Case ReportTurk J Endocrinol Metab 2019;23:64-67

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Address for Correspondence: Müge Keskin, University of Health Sciences Keçiören Training and Research Hospital,Clinic of Endocrinology and Metabolism, Ankara, Turkey

Phone: +90 312 356 90 00 E-mail: keskinmuge@hotmail.comReceived: 08/11/2018 Received in revised form: 19/12/2018 Accepted: 09/01/2019 Available online: 20/03/2019

®Copyright 2019 by Turkish Journal of Endocrinology and Metabolism AssociationTurkish Journal of Endocrinology and Metabolism published by Türkiye Klinikleri

Case Report: Fixed Drug Eruption Causedby Dapagliflozin

Vaka Sunumu: Dapagliflozine Bağlı Fiks İlaç Erüpsiyonu

Clinic of Endocrinology and Metabolism, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey*Clinic of Dermatology, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey

**Clinic of Pathology, University of Health Sciences Keçiören Training and Research Hospital, Ankara, Turkey

IntroductionThe latest treatment modality for T2DM in-cludes SGLT2 inhibitors, which exert an in-sulin-independent action by blocking there-absorption of filtered glucose in kidneys.Dapagliflozin, an SGLT2 inhibitor, is con-

sumed orally, once-daily, and has a half lifeof about 17 hours. SGLT2 inhibitors causethe loss of calories, helping in subsequentweight loss (1). Weight loss is associatedwith the reduction of visceral or subcuta-neous fat. SGLT2 inhibitors provide cardio-

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Type 2 diabetes mellitus (T2DM) is a global health concern. Ithas multifactorial pathophysiology and its incidence is increa-sing day by day. The treatment is mainly targeted at main-taining cardiovascular and renal functions. Administration ofsodium-glucose co-transporter-2 (SGLT2) inhibitors is one ofthe emerging medications for T2DM. It improves glycemia byemploying insulin-independent mechanisms that increase uri-nary glucose excretion. The authors hereby report a case ofa 62-year-old male with T2DM, who was referred to our out-patient clinic for glycemic control. The patient was taking met-formin and gliclazide for five years in addition to dapagliflozin,an SGLT-2 inhibitor, for one year. Physical examination re-vealed a few, sharply-demarcated erythematous plaques onthe patient’s forearm for fifteen days. The patient previouslyhad psoriasis, and to rule out this diagnosis a skin punch bi-opsy was taken from one of the lesions. The histopathologi-cal evaluation was found to be compatible with drug eruption;however, skin patch test performed with dapagliflozin wasnon-reactive. After performing oral provocation test with da-pagliflozin, new erythematous plaques appeared around thesame sites on the forearm. On withdrawing dapagliflozin, thelesions resolved completely. This case gives an insight thatdapagliflozin may also cause drug eruptions, which should bekept in mind, especially in a patient with psoriasis.

Keywords: Dapagliflozin; fixed drug eruption;sodium-glucose co-transporter-2 inhibitors;type 2 diabetes mellitus

Tip 2 diabetes mellitus (Tip 2 DM), global bir sağlık prob-lemidir. Patofizyolojisi multifaktöriyeldir ve insidansı gün-den güne artmaktadır. Tedavide temel hedef, kardiyovas-küler ve renal fonksiyonların korunmasıdır. Sodyum glukozko-transporter-2 (SGTL2) inhibitörleri, Tip 2 DM tedavi-sinde yeni ortaya çıkan ilaçlardan biridir. SGLT-2 inhibitör-leri, insülinden bağımsız mekanizma ile üriner glukozatılımını artırarak glisemiyi düzeltmektedir. Bu çalışmada,glisemik kontrol amaçlı polikliniğimize başvuran 62 yaşın-daki Tip 2 DM’li erkek hasta sunulmuştur. Hasta beş yıldırmetformin, gliklazid; beraberinde bir yıldır da dapagliflo-zin tedavisi almakta idi. Fizik muayenesinde, ön kol üze-rinde keskin sınırlı eritematöz plaklar saptandı. Psöriyazistanısı olan hastada, psöriyazisi ekarte etmek için lezyon-lardan birinden deri biyopsisi alındı. Histopatolojik değer-lendirme ilaç erüpsiyonu ile uyumlu bulunmasına rağmen,dapagliflozin ile yapılan deri yama testi reaktif değildi. Da-pagliflozin ile oral provokasyon testi yapıldığında, ön koldaeski lezyonların yerlerinde eritemli yeni plakların ortayaçıktığı gözlendi. Dapagliflozin tedavisinin kesilmesi ile lez-yonlar tamamen düzeldi. Bu hasta, dapagliflozinin fiks ilaçerüpsiyonuna neden olabileceği ve önceden psöriyazis ta-nısı almış olsa bile bu hastalarda akılda tutulması gerek-tiği konusunda fikir vermektedir.

