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Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials

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Abstract

Purpose

An increasing body of evidence suggests that dipeptidyl-peptidase 4 (DPP-4) inhibitors could play a role in the development of bullous pemphigoid. The knowledge regarding this association is based on case reports, pharmacovigilance database analyses, and observational studies. Data from randomized clinical trials are a relevant source of information on adverse events. Since no single trial has a sufficient power to assess the risk of very rare adverse events, such as pemphigoid, metanalyses of RCTs could be a useful tool for exploring this issue.

Methods

An extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin, omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥24 weeks, and comparing DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for pemphigoid.

Results

A total of 138 eligible trials were identified (61,514 patients in DPP-4 inhibitors and 59,661 patients in the control group). Only six trials reported at least one case of pemphigoid (17 and 1 cases in DPP4i and control groups, respectively). DPP-4 inhibitors were associated with an increased risk of pemphigoid (MH-OR 4.44 [1.31, 15.00], p = 0.020). A separate analysis for trials with linagliptin showed a significant increase of BP with the active drug (MH-OR 4.69 [1.09, 20.22]; p = 0.04).

Conclusions

In conclusion, available data from randomized controlled trials seem to confirm the association between DPP-4 inhibitors and bullous pemphigoid. This association could be limited to one molecule of the class (i.e., linagliptin), although data on other DPP4-i (e.g., vildagliptin) are insufficient to rule out similar detrimental effects.

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Funding

This research was performed as a part of the institutional activity of the unit, with no specific funding. All expenses, including salaries of the investigators, were covered by public research funds assigned to the unit. The paper was drafted and revised by the authors in accordance with ICJME standards for authorship. The corresponding author had full access to all the data in the study, and had final responsibility for the decision to submit for publication.

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Author notes

  1. These authors contributed equally: Giovanni Antonio Silverii, Ilaria Dicembrini

Authors and Affiliations

  1. Diabetology Unit, Careggi Hospital and University of Florence, Florence, Italy

    Giovanni Antonio Silverii, Ilaria Dicembrini, Besmir Nreu, Chiara Montereggi, Edoardo Mannucci & Matteo Monami

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  1. Giovanni Antonio Silverii
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Contributions

M.M and E.M were involved in each of the following points: 1. Design 2. Data Collection 3. Analysis 4. Writing paper. I.D, G.A.S, B.N, and C.M were involved in each of the following points: 1. Data Collection 2. Paper revision.

Corresponding author

Correspondence to Matteo Monami.

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Conflict of interest

G.A.S and I.D have received speaking fees from Astra Zeneca, Novonordisk; C.M has no conflict of interest; B.N is presently employee of Novo Nordisk; M.M has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; E.M has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this paper. M.M is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the paper.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Silverii, G.A., Dicembrini, I., Nreu, B. et al. Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials. Endocrine 69, 504–507 (2020). https://doi.org/10.1007/s12020-020-02272-x

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  • DOI: https://doi.org/10.1007/s12020-020-02272-x

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