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Sulfasalazine-Induced Hypoglycemia in a Patient with Type 2 Diabetes and End-

Stage Renal Disease

Article in AACE Clinical Case Reports · November 2018

DOI: 10.4158/ACCR-2018-0067

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 Case Report

SULFASALAZINE-INDUCED HYPOGLYCEMIA IN A PATIENT

WITH TYPE 2 DIABETES AND END-STAGE RENAL DISEASE

George A. Stamatiades, MD1; Justin B. Echouffo-Tcheugui, MD, PhD1;

Jeffrey R. Garber, MD1,2

ABSTRACT
Abbreviations:
Objective: To demonstrate important points regard- CT = computed tomography; ESRD = end-stage renal
ing the possible hypoglycemic effects of sulfasalazine and disease
suggest possible underlying mechanism(s) accounting for
sulfasalazine-induced hypoglycemia.
Methods: We describe a case of reversible sulfasala- INTRODUCTION
zine-induced hypoglycemia, review the literature, and
discuss a potential mechanism accounting for sulfasala- Drugs constitute the most common cause of hypo-
zine-induced hypoglycemia. glycemia (1). Although insulin and insulin secretagogues,
Results: A 63-year-old man with Crohn disease treated such as sulfonylureas, are the most common drugs that can
with sulfasalazine and type 2 diabetes complicated by end- cause hypoglycemia, several other pharmacologic agents
stage renal disease was admitted for treatment of persis- that are used broadly in clinical practice can cause hypo-
tent hypoglycemia. Insulinoma was initially suspected, glycemia (2). The most commonly reported drugs that
but localization studies including endoscopic ultrasound are associated with hypoglycemia are quinolones, pent-
were negative. This raised the possibility of sulfasalazine- amidine, quinine, beta-blockers, angiotensin-converting
induced hypoglycemia. Three days after sulfasalazine was enzyme agents, and insulin-like growth factor (3). Factors
stopped, he became normoglycemic. Hypoglycemia has that predispose to drug-induced hypoglycemia are restrict-
not recurred since discontinuing sulfasalazine. ed food access, advanced age, liver disease, and impaired
Conclusion: Clinicians should be aware of the poten- renal function (4).
tial hypoglycemic effect of sulfasalazine. Doses should An association between hypoglycemia and sulfasala-
be reduced in patients with impaired renal function, zine has been previously identified, but the evidence in
and it should be discontinued if otherwise unexplained the literature is limited (5). Sulfasalazine, which is clini-
hypoglycemia develops. (AACE Clinical Case Rep. cally useful in treating inflammatory bowel diseases, is a
2018;4:e493-e496) compound that is cleaved in vivo to 5-aminosalicylic acid
and to the intestinal metabolite sulfapyridine, the latter
accounting for most of the adverse effects of sulfasalazine
(6). Sulfapyridine is 60% bioavailable after colonic absorp-
Submitted for publication February 6, 2018
tion and 62% dialyzable (7). It is a sulfonamide, similar in
Accepted for publication June 9, 2018
From the 1Division of Endocrinology, Diabetes and Hypertension, Brigham structure to glyburide, an insulin secretagogue antidiabetic
and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, drug, which has greater hypoglycemic activity compared
and 2Harvard Vanguard Medical Associates, Boston, Massachusetts.
to the other commonly prescribed members of the sulfo-
Address correspondence to Dr. George A. Stamatiades, Division of
Endocrinology, Diabetes and Hypertension, Brigham and Women’s nylureas group, and its duration of action depends on renal
Hospital, 221 Longwood Avenue, Boston, MA 02115. excretion (8).
E-mail: [email protected].
Herein, we present a case of reversible sulfasalazine-
DOI: 10.4158/ACCR-2018-0067
To purchase reprints of this article, please visit: www.aace.com/reprints. induced hypoglycemia in a man with Crohn disease treated
Copyright © 2018 AACE. with sulfasalazine and type 2 diabetes complicated by end-