Anahtar kelimeler: Dapagliflozin; fiks ilaç erüpsiyonu;sodyum glukoz ko-transporter-2 (SGTL2);tip 2 diyabetes mellitus

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https://orcid.org/0000-0001-7710-4631https://orcid.org/0000-0003-2074-4384https://orcid.org/0000-0002-9199-9168https://orcid.org/0000-0003-4715-2557https://orcid.org/0000-0001-8433-4769https://orcid.org/0000-0001-8522-7789https://orcid.org/0000-0003-2334-137X

vascular protection with other beneficial ef-fects like weight loss, decrease in bloodpressure and triglycerides, and also diminishthe progression of kidney diseases (2).SGLT2 inhibitors are generally well-toler-ated; yet, the typical adverse effects includegenital mycotic infections and lower urinarytract infections (3). The available current lit-erature does not report any case of fixeddrug eruption caused by SGLT2 inhibitors.Only a few cutaneous adverse events suchas intense and severe pruritus (4), an in-creased rate of vaginal colonization by can-dida species, and vulvovaginal adverseevents in women with T2DM caused bycanagliflozin (5) have been reported.Drug eruptions can either result from im-munological or non-immunological mecha-nisms. In immunologically mediated drugeruptions, drugs or their metabolites mayact as haptens, thus causing either a spe-cific cell-mediated or humoral response.Fixed drug eruptions (FDE) are the cell-me-diated, delayed type of drug reactions. Itmay present as a single or a few, round,sharply demarcated erythematous and ede-matous plaques anywhere on the body. Afterre-administration of the causative drug, thelesions recur at exactly the same sites.Patch testing and oral provocation havebeen used to identify the suspected agentand check for cross-sensitivities to medica-tions. Management starts with the with-drawal of the suspected drug (6).

Case ReportThe authors hereby report a case of a 62-year-old male having coronary artery dis-ease, with a history of T2DM for 20 years,who was referred to our outpatient clinic forglycemic control. He was on metformin andgliclazide for five years, and dapagliflozinwas given for one year. His initial anthropo-metric measurements were weight: 81 kg,height: 163 cm, and body mass index(BMI): 30.4 kg/m². His blood test showed:fasting blood glucose:118 mg/dL, creati-nine: 1.0 mg/dL, serum alanine amino-transferase: 22 U/L, HbA1c: 7.1%. Aftertreatment with dapagliflozin for 12 months,the patient has lost 6 kg. Physical examina-tion revealed a few, sharply-demarcatederythematous plaques on his forearms,present for fifteen days (Figure 1). The pa-

tient’s past medical history revealed that hehad been affected with psoriasis, and to ruleout this diagnosis a skin punch biopsy wasperformed on one of the lesions. Histopatho-logical evaluation showed parakeratosis,loss in granular layer, subcorneal neu-trophilic infiltration, irregular acanthosis andspongiosis, perifollicular and perivasculareosinophilic and lymphocytic inflammation.Though the skin biopsy was compatible withdrug eruption (Figure 2); however, skinpatch test performed with dapagliflozin wasobserved to be non-reactive. After oralprovocation test with dapagliflozin, new ery-thematous plaques appeared near the samesites on the forearms (Figure 3). When da-pagliflozin was withdrawn, the lesions re-solved completely in seven days. No lesionwas observed after one month of withdrawalof the drug (Figure 4).

