iMDT Corner Page 1 of 9 Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature Juan Yan1, Zheng-Zheng Xie2, Teresa Moran3,4,5,6, Cesare Gridelli7, Mao-Dong Zheng1, Su-Juan Dai8 1 Department of Pharmacy, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China; 2Department of Pharmacy, Beijing Shijitan Hospital, Beijing, China; 3Medical Oncology Department, Catalan Institute of Oncology Badalona, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 4Institut Germans Trias i Pujol, Barcelona, Spain; 5Badalona Applied Research Group in Oncology, Barcelona, Spain; 6Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus Can Ruti, Barcelona, Spain; 7Division of Medical Oncology, ‘S. G. Moscati’ Hospital, Avellino, Italy; 8Department of Pharmacy, Zengchen District People’s Hospital of Guangzhou (Boji-Affiliated Hospital of Sun Yat-sen University), Guangzhou, China Contributions: (I) Conception and design: J Yan, ZZ Xie; (II) Administrative support: MD Zheng; (III) Provision of study materials or patients: J Yan; (IV) Collection and assembly of data: T Moran, C Gridelli; (V) Data analysis and interpretation: SJ Dai; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Zheng-Zheng Xie. Department of Pharmacy, Beijing Shijitan Hospital, No. 10 Tieyi Road, Haidian District, Beijing, China. Email: xie_zhengzheng@126.com. Background: Nivolumab is the first programmed cell death receptor 1 (PD-1) inhibitor approved in China. Compared with chemotherapy, nivolumab has shown advantages of good efficacy and safety in the treatment of a variety of tumors. However, due to its short time of use in China and lack of safety experience, clinical understanding of its adverse reactions has not been sufficiently elucidated. In recent years, cases of diabetic ketoacidosis caused by nivolumab have been reported in the emergency department, which has aroused our concern. Case Description: Here we present a serious case of diabetic ketoacidosis in a 69-year-old woman with invasive mucinous adenocarcinoma of the lung, which occurred following therapy with the PD-1 inhibitor nivolumab and dendritic cell/cytokine-induced killer cell (DC/CIK) immunotherapy. She presented with diabetic ketoacidosis 5 days after the second cycle of nivolumab administration. The patient presented with dry mouth symptoms, a maximum blood glucose of 511.2 mg/dL, hemoglobin A1c (HbA1c) level of 7.4%, urine ketone body value of 3+, and extracellular fluid residual alkali level of −3.8 mmol/L. Normal saline and insulin was initiated. The patient had no history of obesity or family history of diabetes. She received a single dose of 3.75 mg of dexamethasone treatment during this period of time which resulted in cough improvement, but did not explain the onset of the diabetes. She was treated with insulin, sitagliptin phosphate tablets and acarbose tablets. Diabetic ketoacidosis was considered an immune-related toxicity caused by nivolumab, and consequently, treatment with nivolumab was suspended. Patient was maintained under insulin treatment with a blood glucose levels normalization. Conclusions: The incubation period of nivolumab-induced diabetic ketoacidosis is dispersive and the clinical risk is high. Patients need life-long insulin therapy. Blood glucose and HbA1c should be monitored routinely before and during nivolumab immunotherapy to avoid the occurrence of diabetic ketoacidosis. After the occurrence of diabetic ketoacidosis, insulin should be used to actively control blood glucose and do a good job in medication education to ensure long-term compliance of patients. Nivolumab should only be initiated if the patient has a clinical benefit under stable glucose control. Keywords: Diabetic ketoacidosis; immunotherapy adverse effects; nivolumab; programmed cell death receptor 1 inhibitor (PD-1 inhibitor); case report © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Page 2 of 9 Yan et al. Diabetic ketoacidosis induced by nivolumab Submitted Aug 25, 2022. Accepted for publication Nov 10, 2022. doi: 10.21037/atm-22-5211 View this article at: https://dx.doi.org/10.21037/atm-22-5211 history was unremarkable. Since the onset of the disease, Introduction she had