Objective To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. Design Systematic review and pairwise and network meta-analysis. Data sources PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. Eligibility criteria Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. Main outcome measures Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. Data extraction and data synthesis Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. Results A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. Conclusions Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. Systematic review registration PROSPERO CRD42021271647. The study specific summary data included in the meta-analysis can be obtained from the corresponding authors at huabingzhangchn@163.com or liyuxiu@medmail.com.cn.

中文翻译：

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二肽基肽酶 4 抑制剂与 2 型糖尿病的胆囊或胆道疾病：随机对照试验的系统评价和成对和网络荟萃分析

目的探讨二肽基肽酶4抑制剂与胆囊或胆道疾病的相关性。设计系统评价和成对和网络荟萃分析。数据来源 PubMed、EMBASE、Web of Science 和 CENTRAL 从成立到 2021 年 7 月 31 日。资格标准 接受二肽基肽酶 4 抑制剂、胰高血糖素样肽 1 受体激动剂和钠的成年 2 型糖尿病患者的随机对照试验-葡萄糖协同转运蛋白2抑制剂与安慰剂或其他抗糖尿病药物相比。主要结果测量胆囊或胆道疾病、胆囊炎、胆石症和胆道疾病的综合。数据提取和数据合成 两名评价员独立提取数据并评估研究质量。使用建议分级、评估、发展和评估框架 (GRADE) 方法评估每个结果的证据质量。荟萃分析使用汇总优势比和 95% 置信区间。结果 成对荟萃分析共纳入 82 项随机对照试验，104 833 名受试者。与安慰剂或非肠促胰岛素药物相比，二肽基肽酶 4 抑制剂与胆囊或胆道疾病复合风险增加显着相关（优势比 1.22（95% 置信区间 1.04 至 1.43）；风险差异 11（2 至 21 ) 每 10 000 人年更多事件）和胆囊炎（优势比 1.43（1.14 到 1.79）；风险差异 15（5 到 27）更多事件每 10 000 人年），但与胆石症和胆道疾病的风险无关。在二肽基肽酶 4 抑制剂治疗持续时间较长的患者中，往往会观察到这种关联。在对 184 项试验的网络荟萃分析中，与钠-葡萄糖协同转运蛋白 2 抑制剂相比，二肽基肽酶 4 抑制剂增加了胆囊或胆道疾病和胆囊炎的复合风险，但与胰高血糖素样肽 1 受体激动剂相比则没有。结论 二肽基肽酶-4抑制剂在随机对照试验中增加了胆囊炎的风险，尤其是治疗时间较长的情况下，需要医师在临床实践中给予更多的重视。系统评价注册 PROSPERO CRD42021271647。纳入meta分析的研究具体汇总数据可通过huabingzhangchn@163.com或liyuxiu@medmail.com.cn向通讯作者索取。