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Dong H, Li S, Peng Y, Zhang X, Zheng J, Xue C, Zheng Y, Yu Y, Lu X, Hu Z, Cui H. Durvalumab‑induced type 1 diabetes mellitus in lung adenocarcinoma: A case report and literature review. Oncol Lett 2025; 29:277. [PMID: 40247987 PMCID: PMC12005073 DOI: 10.3892/ol.2025.15023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.
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Affiliation(s)
- Huijing Dong
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shengfu Li
- Department of Tuberculosis, Tai Yuan Fourth Peoples (Tuberculosis) Hospital, Taiyuan, Shanxi 030053, P.R. China
| | - Yanmei Peng
- Department of Oncology, Fangshan Hospital Beijing University of Chinese Medicine, Beijing 102400, P.R. China
| | - Xu Zhang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jiabin Zheng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Chongxiang Xue
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yumin Zheng
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yixuan Yu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xingyu Lu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zixin Hu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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Matsuda T, Osaki Y, Sekiya M, Shimano H. Early insulin averts hyperglycemic crisis in slow-onset durvalumab-induced checkpoint inhibitor-associated autoimmune diabetes mellitus. J Rural Med 2025; 20:150-155. [PMID: 40182155 PMCID: PMC11962188 DOI: 10.2185/jrm.2024-030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/21/2024] [Indexed: 04/05/2025] Open
Abstract
Objective Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM), a variant of type 1 diabetes, is a rare immune-related adverse events (irAEs) caused by antibody-based immune checkpoint inhibitors. CIADM typically manifests as fulminant or acute-onset type 1 diabetes in the insulin-depleted state. However, we encountered a patient with slow-onset CIADM who initially presented with hyperglycemia without decreased insulin secretion after treatment with durvalumab (an anti-PD-L1 antibody). Patient A 60-year-old man diagnosed with small-cell lung cancer on durvalumab combined with dexamethasone treatment experienced an increase in glycated hemoglobin (HbA1c) from 6.4% to 7.8% after three cycles. Results Despite preserved endogenous insulin secretion (C-peptide, 2.47 ng/mL with a casual plasma glucose level of 287 mg/dL), basal insulin therapy was initiated considering CIADM. HbA1c levels remained stable (8.5-9.2%) for 3 months but increased to 13.4% at 18 weeks, indicative of CIADM. Declining endogenous insulin secretion resulted in ketosis; however, hyperglycemic crisis was prevented through basal insulin therapy. Conclusion We emphasize that CIADM develops gradually and does not always occur in the course of fulminant or acute-onset type 1 diabetes; therefore, early initiation of insulin in the presence of hyperglycemia is crucial to prevent hyperglycemic crises.
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Affiliation(s)
- Takaaki Matsuda
- Department of Endocrinology and Metabolism, University of
Tsukuba Hospital, Japan
| | - Yoshinori Osaki
- Department of Endocrinology and Metabolism, Institute of
Medicine, University of Tsukuba, Japan
| | - Motohiro Sekiya
- Department of Endocrinology and Metabolism, Institute of
Medicine, University of Tsukuba, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of
Medicine, University of Tsukuba, Japan
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张 培, 高 莹, 吴 红, 张 健, 张 俊. [Fulminant type 1 diabetes mellitus with acute pancreatitis: A case report and literature review]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2024; 56:923-927. [PMID: 39397476 PMCID: PMC11480550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Indexed: 10/15/2024]
Abstract
The objective was to report a relatively rare case of fulminant type 1 diabetes (FT1DM) complicated with acute pancreatitis (AP), to summarize the characteristics as well as experience of diagnosis and treatment, and to explore its pathogenesis. Clinical data of a case of FT1DM complicated with AP in the Department of Endocrinology of our hospital were analyzed retrospectively. A 66-year-old male presented with acute fever and abdominal pain, accompanying with the significantly elevated pancreatic enzymes, and his abdominal CT scan showed exudation around the pancreas. The clinical manifestations mentioned above were consistent with the diagnosis of AP. Five days after onset, the patient developed clinical symptoms, such as obvious thirst, polyuria, polyasthenia and fatigue. Meanwhile, his plasma glucose increased significantly and the diabetic ketoacidosis (DKA) occurred. The patient's fasting and postprandial 2 hours C peptide decreased significantly (all 0.02 μg/L), glycated hemoglobin level was not high (6%), and his islet-related autoantibodies were undetectable. Thus, the patient could be diagnosed with FT1DM. After the treatment of fasting, fluid replacement, anti-infection, somatostatin, anticoagulation and intravenous insulin sequential subcutaneous insulin pump, the patient gained the alleviation of pancreatitis, restoration of oral intake, and relatively stable blood glucose levels. Summarizing the characte-ristics of this case and reviewing the literature, FT1DM complicated with AP was relatively rare in FT1DM. Its common characteristics were described below: (1) Most cases started with AP and the blood glucose elevated within 1 week, or some cases had the simultaneously onset of AP and FT1DM. (2) The clinical course of AP was short and relieved no more than 1 week; Pancreatic imaging could completely return to normal within 1 to 4 weeks after onset. (3) The etiology of AP most was idiopathic; The elevation of pancreatic enzyme level was slight and the recovery was rapidly compared with AP of other etiologies. FT1DM could be complicated with AP, which was different from the physiological manifestations of pancreatic disease in general FT1DM patients. Virus infection mignt be the common cause of AP and FT1DM, and AP might be the early clinical manifestation of some FT1DM. The FT1DM patients developed with abdominal pain was easy to be missed, misdiagnosed and delayed, which should receive more attention in clinic.
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Affiliation(s)
- 培恒 张
- />北京大学第一医院内分泌科，北京 100034Department of Endocrinology, Peking University First Hospital, Beijing 100034, China
| | - 莹 高
- />北京大学第一医院内分泌科，北京 100034Department of Endocrinology, Peking University First Hospital, Beijing 100034, China
| | - 红花 吴
- />北京大学第一医院内分泌科，北京 100034Department of Endocrinology, Peking University First Hospital, Beijing 100034, China
| | - 健 张
- />北京大学第一医院内分泌科，北京 100034Department of Endocrinology, Peking University First Hospital, Beijing 100034, China
| | - 俊清 张
- />北京大学第一医院内分泌科，北京 100034Department of Endocrinology, Peking University First Hospital, Beijing 100034, China
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Iwamoto T, Hidaka S, Sada K, Shibata H. Two cases of conventional fulminant type 1 diabetes: following the depletion process of endogenous insulin secretion and literature review. Diabetol Int 2024; 15:861-866. [PMID: 39469544 PMCID: PMC11512938 DOI: 10.1007/s13340-024-00755-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 08/06/2024] [Indexed: 10/30/2024]
Abstract
Fulminant type 1 diabetes (FT1D) is a rapidly progressive form of diabetes in which the endogenous capacity to secrete insulin is depleted. The onset is unpredictable with conventional FT1D, and a few reports have tracked C-peptide in patients with conventional FT1D pre-onset. In this report, we present two typical cases of conventional FT1D where C-peptide was monitored from the onset of precursor symptoms to the development of diabetic ketoacidosis (DKA). Furthermore, we conducted a literature review and provide a detailed description of the process of C-peptide depletion in conventional FT1D. Case 1 involved a 72-year-old woman who initially presented with fever and fatigue. Case 2 involved a 45-year-old woman with fever, abdominal pain, and acute pancreatitis. In both cases, DKA developed five days after initial symptoms. A noteworthy observation in both cases was the drastic drop in C-peptide, which was detectable at initial presentation but depleted by the time of DKA diagnosis. These cases emphasize the importance of close follow-up of plasma glucose and serum C-peptide in cases presenting with infection and pancreatitis. Our literature review revealed that in conventional FT1D, endogenous insulin secretion becomes deficient in an average of 5.3 days. Regardless of any concomitant acute pancreatitis and/or pancreas enlargement, the period until endogenous insulin secretion became deficient showed no substantial variation. This result supports the concept that progression of conventional FT1D is more rapid than that of immune checkpoint inhibitor-related FT1D, which deplete insulin secretion in approximately 2 weeks. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00755-0.