been asymptomatic. With the advent of immunotherapy, an increasing number Her oncology medical history started in September of patients are receiving this type of therapy as part of 2016, when a chest CT detected nodules in the left lower their antitumor treatment. Immune checkpoint inhibitors lung. Patient denied cough, sputum, hemoptysis, chest (ICIs), which differs from traditional chemotherapy both pain, or fever. In March 2017, a follow-up chest CT which in its mechanism of action and toxicity, arise new medical found an enlargement of such lung nodules which measured problems and challenges for oncologists and other health 41 mm × 23 mm. She underwent a lobectomy and care providers. mediastinal lymph node dissection. Postoperative pathology Nivolumab is a human monoclonal antibody that blocks report indicated infiltrative mucinous adenocarcinoma. The the interaction between programmed cell death receptor tumor reached subpleural tissue and did not break through 1 (PD-1) and its ligands, namely PD-L1 and PD-L2 (1). the elastic layer. The results of pathological were as follows: Nivolumab related adverse events (AEs) were documented Lymph nodes 0/6, NapsinA(−), TTF-1 (individual +), P40 in 74–85% of patients (2). Endocrine related AEs represent (−), ck5/6 (−), ALK (−). The tumor stage was postoperative the most common form of immune related (IR)-AE, being stage T2aN0M0, IB. She has been taking Chinese medicine thyroid alterations the most prevalent (3). However, de novo since her operation. In October 2017, a follow up CT diabetes induced by treatment with immunotherapy occurs showed a left partial pleural thickening accompanied by at low frequency (<1%) (4). a small amount of pleural effusion, and both lungs were Recently, cases of diabetic ketoacidosis have been scattered with chronic inflammation images. In April 2018, reported in patients treated with nivolumab. Here, we she developed a cough and had blood in her sputum. She report a case of diabetic ketoacidosis following treatment received several courses of antibiotic with no improvement. with nivolumab and dendritic cell/cytokine-induced killer In May 2018, additional molecular testing was performed in cell (DC/CIK) immunotherapy. This case study suggests the surgical tissue specimens. BRAF and ROS1 results came this infrequent endocrine IR-AEs might occur early after back as negative, and EGFR was wild type. In August 2018, immunotherapy administration, and biochemical and a PET-CT showed that the left thoracic surgical cavity was imaging examinations should be carried out regularly. For covered with hydrops, and the surrounding tissue of the patients with normal results, it is recommended that blood hydrops had diffused thickening with small nodules and glucose levels be tested every 2 to 3 weeks. We present the increased FDG metabolism, suggesting pleural infiltration. following article in accordance with the CARE reporting Additionally, small intraparenchimatous nodules in left lung checklist (available at https://atm.amegroups.com/article/ tip, suggesting intrapulmonary metastasis were identified, view/10.21037/atm-22-5211/rc). as well as a metabolism increase in both supraclavicular and bilateral mediastinal lymph nodes. Further findings consisted of a solid density patchy lesion, with no increase Case presentation in metabolism consistent with inflammatory lesion. A 69-year-old female was admitted to Beijing Shijitan On September 6, 2018, the pleural fluid inside the left Hospital on October 7, 2018, 2.5 years after she was chest cavity was sticky and difficult to extract. Pleural diagnosed with nodules in her lower left lung, 1.5 years microorganism testing found Bacillus cereus and no fungal after her left lung surgery which confirmed a lung cancer growth. On September 13, bronchoscopy revealed that the diagnosis. The patient had a prior history of hypertension right bronchus and the branch lumen were unobstructed, for more than 20 years, gallstones, and kidney stones, and the mucosa was smooth, there were many white serous no history of diabetes. She had always been in good health secretions in the lumen, and no hemorrhage or new and denied