Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes

Chen, Xuan; Affinati, Alison H.; Lee, Yungchun; Turcu, Adina F.; Henry, Norah Lynn; Schiopu, Elena; Qin, Angel; Othus, Megan; Clauw, D.; Ramnath, Nithya; Zhao, Lili

doi:10.2337/dc21-2213

“…Currently, knowledge about DM-ICIs is scarce, given the low number of available cases due to the exceptional nature of its onset. The identification of risk factors for its development or its association with a favourable tumour response has been the subject of recent research [ 12 , 13 ]. However, aspects such as the description of the clinical course of this diabetes type in the medium/long-term remains scarcely studied.…”

Section: Introductionmentioning

confidence: 99%

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Vera-Gómez

¹

,

Piñar-Gutiérrez

²

,

Guerrero-Vázquez

³

et al. 2022

Journal of Diabetes Research

4

1

0

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Objectives. The aim of this study is to investigate in depth diabetes mellitus associated with immune checkpoint inhibitors (DM-ICIs) by analysing a case series. We also evaluated the clinical impact of flash glucose monitoring (FGM) systems in the management of this entity. Methods. We conducted an observational cohort study of DM-ICIs diagnosed in two hospitals in Seville (Spain). Patients with a new diagnosis of diabetes mellitus (DM) or with sudden worsening of preexisting DM after starting treatment with ICIs, with a random 5 hour-postprandial C-peptide value of <0.6 nmol/L and without possibility of subsequent withdrawal of insulin treatment, were included. Results. A total of 7 cases were identified, mostly males ( n = 6 ; 85.7%), with a mean age of 64.9 years. The mean glycated hemoglobin (HbA1c) upon diagnosis was 8.1%, with diabetic ketoacidosis (DKA) observed in 6 cases (85.7%). Subcutaneous flash glucose monitoring (FGM) systems were used in six cases, with a mean follow-up period of 42.7 weeks. During the first 90 days of use, mean average glucose was 167.5 mg/dL, with a coefficient of variation (CV) of 34.6%. The mean time in the range 70-180 mg/dL (TIR) was 59.7%, with a mean time above range (TAR) 181-250 mg/dL of 27.8% and a mean TAR > 250 mg / dL of 10.2%. The mean time below range (TBR) 54-69 mg/dL was 2%, while the mean TBR < 54 mg / dL was 0.3%. The mean glucose management indicator (GMI) was 7.3%. No significant differences were observed in FGM values for the following 90 days of follow-up. A progressive improvement in all parameters of glycaemic control was observed between the first month of FGM use and the sixth month of FGM use. Of note, there was a decrease in mean CV (40.6% to 34.1%, p = 0.25 ), mean TAR 181-250 (30.3% to 26%, p = 0.49 ), mean TAR > 250 mg / dL (16.3% to 7.7%, p = 0.09 ), mean TBR 54-69 mg/dL (5.2% to 2%, p = 0.16 ), and mean TBR < 54 mg / dL (1.8% to 0.2%, p = 0.31 ), along with an increase in mean values of TIR 70-180 mg/dL (46.5% to 60.5%, p = 0.09 ). The lack of statistical significance in the differences observed in the mean FGM values over the follow-up period may be related to the small sample size. Conclusion. DM-ICI is recognised by a state of sudden-onset insulinopenia, often associated with DKA. The use of FGM systems may be a valid option for the effective management of DM-ICIs and for the prevention of severe hyperglycaemic and hypoglycaemic episodes in this condition.

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“…The reported frequency of insulin-dependent diabetes after treatment with ICIs is 0.84% (11). In this study, 1.1% of all participants were newly diagnosed with insulin-dependent diabetes Antithyroglobulin antibody (TgAb) and antithyroid peroxidase antibody (TPOAb) levels in subjects with and without destructive thyroiditis.…”

Section: Discussionmentioning

confidence: 72%

“…The reported frequency of insulin-dependent diabetes after treatment with ICIs is 0.84% ( 11 ). In this study, 1.1% of all participants were newly diagnosed with insulin-dependent diabetes mellitus after receiving ICIs, which was similar to the previous report.…”

Section: Discussionmentioning

confidence: 99%

Incidence of endocrine-related immune-related adverse events in Japanese subjects with various types of cancer

Iwamoto

¹

,

Kimura

²

,

Iwamoto

³

et al. 2023

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BackgroundImmune checkpoint inhibitors (ICIs), such as cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors, are often used to treat a variety of malignancies. ICIs are known to cause endocrine-related immune-related adverse events (irAEs), but the incidence varies among reports and/or agents. This study evaluated the incidence of endocrine-related irAEs in patients who were treated with ICIs in Japan.MethodThis single-center, retrospective, observational study examined the incidence and clinical characteristics of endocrine-related irAEs in 466 participants who were treated with ICIs at Kawasaki Medical School Hospital.ResultThe mean age of participants with and without endocrine-related irAEs was 69.1 ± 1.8 years and 68.1 ± 1.1 years, respectively, with no difference between them. The overall incidence of any endocrine-related irAEs among the participants was 25.5%. Hypothyroidism was prevalent in 24.3%, hypoadrenocorticism in 3.2%, hypopituitarism in 0.9%, and insulin-dependent diabetes mellitus in 1.1%. Participants receiving combination therapy with CTLA-4 and PD-1 inhibitors had a significantly higher incidence of endocrine-related irAEs than those receiving monotherapy.ConclusionEndocrine-related irAEs correlated significantly with survival and mean observation period. There was substantial difference in the incidence of endocrine-related irAEs among various types of ICIs and types of cancer. We should bear in mind that endocrine testing is necessary during the treatment with ICIs.

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“…Type 1 diabetes can be divided into delayed type 1 diabetes, acute type 1 diabetes, or fulminant type 1 diabetes. Among the IR toxicity of patients treated with ICI, fulminant type 1 diabetes is more common, and some cases have been reported in patients with lung cancer and melanoma ( 7 - 9 ). The onset of fulminant type 1 diabetes is sudden and life-threatening, and the degree of ketoacidosis is relatively severe.…”

Section: Discussionmentioning

confidence: 99%

Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature

Yan¹,

Xie²,

Morán³

et al. 2022

Ann Transl Med

4

0

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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.

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Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes

Cited by 44 publications

References 29 publications

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Incidence of endocrine-related immune-related adverse events in Japanese subjects with various types of cancer

Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature

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