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Journal of Diabetes 7 (2015) 155–157
C A S E R E P O RT
Hypersensitivity reaction to a biosimilar insulin glargine
Héctor GARCÍA-NARES,1 María Isabel LEYVA-CARMONA,2 Neftalí PÉREZ-XOCHIPA1 and
Erwin CHIQUETE3
Departments of 1Endocrinology, and 2Immunology, Regional Hospital 1st of October, ISSSTE, and 3Department of Neurology, The “Salvador
Zubirán” National Institute of Medical Sciences and Nutrition, México, DF, México
Introduction
It is considered that allergy to human recombinant
insulin is an uncommon condition, occurring in no more
than 1% of insulin users.1 To the best of our knowledge,
allergy to insulin analogs is also rare, with no more than
a few case reports in the scientific literature.2–4 In fact,
some desensitization strategies have been proposed by
using insulin analogs like glargine in cases of allergy to
recombinant regular insulin.4–6
Biopharmaceuticals are drugs containing biotechnol-
ogy substances (proteins or polysaccharides) as their
active ingredients, most of them developed with recom-
binant DNA techniques, and therefore, are produced in
living systems.7 Patents of several biopharmaceuticals
have recently expired, or are due to expire.8 This has
provided opportunities for pharmaceutical companies to
produce biosimilars or “follow-on biologics”. These
products are intended to come at lower costs with a
comparable clinical effect. However, sometimes these
drugs differ from conventional generic drugs in several
ways, including the size of the active substance, its com-
plexity, and the very nature of the manufacturing
process.7–9
Major differences in the manufacturing process that
relate with suboptimal clinical outcomes mean that bio-
similars should not be approved and regulated in the
same way as conventional generic drugs, since a high
probability of substandard copies reaching the market
arise when biocomparability is established with tradi-
tional PK assays.7 Therefore, regulatory authorities
around the world are attempting to establish different
approval pathways for biosimilars.10 In some countries it
Correspondence
Erwin Chiquete, Instituto Nacional de Ciencias Médicas y Nutrición
“Salvador Zubirán”, Vasco de Quiroga 15, Distrito Federal, Ciudad
de México, Código Postal 14000, México DF, México.
Tel: +52 5487 0900 ext. 5052
Fax: +52 5655 1076
Email: erwinchiquete@hotmail.com
Received: 30 September 2014; accepted 16 October 2014.
doi: 10.1111/1753-0407.12241
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
has been a common feature that biosimilars are not asso-
ciated with the same pharmacovigilance strategies and
risks management plans that follow biologic innova-
tors.10 Hence, a substandard biosimilar has the potential
of causing adverse reactions and unpredictable clinical
effects that are usually underreported.
Here we report the first case of hypersensitivity reac-
tion to a biosimilar insulin glargine documented by labo-
ratory assays. These abnormal hypersensitivity tests were
present with a different vial of the very same batch asso-
ciated with the clinical reaction, but it was not docu-
mented with the innovative biopharmaceutical product
or with a different batch of the biosimilar compound
(suggesting a non constant quality of the manufacturing
process).
Case report
A 51-year-old woman with type 2 diabetes mellitus was
admitted in April 2013 to her third-level hospital with
shortness of breath, wheezing, chest tightness, headache
and palpitations. Three days before, due to the institu-
tional availability, her health care provider switched her
from the innovative insulin glargine to a biosimilar alter-
native brand. She had a history of hypothyroidism, acute
necrotic hemorrhagic pancreatitis and non-proliferative
retinopathy. She had been on insulin glargine since 2006,
without hypersensitivity reactions. The patient still used
the innovative brand glargine for more than 2 days, but
when she used the very first dose of the biosimilar
glargine chest tightness and wheezing appeared. Given
the recent change from the innovative glargine brand to
the biosimilar product, in view of the acute respiratory
symptoms associated with glargine use, the patient intui-
tively stopped insulin administration without replace-
ment with another insulin formulation. Due to the lack
of glucose-lowering medication, the admission labora-
tory assays revealed serum glucose of 30.33 mmol/L
(546 mg/dL normal range: 70–100 mg/dL), sodium of
129 mmol/L (normal range: 135–146 mmol/L), chloride
129 mmol/L (normal range: 95–105 mmol/L), and potas-
sium 4.0 mmol/L (normal range: 3.5–5.0 mmol/L). She
155
Hypersensitivity to a biosimilar insulin glargine H. GARCÍA-NARES et al.