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Affiliation(s)
- Takamasa Iwamoto
- Department of Diabetes and Metabolism, Koseiren Tsurumi Hospital, Oita, Japan
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan
| | - Shuji Hidaka
- Department of Diabetes and Metabolism, Koseiren Tsurumi Hospital, Oita, Japan
| | - Kentaro Sada
- Department of Diabetes and Metabolism, Koseiren Tsurumi Hospital, Oita, Japan
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan
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Greene A, Penner S, Kunesh J, Altaf A, McGrade W, Niu J. Pembrolizumab induced type 1 diabetes mellitus in a patient with metastatic melanoma and literature review on steroids as a treatment option. J Oncol Pharm Pract 2024; 30:1084-1088. [PMID: 38544442 DOI: 10.1177/10781552241241493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
OBJECTIVE We report a case of a 77-year-old male with metastatic melanoma who developed immune-checkpoint-inhibitor (ICI) induced type 1 diabetes mellitus (T1DM) after seven months of pembrolizumab treatment and required life-long insulin use. This prompted a literature review of best practice guidelines for long-term management of checkpoint-inhibitor induced T1DM including oral steroids as a treatment option similar to other ICI adverse effects. DATA SOURCES AND SUMMARY A literature search on PubMed was conducted to evaluate the efficacy of steroid treatment ICI-induced T1DM in any cancer type. Search terms consisted of "ipilimumab" OR "nivolumab" OR & "pembrolizumab" OR "immune checkpoint" AND "diabetes" OR "type 1 diabetes" AND "cancer" OR "melanoma" OR "carcinoma OR "sarcoma". Inclusion criteria were case reports published after 2015 in which the patient was diagnosed with ICI-induced T1DM or diabetic ketoacidosis where oral steroids were part of the treatment. Exclusion criteria included oral steroids not used as a treatment modality for T1DM, multiple endocrine comorbidities, no response recorded, and previous history of T1DM. 284 abstracts were found with these search terms of which 33 full-text articles were concluded to be eligible and screened and from which 8 records were included. From these 8 articles, there were 12 cases included. CONCLUSION This literature search suggests that ICI-induced T1DM cannot be reversed by steroids and that insulin must be used permanently for treatment management.
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Affiliation(s)
- Adina Greene
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Scott Penner
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Jacqueline Kunesh
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Amal Altaf
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - William McGrade
- Department of Internal Medicine, Banner Health, Sun City, AZ, USA
| | - Jiaxin Niu
- Banner MD Anderson Cancer Center, Gilbert, AZ, USA
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Wei HH, Lai YC, Lin G, Lin CW, Chang YC, Chang JWC, Liou MJ, Chen IW. Distinct changes to pancreatic volume rather than pancreatic autoantibody positivity: insights into immune checkpoint inhibitors induced diabetes mellitus. Diabetol Metab Syndr 2024; 16:26. [PMID: 38254155 PMCID: PMC10804587 DOI: 10.1186/s13098-024-01263-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) are promising treatment options for various cancers. However, their use is associated with immune-related adverse events (irAEs), including ICI-induced diabetes mellitus (ICI-DM). This study aimed to investigate the clinical features of ICI-DM, with a particular focus on alterations to pancreatic volume. METHODS We conducted a retrospective review of 2829 patients who received ICI treatment at the Chang Gung Memorial Hospital, Linkou, between January 2014 and December 2021. New-onset diabetes or diabetic ketoacidosis (DKA) was identified in ten patients receiving ICI therapy. Pancreatic volumes were assessed by manual segmentation of computed tomography (CT) images before and after ICI-DM diagnosis. RESULTS Among these ten patients, nivolumab was the most commonly used ICI (50.0%), followed by pembrolizumab (30.0%) and atezolizumab (20.0%). One patient received combination therapy with nivolumab and ipilimumab. The median age was 63.01 years (range: 40.1 - 87.8). ICI-DM developed after a median of 13.5 cycles (range: 2 - 42) of ICI treatment or 9.85 months (range:1.5 - 21.3) since ICI initiation. The initial presentation was DKA in 60.0% of patients. All patients had low or undetectable C-peptide levels (range: <0.033 - 0.133 nmol/L) and were negative for most type 1 diabetes mellitus (T1DM)-related autoantibodies; only one patient tested positive for glutamic acid decarboxylase antibodies. CT imaging revealed significant pancreatic atrophy, with a median pancreatic volume decrease of 19.92% (P = 0.038) from baseline and sustained significant decline at last follow-up (median - 37.14%, P = 0.012). CONCLUSIONS ICI-DM is often accompanied by pancreatic atrophy and approximately two-thirds of patients initially present with DKA. Although the majority of ICI-DM patients lack T1DM-related autoantibodies, identifying diminished pancreatic volumes through CT imaging provides valuable clues into the subclinical aspects of ICI-DM development, aiding in the prevention of diabetic emergencies. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Hung-Hui Wei
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Guishan Dist, Taoyuan City, 333, Taiwan
| | - Ying-Chieh Lai
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Immuno-Oncology Center of Excellence, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Gigin Lin
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan
- Clinical Metabolomics Core, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
- Immuno-Oncology Center of Excellence, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Cheng-Wei Lin
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Guishan Dist, Taoyuan City, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Ya-Chu Chang
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Guishan Dist, Taoyuan City, 333, Taiwan
| | - John Wen-Cheng Chang
- Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan
- Immuno-Oncology Center of Excellence, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Miaw-Jene Liou
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Guishan Dist, Taoyuan City, 333, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
- Immuno-Oncology Center of Excellence, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
| | - I-Wen Chen
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Guishan Dist, Taoyuan City, 333, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
- Immuno-Oncology Center of Excellence, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
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Al-Taie A, Sheta N. Clinically Approved Monoclonal Antibodies-based Immunotherapy: Association With Glycemic Control and Impact Role of Clinical Pharmacist for Cancer Patient Care. Clin Ther 2024; 46:e29-e44. [PMID: 37932154 DOI: 10.1016/j.clinthera.2023.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/17/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Compared with more conventional, nonspecific therapy options, such as radiotherapy and chemotherapy, monoclonal antibodies (mAbs) constitute a crucial approach of cancer treatment. Multiple autoimmune diseases have been observed during treatment with mAb medications, including autoimmune diabetes mellitus (DM). This study provides a narrative review of clinically approved mAbs in cancer treatment and focuses on the development of hyperglycemia and DM arising from using these therapies. Furthermore, it highlights the critical role of oncology clinical pharmacists in the management of autoimmune DM and patient care while using these medications in an oncology setting. METHODS An extensive literature search was conducted using various sources of electronic databases, such as Scopus, Embase, Web of Science, and PubMed, and search engines, such as Google Scholar, for studies on mAb classification, types, mechanisms of action, pharmacokinetic properties, current clinical applications, and the associated common adverse effects with significant recommendations for patient care in an oncology setting, along with focusing on the proposed mechanisms and clinical studies that reported the association of DM after the use of these therapies. FINDINGS There are 4 types (murine, chimeric, humanized, and human) and 3 classes (unconjugated, conjugated, and bispecific) of mAbs with several mechanisms of action that can destroy cancer cells, including preventing tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, evading programmed cell death, and bypassing immune checkpoints. However, multiple endocrinopathies, autoimmune diseases, and complications were reported from the use of these medications, including the development of autoimmune DM and diabetic ketoacidosis. These autoimmune disorders were reported most with the use of immune checkpoint inhibitors, including inhibitors of the programmed cell death protein 1 (nivolumab and pembrolizumab), its ligand (atezolizumab, avelumab, and durvalumab), and cytotoxic T-lymphocyte-associated protein 4 (ipilimumab). IMPLICATIONS mAbs are considered important approaches for the treatment of many cancer types. However, a high incidence of hyperglycemia, type 1 DM, and diabetic ketoacidosis is observed with the use of these medications, particularly immune checkpoint inhibitors. It is important for oncologic clinical pharmacists to be involved in addressing these autoimmune disorders from the use of these immunotherapies via the provision of patient education, medication adherence support, close monitoring, and follow-up, which will lead to better health-related outcomes and improved patient quality of life.
