Association of Bullous Pemphigoid With Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes

Abstract

The association of bullous pemphigoid (BP) with the use of dipeptidylpeptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established. OBJECTIVES Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP. MAIN OUTCOMES AND MEASURES Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes. RESULTS Eighty-two patients with BP and 328 age-and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitorassociated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes. CONCLUSIONS AND RELEVANCE Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.

Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

“…Likewise, a similar increase was also observed in a Japanese pharmacovigilance database, particularly among patients treated with vildagliptin, linagliptin, or teneligliptin (Arai, Shirakawa, Konishi, Sagawa, & Terauchi, 2018). Several observational studies (all case-control designs) have also been conducted and it was reported that a significantly increased or a trend towards an increased risk of BP is associated with the usage of DPP4is with odds ratios ranging between 1.58 and 3.16 (Benzaquen et al, 2018;Kridin & Bergman, 2018;Lee, Lee, Yoon, & Kim, 2019;Plaquevent, et al, 2019;Varpuluoma et al, 2018). Moreover, Benzaquen et al has reported that application of DPP4is increases the risk of BP of almost 3-fold, and the increase is associated with vildagliptin rather than other gliptins (Benzaquen et al, 2018).…”

“…Increased risk in T2DM patients (Aouidad et al, 2013;Arai et al, 2018;Bene, et al, 2016;Benzaquen et al, 2018;Douros et al, 2019;Garcia et al, 2016;Kridin & Bergman, 2018;Lee et al, 2019;Plaquevent, et al, 2019;Varpuluoma et al, 2018) Taken together, these existing studies fail to strongly support the clinical application of DPP4is in either glucose control or β cell preservation in T1DM patients. The contrary conclusions obtained from the above clinic trials may be attributed to different baseline characteristics of the included patients (such as c-peptide levels, HbA1c, and disease duration), distinct follow-up lengths, different sample size, and other variables.…”

“…Accordingly, it is speculated that off-target inhibition on other members of DPP family, such as DPP8 and DPP9 may cause the pathophysiology of gliptin-related BP . However, patients treated with linagliptin, which is a high selective DPP4i, showed an equal risk of BP as well (Baetta & Corsini, 2011), when compared with vildagliptin (Kridin & Bergman, 2018). Therefore, it is assumed that the DPP4i itself rather than the off-target effect contributes to the high risk of BP suffering.…”

Dipeptidyl peptidase‐4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta‐analysis

“…Kridin and colleagues conducted a retrospective case–control study amongst patients with diabetes in a tertiary referral centre for autoimmune bullous diseases in northern Israel. 82 BP cases were age‐ and gender‐matched with 328 controls.…”

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

“…The results of this large population‐based cohort study revealed that the use of DPP‐4 inhibitors was significantly related to an increased risk of BP with an aHR of 2.382 ( P = 0.017). The previous studies have elucidated the association between DPP‐4 inhibitors and BP . In 2019, a large population‐based cohort study of 8569 DPP‐4 inhibitor users and 160 205 non‐DPP‐4 inhibitor users was published by using the UK Clinical Practice Research Datalink .…”