Copyright © 2018 AACE AACE CLINICAL CASE REPORTS Vol 4 No. 6 November/December 2018 e493
e494 Sulfasalazine-Induced Hypoglycemia, AACE Clinical Case Rep. 2018;4(No. 6) Copyright © 2018 AACE

stage renal disease (ESRD), who was initially believed to cated he had insulin-mediated hypoglycemia. Therefore,
have an insulinoma. non–insulin-mediated causes were not in the differential,
limiting the differential diagnosis to causes of inappropri-
CASE REPORT ate insulin secretion besides insulinoma: factitious insu-
lin use nesidioblastosis and drug-induced hypoglycemia.
A 63-year-old man with prior medical history of The elevated C-peptide levels ruled out exogenous insu-
Crohn disease, hypothyroidism, coronary artery disease, lin administration. Moreover, the fact that he did not have
and 30-year history of type 2 diabetes mellitus (T2DM) any visitors and he was blind made factitious insulin use
complicated by 14 years of ESRD on hemodialysis, reti- or commonly prescribed oral hypoglycemic agents such
nopathy (legally blind), autonomic neuropathy with gastro- as sulfonylureas as a possible cause of the hypoglycemia
paresis, and significant peripheral neuropathy was admit- very unlikely. Nesidioblastosis could not be ruled out on
ted for treatment of recurrent hypoglycemia. the basis of negative imaging studies (10). However, in
T2DM was diagnosed on routine screening 30 the absence of prior gastric bypass surgery, drug-induced
years prior to admission. Hemoglobin A1c levels ranged hypoglycemia seemed more likely and was explored next.
between 5 and 7% (31 and 53 mmol/mol) until 3 months Hypercalcemia by increasing beta-cell responsiveness
prior to admission, when it dropped to 4.3% (23 mmol/ to sulfonylureas and hypothyroidism were excluded as
mol). He was initially treated with oral agents and then possible etiologies or predisposing him to hypoglycemia,
transitioned to insulin therapy, which he had been taking as calcium and thyroid-stimulating hormone levels were
for more than 20 years. Six months prior to admission, normal (8.9 mg/dL and 4.76 µIU/mL, respectively).
he was taking glargine 25 units and sliding-scale insulin Drug-induced hypoglycemia via insulin secretion
aspart. Comorbidities and complications included coronary was thought to be the most probable cause of the persis-
artery disease with ischemic cardiomyopathy, peripheral tent hypoglycemia. Among the medications he was taking
vascular disease, ESRD on hemodialysis (3 times a week), (Table 1), the only one that has been reported to cause
and diabetic retinopathy. He then frequently was hypogly- hypoglycemia, especially among people with diabetes on
cemic even after insulin was discontinued. His episodes insulin or sulfonylurea, was sulfasalazine (5). Moreover,
of hypoglycemia were symptomatic, limited to tremor, he was taking 3 g daily, whereas the daily dose for patients
nausea, and lightheadedness. The episodes of hypoglyce- on dialysis should not exceed 500 mg (11).
mia were not related to the timing of his meals. His self- It was therefore possible that the hypoglycemic effect
monitored blood glucose values ranged from 50 to 90 mg/ of sulfasalazine became manifest because it was taken
dL. Administration of glucose tabs or food when tolerated in excessive amounts for someone with ESRD, who was
led to the resolution of the symptoms. He had gallbladder malnourished, had inadequate caloric intake, and delayed
resection 3 months prior to admission for chronic abdomi- gastric emptying (documented on nuclear medicine testing).
nal pain and gallstone pancreatitis. During the 2 months
prior to admission due to abdominal discomfort, he ate less Outcome and Follow-Up
and lost approximately 30 pounds. Sulfasalazine was stopped, and he ceased to have
episodes of hypoglycemia in the hospital. His blood
Investigation sulfonamide levels 48 hours after stopping the medication
He was initially evaluated at an outside hospital for were above the upper limit of therapeutic range (9.2 μg/
recurrent hypoglycemia. His work-up showed insulin mL [reference, 5.0 μg/mL] and 13 μg/mL [reference, 5.0
level 8 μIU/mL with elevated pro-insulin level 8.3 pmol/L μg/mL]), lending support to the hypothesis. The serum
(normal, <8.0 pmol/L) and elevated C-peptide of 5.2 ng/ half-life of sulfasalazine is 6 or 14 hours, depending on
mL (normal, 0.8 to 3.5 ng/mL) with corresponding plasma the genetic phenotype (6). However, since sulfasalazine is
glucose level of 48 mg/dL. Anti-insulin antibodies were renally excreted, the half-life in ESRD may be increased
negative, and a computed tomography (CT) scan of the to 50 hours (12). After 72 hours, he became normogly-
pancreas was normal. He was referred to Brigham and cemic and was discharged off sulfasalazine and insulin
Women’s Hospital Surgical Oncology Department for eval- (Fig. 1). Posthospitalization, the hypothesis of toxicity
uation for possible surgery for insulinoma. While hospi- of sulfasalazine was verified. He underwent continuous
talized, he frequently had blood sugars below 55 mg/dL, glucose monitoring, which did not detect any hypoglyce-
which occurred with inappropriately normal insulin levels. mia. Hypoglycemia has not recurred since discontinuing
A CT of the abdomen and pelvis for evaluating pancre- sulfasalazine.
atic lesions and an endoscopic ultrasound showed diffuse
mild pancreatic parenchymal atrophy but did not show a DISCUSSION
mass, making the diagnosis of insulinoma very unlikely,
since the overall sensitivity for combined CT and endo- Our case report demonstrates important points regard-
scopic sonography is reported to be quite high and, in some ing the possible hypoglycemic effects of sulfasalazine.
series, is 100% (9). The inappropriate insulin levels indi- Hypoglycemia induced by sulfasalazine is thought to be
Copyright © 2018 AACE Sulfasalazine-Induced Hypoglycemia, AACE Clinical Case Rep. 2018;4(No. 6) e495

