SUN-585 - From Immune Activation to Insulin Dependence: Nivolumab-Induced Type 1 Diabetes Mellitus

Background
Immune checkpoint inhibitors (ICIs), particularly programmed death-1 (PD-1) inhibitors such as nivolumab, have transformed the management of advanced malignancies. However, these therapies can trigger immune-related adverse events, including rare but potentially life-threatening endocrine complications. Among the most severe is immune checkpoint inhibitor–induced type 1 diabetes mellitus (ICI-T1DM), which often presents abruptly and frequently with diabetic ketoacidosis (DKA). We report a case of nivolumab-induced T1DM presenting as DKA.

Case Presentation
A 69-year-old woman with metastatic melanoma to the lung and pleura, breast ductal carcinoma in situ, HIV on Biktarvy, hypertension, hyperlipidemia, COPD, and hypothyroidism presented with several days of progressive fatigue, polyuria, polydipsia, nausea, and dyspnea. She had been diagnosed with stage IV melanoma in April 2024 and started on nivolumab, with no prior history of diabetes and previously normal fasting glucose levels.

Approximately five months after starting nivolumab, she developed acute metabolic symptoms. On admission, she was tachypneic with mild hypotension. Laboratory evaluation revealed severe hyperglycemia (>600 mg/dL), high anion gap metabolic acidosis, elevated beta-hydroxybutyrate, and positive serum and urine ketones, consistent with DKA. Infectious workup was negative, and there was no recent glucocorticoid exposure. Morning cortisol levels were normal, excluding adrenal insufficiency or hypophysitis.

Endocrine testing demonstrated markedly low C-peptide levels and positive glutamic acid decarboxylase (GAD-65) antibodies, confirming autoimmune beta-cell destruction. Given the abrupt onset, absence of preexisting dysglycemia, and temporal association with nivolumab, a diagnosis of nivolumab-induced T1DM was made.

The patient was treated with intravenous insulin, resulting in rapid resolution of acidosis, and transitioned to a basal–bolus insulin regimen. Nivolumab was held, and she was discharged with endocrinology follow-up and diabetes education.

Discussion
ICI-induced T1DM occurs in approximately 0.2–1% of patients receiving PD-1 inhibitors. It is characterized by sudden onset, rapid and often irreversible beta-cell failure, low or absent C-peptide levels, and frequent presentation with DKA. HbA1c may be only modestly elevated, reflecting the acute nature of disease onset. Although pancreatic autoantibodies are detected in 40–50% of cases, their absence does not exclude the diagnosis. Because endocrine immune-related adverse events may coexist, assessment of adrenal function remains essential.

Conclusion
This case underscores the aggressive and unpredictable nature of nivolumab-induced T1DM and highlights the need for vigilant glucose monitoring, early symptom recognition, and prompt evaluation to prevent life-threatening DKA.

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