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Vildagliptin Significantly Increases the Risk of Bullous Pemphigoid: A Finnish Nationwide Registry Study

Open ArchivePublished:February 07, 2018DOI:https://doi.org/10.1016/j.jid.2018.01.027

      Abbreviations:

      BP (bullous pemphigoid), DPP-4i (dipeptidyl peptidase-4 inhibitor)
      Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease (
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ). BP has become more common over the past two decades (
      • Försti A.K.
      • Jokelainen J.
      • Timonen M.
      • Tasanen K.
      Increasing incidence of bullous pemphigoid in northern Finland: a retrospective database study in Oulu University Hospital.
      ,
      • Joly P.
      • Baricault S.
      • Sparsa A.
      • Bernard P.
      • Bedane C.
      • Duvert-Lehembre S.
      • et al.
      Incidence and mortality of bullous pemphigoid in France.
      ,
      • Langan S.M.
      • Smeeth L.
      • Hubbard R.
      • Fleming K.M.
      • Smith C.J.P.
      • West J.
      Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study.
      ). However, the underlying causes of the increasing incidence of BP are poorly understood. Altogether, over 50 drugs have been reported to induce BP (
      • Stavropoulos P.G.
      • Soura E.
      • Antoniou C.
      Drug-induced pemphigoid: a review of the literature.
      ). The use of dipeptidyl peptidase-4 inhibitors (DPP-4i), a class of drug used for the treatment of diabetes, has recently been scrutinized as a risk factor for BP, both in case reports (see Supplementary Table S1 online) and in national pharmacovigilance database reports (
      • Bene J.
      • Moulis G.
      • Bennani I.
      • Auffret M.
      • Coupe P.
      • Babai S.
      • et al.
      Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: A case-noncase study in the french pharmacovigilance database.
      ,
      • García M.
      • Aranburu M.A.
      • Palacios-Zabalza I.
      • Lertxundi U.
      • Aguirre C.
      Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database.
      ), but large population-based studies are lacking. In this study we investigated the potential association between DPP-4i and BP using data from Finnish national registries.
      Populations (Table 1), databases used, and statistical analysis are described in the Supplementary Materials online. After adjusting for diabetes and several neurological disorders, the use of any DPP-4i was associated with a significantly increased risk of BP compared with the control population (Table 2). The use of vildagliptin was associated with 10-fold elevated risk for BP. Combination therapy regimens containing metformin and sitagliptin or vildagliptin were associated with an increased risk of BP, but metformin alone was not associated with a difference in BP risk. A sensitivity analysis supported these findings (Table 2, and see Supplementary Table S2 online). The use of DPP-4i had no significant impact on patient age at BP diagnosis when subjects who had received a DPP-4i were compared with those who had not (77.7 vs. 76.7 years), starting from 2007 when the first DPP-4i was approved in Finland. The mean latency from vildagliptin exposure to BP diagnosis was 449 days (see Supplementary Table S3 online). In women, the risk of having BP diagnosis after DPP-4i medication was heightened compared with men (see Supplementary Table S4 online).
      Table 1Characteristics of bullous pemphigoid patients and basal cell carcinoma control individuals from the Finnish Care Register for Heath Care
      CharacteristicPatients (n = 3,397)Control Individuals (n = 12,941)
      Age, sex, and year of the diagnosis matched in 1:4 ratio. Because of the availability of drug reimbursement data, 579 patients had fewer than four basal cell carcinoma control individuals.
      Female, n (%)2,028 (59.7)7,766 (60.0)
      Male, n (%)1,369 (40.3)5,175 (40.0)
      Age in years, mean76.676.7
      Diabetes, n (%)757 (22.3)1,837 (14.2)
