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

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.

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.

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).

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.