1. Presenter: Wen-Ching Lan Date: 2018/08/01
Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.
Devin Abrahami, Antonios Douros, Hui Yin, Oriana Hoi Yun Yu, Christel Renoux, Alain Bitton, Laurent Azoulay
BMJ 2018
Presenter: Wen-Ching Lan
Date: 2018/08/01

2. Introduction
The use of dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes has increased considerably .
These effects are mediated by inhibition of the dipeptidyl peptidase-4 enzyme leading to a rise in glucagon-like peptide 1 concentrations.
studies in mouse models of inflammatory bowel disease suggest that treatment with dipeptidyl peptidase-4 inhibitors results in decreased disease activity.
The association between dipeptidyl peptidase-4 enzyme concentrations and incident inflammatory bowel disease has not been studied. 1

3. Objective
To assess whether the use of dipeptidyl peptidase-4 inhibitors is associated with the incidence of inflammatory bowel disease in patients with type 2 diabetes. 2

4. Methods
Data source
This study used data from the Clinical Practice Research Datalink (CPRD), a primary care database from the UK.
The CPRD records demographic and lifestyle information, prescription data, referrals, and diagnoses for more than 15 million patients in more than 700 general practices. 3

5. Methods Study population
A cohort of patients, at least 18 years of age, starting antidiabetic drugs between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017.
Cohort entry was the date of this new antidiabetic prescription.
All patients were followed starting six months after cohort entry until an incident diagnosis of inflammatory bowel disease or censored on an incident diagnosis of ischaemic colitis or diverticulitis, death from any cause. 4

6. Methods 5

7. Methods Exposure assessment
dipeptidyl peptidase-4 inhibitors (alone or in combination with other antidiabetic drugs) as a time varying variable.
patients were considered exposed starting six months after their first prescription until the end of the follow-up period
secondary exposure
The first assessed the association according to cumulative duration of dipeptidyl peptidase-4 inhibitor use.
we defined in a time dependent fashion as the time between the first dipeptidyl peptidase-4 inhibitor prescription and time of event. 6

8. Methods Potential confounders
age, sex, year of cohort entry, BMI, alcohol related disorders, and smoking status.
haemoglobin A1c, microvascular and macrovascular (myocardial infarction, stroke, peripheral arteriopathy) complications of diabetes, duration of treated diabetes, and antidiabetic drugs
aspirin, non-steroidal anti-inflammatory drugs, hormonal replacement therapy, oral contraceptives, other autoimmune conditions 7

9. Statistical analysis
Poisson distribution
time dependent Cox proportional hazards models
(adjusted for the potential confounders)
Secondary analyses
five predefined duration categories (≤1 year, years, years, years, and >4 years).
three predefined categories (≤2 years, years, and >4 years).
to investigate the possibility of a drug specific effect (sitagliptin, saxagliptin, and other)
by stratifying on type of inflammatory bowel disease (Crohn’s disease, ulcerative colitis, and unspecified disease). 8

10. Statistical analysis Sensitivity analyses
increased the exposure lag period to one year.
linically relevant supporting events
competing risk analysis
stratified the cohort by age at cohort entry
redefined as receipt of at least four prescriptions within a 12 month moving window; 9

11. Statistical analysis Ancillary analyses
The first used insulin as a negative control exposure, a last line treatment that has not been associated with inflammatory bowel disease.
The second was a head to head comparison of patients newly treated with dipeptidyl peptidase-4 inhibitors versus insulin between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017. 10

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16. Discussion
This is the first observational study to specifically investigate the association between the use of dipeptidyl peptidase-4 inhibitors and the incidence of inflammatory bowel disease.
That an increased risk with dipeptidyl peptidase-4 inhibitors may be associated with ulcerative colitis.
additional studies are also needed to understand the possible mechanism through which dipeptidyl peptidase-4 inhibitors may increase the risk of inflammatory bowel disease. 15

17. Strengths and limitations of study
excluded prevalent users, thus eliminating biases associated with their inclusion.
used a time dependent exposure definition
Limitations
Misclassification (type 2 diabetes, inflammatory bowel disease, prescriptions are written not by specialists )
all observational studies, residual confounding from unknown or unmeasured variables remains possible. 16

18. Conclusions
The results of this large population based cohort study indicate that the use of dipeptidyl peptidase-4 inhibitors is associated with an overall 75% increase in the risk of inflammatory bowel disease in patients with type 2 diabetes. 17

19. Thanks for listening.