Table 1 Results of the human basophil degranulation tests practiced with two batches of the biosimilar glargine insulin, with the innovative
molecule and with human recombinant short-acting insulin as reference†

Results of
the basophil
Insulin compound Batch Dilution degranulation tests

Biosimilar glargine (Bonglixan) LPTP-12D067 1:10 54.0%

Biosimilar glargine (Bonglixan) LPTP-12K199 1:10 23.1%
Innovative glargine (Lantus) LF034A 1:10 3.8%
HR insulin (Novolin-N) NS 1:10 21.4%
Biosimilar glargine (Bonglixan) LPTP-12D067 1:100 32.8%
Biosimilar glargine (Bonglixan) LPTP-12K199 1:100 21.1%
Innovative glargine (Lantus) LF034A 1:100 15.4%
HR insulin (Novolin-N) NS 1:100 5.4%
Biosimilar glargine (Bonglixan) LPTP-12D067 1:1000 35.7%
Biosimilar glargine (Bonglixan) LPTP-12K199 1:1000 19.2%
Innovative glargine (Lantus) LF034A 1:1000 11.5%
HR insulin (Novolin-N) NS 1:1000 16.1%

†
The normal reference value of these degranulation tests is expected to be <30%. The abnormal tests results are shown in bold italics. A
different vial of the same batch associated with the adverse clinical event was tested. Brand names are shown as marketed in Mexico.
HR, human recombinant; NS, not specified.

received intravenous liquids resuscitation and short-
acting insulin. On admission no local reactions were
noticed in the sites of biosimilar glargine injection;
however, due to the persistent respiratory findings sug-
gesting bronchial spasm, basophil degranulation tests
were practiced by the Department of Immunology to
investigate the possibility of hypersensitivity reaction to
the biosimilar glargine (Table 1). These tests revealed
that abnormal basophil degranulation was evoked by a
specific batch of the biosimilar glargine alternative (the
same that caused the abnormal reaction), and not repro-
duced by the innovative molecule or NPH insulin (to
discard primary human insulin allergy). The results of
these tests prompted the re-initiation of the innovative
glargine brand in May 2013, without observing hyper-
sensitivity events, and with the associated improvement
of serum glucose levels. Until now, the patient has used
the innovative glargine for almost 8 years without any
local or systemic allergic reaction. Therefore, the patient
has not been diagnosed with insulin or glargine allergy.
(contaminant antigens) of the biosimilar batch could
evoke the hypersensitivity reaction.
This report has limitations that should be addressed
for its correct interpretation. A case of allergy could
not be firmly established due to the lack of re-challenge
tests. Also no anti-insulin antibodies were determined.
Nonetheless, this case report helps to stress that the
complex manufacturing processes of biologic drugs
should ideally be monitored by the governmental regu-
latory agencies, and that immunology tests should be
performed when a hypersensitivity reaction is sus-
pected, without generalization of the adverse reaction
to the innovative compounds.
Acknowledgements
There was no funding received for this particular report.
Nonetheless, this report received editorial support from
Sanofi Mexico. The company did not participate in data
collection, analysis of data, funding or decision to submit
for publication.

Discussion
To or knowledge, this is the first case report of allergy to
a biosimilar insulin, which was not shared with the inno-
vative molecule or a different batch of the biosimilar
glargine, which strongly suggests batch-to-batch vari-
ability with clinical implications. The abnormal basophil
degranulation response to a specific batch of the biosimi-
lar compound suggests that accompanying byproducts
Disclosures
Dr Héctor García-Nares, Dr Isabel Leyva-Carmona and
Dr Neftalí Pérez-Xochipa report no competing disclo-
sures. Dr Erwin Chiquete has received research grants
from Sanofi and has served as research adviser for
Sanofi, Novartis, and Genzyme, and has received
speaker honoraria from Novartis, Genzyme, and Ferrer
Grupo.

156 © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
H. GARCÍA-NARES et al.
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