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Affiliation(s)
- Anmar Al-Taie
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye.
| | - Najat Sheta
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye
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Bhanderi H, Khalid F, Bodla ZH, Muhammad T, Du D, Meghal T. Autoimmune diabetes from pembrolizumab: A case report and review of literature. World J Clin Oncol 2023; 14:535-543. [PMID: 38059185 PMCID: PMC10696214 DOI: 10.5306/wjco.v14.i11.535] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/13/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Immunotherapy, specifically the use of checkpoint inhibitors such as pembrolizumab, has become an important tool in personalized cancer therapy. These inhibitors target proteins on T-cells that regulate the immune response against tumor cells. Pembrolizumab, which targets the programmed cell death 1 receptor on T-cells, has been approved for the treatment of metastatic melanoma and non-small cell lung cancer. However, it can also lead to immune-related side effects, including pneumonitis, colitis, thyroid abnormalities, and rare cases of type 1 diabetes. CASE SUMMARY The case presented involves an adult patient in 30s with breast cancer who developed hyperglycemia after receiving pembrolizumab treatment. The patient was diagnosed with diabetic ketoacidosis and further investigations were performed to evaluate for new-onset type 1 diabetes. The patient had a history of hypothyroidism and a family history of breast cancer. Treatment for diabetic ketoacidosis was initiated, and the patient was discharged for close follow-up with an endocrinologist. CONCLUSION This literature review highlights the occurrence of diabetic ketoacidosis and new-onset type 1 diabetes in patients receiving pembrolizumab treatment for different types of cancer. Overall, the article emphasizes the therapeutic benefits of immunotherapy in cancer treatment, particularly pembrolizumab, while also highlighting the potential side effect of immune-related diabetes that can occur in a small percentage of patients. Here we present a case where pembrolizumab lead to development of diabetes after a few cycles highlighting one of the rare yet a serious toxicity of the drug.
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Affiliation(s)
- Hardikkumar Bhanderi
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Farhan Khalid
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Zubair Hassan Bodla
- Department of Internal Medicine, University of Central Florida College of Medicine, Gainesville, FL 32303, United States
| | - Tayyeb Muhammad
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Doantrang Du
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Trishala Meghal
- Department of Hematology-Oncology, Monmouth Medical Center, Long Branch, NJ 07740, United States
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Daetwyler E, Zippelius A, Danioth S, Donath MY, Gut L. Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. Front Immunol 2023; 14:1248919. [PMID: 37965350 PMCID: PMC10640970 DOI: 10.3389/fimmu.2023.1248919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/10/2023] [Indexed: 11/16/2023] Open
Abstract
Background Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including metastatic renal cell carcinoma. However, ICI treatment can lead to endocrine immune-related adverse events (irAEs) by overstimulating the patient's immune system. Here, we report a rare case of a new onset of diabetes mellitus (DM), caused by nivolumab, and we discuss the feasible treatment options with a focus on TNF antagonism. Case presentation A 50-year-old man was diagnosed with metastatic renal cell carcinoma. Due to systemic progression, a combined immunotherapy with ipilimumab and nivolumab was initiated, according to the current study protocol (SAKK 07/17). The administration of ipilimumab was stopped after 10 months, due to partial response as seen in the computer tomography (CT), and nivolumab was continued as monotherapy. Fourteen months after the start of the treatment, the patient was admitted to the emergency department with lethargy, vomiting, blurred vision, polydipsia, and polyuria. The diagnosis of DM with diabetic ketoacidosis was established, although autoantibodies to β-cells were not detectable. Intravenous fluids and insulin infusion treatment were immediately initiated with switching to a subcutaneous administration after 1 day. In addition, the patient received an infusion of the TNF inhibitor infliximab 4 days and 2 weeks after the initial diagnosis of DM. However, the C-peptide values remained low, indicating a sustained insulin deficiency, and the patient remained on basal bolus insulin treatment. Two months later, nivolumab treatment was restarted without destabilization of the diabetic situation. Conclusions In contrast to the treatment of other irAEs, the administration of corticosteroids is not recommended in ICI-induced DM. The options for further treatment are mainly based on the low numbers of case series and case reports. In our case, the administration of infliximab-in an attempt to salvage the function of β-cells-was not successful, and this is in contrast to some previous reports. This apparent discrepancy may be explained by the absence of insulin resistance in our case. There is so far no evidence for immunosuppressive treatment in this situation. Prompt recognition and immediate start of insulin treatment are most important in its management.
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Affiliation(s)
- Eveline Daetwyler
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Alfred Zippelius
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Simona Danioth
- Clinic for Endocrinology, Diabetes & Metabolism, Luzern Cantonal Hospital, Luzern, Switzerland
| | - Marc Y. Donath
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
| | - Lara Gut
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
- Clinic for Endocrinology & Diabetes, Medical University Clinic Baselland, Liestal, Switzerland
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Gao Y, Zhong M, Gan L, Xiang C, Li L, Yan Y. Immune checkpoint inhibitor- and phosphatidylinositol-3-kinase inhibitor-related diabetes induced by antineoplastic drugs: two case reports and a literature review. Front Endocrinol (Lausanne) 2023; 14:1236946. [PMID: 37732122 PMCID: PMC10509015 DOI: 10.3389/fendo.2023.1236946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/17/2023] [Indexed: 09/22/2023] Open
Abstract
Immune checkpoint inhibitor (ICI)- and phosphatidylinositol-3-kinase inhibitor (PI3Ki)-related diabetes mellitus are common side effects of anti-tumor drug use that present mainly as hyperglycemia. Here, we present two case reports of diabetes mellitus caused by the use of tremelimumab and apalutamide, respectively, in cancer treatment, and a comprehensive, comparative review of the literature on these forms of diabetes. Case 1 presented with diabetic ketoacidosis and was diagnosed with ICI-related diabetes mellitus and treated with insulin. Case 2 was diagnosed with PI3Ki-related diabetes mellitus, and her blood glucose level returned to normal with the use of metformin and dapagliflozin. We systematically searched the PubMed database for articles on ICI- and PI3Ki-related diabetes mellitus and characterized the differences in clinical features and treatment between these two forms of diabetes.
