Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trialsBMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-068882 (Published 28 June 2022) Cite this as: BMJ 2022;377:e068882
- Liyun He, doctoral student,
- Jialu Wang, masters student,
- Fan Ping, associate chief physician,
- Na Yang, doctoral student,
- Jingyue Huang, scientific assistant,
- Wei Li, associate chief physician,
- Lingling Xu, chief physician,
- Huabing Zhang, chief physician,
- Yuxiu Li, chief physician
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Correspondence to: H Zhang
- Accepted 13 May 2022
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.
Dipeptidyl peptidase-4 inhibitors are widely used in the treatment of type 2 diabetes.123 Given the large population of patients with type 2 diabetes receiving dipeptidyl peptidase-4 inhibitors worldwide,23 any safety concerns deserve attention.
Dipeptidyl peptidase-4 inhibitors enhance the bioavailability of endogenous glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide,2 both of which might affect postprandial gallbladder motility,45 raising concerns about the risks of gallbladder or biliary diseases with dipeptidyl peptidase-4 inhibitors. Early studies have proposed associations between gallbladder related events and incretin based drugs, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists.467 However, the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases remains unclear. Therefore, we aimed to do a systematic review and meta-analysis of randomised controlled trials to evaluate the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases in patients with type 2 diabetes.
The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement for traditional pairwise meta-analysis and the PRISMA extension for network meta-analysis.89 The study protocol was prospectively registered (PROSPERO CRD 42021271647).
Study sources, searches, and identification
We searched PubMed, the Cochrane Library, EMBASE, and Web of Science for randomised controlled trials of dipeptidyl peptidase-4 inhibitors up to 31 July 2021. Three reviewers (LH, HZ, and JW) independently did literature searches with designed search strategies (supplementary table A). We also screening the reference lists of relevant systematic reviews and manually searched for grey literature in Google Scholar and public repositories.1011 Four reviewers (LH, HZ, FP, and NY) independently identified the eligible studies according to the pre-formulated inclusion and exclusion criteria (supplementary table B). We included parallel group randomised controlled trials in adults with type 2 diabetes in the traditional pairwise meta-analysis if they compared dipeptidyl peptidase-4 inhibitors with placebo or non-incretin drugs, and we included them in the network meta-analysis if they compared dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors with one another or with other antidiabetes drugs, placebo, or standard care. Disagreements or conflicts were resolved by discussion with other team members.
Data extraction and quality assessment
We extracted data from published articles and supplements, as well as public repositories. We assessed the risk of bias of eligible studies with the revised Cochrane risk of bias tool for randomised trials.12 We evaluated the certainty of the evidence from traditional pairwise meta-analysis and network meta-analysis by using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) for each outcome.131415 Details about data extraction and quality assessment are in the supplementary methods.
Definition of outcomes
The outcomes were the composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. We identified the gallbladder or biliary diseases on the basis of the classifications in the Medical Dictionary for Regulatory Activities (MedDRA) version 22.0. The composite of gallbladder or biliary diseases incorporated cholelithiasis, cholecystitis, other gallbladder disorder, and biliary diseases. Cholecystitis, cholelithiasis, and biliary diseases were captured with the preferred terms, and we also included the lowest level terms that fell into the preferred terms listed above. Biliary diseases (preferred terms) included bile duct stone, bile duct obstruction, bile duct stenosis, biliary colic, biliary fistula, biliary cyst, and cholangitis.
Data synthesis and analysis
We did pairwise meta-analyses for dipeptidyl peptidase-4 inhibitors versus non-incretin based drugs or placebo. We assessed substantial heterogeneity by using χ2 tests (statistical heterogeneity: P<0.10) and τ2 (low: <0.04; low-moderate: 0.04-0.16; moderate-high: 0.16-0.36; high: >0.36).1617 We calculated odds ratios and 95% confidence intervals by using fixed effect models with the Mantel-Haenszel method, and applied a correction proportional to the reciprocal of the size of the contrasting study arm to handle the zero events.181920 We evaluated absolute risk differences on the basis of the calculated odds ratio and the mean event rate across the control groups for outcomes.1821 We converted event rates into annual incidences for each outcome.