any history of smoking or drinking. She also organisms were found. With full informed consent, the denied any history of drug or food allergies. Her family patient was treated with nivolumab and DC/CIK cells. On © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Annals of Translational Medicine, Vol 10, No 22 November 2022 Page 3 of 9 September 18, she was given an intravenous injection of than normal after meals. Doctors fully communicated nivolumab (140 mg) with no relevant AEs. On September with the patient, and according to the patient’s disease 21, her peripheral blood was extracted for DC/CIK cell and physical condition, treatment with nivolumab was culture. suspended, and only DC/CIK immunotherapy was used The patient was admitted for the second cycle of to treat lung cancer. During the treatment, the patient’s treatment. On October 9, she was given an intravenous fasting blood glucose was within the normal range, and no injection of nivolumab (140 mg) for the second time. The AEs occurred. After discharge, the patient was followed first cycle of DC/CIK cells was administered intravenously up on December 2. She took her medication regularly and on October 10, 12, and 15. On October 14, she presented her fasting blood glucose was in the normal range. Since severe dizziness after getting up in the morning, and her no complications appeared after the third course of therapy blood sugar levels were 426.6 mg/dL. Results of blood with DC/CIK, nivolumab was definitively halted. After routine examination showed ketone body (2+). These findings 5 cycles of DC/CIK immunotherapy, the patient was treated suggested a diabetic ketosis. Under the Endocrinologist in another hospital due to disease progression (see Figure 1). supervision, treatment with an intravenous infusion of Diabetic ketoacidosis is one of the hyperglycemic 0.9% Sodium chloride injection (500 mL) plus insulin (4 U) crisis and one of acute complications of diabetes mellitus. intravenous infusion was started and blood glucose levels The main clinical manifestations were hyperglycemia, were closely monitor. After a short-term infusion, blood hyperketone and metabolic acidosis. When the condition is glucose dropped below 325 mg/dL. Supportive therapy with serious, acidosis and water electrolyte metabolic disorder are an intravenous infusion of 5% glucose injection (500 mL) aggravated, it may lead to varying degrees of consciousness plus insulin injection (6 U) and potassium chloride (10 mL) disturbance and coma, and even lead to death. There was was adjusted. a large time difference from the onset of ICIs to diabetic On October 15, her blood sugar rose again to ketoacidosis. All patients receiving ICIs should be on high 500.4 mg/dL. The Endocrinology Department was alert for ICIs-related diabetes when they present with consulted again, and a new panel confirmed diabetic typical symptoms of diabetes such as polyphagia, polydipsia, ketoacidosis according to high blood glucose, a hemoglobin weight loss, and fatigue. If the patient has normal blood A1c level of 7.4, urine ketone body value of 3+, extracellular glucose in the past, the admission with hyperglycemia, fluid residual alkali level of −3.8 mmol/L, residual alkali outbreak of diabetes mellitus and other laboratory results level of −3.3 mmol/L, and lactic acid level of 2.1 mmol/L. and clinical manifestations can be basically confirmed. At that moment, the treatment regimen consisted of 8 IU This case report provides essential clinical information of neutral insulin injection intravenously administered at and reference for diagnosis of ICIs induced diabetes 10 AM and 6 IU of neutral insulin injection intravenously ketoacidosis. administered at 11 AM, 1 PM, 3 PM, and 4 PM. All procedures performed in this study were in On October 16, her blood sugar was 290.16 mg/dL and accordance with the ethical standards of the institutional she had a ketone body value of 2+. Subsequently, insulin and/or national research committee(s) and with the therapy was adjusted at 6 IU of neutral insulin injection was Declaration of Helsinki (as revised in 2013). Written intravenously administered at 10 AM, 1 PM, 4 PM, and 