Unintentional sulfonylurea toxicity due to a drug–drug interaction: a case report
Gunaratne et al. BMC Res Notes
Unintentional sulfonylurea toxicity due to a drug-drug interaction: a case report
Keith Gunaratne 3
Emily Austin 1 2 3
Peter E. Wu 0 1 3
0 Division of General Internal Medicine, University Health Network , 200 Elizabeth St. 14EN206, Toronto, ON M5G 2C4 , Canada
1 Division of Clinical Pharmacology & Toxicology, University of Toronto , Toronto, ON , Canada
2 Division of Emergency Medicine, University of Toronto , Toronto, ON , Canada
3 Department of Medicine, University of Toronto , Toronto, ON , Canada
Background: Sulfonylureas are widely used for type 2 diabetes mellitus, but these medications carry a risk of hypoglycemia. Drug-drug interactions that inhibit sulfonylurea metabolism and thus increase systemic exposure can cause unintentional sulfonylurea toxicity. Case presentation: A 56-year-old man presented with severe, recurrent hypoglycemia. He had a history of type 2 diabetes mellitus and was taking the sulfonylurea gliclazide with no prior episodes of hypoglycemia. The onset of his hypoglycemia occurred within days after starting voriconazole and subsequently fluconazole for a fungal pneumonia. Unintentional sulfonylurea toxicity developed due to an adverse drug-drug interaction between gliclazide and these antifungals. Azole antifungals inhibit the metabolism of sulfonylureas resulting in increased systemic exposure and consequent toxicity. After the diagnosis of sulfonylurea toxicity was recognized, the patient was treated initially with dextrose and then administered octreotide to prevent recurrent hypoglycemia. He was successfully managed, his hypoglycemic episodes resolved, and his medications were adjusted to avoid any further adverse interactions. Conclusions: Adverse drug-drug interactions continue to pose challenges to clinicians. Both individual vigilance and system wide strategies are needed to prevent and mitigate consequences. This case highlights an important drug-drug interaction and reviews the presentation, management and antidotal therapy of sulfonylurea toxicity.
Education; Toxicology; Pharmacology; Drug-interaction
Sulfonylureas are commonly used for type 2 diabetes
mellitus. These compounds stimulate
glucose-independent endogenous insulin release [
] and carry an
inherent risk of hypoglycemia, particularly in the setting of
intentional overdose or due to adverse drug interactions.
Sulfonylureas are extensively metabolized by the hepatic
cytochrome P450 (CYP) 2C9 isoform and medications
that inhibit this enzyme can result in impaired
sulfonylurea metabolism, increased exposure and consequent
We present a case of severe, recurrent hypoglycemia in
a patient taking the sulfonylurea gliclazide who was
prescribed voriconazole followed by fluconazole, two
inhibitors of the hepatic CYP2C9 enzyme. Once recognized,
this unintentional overdose was successfully managed
initially with dextrose, and then octreotide.
A 56-year-old man presented to the emergency
department with new onset hypoglycemia. He had a history of
type 2 diabetes treated with metformin (2500 mg orally
daily in divided doses), gliclazide modified release (90 mg
orally daily), and a multiple daily injection insulin
regimen (insulin glargine 18 units subcutaneously at night
and insulin lispro 6 units subcutaneously with meals).
He was adherent with all medications and had never
developed hypoglycemia. Past medical history was
notable for a bone marrow transplantation for myelofibrosis
8 months prior and long-term treatment with prednisone
(5 mg orally daily), resulting in an immunocompromised
One week before presentation, he was evaluated in
clinic for persistent cough. Findings on a Computed
Tomography scan of the thorax were suspicious for
fungal pneumonia, and he was empirically treated with
voriconazole (200 mg orally twice daily). He was
reassessed in clinic 6 days later reporting lethargy, visual
disturbances, and hallucinations. Voriconazole
intolerance was suspected, as visual disturbances and
hallucinations are well described side effects [
], and his antifungal
was switched to fluconazole (480 mg orally daily).
