Endocrine Abstracts

Introduction: Immunotherapy has revolutionized the treatment of cancer. Nivolumab, an anti-programmed cell death 1(PD-1) antibody, is used to treat several malignancies refractory to standard chemotherapy. While highly effective at prolonging patient survival, these agents can induce a wide range of endocrine immune-related adverse events (irAEs), including hypophysitis, thyroid dysfunction, and, uncommonly, type 1 diabetes (T1DM). Here we describe a rare case of PD-1 inhibitor induced fulminant type 1 diabetes (FD).Case Report:A 55-year-old African American female was diagnosed with stage III B squamous cell carcinoma of the lung in 2013. She was not a surgical candidate and received 6 cycles of carboplatin and gemcitabine as well as salvage radiation. One year later, there was disease progression with involvement of the brain, adrenal glands, and gluteal muscle. In 2015 she began treatment with nivolumab. Cycle 4 was delayed, as she developed autoimmune hepatitis, for which she received high dose steroids. After normalization of liver function tests, nivolumab was restarted. After 8 months, she presented for cycle 13 reporting extreme fatigue, dry mouth, nausea, polyuria and polydipsia. Laboratory tests at the time of hospitalization revealed a blood glucose of 467 mg/dl (70–105). She had ketonuria without ketoacidosis. Unexpectedly, her glycosylated hemoglobin (HbA1c) was only 7.1%, suggesting rapid onset of hyperglycemia. Serum anti-glutamic acid decarboxylase antibody and anti-islet-cell antibody were negative, and C-peptide was 0.42 ng/ml (0.8–3.85), consistent with a diagnosis of FD. HLA-typing was not performed. Insulin therapy was initiated, and she was discharged on a basal/bolus insulin regimen. Given wide glycemic excursions, the patient was eventually transitioned to insulin pump therapy with a continuous glucose monitor. Nivolumab was not restarted.

Discussion: FD is a severe subtype of T1DM, characterized by the complete loss of pancreatic beta cells at disease onset. Initially described in Japan in 2000, cases have been reported primarily in East Asia. FD is characterized by rapid onset of hyperglycemia combined with ketoacidosis or ketonuria and the absence of islet-cell autoantibodies. Out of the 24 cases of diabetes thus far reported as a side effect of anti-PD-1 treatment, 10 (42%) are consistent with FD, with unusually low HbA1c at diagnosis (under 8.7%) and low or undetectable c-peptide. Given increasing oncologic indications for anti-PD1, it is important that physicians be made aware of this rare, but potentially life-threatening, adverse reaction. Frequent biochemical monitoring and early recognition of hyperglycemia are critical in optimizing treatment outcomes.