9 PM. informed consent was obtained from the patient for On October 17, she had a ketone body value of 1+, and 6 IU publication of this case report. A copy of the written of neutral insulin injection was intravenously administered at consent is available for review by the editorial office of this 9 AM. Her blood sugar was 264.6 mg/dL and she felt well journal. enough to be discharged. She was recommended to start on oral antidiabetics with sitagliptin phosphate tablets (100 mg) Discussion taken before breakfast and acarbose tablets (100 mg, tid). She was advised to monitor her blood sugar levels every day. Here, we report the case of a patient treated with an On November 2, the patient was admitted to hospital intravenous injection of nivolumab (140 mg) on September for further anticancer treatment, and her blood glucose 18 with good tolerance. She was given an intravenous before sleep was 243 mg/dL. Between November 5 and 7, injection of nivolumab (140 mg) for the second time her blood sugar levels were 85.8, 66.6, and 84.6 mg/dL, on October 9 in combination with DC/CIK cells was respectively, and her blood sugar levels were still higher administered intravenously the following day. On October © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Page 4 of 9 Yan et al. Diabetic ketoacidosis induced by nivolumab Operation, adenocarcinoma of Blood sugar (23.7 mmoL/L) Blood sugar (14.7 mmoL/L), the lung, postoperative stage ketone body (2+) went home, sitaglipin phosphate tablets T2aN0M0, IB 0.9% NS (500 mL) + RI (4U) (100 mg) taken it before breakfast; intravenous infusion acarbose tablets (100 mg, tid) Nivolumab (140 mg, q3w) + DC/CIK cells 2016/9 2018/8 2018/10/9 2018/10/15 2018/11/5 2018/12/2 2017/3/21 2018/9/18 2018/10/14 2018/10/17 Continue to take CT, PET-CT, biopsy Blood sugar (27.8 mmoL/L) hypoglycemic showed metastasis ketone body (3+), diabetic medications, euglycemia CT examination ketoacidosis, insulin injection revealed nodules in Nivolumab the lower left lung (140 mg, q3w) + Continue to take hypoglycemic DC/CIK cells medications, stop nivolumab, go on DC/CIK immunotherapy Figure 1 The timeline of diagnosis, treatment, and follow-up. PET-CT, positron emission tomography-computed tomography; DC/CIK, dendritic cell/cytokine-induced killer; NS, normal saline; RI, regular insulin. 14, she presented the first episode of diabetic ketosis. The patient had no history of obesity or family history She had no prior history of personal or family history of of diabetes. She received a single dose of 3.75 mg of diabetes. There was a total of 28 days between the first dexamethasone treatment during this period of time which administration and the occurrence of the patient’s severe resulted in cough improvement, but did not explain the symptoms. After insulin treatment, the patient’s symptoms onset of the diabetes. The causal relationship between were reduced and blood sugar levels became normal. nivolumab and diabetic ketoacidosis was assessed using the Although diabetes is a rare IR-AE, it has been reported Naranjo Probability of Adverse Effects Scale (10), with a that it generally appears 6 weeks after medication. Type 1 score of 6 in this case. It suggested that diabetic ketoacidosis diabetes may occur after 4 weeks. In our case, Hemoglobin was caused by nivolumab. The main limitations to establish A1c levels were not tested before use of nivolumab. a causal relationship between nivolumab and diabetic onset ICI affect T cell immune function. T cells infiltrate the in this case were that diabetes susceptibility genes were organ and cause an immune activation response (5,6), which not tested and the risk of abnormal blood glucose was not destroys pancreatic beta cells and leads to absolute insulin evaluated and baseline. deficiency, namely type 1 diabetes. Type 1 diabetes can be We reviewed the literature and collected a total of 33 divided into delayed type 1 diabetes, acute type 1 diabetes, reported cases of type 1 diabetes caused by nivolumab or fulminant type 1 diabetes. Among the IR toxicity of through literature retrieval (8,11). Of the 33 cases, 16 were patients treated with ICI, fulminant type 1 diabetes