Incidentally, after starting antifungal therapy, he had not
required any short-acting insulin due to glucose
readings of 54–72 mg/dL (3.0–4.0 mmol/L) (reference range
72–126 mg/dL; 4.0–7.0 mmol/L).
The day after initiating fluconazole, he presented to a
follow-up appointment at 1800 h weak and tremulous.
His capillary glucose was 31 mg/dL (1.7 mmol/L). He was
given orange juice, felt better, and sent to the emergency
department, where a repeat measurement at 2000 h was
34 mg/dL (1.9 mmol/L). He consumed more juice and
a sandwich, his symptoms improved and subsequent
hourly glucose measurements ranged between 68 and
106 mg/dL (3.8–5.9 mmol/L). At 0100 h his glucose was
106 mg/dL (5.9 mmol/L) and he fell asleep.
At 0430 h, he was woken for reassessment. He was
confused, lethargic and glucose was 25 mg/dL (1.4 mmol/L).
The recurrent nature of his hypoglycemia in the setting of
recent azole antifungal co-prescription was concerning
for gliclazide toxicity due to an adverse drug interaction.
He was treated with a 50 cc bolus of 50% dextrose
followed by a 100 cc per hour infusion of 10% dextrose.
In consultation with the regional poison centre, he was
given octreotide 75 μg subcutaneously for suspected
sulfonylurea toxicity and the intravenous dextrose was
discontinued as his blood sugar normalized. One further
dose of octreotide was administered 6-h later and his
hypoglycemic episodes abated with no recurrence during
hospitalization. His gliclazide was held and his medical
records were updated to document this interaction.
Discussion and conclusions
Sulfonylureas stimulate insulin release independent of
plasma glucose concentration, thereby creating a risk
for hypoglycemia. Hypoglycemia can occur due to
accidental ingestion, intentional overdose [
], or as a result
of adverse drug–drug interactions [
are metabolized by CYP2C9 and the most common
drug–drug interaction causing toxicity is inhibition of
this enzyme [
]. The azole antifungals voriconazole and
fluconazole are examples of CYP2C9 inhibitors and there
are many commonly prescribed drugs that can inhibit or
induce this enzyme (Table 1) [
1, 2, 5, 6
retrospective study of 3884 patients on sulfonylureas revealed that
20% were co-prescribed a CYP2C9 inhibitor and were
more likely (12.8% vs. 8.9%) to have a fasting glucose
below 72 mg/dL (4 mmol/L) . Another retrospective
population-based study of 909 elderly patients on
sulfonylureas admitted to hospital with hypoglycemia were
more than six times as likely to have been prescribed
cotrimoxazole (a CYP2C9 inhibitor) in the previous week
than matched controls [
The management goals of sulfonylurea toxicity are to
restore and maintain euglycemia. The initial
hypoglycemic episode will require an intravenous (IV) dextrose
bolus, followed by complex carbohydrates; however,
ongoing IV dextrose use can complicate recovery and
should be avoided. Glucose independently stimulates
insulin release, thus ongoing administration of dextrose
in the setting of sulfonylurea toxicity will perpetuate a
dangerous cycle of recurrent hypoglycemia [
Octreotide is a long-acting somatostatin analog that prevents
the secretion of insulin downstream of sulfonylurea
action. It is recommended as part of sulfonylurea toxicity
management to prevent recurrent hypoglycemia [
prospective randomized study of 40 emergency
department patients with sulfonylurea-induced hypoglycemia
demonstrated higher glucose levels and fewer episodes
of recurrent hypoglycemia over an 8-h period after
treatment with octreotide 75 μg subcutaneously compared to
There is limited published data to guide dosing
protocols for octreotide. A recommended strategy is
octreotide 50–100 μg subcutaneously every 6–12 h as needed
]. Patients require observation for a minimum of 12-h
after the last octreotide dose to ensure no recurrence of
]. Octreotide is well tolerated and only
minor adverse events have been associated with its use
This case also highlights the importance of
vigilance for drug–drug interactions, and the need for
better systems to aid in identifying clinically significant
interactions. Drug–drug interactions are innumerable
and it is unreasonable to expect clinicians to recall every
potential interaction. However, whenever new
medications are started it is sensible for clinicians to search for
interactions between the new drug and any high-risk
medications with narrow therapeutic indices (e.g. oral
antihyperglycemics, anticoagulants, opioids).
