Abstract
Voriconazole-induced hypoglycemia in non-diabetic patients has rarely been reported. We describe a non-diabetic man, aged 50 years, without hepatic or renal dysfunction who developed severe prolonged hypoglycemia about 28 hours after initiating therapeutic dose of intravenous (IV) voriconazole therapy for invasive pulmonary aspergillosis. He required continuous IV infusion of dextrose solutions to maintain euglycemia. He recovered from hypoglycemia after discontinuation of voriconazole. Higher than normal plasma insulin (30.4 μU/mL) as well as C-peptide (10.04 ng/mL) levels were observed, which reached normal levels after he recovered from hypoglycemia. The temporal association between voriconazole administration and hypoglycemia occurrence led to probability that it was voriconazole-induced. The voriconazole trough level (8.9 μg/mL) checked during the hypoglycemia episode was elevated. The mechanism of hypoglycemia may be strongly attributed to insulinemia resulting from high voriconazole concentration. There is a possibility of genetic polymorphisms in the hepatic cytochrome P450 2C19 isoenzyme in this patient, which altered the voriconazole metabolism, causing high trough levels associated with hypoglycemia. This case suggests that voriconazole has a propensity to alter glucose homeostasis in the absence of liver and kidney dysfunction, and it may induce hypoglycemia without drug over dosage or drug interaction that clinicians should be vigilant about.
Unexpected adverse drug reactions continue to pose challenges to clinicians. Voriconazole is a broad-spectrum, triazole, antifungal agent highly effective in the treatment of invasive aspergillosis and is widely used in high-risk populations.1,2 Although voriconazole often causes several adverse reactions including visual hallucinations, cognitive dysfunction, hepatotoxicity, and rash, hypoglycemia has rarely been reported in the literature.3,4 Some case reports and experimental studies have documented unexpected life-threatening hypoglycemia in diabetic patients resulting from the drug-drug interaction between oral hypoglycemic agents (particularly sulfonylureas) and co-administered voriconazole, even at normal therapeutic doses.5-7 Rarely, voriconazole can cause hypoglycemia, even without an identified drug interaction or over dosage, especially in patients with hepatic or kidney dysfunction.8,9 Further literature search reveals that voriconazole-induced hypoglycemia has not been previously reported in non-diabetic patients with normal liver and renal function.
We describe the first case of severe hypoglycemia developed after initiation of a therapeutic dose of intravenous (IV) voriconazole in a non-diabetic patient with normal liver and kidney function, without any identified drug interactions. The temporal association between voriconazole administration and the onset of hypoglycemia suggests that voriconazole strongly contributed to this event. Hypoglycemia is probably attributable to high voriconazole concentration.
Case Presentation
A non-diabetic man, aged 50 years, with a history of relapsed diffuse large B-cell lymphoma who had been treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy followed by two cycles of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was admitted in a conscious state with complaints of fever, cough, chest pain, and dyspnea for the past 15 days. Complete blood count revealed pancytopenia with severe neutropenia. Contrast-enhanced computed tomography of the chest showed consolidation with ground glass opacity in the left upper lobe and nodules with surrounding ground glass opacity bilaterally in the lungs, a few of the nodules showed internal cavitation likely to be fungal pneumonia. Microscopic sputum examination showed septate fungal hyphae. Serum galactomannan was positive (index 2.40, normal range: <0.5). Blood and sputum cultures were negative for bacterial and atypical pathogens, but sputum culture showed growth of Aspergillus fumigatus. A diagnosis of febrile neutropenia with invasive pulmonary aspergillosis was made necessitating starting IV voriconazole as per protocol (two loading doses of 6 mg/kg, then 4 mg/kg every 12 hours). On day 1 of voriconazole treatment, his plasma glucose level, electrolyte levels, and liver and renal function tests were normal. After the third dose, 28 hours after commencing voriconazole therapy, the patient developed an episode of slurring of speech, drowsiness, profound sweating, dizziness, and confusion. He was noted to have hypoglycemia with plasma glucose level of 39 mg/dL. Electrolyte levels were found to be normal. He received multiple boluses of 25% dextrose, but plasma glucose level was continuously low. Hence, he was treated with 10% dextrose by continuous infusion to maintain euglycemia. All concomitant medication were checked strictly in search of dispensing errors of any hypoglycemic agents. There was no history of accidental insulin injection. He was receiving IV meropenem, amikacin, ranitidine, and paracetamol. No drug-drug interactions were observed to cause hypoglycemia. Plasma insulin level was 30.4 μU/mL (normal range, 2.6-24.4 μU/mL) and plasma C-peptide level was 10.04 ng/mL (normal range, 0.81-3.85 ng/mL). Thyroid hormone, cortisol, human growth hormone, and acetone levels were within normal limits. Magnetic resonance imaging (MRI) of the pancreas did not reveal any lesions or pathology (Figure 1). Endocrinology consultation was obtained, and hypoglycemia was attributed to voriconazole therapy. Voriconazole was switched to amphotericin B on the fifth day. Plasma was obtained for determination of voriconazole concentration. The plasma trough level of voriconazole on day 5 of therapy was elevated at 8.9 μg/mL (target therapeutic range, 1.0-5.5 μg/mL). Two days after the discontinuation of voriconazole, hypoglycemia recovered, and he was weaned of 10% dextrose infusion successfully with no additional episodes of hypoglycemia. Repeat plasma insulin and C-peptide levels measured later were found to be within normal range (14.6 μU/mL and 1.8 ng/mL, respectively). We were unable to perform cytochrome P450 (CYP) 2C19 genotype study, as patient refused testing.