is fulminant type 1 diabetes and ketoacidosis occurred in 21 more common, and some cases have been reported in patients. The median onset time of type 1 diabetes was patients with lung cancer and melanoma (7-9). The onset 96.5 days, and the median interval from normal to abnormal of fulminant type 1 diabetes is sudden and life-threatening, blood glucose was 2 weeks. The main clinical symptoms and the degree of ketoacidosis is relatively severe. The were polyuria and polydipsia, fatigue of varying degrees, islets are completely destroyed in a short period of time and and nausea/vomiting. Blood glucose control was adequate are difficult to recover. At present, the specific etiology is in 27 patients after insulin treatment. Sixteen patients were unknown. If the patient is not diagnosed and treated timely, restarted with nivolumab without further complications. Of it often leads to death in a short time, which is mostly the 21 patients with ketoacidosis, there were 6 patients with common in East Asian people. lung cancer. Among the lung cancer patients, there were © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Annals of Translational Medicine, Vol 10, No 22 November 2022 Page 5 of 9 3 women aged 47, 34, and 56. They developed ketoacidosis Questions to be further discussed and 24, 28, and 33 days after using nivolumab (Table 1). considered In the above literature analysis, it can be concluded Question 1: Is it necessary to test for diabetes susceptibility that the incubation period of nivolumab-induced diabetic genes to avoid the risk of developing diabetes before using ketoacidosis is dispersive and the clinical risk is high. Patients ICIs? need life-long insulin therapy. Blood glucose and HbA1c should be monitored routinely before and during nivolumab Teresa Moran: ICI-related T1DM is considered a rare AE. immunotherapy to avoid the occurrence of diabetic However, with an increased number of patients with any ketoacidosis. After the occurrence of diabetic ketoacidosis, tumor exposed to ICI and ICI combinations, the number insulin should be used to actively control blood glucose and of such AE is expected to increase. A recent review in the do a good job in medication education to ensure long-term literature investigated potential predictive risk factors, compliance of patients. Nivolumab should only be initiated if including pre-treatment islet antibodies and human leukocyte the patient has a clinical benefit under stable glucose control. antigen (HLA) status (33). An important 60–80% of patients According to the guidelines and expert consensus related carried pretreatment GAD antibody. In addition, HLA- to toxicity management of The European Society for typing in these series demonstrated high risk alleles for Medical Oncology and The Society for Immunotherapy developing T1DM in some of them. of Cancer, the patient had grade 3 immune-related type While there is no firm clinical recommendation, we 1 diabetes with ketoacidosis. In accordance with the advocate for pre-treatment islet antibodies and HLA status treatment of new-onset type 1 diabetes, the patient was study in a large cohort of patients including different tumor suspended from using nivolumab. At the same time, the types, in different clinical stages and with different ICI patient’s blood glucose were strictly managed, with the and ICI combinations. This may help to clarify if ICI act objective of maintaining her HbA1c level at <8.0% for a as an accelerator or initiator of type 1 diabetes and may long time. There is no evidence that stopping nivolumab identify those patients at higher risk of developing such relieves diabetes, and since the onset of diabetes is usually complication. permanent, the French guidelines recommend continuing insulin therapy even if the immunotherapy drugs are Question 2: What is the pathogenesis of diabetes associated discontinued. Therefore, patients need to establish baseline with ICIs? endocrine function before using ICI, since in the early days after nivolumab, patients might be prone to ketoacidosis. Teresa Moran: Type 1 diabetes mellitus (T1DM) results These baseline tests may be critical for the patients