      Neurological disease, n (%)
      Alzheimer disease, vascular dementia, other/unspecified dementia, Parkinson disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and epilepsy.
      1,519 (44.7)3,949 (30.5)
      1 Age, sex, and year of the diagnosis matched in 1:4 ratio. Because of the availability of drug reimbursement data, 579 patients had fewer than four basal cell carcinoma control individuals.
      2 Alzheimer disease, vascular dementia, other/unspecified dementia, Parkinson disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and epilepsy.
      Table 2Metformin and dipeptidyl peptidase-4 inhibitor drugs used by bullous pemphigoid patients and basal cell carcinoma control individuals obtained from the database of the Social Insurance Institution of Finland and odds ratios for bullous pemphigoid
      DrugGroupTotal
      Including patients and control individuals with disease diagnosed after the drug in question had been approved for use in Finland.
      n (%)Crude OR (95% CI)Adjusted OR (95% CI)
      OR adjusted for diabetes.
      Adjusted OR (95% CI)
      OR adjusted for diabetes, Alzheimer disease, vascular dementia, other/unspecified dementia, Parkinson disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and epilepsy.
      Combinations of oral blood glucose-lowering drugs
       Metformin and sitagliptinPatients1,62127 (1.7)3.95 (2.30–6.78)2.34 (1.20–4.57)2.40 (1.22–4.73)
      Control individuals6,41129 (0.5)ReferenceReferenceReference
       Metformin and vildagliptinPatients1,77714 (0.8)6.59 (2.75–15.8)4.21 (1.59–11.10)6.71 (2.00–22.50)
      Control individuals6,9899 (0.1)ReferenceReferenceReference
      Dipeptidyl peptidase-4 inhibitorsPatients1,917124 (6.5)3.45 (2.69–4.44)2.13 (1.51–3.00)2.19 (1.55–3.11)
      Control individuals7,536153 (2.0)ReferenceReferenceReference
       SitagliptinPatients1,91779 (4.1)2.37 (1.78–3.17)1.36 (0.93–1.99)1.37 (0.93–2.01)
      Control individuals7,536135 (1.8)ReferenceReferenceReference
       VildagliptinPatients1,80749 (2.7)11.8 (6.71–20.8)8.66 (4.06–18.50)10.4 (4.56–23.80)
      Control individuals7,15217 (0.2)ReferenceReferenceReference
       SaxagliptinPatients1,2951 (0.1)
      Control individuals5,1572 (0.0)
       LinagliptinPatients8482 (0.2)
      Control individuals3,4881 (0.0)
      Biguanides
       MetforminPatients3,397432 (12.7)1.49 (1.32–1.68)1.00 (0.84–1.18)1.05 (0.88–1.24)
      Control individuals12,9411,178 (9.1)ReferenceReferenceReference
      Abbreviations: CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitor; OR, odds ratio.
      1 Including patients and control individuals with disease diagnosed after the drug in question had been approved for use in Finland.
      2 OR adjusted for diabetes.
      3 OR adjusted for diabetes, Alzheimer disease, vascular dementia, other/unspecified dementia, Parkinson disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and epilepsy.
      To the best of our knowledge, no previous nationwide registry study has reported an association between vildagliptin and BP. These results concur with previous observations from pharmacovigilance database reports where BP was most frequent with vildagliptin therapy. (
      • Bene J.
      • Moulis G.
      • Bennani I.
      • Auffret M.
      • Coupe P.
      • Babai S.
      • et al.
      Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: A case-noncase study in the french pharmacovigilance database.
      ,
      • García M.
      • Aranburu M.A.
      • Palacios-Zabalza I.
      • Lertxundi U.
      • Aguirre C.
      Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database.
      ). Furthermore, freely available information from the European database of suspected adverse drug reaction supports our findings: by December 2017, 408 vildagliptin-associated suspected pemphigoid cases (of a total of 3,653 adverse drug reactions) were recorded in this database, whereas there were notably fewer pemphigoid cases linked to sitagliptin (173 of the total of 12,439 adverse drug reactions) (

