Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus

J Clin Endocrinol Metab. 2018 Sep 1;103(9):3144-3154. doi: 10.1210/jc.2018-00728.


Context: Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.

Evidence acquisition: Systematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms "diabetes" or "ketoacidosis" and "pembrolizumab," "nivolumab," "PD-1 inhibitor," or "immunotherapy." Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers.

Evidence synthesis: We provide an overview of all published cases (n = 42) of PD-1 inhibitor-induced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and glutamic acid decarboxylase antibody-positive diabetes mellitus, in a patient with a diabetes-prone HLA genotype. She presented with diabetic ketoacidosis during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (β-cell antibodies and HLA type), treatment, and a screening protocol.

Conclusions: Because the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents, Immunological / adverse effects*
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • Diabetes Mellitus, Type 1 / chemically induced*
  • Diabetes Mellitus, Type 1 / immunology
  • Female
  • Humans
  • Immunotherapy / adverse effects
  • Melanoma / drug therapy
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Uveal Neoplasms / drug therapy


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • Programmed Cell Death 1 Receptor
  • pembrolizumab

Supplementary concepts

  • Uveal melanoma