Accelerated Progression of Prediabetes to Insulin-Dependent Diabetes After 9 Cycles of Nivolumab

Abstract

Abstract Introduction: Diabetes mellitus have been reported in around 1% of patients receiving immune checkpoint inhibitors (ICI) resultingin immune checkpoint inhibitor induced diabetes mellitus (ICI-DM). 4 phenotypes of ICI-DM exist: acute autoimmuneinsulin-dependent diabetes, decompensation of prediabetes or type 2 diabetes, autoimmune pancreatitis, andautoimmune lipoatrophy. Clinical Case: A 52-year-old man was diagnosed with stage IIIb malignant melanoma. Two months following local excision, he wasstarted on nivolumab every 4 weeks planned for 1 year. His past medical history was significant for prediabetes,hypertension, obesity (BMI 33.27 kg/m²), primary hypogonadism, adult attention deficit disorder, obstructive sleepapnea, gastric ulcer, and gastroesophageal reflux disease. He denied tobacco use but reported semi-daily use ofmarijuana and alcohol. His baseline HbA1c was 6.0%. After the 8th cycle of nivolumab, he reported several bloodglucose readings in the 200 mg/dL range. He was thought to have progressed to type 2 diabetes and metformin wasstarted. Glipizide was added shortly thereafter due to persistent hyperglycemia. At the 9th cycle of nivolumab, hisHbA1c was 8.2%. In 1 week from this time, the patient developed abdominal pain, nausea, and persistent vomiting. Hewas found to be in DKA with blood glucose of 278 mg/dL, bicarbonate of 9.3 mmol/L, anion gap of 21, and arterial pHof 7.22. He was treated in the ICU per standard DKA care. His C-peptide was 0.5 ng/mL (reference 0.8–3.5) withconcomitant plasma glucose of 229 mg/dL. Autoantibody screening was negative including glutamic aciddecarboxylase antibody (anti-GAD), insulin antibody, insulin antigen-2 (IA-2) autoantibody, and zinc transporter 8antibody. The patient was discharged home on multiple daily injections of insulin but he struggled with diabetes carewhich proved to be of brittle nature requiring CGM use. Two months after completion of nivolumab treatment, thepatient reported epigastric abdominal pain with frequent nausea and occasional vomiting of few weeks duration. He wasdiagnosed with subacute pancreatitis based on symptoms and elevated lipase. There was no evidence of gallstones. Although immunotherapy-related pancreatitis was considered, we decided to try alcohol cessation first hoping to avoidthe need to use prednisone. Over several weeks, lipase normalized and his symptoms completely resolved. Conclusion: In this case, nivolumab resulted in progressive beta-cell failure and complete insulin dependence in a person with ahistory of prediabetes. Not all pancreatitis cases in the settings of immunotherapy use are immune-related adverseevents (irAE). Usual causes, e.g. alcohol, should still be considered. With cessation of alcohol, pancreatitis fullyresolved leading to avoidance of prednisone which would likely have worsened diabetes management in this patientwith brittle diabetes.