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Affiliation(s)
- Yue Gao
- Department of Endocrinology, Xiaogan Hospital Affiliated with Wuhan University of Science and Technology, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
- Medical College, Wuhan University of Science and Technology, Wuhan, China
| | - Mingyao Zhong
- Medical College, Wuhan University of Science and Technology, Wuhan, China
| | - Lulu Gan
- Medical College, Wuhan University of Science and Technology, Wuhan, China
| | - Cheng Xiang
- Department of Endocrinology, Xiaogan Hospital Affiliated with Wuhan University of Science and Technology, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
| | - Ling Li
- Department of Endocrinology, Xiaogan Hospital Affiliated with Wuhan University of Science and Technology, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
| | - Yimin Yan
- Department of Endocrinology, Xiaogan Hospital Affiliated with Wuhan University of Science and Technology, The Central Hospital of Xiaogan, Xiaogan, Hubei, China
- Medical College, Wuhan University of Science and Technology, Wuhan, China
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11
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Huang Y, Zhang W, Xu C, Li Q, Zhang W, Xu W, Zhang M. Presence of PD-1 similarity genes in monocytes may promote the development of type 1 diabetes mellitus and poor prognosis of pancreatic cancer. BMJ Open Diabetes Res Care 2023; 11:11/3/e003196. [PMID: 37130628 PMCID: PMC10163525 DOI: 10.1136/bmjdrc-2022-003196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 04/15/2023] [Indexed: 05/04/2023] Open
Abstract
INTRODUCTION To identify proteins and corresponding genes that share sequential and structural similarity with programmed cell death protein-1 (PD-1) in patients with type 1 diabetes mellitus (T1DM) via bioinformatics analysis. RESEARCH DESIGN AND METHODS All proteins with immunoglobulin V-set domain were screened in the human protein sequence database, and the corresponding genes were obtained in the gene sequence database. GSE154609 was downloaded from the GEO database, which contained peripheral blood CD14+ monocyte samples from patients with T1DM and healthy controls. The difference result and the similar genes were intersected. Analysis of gene ontology and Kyoto encyclopedia of genes and genomes pathways was used to predict potential functions using the R package 'cluster profiler'. The expression differences of intersected genes were analyzed in The Cancer Genome Atlas pancreatic cancer dataset and GTEx database using t-test. The correlation between the overall survival and disease-free progression of patients with pancreatic cancer was analyzed using Kaplan-Meier survival analysis. RESULTS 2068 proteins with immunoglobulin V-set domain similar to PD-1 and 307 corresponding genes were found. 1705 upregulated differentially expressed genes (DEGs) and 1335 downregulated DEGs in patients with T1DM compared with healthy controls were identified. A total of 21 genes were overlapped with the 307 PD-1 similarity genes, including 7 upregulated and 14 downregulated. Of these, mRNA levels of 13 genes were significantly increased in patients with pancreatic cancer. High expression of MYOM3 and HHLA2 was significantly correlated with shorter overall survival of patients with pancreatic cancer, while high expression of FGFRL1, CD274, and SPEG was significantly correlated with shorter disease-free survival of patients with pancreatic cancer. CONCLUSIONS Genes encoding immunoglobulin V-set domain similar to PD-1 may contribute to the occurrence of T1DM. Of these genes, MYOM3 and SPEG may serve as potential biomarkers for the prognosis of pancreatic cancer.
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Affiliation(s)
- Yuquan Huang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wenchuan Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Can Xu
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qingxia Li
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Wu Zhang
- Clinical School of Medicine, North China University of Science and Technology, Tangshan, Hebei, China
| | - Wanfeng Xu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Mingming Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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12
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Percik R, Criseno S, Adam S, Young K, Morganstein DL. Diagnostic criteria and proposed management of immune-related endocrinopathies following immune checkpoint inhibitor therapy for cancer. Endocr Connect 2023; 12:e220513. [PMID: 36884258 PMCID: PMC10160541 DOI: 10.1530/ec-22-0513] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/07/2023] [Indexed: 03/09/2023]
Abstract
Checkpoint inhibitors are now widely used in the management of many cancers. Endocrine toxicity is amongst the most common side effects. These endocrinopathies differ from most other immune-related toxicities in frequently being irreversible and rarely requiring cessation of checkpoint inhibitor therapy. This review considers an approach to the presentation and diagnosis of endocrinopathies, compared to classical endocrine diagnosis, suggesting improvements to classification and treatment based on fundamental endocrine principles. These will help to align management with other similar endocrine conditions and standardise the diagnosis and reporting of endocrine toxicity of checkpoint inhibitors to improve both endocrine and oncological care. In particular, the importance of considering any inflammatory phase (such as painful thyroiditis or hypophysitis resulting in the pituitary enlargement), from the endocrine consequences (transient hyperthyroidism followed by hypothyroidism, pan-hypopituitarism or isolated adrenocorticotrophic hormone deficiency), is highlighted. It is also important to consider the potential confounder of exogenous corticosteroids in adrenal suppression.
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Affiliation(s)
- Ruth Percik
- Institute of Endocrinology, Diabetes and Metabolism, Sheba Medical Centre, Ramat Gan, Israel
| | - Sherwin Criseno
- Department of Endocrinology, University Hospital Birmingham, Birmingham, UK
| | - Safwaan Adam
- Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, UK
| | | | - Daniel L Morganstein
- Department of Endocrinology, Chelsea and Westminster Hospital, London, UK
- Royal Marsden Hospital, London, UK
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13
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Deligiorgi MV, Trafalis DT. A Concerted Vision to Advance the Knowledge of Diabetes Mellitus Related to Immune Checkpoint Inhibitors. Int J Mol Sci 2023; 24:ijms24087630. [PMID: 37108792 PMCID: PMC10146255 DOI: 10.3390/ijms24087630] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/03/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
The rubric of immune-related (ir) diabetes mellitus (DM) (irDM) encompasses various hyperglycemic disorders related to immune checkpoint inhibitors (ICPis). Beyond sharing similarities with conventional DM, irDM is a distinct, yet important, entity. The present narrative review provides a comprehensive overview of the literature regarding irDM published in major databases from January 2018 until January 2023. Initially considered rare, irDM is increasingly being reported. To advance the knowledge of irDM, the present review suggests a concerted vision comprising two intertwined aspects: a scientific-centered and a patient-centered view. The scientific-centered aspect addresses the pathophysiology of irDM, integrating: (i) ICPi-induced pancreatic islet autoimmunity in genetically predisposed patients; (ii) altered gut microbiome; (iii) involvement of exocrine pancreas; (iv) immune-related acquired generalized lipodystrophy. The patient-centered aspect is both nurtured by and nurturing the four pillars of the scientific-centered aspect: awareness, diagnosis, treatment, and monitoring of irDM. The path forward is a multidisciplinary initiative towards: (i) improved characterization of the epidemiological, clinical, and immunological profile of irDM; (ii) standardization of reporting, management, and surveillance protocols for irDM leveraging global registries; (iii) patient stratification according to personalized risk for irDM; (iv) new treatments for irDM; and (v) uncoupling ICPi efficacy from immunotoxicity.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology-Clinical Pharmacology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios T Trafalis
- Department of Pharmacology-Clinical Pharmacology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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14
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Dos Santos Haber JF, Barbalho SM, Sgarbi JA, de Argollo Haber RS, de Labio RW, Laurindo LF, Chagas EFB, Payão SLM. The Relationship between Type 1 Diabetes Mellitus, TNF-α, and IL-10 Gene Expression. Biomedicines 2023; 11:biomedicines11041120. [PMID: 37189738 DOI: 10.3390/biomedicines11041120] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is one of the major chronic diseases in children worldwide. This study aimed to investigate interleukin-10 (IL-10) gene expression and tumor necrosis factor-alpha (TNF-α) in T1DM. A total of 107 patients were included, 15 were T1DM in ketoacidosis, 30 patients had T1DM and HbA1c ≥ 8%; 32 patients had T1DM and presented HbA1c < 8%; and 30 were controls. The expression of peripheral blood mononuclear cells was performed using the reverse transcriptase-polymerase chain reaction in real time. The cytokines gene expression was higher in patients with T1DM. The IL-10 gene expression increased substantially in patients with ketoacidosis, and there was a positive correlation with HbA1c. A negative correlation was found for IL-10 expression and the age of patients with diabetes, and the time of diagnosis of the disease. There was a positive correlation between TNF-α expression with age. The expression of IL-10 and TNF-α genes showed a significant increase in DM1 patients. Once current T1DM treatment is based on exogenous insulin, there is a need for other therapies, and inflammatory biomarkers could bring new possibilities to the therapeutic approach of the patients.