We assessed the effects of duration of treatment (≥26 weeks or <26 weeks), specific dipeptidyl peptidase-4 inhibitors, and types of control (pure or active controls) on gallbladder or biliary diseases. We evaluated publication bias by visual assessment of asymmetry of the funnel plots and the Egger's asymmetry test.2223 We did sensitivity analyses by using different pooling methods,24 using random effect models, including double zero studies,25 and omitting each study.
We did network meta-analyses of randomised controlled trials with the frequentist method,26 comparing dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors. We used fixed effect models to calculate the overall odds ratios and 95% confidence intervals and to evaluate the heterogeneities between studies for sparse network meta-analysis.27 We used forest plots and league tables of the effects to visualise comparisons of network estimations. We evaluated global inconsistency across different designs of treatment comparisons in the network by a design-by-treatment model with a generalised Q test.2829 We used node splitting analysis to evaluate local inconsistency between direct and indirect results within each treatment comparison.303132 We used comparison adjusted funnel plots to examine small study effects.33 We did sensitivity analysis by using random effects models to pool the results.
We used the meta, netmeta package in R (version 4.0.2) and Stata 15 for all analyses. Statistical significance was set at two tailed P<0.05.
Patient and public involvement
Patients and the public were not involved in the planning, design, and implementation of the study, as this study used secondary data. No patients were asked to advise on interpretation or writing up of the manuscript.
Study selection and characteristics of studies included
We included 82 randomised controlled trials (fig 1) with 104 833 participants with type 2 diabetes in the traditional pairwise meta-analysis.343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115 Characteristics of studies and participants included in the pairwise meta-analysis are shown in table 1 and supplementary table C. The average age of participants was 59.4 years, and 39.7% (n=41 618) were female. The mean body mass index was 29.7, and mean haemoglobin A1c was 8.1%. Almost all trials documented gallbladder or biliary diseases as serious adverse events.
Risk of bias and quality of evidence
The risk of bias of eligible studies is shown in supplementary table D and supplementary figure A. Sixty seven (82%) of 82 trials had low risks or some concerns of bias across all five domains evaluated. The quality of evidence for outcomes in pairwise meta-analysis was rated as moderate or low in the comparisons between dipeptidyl peptidase-4 inhibitors and placebo or non-incretin drugs (table 2; table 3).
Association of dipeptidyl peptidase-4 inhibitors with gallbladder or biliary diseases
We found a significant association between dipeptidyl peptidase-4 inhibitors and an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95% confidence interval 1.04 to 1.43); τ2=0.027; absolute risk difference 11 (2 to 21) more events per 10 000 person years) compared with placebo or non-incretin drugs (table 2; fig 2; supplementary figure B). Dipeptidyl peptidase-4 inhibitors significantly increased the risk of cholecystitis (odds ratio 1.43 (1.14 to 1.79); τ2=0; absolute risk difference 15 (5 to 27) more events per 10 000 person years) but not of cholelithiasis or biliary diseases (fig 2; supplementary figure B).
Effects of duration of treatment, specific dipeptidyl peptidase-4 inhibitors, and types of control
Dipeptidyl peptidase-4 inhibitors with a longer duration of treatment (≥26 weeks) were significantly associated with increased risks of the composite of gallbladder or biliary diseases (odds ratio 1.24, 1.04 to 1.48) and cholecystitis (1.51, 1.17 to 1.95), but those with a shorter duration (<26 weeks) were not (supplementary figure C). When we classified the duration of treatment into four groups, we observed a stepwise increase in the risk of outcomes as the duration of treatment increased (supplementary table E), although the group differences were not significant (P value for interaction >0.05).
The modified effects of specific dipeptidyl peptidase-4 inhibitors on the risks of cholecystitis were not significant (supplementary figure D). We observed no significant differences between pure and active controls for the outcomes (supplementary figure E).
After use of different pooling methods and random effect models and inclusion of double arm, zero events studies (supplementary tables F-H), the results did not change for any outcomes. When we omitted each trial one by one (supplementary figure F) or removed the CAROLINA and CARMELINA trials simultaneously (supplementary table I), the results of outcomes remained stable, except for the composite of gallbladder or biliary diseases.
We observed no publication bias in the included studies for the composite of gallbladder or biliary diseases, cholelithiasis, cholecystitis, or biliary diseases when we used Egger’s test (table 2). The funnel plots were visually symmetrical (supplementary figure G) in traditional pairwise meta-analysis.
