Nivolumab-Induced Type 1 Diabetes with Recurrent Diabetes Ketoacidosis

With advance in cancer immunotherapy, antibodies targeting programmed death 1 receptor (PD-1) such as nivolumab have shown promise in multiple malignancies. Despite clinical benefits, Immune checkpoint inhibitors (ICPi) have been associated with immune related adverse events (irAEs), targeting various organ system. Different endocrinopathies have been identified with ICPi, and type 1 diabetes mellitus is one of rare irAEs with prevalence less than 1%. These patients often present in critical conditions of severe hyperglycemia or diabetic ketoacidosis (DKA) and close monitoring of glucose level is important in managing patients with such irAEs. We describe a patient who had recurrent DKA while receiving nivolumab.

Case Description:

A 63-year-old male with past medical history significant for pre-diabetes, obesity BMI 34, and malignant melanoma of left posterior thigh stage IIIC presented with nausea, vomiting, and abdominal pain. He presented a week after receiving his second cycle of nivolumab. He was found to have blood glucose (BG) level of 773 mg/dL, anion gap of 25, bicarbonate of 6 (22-30 mmol/L), and beta-hydroxybutyrate of 135 (0.2-2.81 mg/dL). BG level before receiving first cycle of nivolumab was normal. BG level was 179 mg/dL before receiving second cycle of nivolumab. At that time, observation was elected since patient had no hyperglycemia symptoms. Patient was treated for DKA and was eventually started on basal-bolus insulin. Further testing revealed low c-peptide 0.3 (0.8-3.5 ng/mL) with BG of 339 mg/dL and elevated glutamic acid decarboxylase antibody, 11.8 (0-5 IU/mL). Patient was diagnosed with nivolumab-induced type 1 diabetes. Nivolumab was discontinued by oncology team. Patient however continued to require basal-bolus insulin to control his diabetes. Few months later, he was diagnosed with metastasis to the brain and lung, for which he received whole brain radiation. Dual immunotherapy with nivolumab and ipilimumab was reinitiated. Ten days later, he presented to emergency with nausea and vomiting, found to be in DKA. Patient recovered from DKA. Patient required higher insulin doses to achieve better diabetes control indicating that there was progressive decline in endogenous insulin secretion.

Discussion:

It is essential for clinicians to be aware that nivolumab can induce rapid onset type 1 diabetes. Educating patients about signs of hyperglycemia and prompt recognition of elevated blood glucose level on basic metabolic panel with each cycle of nivolumab will help to diagnose diabetes early and start insulin to prevent progression to diabetes ketoacidosis.