Magnetic imaging resonance imaging (MRI) of the pancreas revealing no any lesions or pathology
Discussion
In this case, we have reported hypoglycemia in a non-diabetic patient with normal liver and kidney function tests who had received IV voriconazole therapy at a normal therapeutic dose. The patient’s baseline plasma glucose level before starting voriconazole treatment was within normal limits, and other medications that can cause hypoglycemia were not introduced. The time from initiating voriconazole therapy to the development of hypoglycemia was relatively short (28 hours). Hypoglycemia was corrected after stopping voriconazole treatment. These findings suggest a strong association between voriconazole and hypoglycemia. According to the Naranjo adverse drug reaction probability scale, it is probable (total score of 7) that hypoglycemia was related to voriconazole therapy in this case.10 According to World Health Organization-Uppsala Monitoring Centre (WHO-UMC) casualty assessment criteria, a probable/likely adverse drug reaction is a clinical event or laboratory test abnormality, with a reasonable time sequence to drug administration, unlikely to be attributed to disease or other drugs and which follows a clinically reasonable response to withdrawal.10 A close relationship between voriconazole administration and development of hypoglycemia with an abnormality in laboratory tests and a reversal of hypoglycemia on withdrawal of the drug was present in our case. Whipple’s triad9 (symptoms consistent with hypoglycemia, a low plasma glucose concentration and resolution of hypoglycemic symptoms by glucose administration) was also present in our case. Moreover, higher than normal plasma insulin and C-peptide levels were detected. This is suggestive of either an increased secretion or decreased breakdown of endogenous insulin. MRI of the pancreas did not reveal any lesions or pathology. Hence, hypoglycemia was attributed to voriconazole therapy. However, the exact interaction between insulin and voriconazole could not be established. As plasma trough voriconazole level on day 5 of therapy (before stopping voriconazole therapy) was elevated.11 It may be that hyperinsulinemia and resulting hypoglycemia was related to voriconazole concentration, although this is difficult to prove or disprove. Therefore, above-mentioned clinical and laboratory findings suggest the probable mechanism of hypoglycemia in our case is the result of increased plasma voriconazole levels, causing either increased secretion or decreased breakdown of endogenous insulin resulting in altered glucose homeostasis.
There are few case reports available in the literature that describe hypoglycemia in non-diabetic patients receiving voriconazole treatment. The exact mechanism of voriconazole-induced hypoglycemia is still unclear. In a case reported by Boyd et al.,2 hypoglycemia associated with voriconazole was thought to be due to underlying liver dysfunction that might have impaired the metabolism of voriconazole, leading to very high voriconazole concentrations. In another case reported by Ghatak et al.,9 voriconazole induced hypoglycemia was likely due to the propensity of voriconazole to alter glucose homeostasis due to decreased degradation of insulin in the presence of underlying kidney dysfunction.
Previous studies have demonstrated that the adverse reactions of voriconazole therapy are associated with a high plasma trough concentration (Cmin).12,13 Therefore, voriconazole-associated hypoglycemia may also be concentration-dependent. There is considerable individual variation in plasma concentrations of voriconazole.2 Several factors have been found to be associated with wide fluctuation in plasma levels of voriconazole after standard therapeutic dose administration.4,14 Elevated plasma voriconazole levels may be caused by liver dysfunction, genetic polymorphisms in isoenzyme CYP2C19, or drugs that inhibit this enzyme.2 Voriconazole is metabolized in vivo by the hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4, among which CYP2C19 plays a major role.14 Voriconazole N-oxide, a major metabolite, inhibits the metabolic activity of these enzymes and increases voriconazole level.5,14 CYP2C19 gene polymorphism can lead to rapid or slow metabolism of voriconazole, resulting in a 30%–50% change in plasma concentration.15 Poor metabolizers with homozygous mutation of CYP2C19 alleles is more common in Asians (15%–20%) than the Caucasian or African American populations (3%–5%).16 Slow metabolism of voriconazole leads to elevated plasma concentrations that can exceed the range of its target trough concentration, thus leading to the increased risk of adverse events and side effects (including hypoglycemia).17 That is why voriconazole can cause unexpected adverse effects including hypoglycemia in patients with normal liver and kidney function, even at normal therapeutic doses. In our case, the patient did not receive any drugs known to interfere with voriconazole metabolism. This finding suggests voriconazole-associated hypoglycemia in our case may be related to the increased plasma trough voriconazole level caused by its poor metabolism, probably resulting from genetic polymorphism of CYP2C19 enzyme.
Conclusion
The present case report showed that non-diabetic patients without dysfunction of liver and kidney who receive a therapeutic dose of voriconazole may develop rapid and unexpected life-threatening hypoglycemia due to increased plasma voriconazole concentrations, likely caused by CYP2C19 gene polymorphism. However, further studies are needed to prove the above probability. We, therefore, suggest that plasma glucose level should be monitored frequently in patients receiving voriconazole. In addition, it is advisable to measure plasma voriconazole levels if hypoglycemia is detected during therapy. According to the plasma trough level, an adjustment of voriconazole dose or its discontinuation should be considered.
Footnotes
Disclosures: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Statement Ethical approval for this case report was given by the Institutional Ethics Committee (SNMC/IEC/IIP/2024/199). The patient provided written informed consent for the publication of this case report.
Data Availability Statement All relevant data of this case report are available from the corresponding authors upon reasonable request.
- Received February 23, 2025.
- Revision received September 22, 2025.
- Accepted September 25, 2025.
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