DiscussionSGLT2 inhibitors like dapagliflozin,canagliflozin, empagliflozin, and ipragliflozinform the novel therapeutic approach forT2DM. The most common adverse effects ofthese drugs include female genital mycoticinfections and benign urinary tract infections(7). These drugs can be classified as ‘nutri-ent load reducer’s’ group among the antihy-perglycemic agents, which have been shownto improve cardiovascular and renal out-comes, with low hypoglycemia risk (8). De-spite all these beneficial effects, skin lesionswhich may develop due to SGLT2 inhibitorsshould not be overlooked. To the bestknowledge of the authors, this study is thefirst report showing fixed drug eruption

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Turk J Endocrinol Metab Keskin et al.2019;23:64-67 Fixed Drug Eruption Caused by Dapagliflozin

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Figure 1: Erythematous plaques on his forearms.

caused by dapagliflozin. Drug eruptionmechanisms with dapagliflozin have notbeen investigated earlier. In a previousstudy on Japanese population, six SGLT-2

inhibitors have been evaluated for possibleskin reactions wherein serious generalizedrashes, eruptions, urticaria, erythema, andeczema and subcutaneous tissue disorderswith ipragliflozin alone were observed.Ipragliflozin is stored in the skin tissue, andinteracts with melanin; therefore skin reac-tions might be related to the disturbed skintissue homeostasis (9). Such reactions,however, were not observed with da-pagliflozin in the present study.Recent studies have also reported fixed drugeruptions with SGLT2 inhibitors (10), for ex-ample, drug eruptions with ipragliflozin (11)and Fournier’s gangrene with empagliflozin,though not with dapagliflozin (12). U.S.Food and Drug Administration (FDA) re-cently issued a safety warning about a rare,but serious, skin infection in patients treatedwith SGLT2 inhibitors, i.e., necrotizing fasci-itis (gangrene) of the perineum on andaround the genitals, also referred to asFournier’s gangrene (13). Adverse cuta-neous drug reactions are recognized asmajor health problems worldwide, causing aconsiderable financial burden for the health-care systems. SGLT2 inhibitors are in use inEurope since only a few years, and their ad-verse effects are yet to be clarified. The au-thors suggest that FDE must be added tothe list of side-effects of SGTL2 inhibitors asa rare cutaneous reaction. Though drugeruption caused by dapagliflozin is a rarecondition, this possibility should be kept inmind, especially while dealing with psoriasispatients.

Source of FinanceDuring this study, no financial or spiritualsupport was received neither from any phar-maceutical company that has a direct con-nection with the research subject, nor froma company that provides or produces med-ical instruments and materials which maynegatively affect the evaluation process ofthis study.

Conflict of InterestNo conflicts of interest between the authorsand / or family members of the scientific andmedical committee members or members ofthe potential conflicts of interest, counsel-ing, expertise, working conditions, shareholding and similar situations in any firm.

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Figure 2: Psoriasiform epidermal hyperplasia and der-mal perivascular inflammation with eosinophilic infiltra-tion (40X HE).

Figure 4: No lesion was observed after one month of da-pagliflozin withdrawal.

Figure 3: Recurrens after oral provocation test near thesame sites of former lesions

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Authorship ContributionsIdea/Concept: Müge Keskin; Design: MügeKeskin, Arzu Or Koca; Control/Supervision:Müge Keskin, Derun Taner Ertuğrul; DataCollection and/or Processing: Müge Keskin,Mustafa Altay; Analysis and/or Interpreta-tion: Müge Keskin, Arzu Or Koca; LiteratureReview: Müge Keskin, Murat Dağdeviren;Writing the Article: Müge Keskin, DerunTaner Ertuğrul; Critical Review: Müge Ke-skin, Murat Dağdeviren; References andFundings: Müge Keskin, Mustafa Altay.

References1. Kim Y, Babu AR. Clinical potential of sodium-glucose

cotransporter 2 inhibitors in the management oftype 2 diabetes. Diabetes Metab Syndr Obes.2012;5:313-327. [PubMed] [PMC]

2. Santos LL, Lima FJC, Sousa-Rodrigues CF, BarbosaFT. Use of SGLT-2 inhibitors in the treatment of type2 diabetes mellitus. Rev Assoc Med Bras (1992).2017;63:636-641. [Crossref] [PubMed]

3. Nauck MA. Update on developments with SGLT2 in-hibitors in the management of type 2 diabetes.Drug Des Devel Ther. 2014;8:1335-1380. [Cros-sref] [PubMed] [PMC]

4. Vasapollo P, Cione E, Luciani F, Gallelli L. General-ized İntense pruritus during canagliflozin treatment:İs it an adverse drug reaction? Curr Drug Saf.2018;13:38-40. [Crossref] [PubMed]

