This systematic review and meta-analysis evaluated the association between DPP-4 inhibitors and gallbladder or biliary diseases in patients with type 2 diabetes. It analyzed data from 82 randomized controlled trials involving over 100,000 participants. The analysis found that DPP-4 inhibitors were associated with a small increased risk of gallbladder or biliary diseases and cholecystitis compared to placebo or other antidiabetes drugs. The risk was higher with longer durations of DPP-4 inhibitor treatment of 26 weeks or more. DPP-4 inhibitors also showed a higher risk of cholecystitis compared to SGLT-2 inhibitors, though a similar risk as GLP-1 receptor agonists. The overall absolute risk increase was

1. Journal reading
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

2. JOURNAL
READING

3. INTRODUCTION
Enhance the bioavailability of endogenous
glucagon-like peptide-1 and glucose dependent
insulinotropic polypeptide
Both of which might affect postprandial
gallbladder motility
Dipeptidyl
peptidase-
4 inhibitors
Type 2
diabetes
treatment
Risks of gallbladder or biliary
diseases (?)
Early studies have proposed
associations between gallbladder
related events and incretin based
drugs, including DPP-4 inhibitor
and GLP-1 receptor agonis

4. To evaluate the association between
DPP-4 inhibitors and gallbladder or
biliary diseases in patients with type 2
diabetes.
AIM

5. METHODS
Guideline : PRISMA and PRISMA extension for network meta-analysis
Design : Systematic review and Meta Analysis
Study sources, searches, and identification
Database : PubMed, the Cochrane Library, EMBASE and Web of Science,
Gray literature in Google Scholar and public repositories
Date : Up to 31 July 2021
Topics : Randomised controlled trials of DPP-4 inhibitors
Grouping : DPP-4 inhibitor & placebo → pairwise meta-analysis
DPP-4 inhibitor & other antidiabetes drug → network meta analysis

6. METHODS
Risk assessment : Cochrane risk of bias tool for randomized trials
Certainty of the evidence : Grading of Recommendations, Assessment,
Development and Evaluations framework
Deta extraction and quality assessment
Definition of outcome
The gallbladder or biliary diseases was identified on the basis of the
classifications in the Medical Dictionary for Regulatory Activities
(MedDRA) version 22.0.

7. METHODS
• Substantial heterogeneity was assessed by using χ2 tests
• Odds ratios and 95% confidence intervals was calculated by using fixed effect
models with the Mantel-Haenszel method
• Researcher evaluated absolute risk differences on the basis of the calculated odds
ratio and the mean event rate across the control groups for outcomes
• Publication bias was assessed by visual assessment of asymmetry of the funnel
plots and the Egger’s asymmetry test.
• Sensitivity analyses were carried out by using different pooling methods,24 using
random effect models
• Meta analysis was carried out with pairwise and network method. Results will be
presented with forest plot and league tables
• The meta, netmeta package in R (version 4.0.2) and Stata 15 was used for all
analyses.
Data synthesis and analysis

8. PRISMA flow
diagram
82 randomised controlled trials with
104.833 participants with type 2
diabetes in the traditional pairwise
meta-analysis

9. Characteristics of studies and participants in pairwise meta-analysis

10. Characteristics of studies and participants in pairwise meta-analysis

11. Characteristics of studies and participants in pairwise meta-analysis

12. GRADE profile of DPP-4 inhibitors and risk of gallbladder or biliary diseases in patients
with type 2 diabetes compared with placebo or non-incretin drugs in pairwise meta-
analyses

13. RESULTS
Baseline characteristics
• The average age of participants was 59.4 years, and 39.7% (n=41 618) were female.
• The mean bodyBMI was 29.7, and mean HbA1c was 8.1%.
• Almost all trials documented gallbladder or biliary diseases as serious adverse
events.
Risk of bias and quality of evidence
• 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 DPP-4 inhibitors and placebo or non-
incretin drugs

14. Risks of cholecystitis, cholelithiasis, and biliary disease in patients
taking dipeptidyl peptidase-4 inhibitors
• There is a significant association between DPP-4 inhibitors and an increased risk of the
composite of gallbladder or biliary diseases (odds ratio 1.22) compared with placebo or
nonincretin drugs
• DPP-4 inhibitors significantly increased the risk of cholecystitis (odds ratio 1.43) but not of
cholelithiasis or biliary diseases