from the autoimmune destruction of the insulin-producing management. Then considering prior recommendations, βcells of the endocrine pancreas, and this destruction patients on nivolumab should have their blood sugar occurred in a T cell dependent mechanism. A genetic monitored regularly for the first months of clinical use (32). background including both major histocompatibility In conclusion, as the first PD-1 inhibitor in China, complex (MHC) and non-MHC genes has been nivolumab has brought hope for the survival of most associated with the risk of T1DM (34,35). Several HLA patients with advanced cancer. However, nivolumab is also genotypes have been associated with a high risk to associated with a risk of ketoacidosis, a clinical risk that develop autoimmune diabetes mellitus, however over requires lifelong insulin treatment. In clinical practice, 90% of type 1 diabetics carry either DR3-DQ2 or DR4- blood glucose should be routinely monitored before and DQ8, and up to 30% have both haplotypes (DR3/DR4 during nivolumab treatment to avoid the occurrence of heterozygotes), which is associated with the greatest risk for ketoacidosis. In addition, diabetes susceptibility gene testing the development of autoimmune diabetes (36). Other non- might help to evaluate the risk of abnormal blood glucose HLA factors which regulate antiviral response, lymphocyte levels. After the occurrence of nivolumab-induced diabetes, activation, peripheral tolerance, and chemokine and insulin should be used to actively control blood glucose cytokine functions have been related to the risk of T1DM and medication education should be given to ensure long- occurrence. In addition, several autoantigens isolated from term medication compliance of patients. Restarting on pancreatic islet cells are associated with the development of nivolumab after an episode of diabetic ketoacidosis should autoimmune DM. These include including GAD, insulin, be an individualized decision. insulinoma-associated protein 2 (IA-2), and zinc transporter © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Page 6 of 9 Yan et al. Diabetic ketoacidosis induced by nivolumab Table 1 Case analysis of literature on diabetic ketoacidosis caused by nivolumab Number (Ref.) Sex Age (years) Cancer Dose Occurrence time Initial symptoms Treatment Stop/go on nivolumab Outcome No. 1 (12) Female 54 Melanoma 2 mg/kg, q3w After 16 cycles Excessive drinking and urination, severe fatigue, Insulin therapy (route of administration unknown) Go on Continue insulin therapy delirium, fever, cold No. 2 (13) Female 68 Melanoma 3 mg/kg, q3w Seven days after the 28th cycle Abdominal pain, nausea, vomiting, severe fatigue, Intravenous insulin and fluid replacement therapy Stop Continue insulin therapy excessive drinking, and urination No. 3 (14) Male 77 Renal cell carcinoma 3 mg/kg, q2w Fifteen days after the 6th cycle Fatigue, nausea, vomiting Insulin therapy (route of administration unknown) Go on Continue insulin therapy No. 4 (15) Male 73 Lung cancer 3 mg/kg, q2w Twenty-one days after the 11th cycle Excessive drinking and urination, nausea, and Insulin therapy (route of administration unknown) Stop (aggravation of Not described vomiting pneumonia) No. 5 (16) Male 31 NSCLC Unknown Thirteen days after the first cycle Fatigue, excessive urination, excessive drinking Intravenous insulin therapy Go on Continue insulin therapy No. 6 (17) Male 73 Melanoma 3 mg/kg, q2w Before the 4th cycle Palpitations, fatigue Intravenous insulin and fluid replacement therapy Go on Continue insulin therapy No. 7 (18) Male 52 Melanoma Ipi 3 mg/kg + nivo 3 mg/kg, q3w Eighteen days after the 3rd cycle Polyuria, polydipsia, nausea, vomiting, weight loss Insulin subcutaneous therapy Stop Continue insulin therapy No. 8 (19) Female 74 Melanoma 2 mg/kg, q3w Thirteen days after the 6th cycle Nausea, vomiting, polyuria, dizziness Intravenous insulin and fluid replacement therapy Stop Continue insulin therapy No. 9 (20) Male 51 Renal cell carcinoma Unknown The 45th day Nausea, fatigue Control blood glucose, the specific treatment plan is Stop Continue insulin therapy unknown No. 10 (21) Female 55 Melanoma 2 mg/kg, q3w The 12th