5. Nyirjesy P, Zhao Y, Ways K, Usiskin K. Evaluation ofvulvovaginal symptoms and Candida colonization inwomen with type 2 diabetes mellitus treated withcanagliflozin, a sodium glucose co-transporter 2 in-hibitor. Curr Med Res Opin. 2012;28:1173-1178.[Crossref] [PubMed]

6. Shear NH, Knowles SR. Cutaneous reactions todrugs. In: Goldsmith LA, Katz SI, Gilchrest BA,

paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Der-matology in General Medicine (8th ed). New York:Mc Graw-Hill; 2012;2121-2610.

7. Scheen AJ. Pharmacodynamics, efficacy and safetyof sodium-glucose co-transporter type 2 (SGLT2) in-hibitors for the treatment of type 2 diabetes melli-tus. Drugs. 2015;75:33-59. [Crossref] [PubMed]

8. Kalra S, Ghosh S, Aamir AH, Ahmed T, Amin MF,Bajaj S, Baruah MP, Bulugahapitiya U, Das AK, GiriM, Gunatilake S, Mahar SA, Pathan MF, Qureshi NK.Raza SA, Sahay R, Shakya S, Shreshta D, Soma-sundaram N, Sumanatilleke M, Unnikrishnan AG,Wijesinghe AM. Safe and pragmatic use of sodium-glucose co transporter 2 inhibitors in type 2 dia-betes mellitus: South Asian Federation of EndocrineSocieties consensus statement. Indian J EndocrinolMetab. 2017;21:210-230. [Crossref] [PubMed][PMC]

9. Sakaeda T, Kobuchi S, Yoshioka R, Haruna M, Taka-hata N, Ito Y, Sugano A, Fukuzawa K, Hayase T,Hayakawa T, Nakayama H, Takaoka Y, Tohkin M.Susceptibility to serious skin and subcutaneous tis-sue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2)inhibitors. Int J Med Sci. 2018;15:937-943. [Cros-sref] [PubMed] [PMC]

10.Damiani G, Loite U, Ramoni S, Marzano AV. Possiblenew inflammatory side-effect of SGLT2-inhibitors:fixed drug eruption. J Diabetes Complications.2016;30:1530-1531. [Crossref] [PubMed]

11.Saito-Sasaki N, Sawada Y, Nishio D, Nakamura M.First case of drug eruption due to ipragliflozin: casereport and review of the literature. Dermatol.2017;58:236-238. [Crossref]

12.Kumar S, Costello AJ, Colman PG. Fournier’s gan-grene in a man on empagliflozin for treatment ofType 2 diabetes. Diabet Med. 2017;34:1646-1648.[Crossref] [PubMed]

13.U.S. Food and Drug Administration. Drug safetycommunication: FDA warns about rare occurrencesof a serious infection of the genital area with SGLT2inhibitors for diabetes. 2018 Aug 29.

https://www.ncbi.nlm.nih.gov/pubmed/28887847https://doi.org/10.1111/dme.13508https://doi.org/10.1111/ajd.12502https://www.ncbi.nlm.nih.gov/pubmed/27591031https://doi.org/10.1016/j.jdiacomp.2016.08.002https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036094https://www.ncbi.nlm.nih.gov/pubmed/30008607https://doi.org/10.7150/ijms.22224https://doi.org/10.7150/ijms.22224https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240067https://www.ncbi.nlm.nih.gov/pubmed/28217523https://doi.org/10.4103/2230-8210.196029https://www.ncbi.nlm.nih.gov/pubmed/25488697https://doi.org/10.1007/s40265-014-0337-yhttps://www.ncbi.nlm.nih.gov/pubmed/22632452https://doi.org/10.1185/03007995.2012.697053https://www.ncbi.nlm.nih.gov/pubmed/27048192https://doi.org/10.2174/1574886311666160405110515https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166348https://www.ncbi.nlm.nih.gov/pubmed/25246775https://doi.org/10.2147/DDDT.S50773https://doi.org/10.2147/DDDT.S50773https://www.ncbi.nlm.nih.gov/pubmed/28977090https://doi.org/10.1590/1806-9282.63.07.636https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437808https://www.ncbi.nlm.nih.gov/pubmed/22977310