Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population

Abstract

Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped. The observed frequencies of intake of the whole gliptin class and that of vildagliptin in the BP population were higher than those in the general population after age standardization (whole gliptin class: 6.0%; 95% confidence interval ¼ 4.9e7.1% vs. 3.6%, observed-to-expected drug intake ratio ¼ 1.7; 95% confidence interval ¼ 1.4e2.0; P < 0.0001; vildagliptin ¼ 3.3%; 95% confidence interval ¼ 2.5e4.1% vs. 0.7%, ratio ¼ 4.4; 95% confidence interval ¼ 3.5e5.7; P < 0.0001). The association of any gliptinþmetformin was also higher than in the general population, ratio ¼ 1.8 (95% confidence interval ¼ 1.3e2.4; P < 0.0001). Gliptin-associated BP had no specific clinical characteristics. Gliptin was stopped in 48 (45.3%) cases. Median duration to achieve disease control, rate, and delay of relapse were not different whether gliptin was stopped or continued. This study strongly supports the association between gliptin intake, particularly vildagliptin, and the onset of BP.

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.…”

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

“…There were three pharmacovigilance studies which reported proportion of patients with DPPI use in BP versus comparator groups; however, the comparator group were patients with non‐BP complications, and the comparison is likely to overestimate the effect size; thus, these studies were excluded from analysis. One French study compared frequency of gliptin intake in BP patients compared with general population subjects; however, it did not have a case–control design and lacked multivariate adjustment, and hence was excluded.…”

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 .…”

“…The previous studies have elucidated the association between DPP-4 inhibitors and BP. [12][13][14][15][16][17] 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. 18 The results revealed a significant association between DPP-4 inhibitors and BP (47.3 vs 20.0 per 10 5 person-years; HR, 2.21; 95% CI, 1.45-3.38).…”