month Vomiting, delirium, excessive drinking and Insulin subcutaneous therapy Go on Continue insulin therapy urination No. 11 (22) Male 54 Melanoma Ipi 3 mg/kg + nivo 3 mg/kg, q3w After the 6th cycle Fatigue, myalgia, nausea, vomiting Insulin was administered intravenously and fluid rehydration Stop Continue insulin therapy was followed by subcutaneous insulin injection No. 12 (23) Male 83 Maxillary sinus 240 mg/kg, q2w The 3rd month No subjective symptoms Insulin therapy (route of administration unknown) Stop (because of colitis) Continue insulin therapy squamous cell carcinoma No. 13 (24) Female 47 Lung cancer 3 mg/kg, q2w Ten days after the 2nd cycle (24 days) Excessive drinking and urination, weight loss, Insulin was administered intravenously and fluid rehydration Go on Continue insulin therapy vomiting, confusion, fatigue, dehydration, low was followed by subcutaneous insulin injection blood pressure No. 14 (25) Male 66 Melanoma 2 mg/kg, q3w Ten days after the 6th cycle Nausea, vomiting, anorexia Insulin was administered intravenously and fluid rehydration Go on Continue insulin therapy was followed by subcutaneous insulin injection No. 15 (26) Female 34 Lung cancer 3 mg/kg, q2w Ten days after the 2nd cycle (28 days) Abdominal pain, nausea, fatigue Intravenous insulin and fluid replacement therapy Go on Continue insulin therapy No. 16 (9) Female 56 Lung cancer Dose unknown, q2w Five days after the 3rd cycle (33 days) Excessive drinking and urination, coma, agitation, Insulin was administered intravenously and fluid rehydration Go on Continue insulin therapy was followed by subcutaneous insulin injection No. 17 (27) Male 42 Lung cancer 3 mg/kg, q2w Eighteen days after the 4th cycle No subjective symptoms Insulin was administered intravenously and fluid rehydration Stop (poor blood sugar Continue insulin therapy was followed by subcutaneous insulin injection control) No. 18 (28) Male 49 Renal cell carcinoma 3 mg/kg, q2w After the 21st cycle Fatigue, drowsiness, weight loss, and excessive Insulin was administered intravenously and fluid rehydration Go on Continue insulin therapy drinking and urination was followed by subcutaneous insulin injection No. 19 (29) Female 59 Metastatic mucosal Dose unknown, ipilimumab/ Three days after receiving the 3rd cycle Nausea, vomiting and generalized weakness Insulin Do not mention it Do not mention it melanoma nivolumab No. 20 (30) Female 60 Advanced renal cell Nivolumab (3 mg/kg) and Seven months (216 days) after the first General malaise, hyperglycemia, metabolic Injections of insulin Stop Continue insulin therapy carcinoma ipilimumab (1 mg/kg), q3w administration and about half a year acidosis, and presence of ketone bodies in urine (174 days) after the last administration No. 21 (31) Male 77 Metastatic high-grade 200 mg, q2w After 15 cycles Worsening fatigue, polyuria, and polydipsia of Intravenous insulin Stop Continue insulin therapy neuroendocrine tumor 1 week’s duration Ipi, ipilimumab; nivo, nivolumab; NSCLC, non-small cell lung cancer. © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Annals of Translational Medicine, Vol 10, No 22 November 2022 Page 7 of 9 (ZnT8) (37). Postmortem histopathological studies of the approach. Patients with new onset hyperglycaemia without pancreas from type 1 diabetics have demonstrated that the DKA should be started on subcutaneous insulin. Patients majority of infiltrating immune cells are CD8+ T cells. The should be referred to the diabetes team for education, PD-1-PD-L1 pathway seems to provide a protective effect training on safe insulin administration and follow up (43). against βcell autoimmunity, and in some patients, blocking with ICIs may lead to autoimmune diabetes mellitus and Acknowledgments insulin dependence (38). However, the pathogenic mechanism underlying The authors acknowledge AME Editing Service for editing ICI-related T1DM remains to be fully elucidated. ICI the manuscript. treatment may lead to pancreatitis affecting endocrine and Funding: This study was supported by Hebei Province exocrine pancreatic function. A presumed autoimmune- Foundation for “333 Talent Project” (No. A202001019). mediated pancreatitis