Bullous pemphigoid induced by dipeptidyl peptidase-4 (DPP-4) inhibitors: a pharmacovigilance-pharmacodynamic/pharmacokinetic assessment through an analysis of the vigibase®

ABSTRACT

Objectives: To examine the signals of bullous pemphigoid (BP) with dipeptidyl peptidase-4 inhibitors (DPP-4i) in VigiBase® and the potential role of their pharmacodynamic/pharmacokinetic parameters in the occurrence of BP.

Methods: Case/non-case analyses were performed in VigiBase® to examine the signal of BP [reporting odds ratio (ROR)] for gliptins. Secondly, the authors performed linear regression analyses to explore the association between DPP-4i signals for BP and their affinities toward 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-4i. The ROR for pooled DPP-4i 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.

KEYWORDS:

• Dipeptidyl peptidase-4 inhibitors
• bullous pemphigoid
• VigiBase
• drug safety
• diabetes

Acknowledgments

This work was supported by funds from the Regional Centre of Pharmacovigilance of Lombardy (to EC) the Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA, to EC) and by the Italian Ministry of Health (Ricerca Corrente 2018, to MP), which are gratefully acknowledged. F Mazhar is enrolled in the PhD in Experimental and Clinical Pharmacological Sciences, University of Milano, which supports his fellowship. The funding public institutions had no role in any part of the work.

Author contributions

C Carnovale conceptualized and designed the study, interpreted the data drafted the manuscript, revised and approved the final manuscript as submitted. F Mazhar participated in the conceptualization and design of the study, carried out the initial analyses, revised the manuscript and approved the final manuscript as submitted. E Arzenton, U Moretti and M Pozzi participated in the conceptualization and design of the study, participated in the analysis and interpretation of the data, revised the article, and approved the final article as submitted. G Mosini, O Leoni and M Scatigna participated in the conceptualization and design of the study, participated in the analysis and interpretation of the data, revised the article, and approved the final article as submitted. E Clementi participated in the conceptualization and design of the study, participated in the analysis and interpretation of the data, coordinated and supervised data collection, critically reviewed the manuscript and approved the final manuscript as submitted. S Radice conceptualized and designed the study, interpreted the data, coordinated and supervised data collection, critically reviewed the manuscript and approved the final manuscript as submitted.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This paper was not funded.