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. 2022 Jun 28:377:e068882.
doi: 10.1136/bmj-2021-068882.

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials

Liyun He  1 , Jialu Wang  1 , Fan Ping  1 , Na Yang  1 , Jingyue Huang  1 , Wei Li  1 , Lingling Xu  1 , Huabing Zhang  1 , Yuxiu Li  1
Affiliations

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials

Liyun He et al. BMJ. .

Abstract

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Beijing Natural Science Foundation, National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences, and Training Program for Excellent Talents in Dongcheng District for the submitted work; no financial relationship with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
PRISMA flow diagram. DPP-4=dipeptidyl peptidase-4; GDM=gestational diabetes mellitus; GLP-1=glucagon-like peptide-1; RCT=randomised controlled clinical trial; T1DM=type 1 diabetes mellitus
Fig 2
Fig 2
Risks of cholecystitis, cholelithiasis, and biliary disease in patients taking dipeptidyl peptidase-4 inhibitors (DPP-4i). Absolute risk difference (ARD) is number of events per 10 000 person years. Control groups=placebo or non-incretin drugs. CI=confidence interval
Fig 3
Fig 3
Network plots of comparisons of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in network meta-analyses. Size of circle in each network is proportional to number of participants randomly assigned to treatment comparison. Width of each line is proportional to number of trials comparing two connected treatments. Number provided for each treatment class (in parentheses) indicates number of patients randomised to treatment in network. Controls are placebo or other antidiabetes drugs (excluding DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors); k indicates number of comparisons; n indicates number of patients per comparison
Fig 4
Fig 4
Estimates in network meta-analysis comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Controls are placebo or other antidiabetes drugs (excluding DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors). No of studies indicates number of studies in direct comparison. CI=confidence interval
See this image and copyright information in PMC

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