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GLP-1 Analogs and SGLT2 Inhibitors Do Not Increase Risk of Bullous Pemphigoid

  • Outi Varpuluoma
    Affiliations
    PEDEGO Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland

    Department of Dermatology, Oulu University Hospital, University of Oulu, Oulu, Finland

    Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
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  • Jari Jokelainen
    Affiliations
    The Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Finland

    Unit of General Practice, Oulu University Hospital, Oulu, Finland
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  • Laura Huilaja
    Affiliations
    PEDEGO Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland

    Department of Dermatology, Oulu University Hospital, University of Oulu, Oulu, Finland

    Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
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  • Kaisa Tasanen
    Correspondence
    Corresponding author
    Affiliations
    PEDEGO Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland

    Department of Dermatology, Oulu University Hospital, University of Oulu, Oulu, Finland

    Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
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Open AccessPublished:June 07, 2021DOI:https://doi.org/10.1016/j.jid.2021.05.015

      Abbreviations:

      BP (bullous pemphigoid), DM (diabetes mellitus), DPP-4i (dipeptidyl peptidase-4 inhibitor)
      To the Editor
      The association of bullous pemphigoid (BP) and dipeptidyl peptidase-4 inhibitors (DPP-4is) used for diabetes mellitus (DM) has recently attracted special interest in the field of BP research. (
      • Nishie W.
      • Tasanen K.
      Gliptin-associated bullous pemphigoid: a valuable model of the mechanism of breakdown of immune tolerance against BP180.
      ;
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.
      ). However, other diabetes drugs have been studied to a lesser extent in this context. In our previous case-control study of 3,397 patients with BP diagnosed in Finland between 1997 and 2013, we did not find increased risk of BP associated with oral DM drugs other than DPP-4is (
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Tasanen K.
      • et al.
      Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: a Finnish nationwide case-control study.
      ). However, owing to the limited number of either cases or controls on newer drugs, we were unable to study all the DM drugs in the Finnish market. This study aims to analyze the association of DM drugs and BP, especially focusing on the newer regimens.
      This is a retrospective case-control study of patients with BP older than 40 years diagnosed in Finland between 1 January 1997 and 31 December 2018. Data on patient records were obtained from the Finnish Care Register for Health Care. Patients were selected by a diagnosis of BP (International Classification of Diseases-10 code L12.0). The control population was composed of patients diagnosed with basal cell carcinoma and matched by age, sex, and year of diagnosis (within 2 years) in a 1:4 ratio. Data on purchased DM drugs for the 2 years immediately preceding diagnosis were obtained from the drug reimbursement register of the database of the Social Insurance Institution of Finland (Supplementary Table S1). Associations between DM drug usage and BP were evaluated using a conditional logistic regression model. Results were adjusted with DM, several neurological diseases, and use of aldosterone antagonists, anticholinergics, antipsychotics, and dopaminergic drugs that have been associated with increased risk for BP (
      • Liu S.D.
      • Chen W.T.
      • Chi C.C.
      Association between medication use and bullous pemphigoid: a systematic review and meta-analysis.
      ). Because several new DM drugs were approved for use in Finland during the study period, for these drugs, we included only cases and controls diagnosed after the approval. Methods and databases are described in detail in our previous studies (
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.
      ,
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Tasanen K.
      • et al.
      Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: a Finnish nationwide case-control study.
      ).
