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

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