Immune checkpoint inhibitor therapy and risk of type 1 diabetes mellitus in metastatic cancer patients

Ming-Hsun Lin¹, Ren-Hua Ye², Hong-Jie Jhou³, Hsin-Yu Chen⁴, Li-Ting Kao^{5

6

7}, Tina Yi-Jin Hsieh⁸, Yu-Han Chen⁹, Andrea Yue-En Sun¹⁰, Xiaoyi Zhang¹¹, Ming-Shen Dai², Ching-Liang Ho^{2

12}, Po-Huang Chen^#¹³, Cho-Hao Lee^#¹⁴

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
² Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
³ Neurological Institute, Changhua Christian Hospital, Changhua, Taiwan.
⁴ Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan.
⁵ Graduate Institute of Life Sciences, National Defense Medical University, Taipei, Taiwan.
⁶ School of Pharmacy, National Defense Medical University, Taipei, Taiwan.
⁷ Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.
⁸ Department of Obstetrics & Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁹ Department of Internal Medicine, Englewood Hospital and Medical Center, Englewood, NJ, USA.
¹⁰ College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹¹ Department of Internal Medicine, NYC Health + Hospitals/Jacobi, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Division of Hematology and Oncology, Medical Department, Taipei Tzu Chi Hospital, Taipei, Taiwan.
¹³ Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. chenpohuang@hotmail.com.
¹⁴ Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. drleechohao@gmail.com.

^# Contributed equally.

PMID: 41044787
PMCID: PMC12495861
DOI: 10.1186/s13098-025-01940-0

Immune checkpoint inhibitor therapy and risk of type 1 diabetes mellitus in metastatic cancer patients

Ming-Hsun Lin et al. Diabetol Metab Syndr. 2025.

. 2025 Oct 3;17(1):377.

doi: 10.1186/s13098-025-01940-0.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
² Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
³ Neurological Institute, Changhua Christian Hospital, Changhua, Taiwan.
⁴ Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan.
⁵ Graduate Institute of Life Sciences, National Defense Medical University, Taipei, Taiwan.
⁶ School of Pharmacy, National Defense Medical University, Taipei, Taiwan.
⁷ Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.
⁸ Department of Obstetrics & Gynecology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁹ Department of Internal Medicine, Englewood Hospital and Medical Center, Englewood, NJ, USA.
¹⁰ College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹¹ Department of Internal Medicine, NYC Health + Hospitals/Jacobi, Albert Einstein College of Medicine, Bronx, NY, USA.
¹² Division of Hematology and Oncology, Medical Department, Taipei Tzu Chi Hospital, Taipei, Taiwan.
¹³ Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. chenpohuang@hotmail.com.
¹⁴ Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan. drleechohao@gmail.com.

^# Contributed equally.

PMID: 41044787
PMCID: PMC12495861
DOI: 10.1186/s13098-025-01940-0

Abstract

Aims: To assess the risk of new-onset type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA) in metastatic cancer patients treated with immune checkpoint inhibitors (ICIs) compared to those receiving non-ICI therapies.

Method: A retrospective cohort study using TriNetX global electronic health records (2014-2025) from multiple healthcare systems. Adult metastatic cancer patients initiating ICI or non-ICI therapy were included. Patients with preexisting diabetes within 6 months were excluded. After 1:1 propensity score matching, 25,463 patients remained in each group. Outcomes were identified by ICD-10 codes.

Results: Median follow-up was 764 days (ICI) vs. 692 days (non-ICI). ICI use was associated with a higher risk of T1DM (HR, 2.35; 95% CI, 1.81-3.04) and DKA (HR, 10.58; 95% CI, 4.21-26.59). Cumulative incidence analyses supported these findings, with ICIs showing higher risks of T1DM (0.75% vs. 0.32%; RR, 2.32 [95% CI, 1.79-3.00]) and DKA (0.20% vs. 0.04%; RR, 5.00 [95% CI, 2.54-9.86]). Subgroup analyses identified elevated baseline HbA1c (> 6.0%), male sex, white race, and dual checkpoint blockade as high-risk factors.

Conclusion: ICIs significantly increase the risk of T1DM and DKA. These findings highlight the need for vigilant glycemic monitoring in cancer patients treated with ICIs, especially within identified high-risk subgroups.

Keywords: Cancer immunotherapy; Diabetic ketoacidosis; Immune checkpoint inhibitors; Immune-Related adverse events; Propensity score matching; Type 1 diabetes.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of Tri-Service General Hospital (TSGHIRB No.: E202516013). As the data used were de-identified and released for research purposes, informed consent from the participants was waived. Competing interests: The authors declare no competing interests. Declaration of generative AI in scientific writing: AI-assisted technology (ChatGPT by OpenAI) was used solely to refine language and formatting. The overall structure, content, and scientific interpretation were entirely determined by the authors.

Figures

**Fig. 1**
Diabetes-Related Clinical Outcomes Comparison and Hazard Ratio Analysis. **Panel** A: Risk Comparison Between Treatment Groups. Bar chart showing the incidence (%) of diabetes-related outcomes in cancer patients treated with immune checkpoint inhibitors (red) versus conventional chemotherapy (blue). Risk ratios with 95% confidence intervals and significance levels are displayed for each outcome. ** indicates P < 0.01. **Panel** B: Hazard Ratio Analysis with 95% Confidence Intervals. Forest plot showing the hazard ratios for diabetes-related outcomes comparing immune checkpoint inhibitor therapy to conventional chemotherapy. Hazard ratios are displayed on a logarithmic scale, with values > 1 indicating higher risk with immune checkpoint inhibitor therapy

**Fig. 2**
Cumulative Incidence of Type 1 Diabetes and Type 1 DKA Following Cancer Treatment. Kaplan-Meier curves showing the cumulative incidence of Type 1 Diabetes (left panel) and Type 1 Diabetic Ketoacidosis (right panel) in patients treated with immune therapy (red lines) versus chemotherapy (blue lines). The hazard ratio for Type 1 Diabetes was 2.345 (95% CI: 1.809–3.041, P < 0.001) and for Type 1 DKA was 10.578 (95% CI: 4.208–26.591, P < 0.001). The number of patients at risk at different time points is shown below each graph

**Fig. 3**
Subgroup Hazard Ratios for New-Onset T1DM after ICI vs. non-ICI. Hazard ratios with 95% confidence intervals for developing Type 1 Diabetes with immune checkpoint inhibitor therapy versus non-ICI therapy, stratified by demographic and clinical characteristics. Values shown on the right represent hazard ratios with corresponding 95% confidence intervals. The figure demonstrates consistently increased risk across most subgroups, with particularly elevated risk among males, white patients, those with HbA1c ≥6, and patients receiving dual immunotherapy

**Fig. 4**
Subgroup Hazard Ratios for T1DM-associated DKA after ICI vs. non-ICI. Hazard ratios with 95% confidence intervals for developing Type 1 Diabetic Ketoacidosis with immune checkpoint inhibitor therapy versus non-ICI therapy, stratified by demographic and clinical characteristics. The forest plot demonstrates markedly higher risk in most subgroups, with particularly elevated hazard ratios for patients with HbA1c ≥ 6 (HR 9.27), white patients (HR 7.64), and males (HR 6.58)

See this image and copyright information in PMC

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Immune checkpoint inhibitor therapy and risk of type 1 diabetes mellitus in metastatic cancer patients

Affiliations

Immune checkpoint inhibitor therapy and risk of type 1 diabetes mellitus in metastatic cancer patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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