      We obtained data on drug use from 5,079 patients and 19,663 controls. The characteristics of the study populations are shown in Table 1. DM drugs used and their associations with BP or basal cell carcinoma are shown in Table 2. DPP-4is were associated with a 2-fold increased risk for BP. Of DPP-4is, vildagliptin was associated with the highest risk. Linagliptin, sitagliptin, and combinations of metformin with vildagliptin and linagliptin were also associated with increased risk of BP. Sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs were not associated with increased BP risk. After adjustments, metformin, repaglinide, pioglitazone, and the combination of metformin and pioglitazone seemed to be associated with increased risk for BP. To rule out the possible effect of DPP-4i use, we performed further analyses for all aforementioned drugs using only data from those cases and controls who had not used DPP-4is during the study period. In these analyses, no statistically significant associations between metformin, repaglinide, pioglitazone, or metformin-pioglitazone combination and BP were found (data not shown).
      Table 1Characteristics of Bullous Pemphigoid Cases and Basal Cell Carcinoma Controls Retrieved from the Finnish Care Register for Health Care
      CharacteristicCases n = 5,079 (%)Controls n = 19,663 (%)
      Matched by age, sex, and year of diagnosis in a 1:4 ratio. Owing to the lack of data in the drug imbursement register, 581 cases had fewer than the intended 4 controls.
      Female2,968 (58.44)11,523 (58.60)
      Male2,111 (41.56)8,140 (41.40)
      Age, y, mean (range)77.6 (40–104)77.7 (40–104)
      1 Matched by age, sex, and year of diagnosis in a 1:4 ratio. Owing to the lack of data in the drug imbursement register, 581 cases had fewer than the intended 4 controls.
      Table 2Diabetes Drugs Used by Bullous Pemphigoid Cases and Basal Cell Carcinoma Controls 2 Years Before the Diagnosis and OR for Bullous Pemphigoid
      Diabetes DrugGroup
      Including cases and controls diagnosed after the drug in question had been approved for use in Finland; see Supplementary Table S1.
      Totaln (%)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.
      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, epilepsy, dopaminergic agents (The Anatomical Therapeutic Chemical-code N04B), anticholinergic agents (N04A), aldosterone antagonists (C03DA), and antipsychotic agents (N05A).
      BiguanidesCase5,079758 (14.9)1.72 (1.57–1.89)1.19 (1.04–1.35)1.22 (1.07–1.39)1.21 (1.06–1.38)
      Control19,6631,852 (9.4)ReferenceReferenceReferenceReference
       MetforminCase5,079758 (14.9)1.72 (1.57–1.89)1.19 (1.04–1.35)1.22 (1.07–1.39)1.21 (1.06–1.38)
      Control19,6631,852 (9.4)ReferenceReferenceReferenceReference
      SulfonylureasCase5,079269 (5.3)1.58 (1.36–1.82)1.13 (0.91–1.39)1.15 (0.93–1.42)1.16 (0.94–1.44)
      Control19,663675 (3.4)ReferenceReferenceReferenceReference
       GlipizideCase5,07936 (0.7)1.47 (0.99–2.17)1.55 (0.87–2.77)1.56 (0.87–2.82)1.55 (0.86–2.79)
      Control19,66392 (0.5)ReferenceReferenceReferenceReference
       GlimepirideCase5,042235 (4.7)1.58 (1.35–1.84)1.09 (0.87–1.35)1.11 (0.89–1.38)1.12 (0.90–1.40)
      Control19,510590 (3.0)ReferenceReferenceReferenceReference
      Combinations of oral blood glucose–lowering drugsCase4,194113 (2.7)2.87 (2.24–3.66)1.93 (1.42–2.63)2.02 (1.48–2.75)1.97 (1.44–2.70)
      Control16,282160 (1.0)ReferenceReferenceReferenceReference
       Metformin and rosiglitazoneCase4,19411 (0.3)1.38 (0.69–2.77)2.20 (0.87–5.57)2.21 (0.87–5.59)2.21 (0.87–5.59)
      Control16,28232 (0.2)ReferenceReferenceReferenceReference
       Metformin and pioglitazoneCase3,74211 (0.3)3.79 (1.63–8.77)3.90 (1.18–12.9)3.81 (1.14–12.7)3.96 (1.02–15.4)
      Control14,37412 (0.1)ReferenceReferenceReferenceReference
       Metformin and sitagliptinCase3,30362 (1.9)2.67 (1.93–3.69)1.38 (0.91–2.09)1.42 (0.93–2.16)1.40 (0.91–2.13)
      Control12,56794 (0.7)ReferenceReferenceReferenceReference
       Metformin and vildagliptinCase3,45926 (0.8)4.80 (2.70–8.56)3.45 (1.78–6.67)4.36 (2.10–9.05)4.83 (2.22–10.5)
      Control13,19222 (0.2)ReferenceReferenceReferenceReference
       Metformin and linagliptinCase2,1747 (0.3)13.6 (2.82–65.5)10.3 (1.40–75.4)17.9 (1.64–196)16.5 (1.33–205)
      Control8,0952 (0.0)ReferenceReferenceReferenceReference
       Metformin and dapagliflozinCase1,7710 (0.0)
      Control6,4782 (0.0)
       Metformin and empagliflozinCase1,5490 (0.0)
      Control5,2712 (0.0)
