Collateral damage: Insulin-dependent diabetes induced with checkpoint inhibitors
Open accessAbstract
Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti–PD-1 or anti–PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti–PD-1 or –PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.
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The majority of immune checkpoint inhibitor-related cases of type 1 diabetes occur in people with high-risk HLA-DR4 (present in 76% of individuals), whereas other high-risk HLA alleles are not more common than those in the general population.
“To date, the majority of immune checkpoint inhibitor -related cases of type 1 diabetes occur in people with high-risk HLA-DR4 (present in 76% of individuals), whereas other high-risk HLA alleles are not more common than those in the general population (67).”
From 2. Diagnosis and Classification of Diabetes: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [67]
Immune checkpoint inhibitor-related type 1 diabetes occurs in just under 1% of checkpoint inhibitor-treated individuals but most commonly occurs with agents that block the programmed cell death protein 1/programmed cell death ligand 1 pathway alone or in combination with other checkpoint inhibitors.
“This immune-related adverse event occurs in just under 1% of checkpoint inhibitor -treated individuals but most commonly occurs with agents that block the programmed cell death protein 1/programmed cell death ligand 1 pathway alone or in combination with other checkpoint inhibitors (67).”
From 2. Diagnosis and Classification of Diabetes: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [67]
This immune-related adverse event occurs in just under 1% of checkpoint inhibitor-treated individuals but most commonly occurs with agents that block the programmed cell death protein 1/programmed cell death ligand 1 pathway alone or in combination with other checkpoint inhibitors.
“This immune-related adverse event occurs in just under 1% of checkpoint inhibitortreated individuals but most commonly occurs with agents that block the programmed cell death protein 1/programmed cell death ligand 1 pathway alone or in combination with other checkpoint inhibitors (66).”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [66]
Profound insulin deficiency associated with immune checkpoint inhibitor use may present with hyperglycemia and diabetic ketoacidosis.
“A new and emerging issue is the development of profound insulin deficiency associated with the use of immune check-point inhibitors, which may present with hyperglycemia and diabetic ketoacidosis (DKA) (4).”
Whether steroid-sparing regimens lower posttransplant diabetes risk remains unclear, with mixed study results.
“It is still unclear if steroid-sparing regimens decrease the risk of PTDM with studies showing mixed results.1591–1595”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1593]
The Clinical and Biologic Significance section discusses glucocorticoids in checkpoint-inhibitor-induced diabetes, not diabetes after transplantation. Searches for steroid-sparing regimens, PTDM, and posttransplant diabetes found no passage addressing whether those regimens reduce PTDM risk or whether study results are mixed. No page numbers were available in our copy. (LLM, conf=0.75)
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- Authors
- Stamatouli, A. M., Quandt, Z., Perdigoto, A. L., Clark, P. L., Kluger, H., Weiss, S. A., Gettinger, S., Sznol, M., Young, A., Rushakoff, R., Lee, J., Bluestone, J. A., Anderson, M., & Herold, K. C.
- Affiliations
- Yale University (US)
- University of California, San Francisco (US)
- Corresponding author
- Herold, Kevan C.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2018-06-24
- Volume
- 67
- Issue
- 8
- Pages
- 1471-1480
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC6054443
- OpenAlex
- W2808896902
- Cited by
- 590
- References
- 51
- Citations by year
- 2026: 41 · 2025: 75 · 2024: 76 · 2023: 90 · 2022: 80 · 2021: 92 · 2020: 69 · 2019: 52 · 2018: 14
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK057846, UC4 DK116290)
- Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D059)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- immune checkpoint inhibitors, type 1 diabetes, anti-PD-1, PD-L1 inhibitors, immune-related adverse events, ketoacidosis, pancreatitis, autoantibodies, HLA-DR4, solid organ cancer, endocrine adverse events
- MeSH terms
- Antineoplastic Agents, Immunological, Insulin Secretion, Animals, Autoimmune Diseases, Diabetes Mellitus, Type 1, Genotype, Humans, Hypoglycemic Agents, Insulin, Isoantibodies, Ketosis, Neoplasms, Pancreas, Pancreatitis, HLA-DR4 Antigen, Models, Immunological, Genetic Predisposition to Disease, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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