PPI使用时间与胰腺癌发生风险之间存在线性关系(χ^(2)线性=6.92,P=0.009),增加1个月的PPI使用时间,其胰腺癌风险将增加2.3%[OR=1.02,95%CI(1.01,1.04),P=0.009]。敏感性分析结果显示,逐步剔除每项研究后发病风险的OR(95%CI)为1.37(1.08,1.74)~1.66(1.22,2.27)。Egger检验未发现发表偏倚(P=0.594)。结论从本meta分析结果看,PPI使用会增加胰腺癌的发生风险,且其使用剂量和持续时间与胰腺癌发生风险有一定的关系。临床上应严格掌握PPI使用的适应证,其使用剂量和时间也需要慎重考虑。

Objective To further evaluate the relation between usage of proton pump inhibitor(PPI)and the risk of pancreatic cancer.Method The observational studies were systematically searched in the databases of PubMed,Embase,Web of Science,Cochrane Library,ClinicalTrials.gov,CNKI,Wanfang,and VIP.The combined odds ratio(OR)and 95%confidence interval(CI)of pancreatic cancer risk were estimated by the corresponding effect model according to the heterogeneous results,and the subgroup analysis,meta-regression,and sensitivity analysis were performed.In addition,the relation between the defined daily dose(DDD)and usage time of PPI and the pancreatic cancer risk were studied by using restricted cubic spline.Results A total of 14 studies were included,including 1601430 subjects.The meta-analysis result showed that usage of PPI was positively correlated with the risk of pancreatic cancer[I 2=98.9%,OR(95%CI)=1.60(1.21,2.11),P<0.001].The subgroup analysis results showed that usage of PPI would increase the risk of pancreatic cancer in the subgroups of literature published before 2018[OR(95%CI)=1.88(1.05,3.38),P=0.034],non-Asian regions[OR(95%CI)=1.37(1.04,1.82),P=0.028],case-control studies[OR(95%CI)=1.59(1.16,2.18),P=0.004],cohort studies[OR(95%CI)=1.65(1.13,2.39),P=0.009],and high-quality studies[OR(95%CI)=1.62(1.19,2.20),P=0.002].The doseresponse curve showed that there was a nonlinear relation between the usage of PPI and the risk of pancreatic cancer(χ^(2) linear=2.27,P=0.132;Pnonlinear=0.039).When the usage of PPI was 800 DDD or less,usage of PPI would increase the risk of pancreatic cancer,but there was no statistical significance when the usage of PPI was more than 800 DDD.The time-effect curve showed that there was a linear relation between the usage time of PPI and the risk of pancreatic cancer(χ^(2) linear=6.92,P=0.009),and the risk of pancreatic cancer would increase by 2.3%if the usage of PPI increased by one month[OR=1.02,95%CI(1.01,1.04),P=0.009].The sensitivity analysis confirmed that the results were stable by gradually eliminating each study,the OR(95%CI)of the risk of pancreatic cancer was 1.37(1.08,1.74)to 1.66(1.22,2.27),and the publication bias was not found by Egger test(P=0.594).Conclusions From the results of this meta-analysis,usage of PPI will increase the risk of pancreatic cancer,and the dosage of PPI and usage time of PPI may be related to the risk of pancreatic cancer.The clinical usage of PPI should be strictly controlled,and the dosage and usage time should also be carefully considered.