Table 1
Medications Prior to Admission
Acetaminophen 650 mg TID
Aspirin 81 mg daily
Carvedilol 3.125 mg BID
Cinacalcet 60 mg daily
Cyclosporine 0.5 mg BID
Dexlansoprazole 60 mg daily
Fenofibrate 145 mg daily
Levothyroxin 75 μg daily
Losartan potassium 25 mg daily
Metoclopramide HCL 4 mg QID
Oxycodone 30 mg as needed
Ropinirole 3 mg nightly Fig. 1. Changes in blood glucose levels from admission (Day 1) to
discharge (Day 11). *Sulfasalazine withdrawal (Day 2). Arrowheads
Sulfasalazine 1,500 mg BID boluses of intravenous glucose (g) that were delivered to the patient. +The
therapeutic blood sulfonamide levels are up to 5 µg/mL.
Zolpidem 10 mg nightly
Abbreviations: BID = twice a day; QID = four times a day;
TID = three times a day.
A
mainly via hyperinsulinemia, as suggested by the high
levels of C-peptide, pro-insulin, and insulin. Although
C-peptide and insulin levels can increase in renal disease
due to compensatory hypersecretion of beta-cells, due to
insulin resistance (13) and delayed clearance, this does not
result in fasting or prolonged repetitive bouts of insulin-
mediated hypoglycemia. Doses that exceed the amounts B
indicated in renal failure, the prolonged half-life of the
medication due to impaired renal function, and malnutri-
tion can exacerbate its hypoglycemic effect (4). It should
be considered in the differential diagnosis of hypoglyce-
mia and may have to be discontinued in order to reverse
it, especially in patients with renal failure who are not on
other blood sugar–lowering agents. Fig. 2. Same sulfanilamide structural group in sulfapyridine and glyburide.
It is hypothesized that the hypoglycemic effect of (A) Sulfapyridine; (B) Glyburide.
sulfasalazine is due to the sulfapyridine component, a
sulfonamide antibiotic. Biochemically, sulfapyridine is glucose production and increase insulin sensitivity via
structurally similar to glyburide, a member of the sulfo- inhibition of the kinase inhibitor of nuclear factor kappa-
nylurea class of oral hypoglycemic agents (Fig. 2). Both B kinase beta subunit, which plays a key role in tissue
are derivatives of the parent compound sulfanilamide (12). inflammation (16-18).
Hence, sulfonamides may cause hypoglycemia with the It is noteworthy that most of the reported cases, includ-
same mechanism of action as sulfonylureas, by binding to ing that reported here, were in patients with impaired renal
pancreatic beta-cells and stimulate insulin release (14,15). function, indicating the contributing role of prolonged
Although there are only 4 reported cases with sulfasalazine- half-life in the hypoglycemic adverse effect of sulfon-
induced hypoglycemia (5), there are 28 published cases of amides (12,19). Chronic renal failure also has clinically
hypoglycemia associated with the use of cotrimoxazole significant effects on drug metabolism and transport (20),
(sulfamethoxazole/ trimethoprim), an antimicrobial drug, suggesting additional reasons for the prolonged elevated
the sulfamethoxazole component of which is a derivative levels of sulfasalazine after discontinuation.
of sulfanilamide, as well (12,14). Another possible mecha-
nism that can contribute further to the glucose-lowering CONCLUSION
effects of sulfasalazine is through the anti-inflammatory
effect of the salicylate component of the drug. Studies In summary, clinicians should be aware of the poten-
have shown that salicylates can both inhibit hepatic tial hypoglycemic effects of treatment with sulfasalazine
 e496 Sulfasalazine-Induced Hypoglycemia, AACE Clinical Case Rep. 2018;4(No. 6) Copyright © 2018 AACE

