Bullous pemphigoid induced by dipeptidyl peptidase-4 (DPP-4) inhibitors: A Pharmacovigilance-Pharmacodynamic/Pharmacokinetic assessment through an analysis of the VigiBase®

Objectives: To examine the signals of bullous pemphigoid (BP) with dipeptidyl peptidase-4 (DPP-4) inhibitors in VigiBase® and the potential role of pharmacodynamic/pharmacokinetic parameters of gliptins in the occurrence of BP. Methods: Case/non-case analyses was performed in VigiBase® to examine the signal of BP [expressed as the reporting odds ratio (ROR)] for gliptins. Secondly, the authors performed linear regression analyses to explore the association between DPP-4 inhibitor signals for BP and their affinities towards different target enzymes (DPP-2, DPP-4, DPP-8 and DPP-9) and their volume of distribution (Vd). Results: A significant BP signal was found for DPP-4 inhibitors. The ROR for pooled DPP-IV inhibitors was 179.48 (95% CI: 166.41- 193.58). The highest ROR was found for teneligliptin 975.04 (801.70-1185.87) and lowest for saxagliptin 18.9 (11.5-30.9). Linear regression analyses showed a considerable trend to significance for the linear correlation between the BP signal and gliptin affinity at DPP-4 (slope=1.316 [-0.4385-3.21], p=0.067, R2=0.40) but not the other enzyme targets, nor for Vd. Conclusion: The findings suggest a clinical relevance of gliptins selectivity for DDP-4 in the development of BP as a result of exposure to these drugs. Future preclinical and clinical studies are needed for a better understanding of this correlation.