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. 2022 Oct 21;14(1):153.
doi: 10.1186/s13098-022-00924-8.

Association of the gallbladder or biliary diseases with dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: a meta-analysis of randomized controlled trials

Meng Yu  1 , Zheng Yang  1 , Chongxin Chen  1 , Yuhuan Lv  1 , Linyu Xiang  1 , Subei Zhao  1 , Rong Li  2
Affiliations

Association of the gallbladder or biliary diseases with dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: a meta-analysis of randomized controlled trials

Meng Yu et al. Diabetol Metab Syndr. .

Abstract

Background: Previous studies have shown inconsistent conclusions regarding the association between incretin-based therapies and the risk of developing gallbladder or biliary diseases. We conducted a meta-analysis to evaluate the risk of gallbladder or biliary diseases associated with dipeptidyl peptidase 4 inhibitors (DPP4i) in patients with type 2 diabetes.

Methods: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched (from inception up to March 14, 2022) for published randomized controlled trials (RCTs) that compared DPP4i with placebo or other glucose-lowering drugs in patients with type 2 diabetes. The outcomes of interest were cholecystitis, cholangitis, cholelithiasis, bile duct stones, and biliary colic. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Subgroup analyses were performed according to patient age, trial duration, and types of DPP4i.

Results: In total, 97,150 participants from 75 eligible RCTs were included in the meta-analysis. DPP4i were associated with an increased risk of composite of gallbladder or biliary diseases (RR 1.20 [95% CI 1.01-1.42]) and cholecystitis (RR 1.38 [95% CI 1.08-1.75]). Among all included trials, DPP4i showed no association with the following manifestations of gallbladder or biliary diseases: cholelithiasis (RR 1.00 [95% CI 0.76-1.32]), cholangitis (RR 0.81 [95% CI 0.39-1.66]), bile duct stones (RR 1.08 [95% CI 0.57-2.05]), and biliary colic (RR 0.72 [95% CI 0.23-2.25]). Subgroup analyses showed that DPP4i were associated with a higher risk of cholecystitis in older patients (RR 1.37 [95% CI 1.03-1.83]) compared with younger patients (RR 1.08 [95% CI 0.89-2.18]) and in those with a longer duration of drug use (RR 1.43 [95% CI 1.08-1.89]) compared with shorter use (RR 1.23 [95% CI 0.74-2.03]).

Conclusions: This systematic review and meta-analysis of RCTs found that the use of DPP4i was associated with an increased risk of cholecystitis, especially in patients of advanced age or in those who were exposed to the drugs for a long period of time.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Study selection
Fig. 2
Fig. 2
Risk of bias of included studies
Fig. 3
Fig. 3
Risk of gallbladder or biliary diseases in DPP4i group compared with placebo and active comparators overall. Gallbladder or biliary diseases include cholecystitis, cholangitis, cholelithiasis, bile duct stone and biliary colic
Fig. 4
Fig. 4
Risk of gallbladder or biliary diseases in DPP4i compared with placebo. Gallbladder or biliary diseases include cholecystitis, cholangitis, cholelithiasis, bile duct stone and biliary colic
Fig. 5
Fig. 5
Subgroup analysis of DPP4i effects on cholecystitis and cholelithiasis events. Subgroup analysis were stratified by subclass of medicines, short versus long duration of follow-up (< 26 vs  ≥ 26 weeeks vs  ≥ 52 weeeks), age (< 60 vs  ≥ 60 years old)
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