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

Abstract

ObjectiveTo examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases.DesignSystematic review and pairwise and network meta-analysis.Data sourcesPubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021.Eligibility criteriaRandomised 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 measuresComposite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases.Data extraction and data synthesisTwo 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.ResultsA 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.ConclusionsDipeptidyl 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 registrationPROSPERO CRD42021271647.

Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)

“…A meta-analysis of 76 RCTs has recently found that compared with placebo or active controls, GLP-1RA treatment was associated with an increased risk of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23–1.52) [ 64 ]. Similar findings were noted with dipeptidyl peptidase-4 inhibitors in another meta-analysis of 82 RCTs, in which they increased the risk of gallbladder or biliary diseases (OR, 1.22; 95% CI, 1.04–1.43) compared with controls [ 65 ]. For both therapeutic classes, this increased risk of gallbladder or biliary diseases has been thought to be driven by the inhibition of the secretion of cholecystokinin by GLP-1, leading to impaired gallbladder motility and contractility [ 64 , 65 ].…”

“…Similar findings were noted with dipeptidyl peptidase-4 inhibitors in another meta-analysis of 82 RCTs, in which they increased the risk of gallbladder or biliary diseases (OR, 1.22; 95% CI, 1.04–1.43) compared with controls [ 65 ]. For both therapeutic classes, this increased risk of gallbladder or biliary diseases has been thought to be driven by the inhibition of the secretion of cholecystokinin by GLP-1, leading to impaired gallbladder motility and contractility [ 64 , 65 ]. Additionally, the weight loss effect of GLP-1RAs may lead to an increased risk of gallbladder disorders [ 64 ].…”

To do one and to get more: Part I. Diabetes and bone

“…89,90 Similar to many large-scale population-based studies, 31,56,63,[83][84][85][86][91][92][93][94][95][96][97][98] many biases, which cannot be totally excluded, may decrease the reliability and reproducibility of the data analysis. Additionally, DPP-4i may increase the risk of cholecystitis in randomized controlled trials, especially with longer treatment duration, 99 although the population-based cohort study did not support the current use of DPP-4i was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral ADA (adjusted HR, 0.99; 95% CI, 0.75-1.32). 100 By contrast, the risk of bile duct and gallbladder disease seemed to be increased in DM treated with GLP-1 receptor analogues currently.…”

Different genders should be considered for the extraglycemic benefits of oral antidiabetic drugs

“…A recent meta-analysis enrolling 82 randomized controlled trials with 104,833 participants showed DPP-4i was significantly associated with an increased risk of the composite of gallbladder or biliary diseases with an odds ratio (OR) of 1.22 (95% CI: 1.04–1.43) compared with placebo or nonincretin drugs. 5 Additionally, compared with sodium-glucose cotransporter-2 inhibitors, DPP-4i also increased the risk of the composite of gallbladder and biliary diseases, as well as cholecystitis. 5 The prevalence and incidence of gallbladder or biliary tract diseases differ between male and female populations.…”

“…5 Additionally, compared with sodium-glucose cotransporter-2 inhibitors, DPP-4i also increased the risk of the composite of gallbladder and biliary diseases, as well as cholecystitis. 5 The prevalence and incidence of gallbladder or biliary tract diseases differ between male and female populations. The male population may have a higher risk of developing gallbladder or biliary tract diseases than the female population.…”