SUN-436 - From Hyperglycemia to Hypoglycemia: Posaconazole-Induced Primary Adrenal Insufficiency in T2DM

Azole antifungals like posaconazole can inhibit adrenal steroidogenesis and cause adrenal insufficiency (AI). Hypoglycemia is an uncommon presenting manifestation of adrenal insufficiency. We describe recurrent hypoglycemia due to posaconazole-induced primary AI in a patient with type 2 diabetes mellitus (T2DM) and acute myeloid leukemia (AML).

A 73-year-old man with hypertension, hyperlipidemia, newly diagnosed T2DM, and AML was admitted for induction chemotherapy. On admission, his blood glucose level was in the 600s, with anion gap metabolic acidosis and beta-hydroxybutyrate level of 2.4 mmol/L, consistent with diabetic ketoacidosis. He was treated with intravenous insulin. As his condition stabilized, he was transitioned to basal-bolus insulin and transferred out of ICU. Hemoglobin A1c was 8.6%. C-peptide levels (1.34 and 2.11 ng/mL with BG 88–90 mg/dL) and negative glutamic acid decarboxylase antibodies were consistent with diagnosis of ketosis-prone diabetes. He was started on decitabine and venetoclax for management of his AML and antifungal prophylaxis with posaconazole. As hyperglycemia improved, insulin requirements rapidly decreased, and insulin was eventually discontinued. Following initiation of posaconazole, he developed recurrent low point-of-care BG values, with nadirs around 42–50 mg/dL and minimal autonomic or neuroglycopenic symptoms. Initially, spurious readings related to poor perfusion and decreased oral intake were suspected. A venous sample later confirmed BG of 45 mg/dL with appropriately suppressed insulin and C-peptide, consistent with non–insulin-mediated hypoglycemia. Further evaluation revealed a random cortisol < 3 µg/dL. Cosyntropin stimulation testing demonstrated an inadequate rise in cortisol from 2.1 to 6 µg/dL at 60 minutes. Adrenocorticotropic hormone was inappropriately elevated, and aldosterone was low, consistent with primary AI. There was no exposure to exogenous glucocorticoids or other medications known to interfere with cortisol synthesis or testing. Given the temporal association, posaconazole-induced primary AI was diagnosed. Hydrocortisone and fludrocortisone replacement were initiated, with resolution of hypoglycemia.

Posaconazole is increasingly used in patients with hematologic malignancies and can cause primary AI through inhibition of adrenal steroidogenesis, notably via CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase). In patients receiving azole therapy, new hypoglycemia or rapidly declining insulin requirements with suppressed insulin and C-peptide should prompt evaluation for AI, even in those with preexisting diabetes. This case underscores AI as underrecognized cause of hypoglycemia, the need for cautious interpretation of point-of-care BG in acutely ill patients, and the importance of early cortisol testing and timely steroid replacement to prevent morbidity.

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