Dipeptidyl peptidase 4 (DPP4) enzyme is an endoprotease that removes N-terminal prolines from intestinal peptides. 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. Inhibition of DPP4 thus raises GLP-1 levels and has a glucose-lowering effect

Alexopoulos, Anastasia-Stefania

Crowley, Matthew J.

Li, Dandan

Silvester, Jocelyn Anne

Wang, Tiansheng

Xu, Yang

Yang, Jeff Y.

Zhan, Siyan

Carolina Digital Repository

https://doi.org/10.1177/2040622320904301 https://doi.org/10.1177/2040622320904301Therapeutic Advances in Chronic Diseasejournals.sagepub.com/home/taj 1Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License  (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Ther Adv Chronic Dis2020, Vol. 11: 1–3DOI: 10.1177/ 2040622320904301© The Author(s), 2020.  Article reuse guidelines:  sagepub.com/journals-permissionsIntroductionDipeptidyl peptidase 4 (DPP4) enzyme is an endo-protease that removes N-terminal prolines from intestinal peptides.1 These peptides include gluca-gon-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 pep-tides. Celiac disease (CD) is a chronic digestive dis-order 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 glu-cose-lowering drugs (GLDs), may increase the pool of gluten peptides with N-terminal prolines, potentially increasing the risk of CD. To investi-gate 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 2018.6MethodsWe 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 compara-tors 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 divid-ing 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 sub-group analyses, we calculated the PRRs of each individual DPP4i (sitagliptin, saxagliptin, linaglip-tin, 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 applica-tion designed to mine data effectively)8 from Q1, 2004 to Q4, 2018. PRR was calculated using STATA 13.0.ResultsIn 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 Assessing the association between dipeptidyl peptidase-4 inhibitors use  and celiac disease through drug  adverse event reportingDandan Li, Jocelyn Anne Silvester, Matthew J. Crowley, Jeff Y. Yang,  Anastasia-Stefania Alexopoulos, Yang Xu, Siyan Zhan and Tiansheng WangReceived: 29 August 2019; revised manuscript accepted: 6 January 2020.Correspondence to: 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 tianwang@unc.eduDandan Li  Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaJocelyn Anne Silvester Harvard Celiac Disease Research Program, Division of Gastroenterology, Hepatology & Nutrition, Boston Children’s Hospital, Boston, MA, USAMatthew J. Crowley Anastasia-Stefania Alexopoulos  Department of Medicine, Duke University School of Medicine, Durham, NC, USAJeff Y. Yang  Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USAYang Xu  Siyan Zhan  Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China904301 TAJ0010.1177/2040622320904301Therapeutic Advances in Chronic DiseaseD Li, JA Silvesterresearch-article20202020Letter to the EditorTherapeutic Advances in Chronic Disease 112 journals.sagepub.com/home/taj(PRR 1.79, 95% CI 1.28–2.51) (Figure 1). No sig-nal of significant higher risk of DPP4i-related CD was found when compared with SGLT2i (PRR 1.46, 95% CI 0.77–2.78).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.DiscussionIn 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 diagno-sis of celiac disease is biologically plausible. Gluten is a substrate for DPP-4, which removes N-terminal proline residues. HLA-DQ2 prefer-entially binds peptides with an N-terminal proline1; therefore, inhibition of DPP-4 may potentiate celiac disease by facilitating presenta-tion 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.5Our 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 com-pared with therapeutic alternatives.In conclusion, we detected a signal for higher risk of CD associated with DPP4i use compared with GLP1RA.AcknowledgementsWe thank John B Buse for expert advice.Author contributionsTW and DL designed the study. DL performed statistical analysis. DL, JAS, JYY, YX, SZ, and TW were involved in data review and inter-pretation. DL wrote the first draft of the paper. JY, JAS, MJC, ASA, YX, and SZ, and TW con-tributed to critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.FundingThe 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.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.D Li, JA Silvester et al.journals.sagepub.com/home/taj 3Conflict of interest statementThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.Statement of GuarantorsDL is the guarantor of this work and had full access to all the data in the study and take respon-sibility of the integrity of the data and the accu-racy of the data analysis.ORCID iDTiansheng Wang  https://orcid.org/0000-0002 -0980-8896References1. Kim CY, Quarsten H, Bergseng E, et al. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A 2004; 101: 4175–4179.2. Brunton S. GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? Int J Clin Pract 2014; 68: 557–567.3. Lundin KE and Sollid LM. Advances in coeliac disease. Curr Opin Gastroenterol 2014; 30: 154–162.4. Liu E, Lee HS, Aronsson CA, et al. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med 2014; 371: 42–49.5. Sjostrom H, Noren O, Krasilnikoff PA, et al. Intestinal peptidases and sucrase in coeliac disease. Clin Chim Acta 1981; 109: 53–58.6. US Food and Drug Administration. FDA Adverse Event Reporting System Data – FAERS Data, https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html (accessed 24 January 2020).7. Evans SJ, Waller PC and Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 2001; 10: 483–486.8. Sarangdhar M, Tabar S, Schmidt C, et al. Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data. Nat Biotechnol 2016; 34: 697–700.Visit SAGE journals online journals.sagepub.com/home/tajSAGE journals

Assessing the association between dipeptidyl peptidase-4 inhibitors use and celiac disease through drug adverse event reporting

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Assessing the association between dipeptidyl peptidase-4 inhibitors use and celiac disease through drug adverse event reporting

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