Reporting of Immune Checkpoint Inhibitor Therapy–Associated Diabetes, 2015–2019
Open accessAbstract
Immune checkpoint inhibitors (ICIs), including cytotoxic T cell–associated protein-4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors, have greatly improved the clinical outcomes of cancer patients (1). However, immune-related adverse effects involving various organs, including endocrine organs, can occur during ICI therapy (2). Cases of diabetes associated with ICI therapy have also been reported, which can be life-threatening (3–5). However, the incidence and characteristics of ICI-associated diabetes mellitus (ICI-DM) remain unclear. Therefore, we conducted a retrospective study with data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), a pharmacovigilance database, to investigate this issue (6). We used the FAERS to identify all reported cases of new-onset diabetes that were associated with ICIs approved by the FDA (i.e., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and cemiplimab) between 1 January 2015 and 31 December 2019. Patients with new-onset type 1 diabetes, fulminant type 1 diabetes, diabetic ketoacidosis (DKA), or diabetic ketosis secondary to ICI therapy were considered to have ICI-DM. Those with DKA or diabetic ketosis secondary to type 2 diabetes or diabetes without detailed subtypes were excluded. We then used the χ …
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Immune checkpoint inhibitors suppress physiologic blocks on immune responses, which can result in autoimmune toxicities, including autoimmune diabetes, with an incidence approximately ≤1%.
“Immune checkpoint inhibitors (ICIs) (agents that block programmed cell death protein 1 [PD-1] and programmed cell death protein ligand 1 [PD-L1]) suppress physiologic blocks on immune responses, which can result in autoimmune toxicities, including autoimmune diabetes (incidence approximately #1%).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [218]
The paper’s opening section identifies PD-1 and PD-L1 inhibitors and says ICI therapy can cause immune-related adverse effects, including diabetes. It does not explain the effect as suppression of physiologic blocks on immune responses, and its reported overall ICI-associated diabetes incidence is approximately 1.27% (735 of 57,683), rather than ≤1%. (LLM, conf=0.88)
Experimental — accuracy not yet measuredICI-diabetes is an insulin-deficient phenotype that presents as acute severe hyperglycemia or DKA and appears to occur more abruptly than type 1 diabetes.
“ICI-diabetes is an insulin-deficient phenotype that presents as acute severe hyperglycemia or DKA and appears to occur more abruptly than type 1 diabetes (216-218).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [218]
In the paper’s main text (page unavailable), 338 of 735 ICI-diabetes cases presented with DKA or diabetic ketosis, supporting that part of the claim. The paper does not establish an insulin-deficient phenotype, document acute severe hyperglycemia, or compare onset speed with type 1 diabetes; it says clinical-course and C-peptide data were unavailable. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOne fine needle aspiration during active ICI-induced thyroiditis showed a lymphocytic infiltrate with CD163+ histiocytes.
“one fine needle aspiration obtained during active ICI-induced thyroiditis showed a lymphocytic infiltrate along with CD163+ histiocytes.46”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [46]
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Cites
Cancer immunotherapy using checkpoint blockade
Ribas, A., & Wolchok, J. D. (2018) · Science · doi:10.1126/science.aar4060 · Cited by 6,791 · see citing works
Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
Postow, M. A., Sidlow, R., & Hellmann, M. D. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1703481 · Cited by 4,849 · see citing works
Collateral damage: Insulin-dependent diabetes induced with checkpoint inhibitors
Stamatouli, A. M., Quandt, Z., Perdigoto, A. L., Clark, P. L., Kluger, H., Weiss, S. A., Gettinger, S., Sznol, M., Young, A., Rushakoff, R., et al. (2018) · Diabetes · doi:10.2337/dbi18-0002 · Cited by 590 · see citing works
Programmed Cell Death-1 Inhibitor–Induced Type 1 Diabetes Mellitus
Clotman, K., Janssens, K., Specenier, P. M., Weets, I., & Block, C. E. M. D. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00728 · Cited by 235 · see citing works
Increased Reporting of Immune Checkpoint Inhibitor–Associated Diabetes
Wright, J. J., Salem, J., Johnson, D. B., Lebrun‐Vignes, B., Stamatouli, A. M., Thomas, J. W., Herold, K. C., Moslehi, J. J., & Powers, A. C. (2018) · Diabetes Care · doi:10.2337/dc18-1465 · Cited by 127 · see citing works
Long-Term Effects of Lifestyle Intervention and Metformin during DPP on Appendicular Lean Mass
Schwartz, A. V., PAN, Q., Hazuda, H. P., Horton, E. S., Hoskin, M. A., Kalyani, R. R., Knowler, W. C., Kriska, A. M., Schlögl, M., & Florez, H. J. (2018) · Diabetes · doi:10.2337/db18-1471-p · Cited by 33 · see citing works
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9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025
American Diabetes Association Professional Practice Committee, ElSayed, N. A., McCoy, R. G., Aleppo, G., Bajaj, M., Balapattabi, K., Beverly, E. A., Briggs Early, K., Bruemmer, D., Echouffo-Tcheugui, J. B., et al. (2025) · Diabetes Care · doi:10.2337/dc25-s009 · Cited by 728 · see citing works
Endocrine toxicities of immune checkpoint inhibitors
Wright, J. J., Powers, A. C., & Johnson, D. B. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00484-3 · Cited by 441 · see citing works
- Authors
- Liu, J., Zhou, H., Zhang, Y., Fang, W., Yang, Y., Huang, Y., & Zhang, L.
- Affiliations
- Sun Yat-sen University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Corresponding author
- Zhang, Li
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2020-05-11
- Volume
- 43
- Issue
- 7
- Pages
- e79-e80
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC7305010
- OpenAlex
- W3023939466
- Cited by
- 55
- References
- 6
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 9 · 2023: 7 · 2022: 17 · 2021: 6 · 2020: 2
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key R&D Program of China (2016YFC0905500, 2016YFC0905503)
- Science and Technology Program of Guangdong (2017B020227001)
- Chinese National Natural Science Foundation (81872499, 81572659, 81772476)
- Science and Technology Program of Guangzhou (201607020031, 201704020072)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- immune checkpoint inhibitors, immune-related adverse events, new-onset diabetes, type 1 diabetes, diabetic ketoacidosis, CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, FDA Adverse Event Reporting System, pharmacovigilance
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