Endocrine Abstracts

Context: Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) are key regulators in T-cell activation and tolerance. Nivolumab (PD-1 inhibitor) and Atezolizumab (PD-L1 inhibitor) are monoclonal antibodies approved for the treatment of several types of advanced cancers. Immune checkpoint inhibition caused by these drugs can result in immune-related adverse events (irAEs) New-onset diabetes mellitus has been reported in fewer than 1% of patients and is a rare but life-threatening irAE, which is often characterized by rapid-onset hyperglycemia and ketoacidosis, with low levels of endogenous insulin secretion. Here we report two cases of new-onset diabetes associated with anti-PD-1 and anti-PD-L1 therapy that showed a rapid fall into insulin-dependence.

Case 1: A 60-year-old man received Atezolizumab for metastatic lung adenocarcinoma. After two doses, he developed hyperglycemia, requiring basal-bolus insulin therapy. After the fourth dose, the patient was admitted to our Departement because of severe weakness, nausea, abdominal pain, and dizziness. Laboratory tests revealed severe hyperglycemia with ketoacidosis, low levels of c-peptide, hyperkalemia, and hyponatremia. Islettyrosine phosphatase 2(IA2) antibodies and anti-glutamic acid decarboxylase (GAD) antibodies were undetectable. Further investigations revealed the DRB1*04 and DQB1*03 haplotypes, which are usually associated with increased susceptibility to T1DM. After resolution of ketoacidosis, due to persistence of mild hyponatremia and hyperkalemia, an adrenal dysfunction was suspected. The evaluation of HPA-axis revealed the presence of a Primary adrenal insufficiency with 21OH –hydroxylase antibodies positivity

Case 2: A 43-year-old woman, affected by a malignant skin melanoma, was treated with nivolumab. After the second cycle, she was diagnosed with transient thyrotoxicosis followed by autoimmune hypothyroidism, requiring replacement therapy with levothyroxine. After the sixth cycle, severe ketoacidosis arose, which required insulin therapy. Antibodies against pancreatic beta cells antibodies were negative. HLA typing revealed DQB1*02; DQB1 *0602; DQA1 *0102 haplotypes that are not usually associated with increased susceptibility to T1DM.

Conclusion: ICIs related ‘fulminant diabetes’ is a rare but potentially life-threatening irAE that manifests with severe ketoacidosis and needs to be diagnosed timely and managed properly. After the first manifestation of ICIs-related diabetes, the beta-cell function is usually permanently impaired, resulting in a long-term need for insulin injection.

Moreover, fulminant diabetes can manifest in the context of an autoimmune polyglandular syndrome, as described in our 2 cases. The coexistence of ketoacidosis and adrenal crisis, although rare, represents an extremely severe combination of iRAEs.