Comparisons between dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors in network meta-analysis
We included 184 trials in a network of comparisons among the three classes of antidiabetes drugs (supplementary figure H; supplementary tables J and K). Network plots of treatment comparisons are shown in figure 3, and network estimates are shown in figure 4 and supplementary table L. Dipeptidyl peptidase-4 inhibitors increased the risks of the composite of gallbladder or biliary diseases (odds ratio 1.32, 1.06 to 1.64) and cholecystitis (1.55, 1.13 to 2.12) compared with sodium-glucose cotransporter-2 inhibitors, as well as compared with placebo or other antidiabetes drugs (fig 4). We found no significant differences between dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists in any outcomes. The results from random effects models were similar to those from fixed effect models (supplementary tables L and M). Table 3 shows the summary of the results from traditional pairwise meta-analysis and the network meta-analysis.
We observed no significant between study heterogeneities, between design inconsistencies, or inconsistencies between direct and indirect treatment comparisons for all outcomes in the network meta-analysis (supplementary tables N and O). We observed no small study effects in the studies included in the network meta-analysis (supplementary figure I). The quality of evidence for results from the network meta-analysis is shown in supplementary table P.
To our knowledge, this is the first study to systematically assess the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. Our findings showed that dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis, which tended to be observed in patients with a longer duration of treatment. The risk of cholecystitis was higher with dipeptidyl peptidase-4 inhibitors than with sodium-glucose cotransporter-2 inhibitors but similar to that with glucagon-like peptide-1 receptor agonists.
Comparison with other studies
Few studies have assessed the effects of dipeptidyl peptidase-4 inhibitors on gallbladder or biliary diseases.2116 A retrospective study enrolled patients with type 2 diabetes and reported no significant associations between dipeptidyl peptidase-4 inhibitors and an increased risk of gallbladder or biliary diseases.7 However, the retrospective design could be associated with various biases and confounding, and the study did not analyse the specific risks of cholecystitis. We noted some discrepancies between the pooled results of our study and those of some large scale randomised controlled trials, such as SAVOR-TIMI trial, and the reasons for this are unknown. Possibly, differences in populations, periods of follow-up, specific dipeptidyl peptidase inhibitors, and reporting of outcomes may play a role. Intriguingly, although we found that glucagon-like peptide-1 receptor agonists increased the risks of cholecystitis compared with sodium-glucose cotransporter-2 inhibitors or controls (placebo or other antidiabetes drugs) in the network meta-analysis, consistent with previous studies,46117 dipeptidyl peptidase-4 inhibitors were not associated with lower risks of cholecystitis than glucagon-like peptide-1 receptor agonists. Furthermore, the results from traditional pairwise meta-analysis were similar to those from the network meta-analysis that simultaneously combined direct and indirect effects.
The gallbladder or biliary effects of dipeptidyl peptidase-4 inhibitors might be attributed to the roles of glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide.5118 Glucagon-like peptide-1 is involved in impaired gallbladder mobility and contractility by inhibiting the secretion of cholecystokinin,118 which could contribute to the development of gallbladder or biliary diseases.4 Additionally, glucose dependent insulinotropic polypeptide was recently reported to play a role in gallbladder relaxation.5
Increased risks of gallbladder or biliary diseases tended to be apparent in patients receiving dipeptidyl peptidase-4 inhibitors for a longer duration, which suggested that a sufficiently long treatment duration was needed to allow the gallbladder or biliary effects of dipeptidyl peptidase-4 inhibitors to be explored. A previous study did not observe the effects of sitagliptin on gallbladder emptying,119 possibly owing to the short treatment duration (12 weeks). More importantly, as the duration of prescriptions for dipeptidyl peptidase-4 inhibitors is usually longer in routine practice than in clinical trials,120 awareness of the role of treatment duration might be of great clinical importance.
Strengths and limitations of study
This study has several strengths. Firstly, this is the first systematic review and meta-analysis pooling the results of randomised controlled trials to assess the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. Secondly, our findings showed the possible effects of the duration of dipeptidyl peptidase-4 inhibitor treatment on gallbladder or biliary diseases. Thirdly, we did network meta-analysis to compare the three antidiabetes drugs.