leading to hyperglycaemia has been proposed (39). Autoantigens from pancreatic islet cells Footnote positivity has been described but are not universal, and some reports have demonstrated the presence of high-risk Reporting Checklist: The authors have completed the CARE HLA alleles for autoimmune diabetes (33). reporting checklist. Available at https://atm.amegroups. com/article/view/10.21037/atm-22-5211/rc Question 3: ICI-related diabetes is uncommon but Conflicts of Interest: All authors have completed the irreversible. How do doctors educate patients in clinical ICMJE uniform disclosure form (available at https://atm. practice? amegroups.com/article/view/10.21037/atm-22-5211/coif). Teresa Moran: A detailed personal and family history of CG received honoraria as speaker bureau or advisory board diabetes, as well as autoimmunity should be recorded. Up member from Bristol Meyers Squibb, Roche, Astra Zeneca, to 70% of the cases of T1DM had other IRAEs and 44% Sanofi, MSD. TM declares consulting/advisory role fees had endocrine-related IRAEs prior or concurrent to the from Roche, Bristol Myers, Boeringher, Astra Zeneca, development of ICI-induced diabetes (especially primary Lilly, and Research funding from Kyowa Kirin. The other thyroid dysfunction) (40). There is controversial data authors have no conflicts of interest to declare. regarding pre-existing type 2 diabetes as a predictor of ICI- diabetes occurrence (33,41). Ethical Statement: The authors are accountable for all Doctors and patients should also be aware that a aspects of the work in ensuring that questions related combination of immunotherapies and/or pre-treatment to the accuracy or integrity of any part of the work are with other immunotherapies before starting ICI appeared to appropriately investigated and resolved. All procedures associate an increased risk of ICI-induced diabetes (40,42). performed in this study were in accordance with the ethical As with other immune related AEs, patients should be standards of the institutional and/or national research educated to recognize any sign or symptom potentially committee(s) and with the Declaration of Helsinki (as related with a T1DM onset, which should prompt revised in 2013). Written informed consent was obtained them to an early consultation. Periodic test before each from the patient for publication of this case report. A copy ICI administration should include glucose levels. New of the written consent is available for review by the editorial onset hyperglycaemia and worsening of hyperglycaemia office of this journal. in patients with pre-existing type 2 diabetes following treatment with ICI should be taken into account. This Open Access Statement: This is an Open Access article is particularly important as patients might also receive distributed in accordance with the Creative Commons steroids that can exacerbate hyperglycaemia. Due to the Attribution-NonCommercial-NoDerivs 4.0 International rapid onset of ICI-related insulin deficiency and potential License (CC BY-NC-ND 4.0), which permits the non- DKA development, plasma levels should be tested in all commercial replication and distribution of the article with acutely unwell patients receiving ICI, and work-up should the strict proviso that no changes or edits are made and the include ketosis and acidosis parameters if hyperglycaemia original work is properly cited (including links to both the is detected. DKA should be managed as per standard formal publication through the relevant DOI and the license). © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211 Page 8 of 9 Yan et al. Diabetic ketoacidosis induced by nivolumab See: https://creativecommons.org/licenses/by-nc-nd/4.0/. polymorphisms. Eur J Dermatol 2017;27:184-5. 13. Sakaguchi C, Ashida K, Yano S, et al. 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Betlazar-Maseh) Cite this article as: Yan J, Xie ZZ, Moran T, Gridelli C, Zheng MD, Dai SJ. Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature. Ann Transl Med 2022;10(22):1256. doi: 10.21037/atm-22-5211 © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2022;10(22):1256 | https://dx.doi.org/10.21037/atm-22-5211