Endocrine Abstracts

Background: Immune checkpoint inhibitors (ICPis) have become a cornerstone of cancer management. Whilst endocrine-related adverse effects are one of the most common immune-related adverse events, ICPi-induced de novo diabetes occurs at low frequencies¹. We describe a case of ICPi-induced de novo type 1 diabetes presenting with severe diabetic ketoacidosis (DKA) in a female with metastatic melanoma.

Case report: A 50-year-old lady was being treated with ICPis for metastatic melanoma. She initially received four cycles of combined ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] checkpoint inhibitor), and nivolumab (a programmed cell death-1 [PD-1] checkpoint inhibitor) therapy followed by maintenance nivolumab. After the tenth cycle of nivolumab, she presented to the emergency department with fatigue, abdominal pain, vomiting, and polyuria. Laboratory investigations confirmed severe DKA as evidenced by plasma glucose of 67 mmol/l, blood ketones >7 mmol/l, and metabolic acidosis (pH:6.91, serum bicarbonate:8mmol/l). Treatment with intravenous fluids, a fixed rate of intravenous insulin infusion at 0.1 units/kg/hour, and electrolyte replacement was commenced immediately. Low-molecular-weight heparin was also prescribed for thromboprophylaxis. Further investigations including liver function tests, amylase, and inflammatory markers were normal. A septic screen excluded an infectious source. Antibodies to glutamic acid decarboxylase, tyrosine phosphatase-related islet antigen 2, islet cell, and insulin were negative. Following resolution of her DKA and review by the diabetologists, diabetes specialist nurses, and caring oncologist the patient was discharged on daily insulin glargine and thrice daily insulin aspart. She remained well upon review at her follow-up appointment where in the interim she was recommenced on nivolumab.

Conclusions: The use of PD-1 inhibitors is associated with an increased risk of type 1 diabetes when compared to CTLA-4 inhibitors, but when PD-1 inhibitors are combined with CTLA-4 inhibitors, this leads to an increased risk of diabetes at an earlier stage^1,2. This case highlights how DKA is the most common presentation of ICPi-induced type 1 diabetes as a result of swift β-cell destruction and resultant insulin deficiency². ICPi-induced type 1 diabetes is irreversible. Hence, such patients require life-long insulin treatment regardless of whether ICPi therapy is withheld². Patients receiving ICPis, especially PD-1 inhibitors, should be informed about the symptoms and signs of diabetes, and to monitor their glucose levels.

References: 1. Liao D, et al. Recent advances in immune checkpoint inhibitor-induced type 1 diabetes mellitus. Int Immunopharmacol. 2023Sep;122:110414.2. Lin C, et al. PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review. Front Public Health. 2022Aug 5;10:885001.