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Han M, Jiang L, Zhao B, Liu X, Yang C, Chen W. Immune Checkpoint Inhibitors-Associated Diabetes and Ketoacidosis Were Found in FDA Adverse Event Reporting System: A Real-World Evidence Database Study. Endocr Pract 2024; 30:887-892. [PMID: 38876180 DOI: 10.1016/j.eprac.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/22/2024] [Accepted: 05/29/2024] [Indexed: 06/16/2024]
Abstract
OBJECTIVE To investigate the risk of developing diabetes and ketoacidosis in clinical patients with immune checkpoint inhibitors (ICIs). METHODS We looked in the FDA Adverse Event Reporting System for reports of ICIs-associated diabetes mellitus (DM) and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions. RESULTS A total of 2110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to 4 proportional imbalance algorithms: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Diabetes and ketoacidosis generally occurred early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%). CONCLUSION The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for postmarketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended.
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Affiliation(s)
- Meifen Han
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lin Jiang
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Bin Zhao
- Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiaojun Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Changqing Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wei Chen
- Beijing Key Laboratory of the Innovative Development of Functional Staples and the Nutritional Intervention for Chronic Disease, Department of Clinical Nutrition, Peking Union Medical College Hospital, Beijing, China.
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Zhu J, Li J, Zheng Y, Gao S, He Z, Qiu K, Yu X, Wu J. Facial palsy induced by immune checkpoint blockade: A systematic analysis of clinical trials and a pharmacovigilance study of postmarketing data. Int Immunopharmacol 2023; 125:111184. [PMID: 37952483 DOI: 10.1016/j.intimp.2023.111184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/31/2023] [Accepted: 11/02/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND To estimate the risk of facial nerve palsy (FP) associated with immune checkpoint inhibitors (ICIs), and to describe its clinical features. METHODS Data from randomized controlled trials (RCTs) and FDA Adverse Event Reporting System (FAERS) database were included. The primary outcome was the risk of FP events associated with ICIs. For data from RCTs, pooled analysis was performed by using risk ratios (RRs) with 95%CIs. In a separate retrospective pharmacovigilance study of FAERS, disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC). RESULTS A total of 21 RCTs (193,05 patients) were included, ICIs were associated with increased risk of FP (OR = 3.07, 95%CI:1.43-6.58). Results of subgroup analysis indicated that OR of ICI-related FP did not vary significantly by tumor type, ICIs treatment schedule, case of events, study design, median PFS and publication status. FAERS pharmacovigilance data identified 274 cases of FP related to ICIs therapy. ICIs were significantly associated with over-reporting frequencies of FP (ROR = 3.03, 95%CI:2.69-3.42; IC = 1.56, 95%CI:1.38-1.76). The median onset time of FP was 5.5 weeks, drug interruption was recorded in 78.0% of cases, with a positive dechallenge in 82.8 % of cases, and 71.7% of cases were recovered or recovering. CONCLUSIONS These data suggest that ICIs were significantly associated with increased risk of FP in both trial settings and in clinical practice.
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Affiliation(s)
- Jianhong Zhu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China
| | - Jianfang Li
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China
| | - Yayuan Zheng
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China
| | - Siyuan Gao
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China; Guangdong Province Hospital for Occupational Disease Prevention and Treatment, PR China
| | - Zhichao He
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China
| | - Kaifeng Qiu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China
| | - Xiaoxia Yu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.
| | - Junyan Wu
- Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, PR China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, PR China.
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Liao D, Liu C, Chen S, Liu F, Li W, Shangguan D, Shi Y. Recent advances in immune checkpoint inhibitor-induced type 1 diabetes mellitus. Int Immunopharmacol 2023; 122:110414. [PMID: 37390646 DOI: 10.1016/j.intimp.2023.110414] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 07/02/2023]
Abstract
As a new group of anticancer drugs, immune checkpoint inhibitors (ICIs) have exhibited favorable antitumor efficacy in numerous malignant tumors. Anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) are three kinds of ICIs widely used in clinical practice. However, ICI therapy (monotherapy or combination therapy) is always accompanied by a unique toxicity profile known as immune-related adverse events (irAEs) affecting multiple organs. The endocrine glands are common targets of irAEs induced by ICIs, which cause type 1 diabetes mellitus (T1DM) when the pancreas is affected. Although the incidence rate of ICI-induced T1DM is rare, it will always lead to an irreversible impairment of β-cells and be potentially life-threatening. Hence, it is vital for endocrinologists and oncologists to obtain a comprehensive understanding of ICI-induced T1DM and its management. In our present manuscript, we have reviewed the epidemiology, pathology and mechanism, diagnosis, management, and treatments of ICI-induced T1DM.