      ThiazolidinedionesCase4,66243 (0.9)2.39 (1.63–3.49)1.79 (1.11–2.89)1.80 (1.11–2.91)1.73 (1.06–2.83)
      Control18,02572 (0.4)ReferenceReferenceReferenceReference
       RosiglitazoneCase4,6628 (0.2)1.12 (0.51–2.47)0.59 (0.20–1.70)0.56 (0.19–1.66)0.56 (0.19–1.66)
      Control18,02528 (0.2)ReferenceReferenceReferenceReference
       PioglitazoneCase4,62235 (0.8)3.16 (2.03–4.92)2.47 (1.44–4.22)2.46 (1.43–4.23)2.37 (1.36–4.10)
      Control17,86844 (0.2)ReferenceReferenceReferenceReference
      DPP-4 inhibitorsCase3,599457 (12.7)3.96 (3.44–4.53)2.42 (2.00–2.93)2.48 (2.04–3.01)2.42 (1.99–2.94)
      Control13,777541 (3.9)ReferenceReferenceReferenceReference
       SitagliptinCase3,599213 (5.9)2.45 (2.05–2.92)1.31 (1.04–1.66)1.31 (1.03–1.66)1.29 (1.02–1.64)
      Control13,777360 (2.6)ReferenceReferenceReferenceReference
       VildagliptinCase3,489126 (3.6)6.59 (4.94–8.79)4.03 (2.72–5.97)4.53 (2.99–6.85)4.50 (2.96–6.83)
      Control13,35080 (0.6)ReferenceReferenceReferenceReference
       SaxagliptinCase2,9773 (0.1)
      Control11,2662 (0.0)
       LinagliptinCase2,530152 (6.0)5.07 (3.96–6.48)3.08 (2.25–4.21)3.23 (2.34–4.46)3.20 (2.32–4.42)
      Control9,523133 (1.4)ReferenceReferenceReferenceReference
      GLP-1 analogsCase3,66115 (0.4)2.57 (1.34–4.92)1.24 (0.51–2.97)1.04 (0.41–2.66)1.08 (0.42–2.78)
      Control14,04723 (0.2)ReferenceReferenceReferenceReference
       ExenatideCase3,6616 (0.2)3.35 (1.13–9.99)2.18 (0.46–10.3)1.99 (0.40–9.81)1.92 (0.37–9.90)
      Control14,0477 (0.0)ReferenceReferenceReferenceReference
       LiraglutideCase3,0559 (0.3)2.37 (1.04–5.42)1.11 (0.37–3.37)0.91 (0.27–3.09)0.94 (0.27–3.22)
      Control11,57415 (0.1)ReferenceReferenceReference
       DulaglutideCase1,6910 (0.0)
      Control5,9702 (0.0)
       LixisenatideCase2,0160 (0.0)
      Control7,4571 (0.0)
      SGLT2 inhibitorsCase2,07639 (1.9)2.77 (1.83–4.19)1.18 (0.67–2.07)1.43 (0.79–2.58)1.40 (0.77–2.54)
      Control7,71558 (0.8)ReferenceReferenceReferenceReference
       DapagliflozinCase2,07613 (0.6)2.36 (1.19–4.69)1.03 (0.38–2.78)1.63 (0.54–4.90)1.59 (0.52–4.85)
      Control7,71522 (0.3)ReferenceReferenceReferenceReference
       EmpagliflozinCase1,73328 (1.6)3.16 (1.92–5.23)1.30 (0.68–2.49)1.38 (0.71–2.67)1.36 (0.70–2.65)
      Control6,26836 (0.6)ReferenceReferenceReferenceReference
      Other blood glucose–lowering drugs, excl. insulinsCase5,07947 (0.9)1.76 (1.24–2.48)1.11 (0.73–1.68)1.13 (0.74–1.73)1.13 (0.74–1.73)
      Control19,663104 (0.5)ReferenceReferenceReferenceReference
       Guar gumCase5,07919 (0.4)1.24 (0.74–2.09)0.90 (0.50–1.63)0.90 (0.50–1.64)0.90 (0.50–1.64)
      Control19,66358 (0.3)ReferenceReferenceReferenceReference
       RepaglinideCase4,92120 (0.4)2.74 (1.55–4.85)1.35 (0.64–2.84)2.92 (1.07–7.98)2.98 (1.10–8.04)
      Control19,01729 (0.2)ReferenceReferenceReferenceReference
      Abbreviations: CI, confidence interval; DPP-4, dipeptidyl peptidase 4.
      1 Including cases and controls diagnosed after the drug in question had been approved for use in Finland; see Supplementary Table S1.
      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.
      4 OR adjusted for diabetes, Alzheimer disease, vascular dementia, other/unspecified dementia, Parkinson disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, epilepsy, dopaminergic agents (The Anatomical Therapeutic Chemical-code N04B), anticholinergic agents (N04A), aldosterone antagonists (C03DA), and antipsychotic agents (N05A).
      This study offers data to support the view that GLP-1 analogs and SGLT2 inhibitors are not associated with increased risk of BP. Previously, one case concerning GLP-1 agonist–related BP had been reported; a 62-year-old male with type 2 DM treated with metformin developed BP 2 months after dulaglutide and insulin were added to the treatment (
      • Fukuda G.
      • Yoshida T.
      • Hirayama A.
      • Umezawa Y.
      • Takemoto M.
      Dulaglutide-related bullous pemphigoid in a patient with type 2 diabetes: a case report.
      ). To the best of our knowledge, no case reports have been published of SGLT2 inhibitor–related BP in the English scientific literature. One patient using empagliflozin was recently reported in a Spanish pharmacovigilance study, but no clinical details of the case were available (
      • Reolid A.
      • Muñoz-Aceituno E.
      • Rodríguez-Jiménez P.
      • González-Rojano E.
      • Llamas-Velasco M.
      • Fraga J.
      • et al.
      Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors. a case series and analysis of cases reported in the Spanish pharmacovigilance database.
