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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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“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: Standards of Care in Diabetes—2024 (2024) · cites this paper as [67]
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“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: Standards of Care in Diabetes—2024 (2024) · cites this paper as [67]
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“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]
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“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).”
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“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]
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- Alzenaidi, 2017, Autoimmune diabetes presented with diabetic ketoacidosis induced by immunotherapy in an adult with melanoma, J La State Med Soc, 169, 49
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Metadata
- 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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