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Affiliation(s)
- Dehua Liao
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China
| | - Chaoyi Liu
- Department of Information, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China
| | - Shanshan Chen
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China
| | - Fen Liu
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China
| | - Wei Li
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China
| | - Dangang Shangguan
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China.
| | - Yingrui Shi
- Department of Radiation Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410011, China.
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Chan JSK, Lee S, Kong D, Lakhani I, Ng K, Dee EC, Tang P, Lee YHA, Satti DI, Wong WT, Liu T, Tse G. Risk of diabetes mellitus among users of immune checkpoint inhibitors: A population-based cohort study. Cancer Med 2023; 12:8144-8153. [PMID: 36647331 PMCID: PMC10134274 DOI: 10.1002/cam4.5616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/12/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are increasingly established cancer therapeutics, but they are associated with new-onset diabetes mellitus (DM). Such risks have not been adequately quantified, and between-class and -sex differences remain unexplored. METHODS This was a prospective cohort study of cancer patients receiving any ICI in Hong Kong between 2013 and 2021. Patients with known DM were excluded. Due to few patients using other ICIs, only programmed cell death 1 inhibitors (PD-1i) and programmed death ligand 1 inhibitors (PD-L1i) were compared, alongside between-sex comparison. When comparing PD-1i against PD-L1i, patients with the use of other ICIs or both PD-1i and PD-L1 were further excluded. Inverse probability treatment weighting (IPTW) was used to minimize between-group covariate imbalances. RESULTS Altogether, 3375 patients were analyzed (65.2% males, median age 62.2 [interquartile range 53.8-69.5] years old). Over a median follow-up of 1.0 [0.4-2.4] years, new-onset DM occurred in 457 patients (13.5%), with a 3-year risk of 14.5% [95% confidence interval 13.3%, 15.8%]. IPTW achieve acceptable covariate balance between sexes, and between PD-1i (N = 622) and PD-L1i (N = 2426) users. Males had significantly higher risk of new-onset DM (hazard ratio 1.35 [1.09, 1.67], p = 0.006), while PD-1i and PD-L1i users did not have significantly different risks (hazard ratio vs PD-L1i 0.81 [0.59, 1.11], p = 0.182). These were consistent in those with at least 1 year of follow-up, and on competing risk regression. CONCLUSION Users of ICI may have a substantial risk of new-onset DM, which may be higher in males but did not differ between PD-1i and PD-L1i.
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Affiliation(s)
| | - Sharen Lee
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Dicken Kong
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Ishan Lakhani
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Kenrick Ng
- Department of Medical OncologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Edward Christopher Dee
- Department of Radiation OncologyMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Pias Tang
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Yan Hiu Athena Lee
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Danish Iltaf Satti
- Cardio‐Oncology Research Unit, Cardiovascular Analytics GroupHong KongChina
| | - Wing Tak Wong
- School of Life SciencesThe Chinese University of Hong KongHong KongChina
| | - Tong Liu
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of CardiologyTianjin Institute of Cardiology, Second Hospital of Tianjin Medical UniversityTianjinChina
| | - Gary Tse
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of CardiologyTianjin Institute of Cardiology, Second Hospital of Tianjin Medical UniversityTianjinChina
- Kent and Medway Medical SchoolUniversity of Kent and Canterbury Christ Church UniversityCanterbury, KentUK
- School of Nursing and Health StudiesHong Kong Metropolitan UniversityHong KongChina
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Xia S, Gong H, Wang YK, Liu L, Zhao YC, Guo L, Zhang BK, Sarangdhar M, Noguchi Y, Yan M. Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database. Front Pharmacol 2023; 14:1129730. [PMID: 37007042 PMCID: PMC10050453 DOI: 10.3389/fphar.2023.1129730] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features.Methods: Reports of PJP recorded in FAERS (January 2004–December 2022) were identified through the preferred term “Pneumocystis jirovecii pneumonia”. Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence.Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed.Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.
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Affiliation(s)
- Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Yi-kun Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Ling Liu
- Hunan University of Chinese Medicine, Hunan, China
| | - Yi-chang Zhao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Bi-kui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
| | - Mayur Sarangdhar
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan
| | - Yoshihiro Noguchi
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Toxicology Counseling Center of Hunan Province, Hunan, China
- *Correspondence: Miao Yan,
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