      European Medicines Agency. EudraVigilance, http://www.adrreports.eu; n.d. (accessed 20 January 2018).

      ). Our results are also in line with those of recent studies reporting elevated risk for BP associated with vildagliptin use (

      Benzaquen M, Borradori L, Berbis P, Cazzaniga S, Valero R, Richard M, et al. Dipeptidyl peptidase-IV inhibitors, a risk factor for bullous pemphigoid. Retrospective multicenter case-control study in France and Switzerland [e-pub ahead of print]. J Am Acad Dermatol 2017; https://doi.org/10.1016/j.jaad.2017.12.038 (accessed 20 December 2017).

      ,
      • Schaffer C.
      • Buclin T.
      • Jornayvaz F.R.
      • Cazzaniga S.
      • Borradori L.
      • Gilliet M.
      • et al.
      Use of dipeptidyl-peptidase IV inhibitors and bullous pemphigoid.
      ).
      From the year 2011, an increasing number of case reports have been published linking DPP-4i and BP (see Supplementary Table S1). Most concern vildagliptin, but some cases have also been reported during linagliptin, sitagliptin, anagliptin, and alogliptin therapy. The latency period between DPP-4i use and the onset of BP in these reports ranges between 1 month and over 4 years (see Supplementary Table S1), and in recent pharmacovigilance reports the mean latency period varied from 6 to 19 months (
      • Bene J.
      • Moulis G.
      • Bennani I.
      • Auffret M.
      • Coupe P.
      • Babai S.
      • et al.
      Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: A case-noncase study in the french pharmacovigilance database.
      ,
      • García M.
      • Aranburu M.A.
      • Palacios-Zabalza I.
      • Lertxundi U.
      • Aguirre C.
      Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database.
      ). In our study, the mean time between vildagliptin intake and BP diagnosis was 449 days. Thus, vildagliptin should be recognized as a possible trigger for BP even when it has been used for more than a year before BP diagnosis. Metformin monotherapy was not associated with BP when adjusted for diabetes and neurological diseases. This implies that for patients with BP diagnosed during metformin-vildagliptin combination therapy, metformin could be safely continued, but withdrawal of vildagliptin should be considered. It is currently unclear whether DPP-4i–associated BP is an actual drug-induced BP, which truly resolves upon cessation of the drug, or rather a drug-aggravated BP, which persists despite cessation of the drug.
      An interesting finding in our study was that women were more likely than men to develop BP after DPP-4i intake (see Supplementary Table S4). In the European pharmacovigilance report, 58% of vildagliptin-, 65% of sitagliptin-, 46% of linagliptin-, and 33% of saxagliptin-related BP patients were men (
      • García M.
      • Aranburu M.A.
      • Palacios-Zabalza I.
      • Lertxundi U.
      • Aguirre C.
      Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database.
      ), and in a recent case-control study, the risk of BP onset after DPP-4i therapy was only seen in males (

      Benzaquen M, Borradori L, Berbis P, Cazzaniga S, Valero R, Richard M, et al. Dipeptidyl peptidase-IV inhibitors, a risk factor for bullous pemphigoid. Retrospective multicenter case-control study in France and Switzerland [e-pub ahead of print]. J Am Acad Dermatol 2017; https://doi.org/10.1016/j.jaad.2017.12.038 (accessed 20 December 2017).

      ). In healthy persons, sex does not affect the pharmacokinetics of vildagliptin (
      • He Y.
      • Sabo R.
      • Campestrini J.
      • Wang Y.
      • Riviere G.
      • Nielsen J.C.
      • et al.
      The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers.
      ), but women are known to be at increased risk for adverse drug reactions in general (
      • Rademaker M.
      Do women have more adverse drug reactions?.
      ). However, further studies are needed to verify the differences between sexes in susceptibility for BP onset during DPP-4i therapy.
      As well as BP, vildagliptin and sitagliptin have been reported to induce polyarthritis (
      • Crickx E.
      • Marroun I.
      • Veyrie C.
      • Le Beller C.
      • Schoindre Y.
      • Bouilloud F.
      • et al.
      DPP4 inhibitor-induced polyarthritis: a report of three cases.
      ,
      • Saito T.
      • Ohnuma K.
      • Suzuki H.
      • Dang N.H.
      • Hatano R.
      • Ninomiya H.
      • et al.
      Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors.
      ). DPP-4i have also been suggested to decrease the risk of autoimmune diseases: in a cohort study of a US insurance database, the use of linagliptin, saxagliptin, or sitagliptin slightly reduced the risk of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and inflammatory bowel disease, but the risk of autoimmune blistering skin diseases was not analyzed in this study (
      • Kim S.C.
      • Schneeweiss S.
      • Glynn R.J.
      • Doherty M.
      • Goldfine A.B.
      • Solomon D.H.
      Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study.
      ). Taken together, currently only limited data are available concerning the association of DPP-4i with other autoimmune diseases.
      A major strength of our study is that the data from the Social Insurance Institution of Finland contain information on medication that patients have actually purchased. Another strength is that we used one of the largest nationwide BP cohorts ever studied (
      • Försti A.K.
      • Huilaja L.
      • Schmidt E.
      • Tasanen K.
      Neurological and psychiatric associations in bullous pemphigoid–more than skin deep?.
      ). Because of the use of routinely collected registry data, we have no certainty that all the BP cases were immunologically confirmed and no access to information of the actual onset of the BP symptoms. It was not possible to analyze any relationship between linagliptin or saxagliptin and BP because few patients used these medications. The use of patients with basal cell carcinoma as a control population may have introduced some confounding factors: compared with age- and sex-matched basal cell carcinoma control individuals, BP patients are more likely to have diabetes, and their diabetes may be more severe. In the future, it will be important to investigate the association between the use of DPP-4i and BP by comparing the incidence of BP in patients treated for diabetes with DPP-4i and those treated with other diabetes medications.
      In conclusion, our nationwide registry study shows a significantly increased risk of BP after the use of vildagliptin. Further studies are required better to understand the pathomechanism that causes the association between DPP-4i and BP.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This study was supported by research grants from the Academy of Finland and the Medical Research Center Oulu.

      Supplementary Material

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