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Affiliation(s)
- Jesselina Francisco Dos Santos Haber
- School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-160, Brazil
- Postgraduate Program of Health and Aging, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
| | - Sandra Maria Barbalho
- School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-160, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia (UNIMAR), Marília 17525-160, Brazil
| | - Jose Augusto Sgarbi
- Postgraduate Program of Health and Aging, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
- Division of Endocrinology and Metabolism, Department of Medicine, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
| | | | - Roger William de Labio
- Department of Genetics, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
| | - Lucas Fornari Laurindo
- School of Medicine, University of Marília (UNIMAR), Avenida Hygino Muzzy Filho, 1001, Marília 17525-160, Brazil
| | - Eduardo Federighi Baisi Chagas
- Postgraduate Program of Health and Aging, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia (UNIMAR), Marília 17525-160, Brazil
| | - Spencer Luiz Marques Payão
- Postgraduate Program of Health and Aging, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
- Department of Genetics, Marilia Medical School (FAMEMA), Monte Carmelo, 800-Fragata, Marília 17519-030, Brazil
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15
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Mulla K, Farag S, Moore B, Matharu S, Young K, Larkin J, Popat S, Morganstein DL. Hyperglycaemia following immune checkpoint inhibitor therapy-Incidence, aetiology and assessment. Diabet Med 2023; 40:e15053. [PMID: 36696014 DOI: 10.1111/dme.15053] [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: 09/20/2022] [Revised: 12/11/2022] [Accepted: 01/23/2023] [Indexed: 01/26/2023]
Abstract
AIMS We systematically studied the presence of hyperglycaemia during treatment with Immune Checkpoint Inhibitors (ICPI) for cancer, in those with and without diabetes at baseline, and determined the cause of new-onset hyperglycaemia, METHODS: Retrospective review of electronic records of those receiving an ICPI for melanoma, lung or renal cancer. RESULTS Overall, 959 participants were included. In this study, 103 had diabetes at baseline (10.7%). Those with lung cancer had the highest frequency of diabetes; 131 people had hyperglycaemia (defined as at least one glucose ≥11.1 mmol/L) in the year after starting an ICPI. The incidence was 55% in those with diabetes at baseline, and 8.6% in those without baseline diabetes. Among 74 with new-onset hyperglycaemia (without pre-existing diabetes) 76% was attributable to steroid induced diabetes, with 9.5% due to ICPI Induced diabetes resembling type 1 diabetes. CONCLUSIONS Hyperglycaemia is common in persons receiving an ICPI for cancer, including 8.6% of those without known diabetes. While much of this is due to glucocorticoid use, care is needed to avoid missing those with ICPI-induced diabetes who are at risk of diabetic ketoacidosis, which is a medical emergency.
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Affiliation(s)
- Kaenat Mulla
- Beta Cell Diabetes Unit, Chelsea and Westminster Hospital, London, UK
| | | | - Benedict Moore
- Beta Cell Diabetes Unit, Chelsea and Westminster Hospital, London, UK
| | | | - Kate Young
- Skin Unit, Royal Marsden Hospital, London, UK
| | | | | | - Daniel Laurence Morganstein
- Beta Cell Diabetes Unit, Chelsea and Westminster Hospital, London, UK
- Lung Unit, Royal Marsden Hospital, London, UK
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16
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Qiu J, Luo S, Yin W, Li X, Zhou Z. Clinical and immunological characteristics of PD-1 associated fulminant type 1 diabetes mellitus. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2023; 48:49-58. [PMID: 36935177 PMCID: PMC10930557 DOI: 10.11817/j.issn.1672-7347.2023.220290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Indexed: 03/21/2023]
Abstract
OBJECTIVES Programmed death 1 (PD-1) associated fulminant type 1 diabetes (PFD) is a rare acute and critical in internal medicine, and its clinical characteristics are still unclear. This study aims to analyze the clinical characteristics of PFD patients to improve clinical diagnosis and treatment. METHODS We retrospectively analyzed the clinical data of 10 patients with PFD admitted to the Second Xiangya Hospital of Central South University, combined with the data of 66 patients reported in the relevant literature, analyzed and summarized their clinical and immunological characteristics, and compared the patients with PFD with different islet autoantibody status. RESULTS Combined with our hospital and literature data, a total of 76 patients with PFD were reported, with the age of (60.9±12.1) years old, 60.0% male and body mass index of (22.1±5.2) kg/m2. In 76 patients, the most common tumors were lung cancer (43.4%) and melanoma (22.4%). Among PD-1 inhibitors, the most common drugs are nivolumab (37.5%) and pembrolizumab (38.9%). 82.2% of PFD patients developed diabetes ketoacidosis. The median onset time from PD-1 related inhibitor treatment to hyperglycemia was 95 (36.0, 164.5) d, and the median treatment cycle before the onset of diabetes was 6 (2.3, 8.0) cycles. 26% (19/73) of PFD patients had positive islet autoantibodies, and the proportion of ketoacidosis in the positive group was significantly higher than that in the negative group (100.0% vs 75.0%, P<0.05). The onset time and infusion times of diabetes after PD-1 inhibitor treatment in the autoantibody positive group were significantly lower than those in the autoantibody negative group (28.5 d vs 120.0 d; 2 cycles vs 7 cycles, both P<0.001). CONCLUSIONS After initiation of tumor immunotherapy, it is necessary to be alert to the occurrence of adverse reactions of PFD, and the onset of PFD with islet autoantibody positive is faster and more serious than that of patients with autoantibodies negative. Detection of islet autoantibodies and blood glucose before and after treatment with PD-1 inhibitors is of great value for early warning and prediction of PFD.
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Affiliation(s)
- Junlin Qiu
- Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Ministry of Education, Key Laboratory of Diabetes Immunology (Central South University); National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Ministry of Education, Key Laboratory of Diabetes Immunology (Central South University); National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.