      ). Another pharmacovigilance study did not find disproportionality between reported pemphigoid cases and other DM drugs when the effect of DPP4is was taken into account (
      • Arai M.
      • Shirakawa J.
      • Konishi H.
      • Sagawa N.
      • Terauchi Y.
      Bullous pemphigoid and dipeptidyl peptidase 4 inhibitors: a disproportionality analysis based on the Japanese adverse drug event report database.
      ). Combinations of DPP-4is and metformin have previously been reported to be associated with increased risk of BP (
      • Plaquevent M.
      • Tétart F.
      • Fardet L.
      • Ingen-Housz-Oro S.
      • Valeyrie-Allanore L.
      • Bernard P.
      • et al.
      Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in the French general population.
      ;
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.
      ), but metformin as monotherapy does not seem to carry such a risk (
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ;
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.
      ). In this study, metformin monotherapy was not associated with increased BP risk when the data were corrected for previous or concomitant DPP-4i medication. In contrast, a recent Taiwanese insurance register study of 124,619 patients with diabetes found metformin to be associated with increased BP risk (
      • Wu C.Y.
      • Wu C.Y.
      • Li C.P.
      • Chou Y.J.
      • Lin Y.H.
      • Chang Y.T.
      Association between dipeptidyl peptidase-4 inhibitors and risk of bullous pemphigoid in patients with type 2 diabetes: a population-based cohort study.
      ). Authors suggest that this finding might be explained by their strict definition of the study group where they excluded patients with neurological diseases. Another Taiwanese study of the same insurance register did not find an association between thiazolidinedione, acarbose, glinide, and sulfonylurea and increased risk for BP (
      • Guo J.Y.
      • Chen H.H.
      • Yang Y.C.
      • Wu P.Y.
      • Chang M.P.
      • Chen C.C.
      The association of dipeptidyl peptidase IV inhibitors and other risk factors with bullous pemphigoid in patients with type 2 diabetes mellitus: a retrospective cohort study.
      ).
      This study strengthens the view of DPP-4is being the most evident risk factor for BP among DM drugs. In studies comparing DPP-4is with other antidiabetic drugs, DPP-4is were associated with increased risk of BP compared with the other second- and third-line antidiabetic drugs (
      • Douros A.
      • Rouette J.
      • Yin H.
      • Yu O.H.Y.
      • Filion K.B.
      • Azoulay L.
      Dipeptidyl peptidase 4 inhibitors and the risk of bullous pemphigoid among patients with type 2 diabetes.
      ) or second-generation sulfonylureas (
      • Lee H.
      • Chung H.J.
      • Pawar A.
      • Patorno E.
      • Kim D.H.
      Evaluation of risk of bullous pemphigoid with initiation of dipeptidylpeptidase–4 inhibitor vs second-generation sulfonylurea.
      ). This study is also in line with recent meta-analyses of case-control studies (
      • Phan K.
      • Charlton O.
      • Smith S.D.
      Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: a systematic review and adjusted meta-analysis.
      ) and of randomized controlled trials concerning DPP-4is (
      • Silverii G.A.
      • Dicembrini I.
      • Nreu B.
      • Montereggi C.
      • Mannucci E.
      • Monami M.
      Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials.
      ) that reported DPP4is being associated with a significantly increased risk of BP.
      The strengths of this study are its use of comprehensive, real-life data on purchased drugs and a nationwide study design that is likely to cover most of the BP cases diagnosed in Finland during the study period. Limitations of the study include the absence of access to the clinical details. Because of the nature of the drug imbursement register, the drugs supplied to hospital inpatients were not included in the study. The choice of control population can be considered a limitation because patients with basal cell carcinoma may represent a selected population.
      This study offers updated data on the relation of BP and DM drugs and strengthens the view of DPP-4is carrying a significantly increased risk of BP. Further studies are needed to understand the pathogenesis of DPP-4i–associated BP.