Collaboration with pharmacists and iterative medication review
would assist in identifying adverse drug interactions.
Sulfonylureas carry an inherent risk of
hypoglycemia due to a mechanism of glucose-independent insulin
release. Unintentional toxicity can occur if sulfonylurea
metabolism is impaired by a co-prescribed medication
that inhibits CYP2C9. In this case, the addition of azole
antifungals was the culprit. Sulfonylurea toxicity is
readily treated if recognized quickly. Management includes
judicious use of intravenous dextrose, ingestion of
complex carbohydrates and administration of octreotide to
prevent recurrent hypoglycemia. Drug–drug interactions
remain a common and preventable source of harm
associated with medical care, both individual vigilance and
system wide changes are necessary to prevent and
mitigate these adverse drug events.
CYP: cytochrome P450.
All authors (KG, EA, PEW) were involved with the design and conception of
the case report, drafting and revising of the manuscript, and reviewing the
literature. All authors read and approved the final manuscript.
We thank Dr. Margaret Thompson, Medical Director of the Ontario Poison
Centre, and Dr. Irfan Dhalla, Associate Professor of Medicine and General Internal
Medicine specialist at the University of Toronto for comments made on an
earlier version of this manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
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Written patient consent has been obtained.
Ethics approval and consent to participate
No funding was received for this case report.
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1. Harrigan RA , Nathan MS , Beattie P . Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment . Ann Emerg Med . 2001 ; 38 : 68 - 78 .
2. Holstein A , Beil W , Kovacs P. CYP2C metabolism of oral antidiabetic drugsimpact on pharmacokinetics, drug interactions and pharmacogenetic aspects . Expert Opin Drug Metab Toxicol . 2012 ; 8 : 1549 - 63 .
3. Levine MT , Chandrasekar PH . Adverse effects of voriconazole: over a decade of use . Clin Transplant . 2016 ; 30 : 1377 - 86 .
4. Glatstein M , Scolnik D , Bentur Y . Octreotide for the treatment of sulfonylurea poisoning . Clin Toxicol . 2012 ; 50 : 795 - 804 .
5. Tirkkonen T , Heikkilä P , Huupponen R , Laine K. Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide . J Intern Med . 2010 ; 268 : 359 - 66 .
6. May M , Schindler C . Clinically and pharmacologically relevant interactions of antidiabetic drugs . Ther Adv Endocrinol Metab . 2016 ; 7 : 69 - 83 .
7. Juurlink DN , Mamdani M , Kopp A , Laupacis A , Redelmeier DA . Drug-drug interactions among elderly patients hospitalized for drug toxicity . JAMA . 2003 ; 289 : 1652 .
8. Klein-Schwartz W , Stassinos GL , Isbister GK . Treatment of sulfonylurea and insulin overdose . Br J Clin Pharmacol . 2016 ; 81 : 496 - 504 .
9. McLaughlin SA , Crandall CS , McKinney PE , Litovitz T , Klein-Schwartz W , Dyer K , et al. Octreotide: an antidote for sulfonylurea-induced hypoglycemia . Ann Emerg Med . 2000 ; 36 : 133 - 8 .
10. Francis M , Langhan T , Prosser J , Hoffman R , Fasano CJ , O'Malley G , et al. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia . Ann Emerg Med . 2008 ; 51 : 795 - 6 .