| | - Wenfeng Yin
- Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Ministry of Education, Key Laboratory of Diabetes Immunology (Central South University); National Clinical Research Center for Metabolic Diseases, Changsha 410011, China
| | - Xia Li
- Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Ministry of Education, Key Laboratory of Diabetes Immunology (Central South University); National Clinical Research Center for Metabolic Diseases, Changsha 410011, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Ministry of Education, Key Laboratory of Diabetes Immunology (Central South University); National Clinical Research Center for Metabolic Diseases, Changsha 410011, China
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17
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Zhang W, Chen J, Bi J, Ding N, Chen X, Wang Z, Jiao Y. Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM. Front Endocrinol (Lausanne) 2023; 13:1084441. [PMID: 36686495 PMCID: PMC9846077 DOI: 10.3389/fendo.2022.1084441] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/14/2022] [Indexed: 01/05/2023] Open
Abstract
Background Combined diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) secondary to immune checkpoint inhibitors (ICIs) is extremely rarely reported among ICIs- diabetes mellitus (DM) cases and is always ignored by physicians. This study aimed to conduct a systematic review to recognize better the rare adverse event of combined DKA-HHS associated with immune checkpoints. Methods A electronic search in Pubmed/Cochrane/Web of Science, complemented by manual searches in article references, was conducted to identify clinical features of ICIs-combined DKA-HHS. Results we identified 106 patients with ICIs- type 1 diabetes mellitus (T1DM) from 82 publications: 9 patients presented a coexistence of metabolic acidosis, severe hyperglycemia, and/or DKA; All patients were not diagnosed as combined DKA-HHS. Compared with ICIs-DKA patients, combined DKA-HHS cases were prone to higher hyperglycemia (1020 ± 102.5 vs 686.7 ± 252.6mg/dL). Moreover, acute kidney injury (87.5% vs 28.6%) and prior chemotherapy (66.7% vs 31.6%) showed higher occurrences with the onset of ICIs-HHS or combined DKA-HHS.B. Conclusions Combined DKA-HHS portends a poor diagnosis in patients with coexistence features of DKA and HHS, which healthcare professionals and patients should be aware of due to differences in treatment. Our observational retrospective case series shows that patients with more risk factors were more likely to develop combined DKA-HHS. We are the first to report this group of patients' clinical characteristics and outcomes.
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Affiliation(s)
- Wenjing Zhang
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jiexiu Chen
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Clinical Pharmacy, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Juan Bi
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Nan Ding
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xin Chen
- Department of Pharmacy, Anhui Provincial Corps Hospital, Chinese Peoples Armed Police Force, Hefei, China
| | - Zhuo Wang
- Department of Pharmacy, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yang Jiao
- Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China
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18
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Pastor Alcaraz A, Marín Martínez L, Kyriakos G, Álvarez Martín MC, Hernández Alonso E. Abrupt-onset diabetes mellitus secondary to pembrolizumab. ENDOCRINOLOGIA, DIABETES Y NUTRICION 2023; 70:71-73. [PMID: 36697277 DOI: 10.1016/j.endien.2022.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/27/2022] [Indexed: 01/25/2023]
Affiliation(s)
- Adrián Pastor Alcaraz
- Servicio de Endocrinología y Nutrición, Hospital General Universitario Santa Lucía, Cartagena, Spain.
| | - Luis Marín Martínez
- Servicio de Endocrinología y Nutrición, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Georgios Kyriakos
- Servicio de Endocrinología y Nutrición, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - María C Álvarez Martín
- Servicio de Endocrinología y Nutrición, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Enrique Hernández Alonso
- Servicio de Endocrinología y Nutrición, Hospital General Universitario Santa Lucía, Cartagena, Spain
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19
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Lee M, Jeong K, Park YR, Rhee Y. Increased risk of incident diabetes after therapy with immune checkpoint inhibitor compared with conventional chemotherapy: A longitudinal trajectory analysis using a tertiary care hospital database. Metabolism 2023; 138:155311. [PMID: 36122764 DOI: 10.1016/j.metabol.2022.155311] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Immune checkpoint inhibitor (ICI) has been emerged as a promising cancer treatment. However, ICI use induces immune-related adverse events, including diabetes mellitus. We compared the risk of new-onset diabetes between patients receiving an ICI and those receiving conventional chemotherapy (CC). METHODS Using a tertiary care hospital database, we included cancer patients without a previous history of diabetes who were treated with either CC or an ICI. One-to-five nearest neighbor propensity matching was applied, and the risk of diabetes was estimated using a Cox proportional hazards model. Latent class growth modeling was performed with a trajectory approach to determine distinct clusters that followed similar glucose trajectory patterns over time. RESULTS Among 1326 subjects, 1105 received CC, and 221 received an ICI. The risk of new-onset diabetes was significantly higher in the ICI group than the CC group (adjusted hazard ratio 2.454, 95 % confidence interval 1.528-3.940; p < 0.001). The ICI group had a higher proportion of subjects in the trajectory cluster with an increasing glucose pattern than the CC group (10.4 % and 7.4 %, respectively). Within the ICI group, the subjects with an increasing glucose pattern were predominantly male and associated with enhanced lymphocytosis after ICI administration. CONCLUSIONS ICI therapy is associated with an increased risk of incident diabetes compared with CC. The glucose levels of patients treated with an ICI, especially males and those with prominent lymphocytosis after ICI treatment, need to be monitored regularly to detect ICI-associated diabetes as early as possible.
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Affiliation(s)
- Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyeongseob Jeong
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Rang Park
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Yumie Rhee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
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20
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Hassan EM, Mushtaq H, Mahmoud EE, Chhibber S, Saleem S, Issa A, Nitesh J, Jama AB, Khedr A, Boike S, Mir M, Attallah N, Surani S, Khan SA. Overlap of diabetic ketoacidosis and hyperosmolar hyperglycemic state. World J Clin Cases 2022; 10:11702-11711. [PMID: 36405291 PMCID: PMC9669841 DOI: 10.12998/wjcc.v10.i32.11702] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 11/08/2022] Open
Abstract
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia state (HHS) are two life-threatening metabolic complications of diabetes that significantly increase mortality and morbidity. Despite major advances, reaching a uniform consensus regarding the diagnostic criteria and treatment of both conditions has been challenging. A significant overlap between these two extremes of the hyperglycemic crisis spectrum poses an additional hurdle. It has well been noted that a complete biochemical and clinical patient evaluation with timely diagnosis and treatment is vital for symptom resolution. Worldwide, there is a lack of large-scale studies that help define how hyperglycemic crises should be managed. This article will provide a comprehensive review of the pathophysiology, diagnosis, and management of DKA-HHS overlap.
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Affiliation(s)
- Esraa Mamdouh Hassan
- Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Hisham Mushtaq
- Medicine, St. Vincent's Medical Center, Bridgeport, CT 06606, United States
| | - Esraa Elaraby Mahmoud
- Medicine, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sherley Chhibber
- Medicine, Mercy Catholic Medical Center, Darby, PA 19025, United States
| | - Shoaib Saleem
- Medicine, Mayo Hospital, Lahore 54000, Punjab, Pakistan
| | - Ahmed Issa
- Medicine, Medical University of the Americas, Nevis, West Indies
| | - Jain Nitesh
- Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Abbas B Jama
- Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Anwar Khedr
- Medicine, BronxCare Health System, Bronx, NY 10457, United States
| | - Sydney Boike
- Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, United States
| | - Mikael Mir
- Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, United States
| | - Noura Attallah
- Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Salim Surani
- Medicine & Pharmacology, Texas A&M University Health Science Center, College Station, TX 77843, United States
- Anesthesiolgy, Mayo Clinic, Rochester, MN 55905, United States
| | - Syed A Khan
- Critical Care Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
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21
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Sano H, Imagawa A. Re-Enlightenment of Fulminant Type 1 Diabetes under the COVID-19 Pandemic. BIOLOGY 2022; 11:1662. [PMID: 36421377 PMCID: PMC9687436 DOI: 10.3390/biology11111662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 12/26/2024]
Abstract
Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes (T1D) that is characterized by the rapid progression to diabetic ketoacidosis against the background of rapid and almost complete pancreatic islet destruction. The HbA1c level at FT1D onset remains normal or slightly elevated despite marked hyperglycemia, reflecting the rapid clinical course of the disease, and is an important marker for diagnosis. FT1D often appears following flu-like symptoms, and there are many reports of its onset being linked to viral infections. In addition, disease-susceptibility genes have been identified in FT1D, suggesting the involvement of host factors in disease development. In most cases, islet-related autoantibodies are not detected, and histology of pancreatic tissue reveals macrophage and T cell infiltration of the islets in the early stages of FT1D, suggesting that islet destruction occurs via an immune response different from that occurring in autoimmune type 1 diabetes. From 2019, coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread worldwide and became a serious problem. Reports on the association between SARS-CoV-2 and T1D are mixed, with some suggesting an increase in T1D incidence due to the COVID-19 pandemic. When discussing the association between COVID-19 and T1D, it is also necessary to focus on FT1D. However, it is not easy to diagnose this subtype without understanding the concept. Therefore, authors hereby review the concept and the latest findings of FT1D, hoping that the association between COVID-19 and T1D will be adequately evaluated in the future.