15. RESULTS
• DPP-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) and cholecystitis
(1.51), but those with a shorter duration (<26 weeks) were not
Effects of duration of treatment, specific DPP-4
inhibitors, and types of control
• After use of different pooling methods and random effect models and
inclusion of double arm, zero events studies, the results did not
change for any outcomes.
Sensitivity analyses

16. Summary findings from pairwise and network meta-analysis

17. RESULTS
Publication bias
• There is no publication bias observed in the included studies for the composite of
gallbladder or biliary diseases, cholelithiasis, cholecystitis, or biliary diseases when
Egger’s test was used
Comparisons between DPP-4 inhibitors, GLP-1 receptor
agonists, and SGLT-2 inhibitors in network meta analysis
• 184 trials in a network of comparisons among the three classes of antidiabetes drugs
were included
• DPP-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 SGLT-2 inhibitors, as well as compared with placebo or other
antidiabetes drugs

18. Network plots of comparisons of DPP-4
inhibitors, glucagon-like peptide-1 (GLP-1)
receptor agonists, and sodiumglucose
cotransporter-2 (SGLT -2) inhibitors in
network meta-analyses

19. 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.

20. 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.

21. DISCUSSION
Comparison with other studies
● A retrospective study enrolled patients with
type 2 diabetes and reported no significant
associations between DPP-4 inhibitors and
an increased risk of gallbladder or biliary
diseases
● There is also some discrepancies between
this pooled results with some large scale
RCT like SAVOR-TIMI
• The risk of cholecystitis was higher with DPP-4 inhibitors
than with SGLT-2 inhibitors but similar to that with GLP-1
receptor agonists
Results from
this study
There is a difference in study
design
There is a difference in
population, periods of follow
up, specific DPP inhibitor
and reporting method

22. DISCUSSION
● The gallbladder or biliary effects of
DPP-4 inhibitors might be attributed
to the roles of GLP-1 and glucose
dependent insulinotropic polypeptide
● Glucose dependent insulinotropic
polypeptide was recently reported to
play a role in gallbladder relaxation
GLP-1 is involved in
impaired gallbladder
mobility and contractility
It inhibit the secretion of
cholecystokinin, which
also contribute to the
disease development

23. DISCUSSION
The longer DPP-4 inhibitor
treatment
The risk of gallbladder or
biliary disease increased
• 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 DPP-4 inhibitors is
usually longer in routine practice than in clinical trials
Awareness of the role of treatment duration might be of
great clinical importance

24. STRENGTHS OF STUDY
The first systematic review and meta analysis pooling the results of RCT to assess
the association between DPP-4 inhibitor and gallbladder or biliary disease
There is a possible effects of the duration of DPP-4 inhibitor treatment on
gallbladder or biliary disease
This study did a meta analysis comparing 3 antidiabetes drug

25. LIMITATIONS OF STUDY
The included studies were not specifically designed to evaluate
the effects of DPP-4 inhibitors on gallbladder or biliary disease
Gallbladder or biliary diseases were not predefined safety
outcomes in the included studies
Patient level data were inaccessible for the meta-analysis

26. POLICY IMPLICATIONS
● Dipeptidyl peptidase-4 inhibitors are
considered to have a good safety profile
● Concerns about potential adverse
events have usually focused on :
 Heart failure
 Bullous pemphigoids
 Pancreatitis
 Severe joint pain
This study highlights the
importance and raises
awareness of the risks of
cholecystitis
However, the overall absolute risk
increase was small (15 cases per
10.000 people per year)
US FDA has released warnings
about the risk of heart failure and
severe joint pain with DPP-4 inhibitor

27. CONCLUSIONS
DPP-4 inhibitors might increase the risk of
cholecystitis in patients with type 2 diabetes.
This findings suggest that physicians should be concerned about
increased risks of cholecystitis in patients with this particular
condition, especially those with longer treatment duration

28. TERIMA KASIH