-
Case ReportTurk J Endocrinol Metab 2019;23:64-67
64
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: [email protected]:
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-
DO
I:10
.251
79/t
jem
.201
8-63
449
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
64
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
65
Turk J Endocrinol Metab Keskin et al.2019;23:64-67 Fixed Drug
Eruption Caused by Dapagliflozin
65
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.
66
Keskin et al. Turk J Endocrinol MetabFixed Drug Eruption Caused
by Dapagliflozin 2019;23:64-67
66
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
-
67
Turk J Endocrinol Metab Keskin et al.2019;23:64-67 Fixed Drug
Eruption Caused by Dapagliflozin
67
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