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Affiliation(s)
- Hiroyuki Sano
- Department of Internal Medicine (I), Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
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22
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Ishiguro A, Ogata D, Ohashi K, Hiki K, Yamakawa K, Jinnai S, Tsutsui K, Takahashi A, Namikawa K, Yamazaki N. Type 1 diabetes associated with immune checkpoint inhibitors for malignant melanoma: A case report and review of 8 cases. Medicine (Baltimore) 2022; 101:e30398. [PMID: 36107581 PMCID: PMC9439787 DOI: 10.1097/md.0000000000030398] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Advanced malignant melanoma (MM) is treated with immune checkpoint inhibitor (ICI) therapy, which often results in several immune-related adverse events. Fulminant type 1 diabetes mellitus (T1DM) is a rare, rapidly progressive, life-threatening disease. Here, we summarize 8 cases of MM with ICI-induced T1DM and describe one case that developed fulminant T1DM due to nivolumab therapy. We retrospectively reviewed patients treated with ICI from 2014 to 2021 at our hospital. The clinical features and risk factors of ICI-induced T1DM were discussed. ICIs were administered to 426 MM patients at our hospital. Among these, nivolumab was administered in 5 cases, pembrolizumab in 1 case, and the combination of nivolumab and ipilimumab in 2 cases. The frequency of ICI-associated T1DM was 1.88%. The mean glycated hemoglobin level at T1DM onset was 8.0 ± 1.0%. Of the patients, 75% were diagnosed with fulminant T1DM, 62.5% developed diabetic ketoacidosis, and 25% had glutamic acid decarboxylase (GAD) antibodies (an early predictive marker for T1DM). The mean interval between the first ICI administration and T1DM development was 201 ± 187 days. The mean duration of resumption was 13 ± 7 days. We should monitor for T1DM development following treatment with ICIs. ICI can be continued to be used to treat MM if insulin therapy successfully controls T1DM. A 67-year-old patient who received adjuvant nivolumab therapy developed fulminant T1DM and thyrotoxicosis 57 days later and tested positive for GAD antibodies. Subsequently, he developed hypophysitis and an isolated adrenocorticotropin deficiency. He continued receiving nivolumab along with self-injected insulin without developing recurrence.
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Affiliation(s)
- Akihiro Ishiguro
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Dai Ogata
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
- *Correspondence: Dai Ogata, Department of Dermatologic Oncology, National Cancer Center Hospital, Tsukiji Campus, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan (e-mail: )
| | - Ken Ohashi
- Department of General Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Kojiro Hiki
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kohei Yamakawa
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shunichi Jinnai
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Keita Tsutsui
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Akira Takahashi
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kenjiro Namikawa
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Naoya Yamazaki
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
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23
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Pastor Alcaraz A, Marín Martínez L, Kyriakos G, Álvarez Martín MC, Hernández Alonso E. Diabetes mellitus de comienzo abrupto secundaria a pembrolizumab. ENDOCRINOL DIAB NUTR 2022. [DOI: 10.1016/j.endinu.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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24
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Lin C, Li X, Qiu Y, Chen Z, Liu J. PD-1 inhibitor-associated type 1 diabetes: A case report and systematic review. Front Public Health 2022; 10:885001. [PMID: 35991054 PMCID: PMC9389003 DOI: 10.3389/fpubh.2022.885001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/22/2022] [Indexed: 12/01/2022] Open
Abstract
Objective This study aimed to summarize the clinical characteristics of programmed death receptor 1 (PD-1) inhibitor-associated type 1 diabetes so as to improve the ability of clinicians to correctly diagnose and treat it. Methods We reported a case of a 70-year-old woman with gastric cancer who developed hyperosmolar hyperglycemic coma during camrelizumab (a PD-1 inhibitor) treatment and was diagnosed with PD-1 inhibitor-associated type 1 diabetes. We conducted a systematic review of 74 case reports of type 1 diabetes associated with PD-1 inhibitor therapy published before June 2022. Results The patient developed type 1 diabetes with hyperosmolar hyperglycemic coma after receiving camrelizumab chemotherapy for 6 months (9 cycles). We searched 69 English articles comprising 75 patients, all of whom had been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and progressed to diabetes after an average of 6.11 (1–28) cycles. Nivolumab combined with ipilimumab (a cytotoxic T lymphocyte-associated protein 4 inhibitor) had the shortest onset (4.47 cycles on average). A total of 76% (57/75) of patients developed diabetic ketoacidosis (DKA) at onset, and 50.67% (38/75) of patients had C-peptide <0.1 ng/mL. Most of the patients were tested for insulin autoantibodies, with a positive rate of 33.33% (23/69); of these, 86.96% (20/23) were tested for glutamate decarboxylase antibody and 46.67% (35/75) were tested for human leukocyte antigen (HLA). HLA-DR4 was the most common type. Conclusions The progression of type 1 diabetes induced by PD-1 inhibitors is relatively rapid. Islet failure often occurs when detected, seriously endangering patients' lives. Patients treated with PD-1 inhibitors should closely monitor their plasma glucose level during treatment to detect, diagnose, and treat diabetes on time.
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25
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Joharatnam-Hogan N, Morganstein DL. Diabetes and Cancer - optimising glycaemic control. J Hum Nutr Diet 2022; 36:504-513. [PMID: 35748508 DOI: 10.1111/jhn.13051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/31/2022] [Indexed: 01/08/2023]
Abstract
Diabetes and cancer are both common and increasingly prevalent conditions, but emerging epidemiological evidence confirms that the risk of developing a number of common cancers is increased in those with type 2 diabetes. The risk of cancer in type 1 diabetes is less clearly defined, and therefore this review will focus on type 2 diabetes. Emerging evidence also supports an influence of diabetes on outcomes of cancer treatment. However, this relationship is bi-directional, with cancer and its treatment impacting on glucose control, whilst there is also emerging evidence that diabetes care can deteriorate after a cancer diagnosis (summarised in Figure 1). Despite these clear links there is a lack of evidence to guide clinicians in how to manage patients with diabetes during their cancer treatment. Although recent UK guidelines have started to address this, with the development of guidance for the management of hyperglycaemia in cancer, there is a clear need for wider guidance on the management of multi-morbidity during cancer, including diabetes and obesity, to incorporate nutritional management We have therefore undertaken a narrative review of the evidence of links between type 2 diabetes and cancer incidence and outcomes, and discuss the challenges to diabetes care during cancer treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
| | - Daniel L Morganstein
- Royal Marsden Hospital, Fulham Roal, London, SW3 6JJ, UK.,Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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26
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Zheng ZK, Wang JL, Li WX, Wu TQ, Chen MS, Zhou ZG. Anti-programmed Cell Death Protein-1 Therapy in Intrahepatic Cholangiocarcinoma Induced Type 1 Diabetes: A Case Report and Literature Review. Front Public Health 2022; 10:917679. [PMID: 35784237 PMCID: PMC9243496 DOI: 10.3389/fpubh.2022.917679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/25/2022] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoint inhibitors, widely used in the treatment of malignancies, can improve the prognosis of patients, while it also can induce various immune-related adverse events, and type 1 diabetes induced by anti-programmed cell death protein-1 is a rare but severe complication. Here we reported a case of type 1 diabetes induced by anti-PD-1 which was to treat intrahepatic cholangiocarcinoma. The case was a 61-year-old female who developed diabetes and ketoacidosis symptoms at the 16th week after anti-PD-1 therapy. Her blood glucose was 30.32 mmol/L, HBA1c was 8.10%, and C-peptide was <0.10 ng/ml. The patient was diagnosed as fulminant type 1 diabetes mellitus complicated with ketoacidosis induced by anti-PD-1, and was treated with massive fluid rehydration, intravenous infusion of insulin and correction of acid-base electrolyte disorder. Hepatectomy was performed after stabilization, and the patient was treated with long-term insulin. Through the case report and literature review, this study aims to improve oncologists' understanding of anti-PD-1 induced type 1 diabetes, so as to make early diagnosis and treatment of the complications and ensure medical safety.