and should discontinue it if otherwise unexplained hypo- 5. Haas RM, Li P, Chu JW. Glucose-lowering effects of sulfasala-
zine in type 2 diabetes. Diabetes Care. 2005;28:2238-2239.
glycemia develops. Sulfasalazine use in patients with 6. Klotz U. Clinical pharmacokinetics of sulphasalazine, its
impaired renal function must be undertaken with caution, metabolites and other prodrugs of 5-aminosalicylic acid. Clin
ensuring that appropriate dose adjustments are made. Pharmacokinet. 1985;10:285-302.
7. Akiyama Y, Sakurai Y, Kato Y, Furuta E, Mimura T.
Finally, further study is required to elucidate the cause of Retrospective study of salazosulfapyridine in eight patients
sulfasalazine-induced hypoglycemia. with rheumatoid arthritis on hemodialysis. Mod Rheumatol.
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ACKNOWLEDGMENT diabetes mellitus. Drug Saf. 2000;22:313-320.
9. Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sonography,
Author contributions: George A. Stamatiades and and a combined protocol for preoperative evaluation of pancreatic
insulinomas. AJR Am J Roentgenol. 2003;181:987-992.
Justin B. Echouffo-Tcheugui researched the data. George 10. Anlauf M, Wieben D, Perren A, et al. Persistent hyperinsulin-
A. Stamatiades wrote the manuscript. Jeffrey R. Garber emic hypoglycemia in 15 adults with diffuse nesidioblastosis:
contributed to the discussion and reviewed and edited the diagnostic criteria, incidence, and characterization of beta-cell
changes. Am J Surg Pathol. 2005;29:524-533.
manuscript. George A. Stamatiades, Justin B. Echouffo- 11. Weiner SM, Bergner R. Dosage and toxicity of antirheu-
Tcheugui, and Jeffrey R. Garber are the guarantors of this matic drugs in renal insufficiency [in German]. Z Rheumatol.
work and, as such, had full access to all of the data in the 2015;74:300-309.
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BMJ Case Rep. 2017;2017.
DISCLOSURE 15. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase
CM. A systematic review and meta-analysis of hypoglycemia and
The authors have no multiplicity of interest to disclose. cardiovascular events: a comparison of glyburide with other secre-
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16. Rena G, Sakamoto K. Salicylic acid: old and new implications for
the treatment of type 2 diabetes? Diabetol Int. 2014;5:212-218.
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