Nevertheless, our study has some limitations. Firstly, the included studies were not specifically designed to evaluate the effects of dipeptidyl peptidase-4 inhibitors on gallbladder or biliary diseases. Secondly, gallbladder or biliary diseases were not predefined safety outcomes in the included studies and hence might be underreported. Although the data might not be fully collected, this is unlikely to bias the associations found. Thirdly, patient level data were inaccessible for the meta-analysis.
Dipeptidyl peptidase-4 inhibitors are considered to have a good safety profile,2 and concerns about potential adverse events have usually focused on heart failure,121 bullous pemphigoids,122123 pancreatitis,124 and severe joint pain.125 The US Food and Drug Administration has released warnings about the risk of heart failure and severe joint pain with dipeptidyl peptidase-4 inhibitors.126127 However, the potential risk of cholecystitis attributed to dipeptidyl peptidase-4 inhibitors has not yet been investigated. This study highlights the importance and raises awareness of the risks of cholecystitis with dipeptidyl peptidase-4 inhibitors for physicians and should encourage researchers to make them predefined safety endpoints. These findings may be also extended to double or triple agonists, including glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, or both.
Although dipeptidyl peptidase-4 inhibitors increased relative risk for cholecystitis in patients with type 2 diabetes, the overall absolute risk increase was small (15 cases per 10 000 people per year). This absolute risk increase should be weighed against the benefits of dipeptidyl peptidase-4 inhibitor treatment.1130
Dipeptidyl peptidase-4 inhibitors might increase the risk of cholecystitis in patients with type 2 diabetes. Our findings suggest that physicians should be concerned about increased risks of cholecystitis in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors in clinical practice, especially with longer treatment durations. Future studies are encouraged to fully report gallbladder or biliary diseases.
What is already known on this topic
Glucagon-like peptide-1 (GLP-1) is involved in the development of impaired gallbladder motility
Liraglutide, an important member of the GLP-1 receptor agonist class, has been reported to be associated with an increased risk of gallbladder or biliary diseases
Glucose dependent insulinotropic polypeptide has also been reported to affect gallbladder motility
What this study adds
Dipeptidyl peptidase-4 (DPP-4) inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases and cholecystitis
DPP-4 inhibitors were not associated with increased risk of cholelithiasis and biliary diseases
Risk of cholecystitis was increased with DPP-4 inhibitors compared with sodium-glucose cotransporter-2 inhibitors but not GLP-1 receptor agonists
Data availability statement
The study specific summary data included in the meta-analysis can be obtained from the corresponding authors at email@example.com or firstname.lastname@example.org.
We thank the staff of the Peking Union Medical College Hospital and all who actively participated in and provided statistical support for the study. We thank Yuelun Zhang, a research associate at the Medical Research Center, Peking Union Medical College Hospital, for his help with resolving the discrepancies in the data extraction and conducting the network meta-analysis.
Contributors: HZ and YL are joint corresponding authors and contributed equally to this work. HZ, LH, and YL conceived and designed the study. LH, HZ, and JW did the relevant literature searches. LH, HZ, FP, NY, and YL screened the articles for inclusion. LH, JW, WL, JH, and LX extracted the data for analysis. LH, HZ, and YL were involved in the quality assessment of the eligible studies. LH, HZ, and JW did the meta-analysis and produced forest plots and summary results under the supervision of HZ and YL. LH, HZ, and YL drafted the manuscript. FP, JH, WL, LX, HZ, and YL critically revised the manuscript for important intellectual content. All authors approved the final manuscript. HZ and YL are the guarantors. The corresponding authors (HZ and YL) attest that all listed authors meet the authorship criteria and that no others that meet the criteria have been omitted.
Funding: This work was partially supported by Beijing Natural Science Foundation (M22014), National Natural Science Foundation of China (91846106), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-002), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019XK320029), and Training Program for Excellent Talents in Dongcheng District (TPETDD2018). HZ received all funding. YL also received financial support from CAMS Innovation Fund for Medical Sciences (2021-1-I2M-002). The funding sources did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
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.
The lead authors (the manuscript’s guarantors) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Dissemination to participants and related patients and public communities: After publication, the findings of this review will be disseminated to appropriate audiences such as academia, clinicians, policy makers, and the general public, through various channels including blogs, press releases, and social media.
Provenance and peer review: Not commissioned; externally peer reviewed.
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