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Affiliation(s)
- Zhi-Kai Zheng
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Jiong-Liang Wang
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Wen-Xuan Li
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Tian-Qing Wu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Min-Shan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Zhong-Guo Zhou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Zhong-Guo Zhou
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27
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Abstract
Type 1 diabetes, in part, has been recently reported as a side effect of immune checkpoint inhibitors (ICIs). The frequency of type 1 diabetes related to ICIs is estimated to be ∼3.5%. However, type 1 diabetes related to ICIs often presents with diabetic ketoacidosis or ketosis within approximately 2 weeks after hyperglycemic symptoms, such as dry mouth, polydipsia, and polyuria, necessitating urgent diagnosis and insulin treatment. Endogenous insulin secretion is depleted within 3 weeks of the clinical onset of type 1 diabetes. Moreover, the positive rate for islet-related autoantibodies has been shown to vary from 5% to 50%, and exocrine pancreatic enzyme levels are mildly increased. Thus, the clinical course of type 1 diabetes associated with ICIs is similar to that of fulminant type 1 diabetes. In this review, we describe the clinical features of type 1 diabetes associated with ICIs.
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Affiliation(s)
- Megumi Tachibana
- Department of Internal Medicine Osaka Medical and Pharmaceutical University 2-7 Daigaku-cho, Takatsuki 569-8686, Japan.
| | - Akihisa Imagawa
- Department of Internal Medicine Osaka Medical and Pharmaceutical University 2-7 Daigaku-cho, Takatsuki 569-8686, Japan.
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28
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[Two Case Reports of Type 2 Diabetes Induced by Immune Checkpoint Inhibitors
Combined with Chemotherapy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:287-290. [PMID: 35477193 PMCID: PMC9051303 DOI: 10.3779/j.issn.1009-3419.2022.102.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have become an important means of cancer treatment, and their application in the clinic is becoming more and more widespread. The adverse reactions caused by ICIs are gradually recognized. Among them, immunotherapy-related diabetes is a rare adverse reaction and type 1 diabetes mellitusis common. With the wide application of ICIs combined with chemotherapy in lung cancer patients, patients with type 2 diabetes mellitus have gradually been discovered during the treatment. However, the effect of continued use of ICIs maintenance therapy on blood glucose and ICIs treatment process in these patients is still unclear. This article reports two cases of type 2 diabetes mellitus induced by immune checkpoint inhibitor combined with chemotherapy, one of whom converted to type 1 diabetes mellitus, in order to increase the understanding of immunotherapy-related diabetes.
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29
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Chiloiro S, Bianchi A, Giampietro A, Milardi D, De Marinis L, Pontecorvi A. The changing clinical spectrum of endocrine adverse events in cancer immunotherapy. Trends Endocrinol Metab 2022; 33:87-104. [PMID: 34895977 DOI: 10.1016/j.tem.2021.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several malignancies, improving patient survival and quality of life. Endocrinopathies have emerged as a clinically significant group of immune-related adverse events (IRAEs). Although the mechanism of ICI toxicities has not been clarified, inhibition of immune checkpoints reduces immune tolerance to autoantigens, resulting in the development of autoimmunity disorders. We report current evidence regarding endocrine IRAEs that may have diagnostic and therapeutic implications. Management should be focused on a multidisciplinary approach to reach a prompt diagnosis and an appropriate and safe treatment.
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Affiliation(s)
- Sabrina Chiloiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy.
| | - Antonio Bianchi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Antonella Giampietro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Domenico Milardi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Laura De Marinis
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
| | - Alfredo Pontecorvi
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Roma, Italy; Unità Operativa Complessa (UOC) Endocrinology and Diabetology, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Roma, Italy
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30
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Zand Irani A, Almuwais A, Gibbons H. Immune checkpoint inhibitor-induced diabetes mellitus with pembrolizumab. BMJ Case Rep 2022; 15:15/1/e245846. [PMID: 35039353 PMCID: PMC8768469 DOI: 10.1136/bcr-2021-245846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
An 81-year-old woman with a background of metastatic melanoma on pembrolizumab with no history of diabetes was brought into the emergency department with polyuria, polydipsia and weight loss. The initial assessment was consistent with severe diabetic ketoacidosis (DKA) and prerenal acute kidney injury with no clinical evidence of infection. The patient was treated with fluid resuscitation and an insulin infusion and eventually transitioned to a basal-bolus insulin regime, which was continued after discharge. Diabetes autoantibody screen returned negative, and she was diagnosed with immune checkpoint inhibitor–induced diabetes mellitus (ICI-induced DM) due to pembrolizumab. The patient has clinically improved and pembrolizumab was continued. The aim of this report is to highlight the importance of recognising ICI-induced DM as a rare immune-related adverse event in patients receiving programmed cell death protein 1/programmed cell death protein-ligand 1 inhibitor therapy and provide clinicians with insight into immune checkpoint endocrinopathies with an emphasis on diabetes and DKA.
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Affiliation(s)
- Anis Zand Irani
- Endocrinology, Gympie Hospital, Gympie, Queensland, Australia
| | - Ahmed Almuwais
- Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Holly Gibbons
- Medicine, Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
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31
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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32
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This S, Valbon SF, Lebel MÈ, Melichar HJ. Strength and Numbers: The Role of Affinity and Avidity in the 'Quality' of T Cell Tolerance. Cells 2021; 10:1530. [PMID: 34204485 PMCID: PMC8234061 DOI: 10.3390/cells10061530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 11/17/2022] Open
Abstract
The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the 'function' and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the 'quality' of anergic and regulatory T cell populations.
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Affiliation(s)
- Sébastien This
- Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; (S.T.); (S.F.V.); (M.-È.L.)
- Département de Microbiologie, Immunologie et Infectiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Stefanie F. Valbon
- Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; (S.T.); (S.F.V.); (M.-È.L.)
- Département de Microbiologie, Immunologie et Infectiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Marie-Ève Lebel
- Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; (S.T.); (S.F.V.); (M.-È.L.)
| | - Heather J. Melichar
- Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; (S.T.); (S.F.V.); (M.-È.L.)
- Département de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada
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33
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Anderson B, Morganstein DL. Endocrine toxicity of cancer immunotherapy: clinical challenges. Endocr Connect 2021; 10:R116-R124. [PMID: 33544091 PMCID: PMC8052567 DOI: 10.1530/ec-20-0489] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 02/04/2021] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune-related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune-related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.
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Affiliation(s)
- Bliss Anderson
- Department of Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Daniel L Morganstein
- Department of Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
- Correspondence should be addressed to D L Morganstein:
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