Introduction
Dipeptidyl peptidase 4 (DPP4) enzyme is an endoprotease that removes N-terminal prolines from intestinal peptides.1 These peptides include glucagon-like peptide-1 (GLP-1), which, as one of the main human incretin hormones produced by the gastrointestinal system, enhances insulin secretion in a glucose-dependent manner.2 Inhibition of DPP4 thus raises GLP-1 levels and has a glucose-lowering effect.
DPP4 also cleaves other clinically relevant peptides. Celiac disease (CD) is a chronic digestive disorder characterized by an immune response to proteins from wheat and related grains.3 Affected individuals display gluten-derived peptides to the immune system on human leukocyte antigen (HLA) haplotype DR3-DQ2 or DR4-DQ8, but only 2–3% of these haplotype carriers develop CD.4 DPP4 cleaves peptides that are over-represented in the gluten epitopes that bind to HLA haplotype DR3-DQ21; although a direct causal link has yet to be established, the activity of intestinal DPP4 is decreased in the acute and remission phases of CD,5 suggesting a possible association between DPP4 level and CD.
DPP4 inhibitors (DPP4i), a common class of glucose-lowering drugs (GLDs), may increase the pool of gluten peptides with N-terminal prolines, potentially increasing the risk of CD. To investigate this potential association, we analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, which contains all adverse drug events (ADEs) spontaneously reported to FDA from the first quarter (Q1) of 2004 to Q4 of 2018.6
Methods
We compared DPP4i versus three groups: GLP-1 receptor agonists (GLP1RA); sodium-glucose cotransporter 2 inhibitors (SGLT2i); and all other non-DPP4i GLDs, excluding insulin. GLP1RA and SGLT2i were selected as comparators since they are new classes of GLDs that may have higher reporting frequency for ADEs similar to DPP4i. The group consisting of all other non-DPP4i GLDs, excluding insulin, was used to limit participants to type 2 diabetes of similar severity.
The proportional reporting ratio (PRR) with 95% confidence interval (CI) was calculated by dividing the reporting ratio of CD events reported for DPP4i by the reporting ratio of CD events reported for the comparator drug. A signal was defined as PRR ⩾ 2 as previous studies.7 In subgroup analyses, we calculated the PRRs of each individual DPP4i (sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin) versus GLP1RA to explore the difference between DPP4i agents. Data was pooled by a query within AERSMine (an open-access multi-cohort analyzing application designed to mine data effectively)8 from Q1, 2004 to Q4, 2018. PRR was calculated using STATA 13.0.
Results
In total, 43 cases of CD were reported in association with DPP4i use. The disproportionality analysis demonstrated that the frequency of CD with DPP4i was significantly higher than that for GLP1RA (PRR 2.66, 95% CI 1.57–4.50), and all other non-DPP4i glucose lowering drugs, excluding insulin (PRR 1.79, 95% CI 1.28–2.51) (Figure 1). No signal of significant higher risk of DPP4i-related CD was found when compared with SGLT2i (PRR 1.46, 95% CI 0.77–2.78).
Figure 1.
Number of celiac disease events and the proportional reporting ratio in different comparisons.
ADE, adverse drug events; GLD, glucose lowering drugs; GLP1RA, glucagon-like peptide-1 receptor agonists; PRR, proportional reporting ratio; SGLT2i, sodium-glucose cotransporter 2 inhibitors.
In the subgroup analysis, no cases of CD related to alogliptin and vidagliptin were found. Compared with GLP1RA, we detected a signal for sitagliptin (PRR 3.15, 95% CI 1.82–5.44), while signals for saxagliptin (PRR 2.57, 95% CI 0.88–7.48) and linagliptin (PRR 1.93, 95% CI 0.66–5.63) were weak due to a low number of events.
Discussion
In our study, the PRR of DPP4i versus GLP1RA was 2.66, suggesting that the inhibition of DPP4i may be associated with a possible higher CD risk.
This association between DPP4i use and diagnosis of celiac disease is biologically plausible. Gluten is a substrate for DPP-4, which removes N-terminal proline residues. HLA-DQ2 preferentially binds peptides with an N-terminal proline1; therefore, inhibition of DPP-4 may potentiate celiac disease by facilitating presentation of gluten peptides by HLA-DQ. Consistent with this, the activity of DPP-4 is depressed in patients with active CD and those in remission.5
Our disproportionality analysis has limitations. Although assessing disproportionality for safety signal is a useful approach to monitor rare adverse events, the FAERS database is prone to reporting bias, missing data, confounding, and cannot be used to calculate incidence; further population-based cohort studies are needed to investigate the possible risk of CD associated with DPP4i compared with therapeutic alternatives.
In conclusion, we detected a signal for higher risk of CD associated with DPP4i use compared with GLP1RA.
Acknowledgments
We thank John B Buse for expert advice.
Footnotes
Author contributions: TW and DL designed the study. DL performed statistical analysis. DL, JAS, JYY, YX, SZ, and TW were involved in data review and interpretation. DL wrote the first draft of the paper. JY, JAS, MJC, ASA, YX, and SZ, and TW contributed to critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and publication of this article: JAS is supported by the National Institutes of Health (NIH) NIDDK T32 DK007760. MJC is supported by a VA HSR&D Career Development Award (CDA 13-261). ASA is supported by the National Institutes of Health under Award Number T32DK007012. JYY is supported by the National Institutes of Health T32 DK007634.
Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Statement of Guarantors: DL is the guarantor of this work and had full access to all the data in the study and take responsibility of the integrity of the data and the accuracy of the data analysis.
ORCID iD: Tiansheng Wang 
https://orcid.org/0000-0002-0980-8896
Contributor Information
Dandan Li, Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Jocelyn Anne Silvester, Harvard Celiac Disease Research Program, Division of Gastroenterology, Hepatology & Nutrition, Boston Children’s Hospital, Boston, MA, USA.
Matthew J. Crowley, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
Jeff Y. Yang, Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA
Anastasia-Stefania Alexopoulos, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Yang Xu, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
Siyan Zhan, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
Tiansheng Wang, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 2101 McGavran-Greenberg Hall, Campus Box 7453, 27599 Chapel Hill, NC 27515, USA.
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