       Data availability statement

      Our data are from the Finnish Care Register for Health Care, maintained by the Finnish Institute for Health and Welfare, and from the drug reimbursement register of Social Insurance Institution of Finland. According to Finnish law and regulations, the data in these registers and documents are confidential. Register authorities can grant permission to use register data and documents for purposes of scientific research.

      ORCIDs

      Conflict of Interest

      OV has received educational grants from Leo Pharma and Novartis Finland. LH has received educational grants from CSL Behring, Takeda, Janssen-Cilag, Novartis, AbbVie, and Leo Pharma; honoraria from Lilly, AbbVie, Takeda, Novartis, Sanofi Genzyme, and Union Chimique Belge Pharma for consulting and/or speaking; and is an investigator for AbbVie. KT has received educational grants from Sanofi Genzyme and honoraria from AbbVie, Novartis, Sanofi Genzyme, Janssen-Cilag and Union Chimique Belge Pharma for consulting and/or speaking. The remaining authors state no conflict of interest.

      Acknowledgments

      This study was supported by research grants from the Sigrid Juselius Foundation and the Academy of Finland.

      Author Contributions

      Conceptualization: OV, KT, LH; Formal Analysis: OV, JJ; Methodology: OV, JJ, KT, LH; Supervision: KT, LH; Writing - Original Draft Preparation: OV; Writing - Review and Editing: OV, KT, LH

      Supplementary Materials

      Supplementary Table S1Diabetes Drugs Included in this Study and Dates of Approval in Finland Obtained from the Finnish Medicines Agency Database
      Diabetes DrugDate of Approval
      Metformin15 March 1967
      Glipizide16 July 1975
      Glimepiride07 July 1997
      Metformin and rosiglitazone20 October 2003
      Metformin and pioglitazone28 July 2006
      Metformin and sitagliptin16 July 2008
      Metformin and vildagliptin14 November 2007
      Metformin and linagliptin20 July 2012
      Metformin and dapagliflozin16 January 2014
      Metformin and empagliflozin27 May 2015
      Rosiglitazone11 July 2000
      Pioglitazone11 October 2000
      Sitagliptin21 March 2007
      Vildagliptin26 September 2007
      Saxagliptin01 October 2009
      Linagliptin28 April 2011
      Exenatide20 November 2006
      Liraglutide30 June 2009
      Dulaglutide21 November 2014
      Lixisenatide01 February 2013
      Dapagliflozin12 November 2012
      Empagliflozin22 May 2014
      Guar gum22 September 1982
      Repaglinide17 August 1998

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