New-onset insulin-dependent diabetes due to nivolumab

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab. Learning points: Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1). Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1. Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents. Patient Demographics: Geriatric, Male, White, United States Clinical Overview: Pancreas, Diabetes, Insulin, Diabetes mellitus type 1, Diabetic ketoacidosis, Autoimmune disorders, Metastatic carcinoma, Hyperglycaemia, Metabolic acidosis, Hyperkalaemia, Hyponatraemia Diagnosis and Treatment: Diabetes mellitus type 1, Diabetic ketoacidosis, Hyperpnoea, Hyperglycaemia, Metabolic acidosis, Dyspnoea, Abdominal pain, Fatigue, Polyuria, Hyponatraemia, Hyperkalaemia, Glucose (blood), X-ray, Ketones (urine), Glucose (blood, fasting), Haemoglobin A1c, C-peptide (blood), CT scan, Red blood cell count, White blood cell count, White blood cell differential count, Platelet count, Sodium, Potassium, Chloride, Bicarbonate, Urea and electrolytes, Albumin, Magnesium, Calcium (serum), Brain natriuretic peptide, Glucose (urine), Urinalysis, Fluid repletion, Nivolumab, Insulin, Insulin Aspart, Insulin glargine, Aspirin, Lisinopril, Tyrosine-kinase inhibitors Related Disciplines: Oncology Publication Details: Unusual effects of medical treatment, March, 2018 Background Understanding how cancer escapes host immune regulation has led to the development of cancer ‘immunotherapy’. In particular, antibodies such as nivolumab, targeting and inhibiting programmed cell death 1 receptor (PD-1(PDCD1)), can result in the preferential activation of T-cells with specificity for cancer (1). Multiple trials have already demonstrated significant response rates and improved survival with nivolumab in multiple neoplasms including melanoma (2, 3, 4, 5, 6, 7, 8, 9, 10, 11), non-small-cell lung cancer (NSCLC) (2, 3, 4, 12, 13, 14, 15) and renal cell carcinoma (RCC) (2, 3, 4, 16, 17). However, inhibition of the PD-1 pathway results in a reduction of ‘self-tolerance’, with an apparent increase in immune-mediated adverse events (AE). Clinical trials investigating the efficacy of nivolumab in cancers have reported increased rates of autoimmune endocrinopathies, including: hypophysitis (5, 7, 8, 10, 11), adrenal insufficiency (4, 5, 7, 10, 12), thyroid disorders (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18) and hyperglycemia (2, 3, 4, 6, 8, 15, 17). We report a patient presenting critically ill with diabetic ketoacidosis (DKA) after receiving nivolumab. In addition, we provide a review of the literature reporting nivolumab-induced diabetes mellitus (DM). Acute care physicians’ awareness of the acute complications of these novel therapies is essential for the timely management of these critically ill patients.