A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia

Yamamoto, Nobuto; Tsurutani, Yuya; Katsuragawa, Sho; Kubo, Hironari; Sunouchi, Takashi; Hirose, Rei; Hoshino, Yoshitomo; Ichikawa, Masahiro; Takiguchi, Tetsuya; Yukawa, Hideki; Arioka, Hitoshi; Saitou, Jun; Nishikawa, Tetsuo

doi:10.2169/internalmedicine.2780-19

Cited by 15 publications

(6 citation statements)

References 23 publications

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“…The HLA phenotype was determined in several case reports whereupon HLA-DR9 (an allele conferring susceptibility to type 1 diabetes) was frequently observed in the patients with type 1 diabetes related to anti-PD-1/PD-L1 therapy (Table 1) [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

Section: Immune Checkpoint Moleculesmentioning

confidence: 99%

Fulminant type 1 diabetes: recent research progress and future prospects

Imagawa

Tachibana

2020

Diabetol Int

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To clarify the clinical and etiological characteristics of fulminant type 1 diabetes, we reviewed data from patients who had developed type 1 diabetes following anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) therapy, and research on pancreatic beta cells derived from induced pluripotent stem (iPS) cells from patients with fulminant type 1 diabetes. As determined from the disease classifications and clinical and genetic characteristics, anti-PD-1/PD-L1 therapy-related type 1 diabetes includes both fulminant type 1 diabetes and acute-onset type 1 diabetes. Using insulin-positive cells derived from iPS cells, beta-cell fragility to inflammatory cytokines, but not its regeneration failure, was observed in fulminant type 1 diabetes. Moreover, severe hyperglycemia was reported as a risk factor of sudden death or cardiac arrest at disease onset, diffusion-weighted magnetic resonance imaging was suggested as an additional tool for making a diagnosis, and the CSAD/lnc-ITGB7-1 locus was genetically associated with fulminant type 1 diabetes. To fully understand fulminant type 1 diabetes, it is important to clarify the molecular mechanisms step by step through multifaceted approaches such as through analyses of the genetic factors, clinical features, histological findings, and cell biology. The careful and detailed study of patients is a great means for clarifying the etiology and pathophysiology of the disease. KeywordsFulminant type 1 diabetes • Immune checkpoint molecules • PD-1 • Induced pluripotent stem cells * Akihisa Imagawa

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Section: Immune Checkpoint Moleculesmentioning

confidence: 99%

Fulminant type 1 diabetes: recent research progress and future prospects

Imagawa

Tachibana

2020

Diabetol Int

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“…Serum amylase, lipase and elastase-1 values were all within the normal limits. The patient had a haplotype of HLA DRB1*09:01-DQB1*03:03 which is significantly more frequent in autoimmune T1D and is also reported in anti-PD-1 antibody-related T1D (10,11,12,13).…”

Section: Investigationmentioning

confidence: 66%

“…Hyperglycemia can be diagnosed by these blood tests. In three case reports, when hyperglycemia was first diagnosed by regular blood tests, C-peptide levels were not depleted (13,16,17). The periods from the onset of diabetes to depletion of C-peptide were 17 days in the case reported by Okamoto et al (16), 12 days in the case reported by Yamamoto et al (13) and 16 days in the case reported by Saito et al (17).…”

Section: Discussionmentioning

confidence: 92%

“…In three case reports, when hyperglycemia was first diagnosed by regular blood tests, C-peptide levels were not depleted (13,16,17). The periods from the onset of diabetes to depletion of C-peptide were 17 days in the case reported by Okamoto et al (16), 12 days in the case reported by Yamamoto et al (13) and 16 days in the case reported by Saito et al (17). As for our patient, the period from the onset of hyperglycemia to DKA was 18 days, so the period until complete depletion of C-peptide was in the range of 18 to 28 days; therefore, the time course of this case was slightly longer than that of the other three cases in the previously mentioned studies.…”

Section: Discussionmentioning

confidence: 99%

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Pembrolizumab-induced fulminant type 1 diabetes with C-peptide persistence at first referral

Kusuki

Suzuki

Mizuno

2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary A 72-year-old man with no history of diabetes was referred to our department due to hyperglycemia during pembrolizumab treatment for non-small-cell lung carcinoma. His blood glucose level was 209 mg/dL, but he was not in a state of ketosis or ketoacidosis. Serum C-peptide levels persisted at first, but gradually decreased, and 18 days later, he was admitted to our hospital with diabetic ketoacidosis (DKA). The patient was diagnosed with fulminant type 1 diabetes (FT1D) induced by pembrolizumab. According to the literature, the insulin secretion capacity of a patient with type 1 diabetes (T1D) induced by anti-programmed cell death-1 (anti-PD-1) antibody is depleted in approximately 2 to 3 weeks, which is longer than that of typical FT1D. Patients with hyperglycemia and C-peptide persistence should be considered for hospitalization or frequent outpatient visits with insulin treatment because these could indicate the onset of life-threatening FT1D induced by anti-PD-1 antibodies. Based on the clinical course of this patient and the literature, we suggest monitoring anti-PD-1 antibody-related T1D. Learning points: Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are increasingly used as anticancer drugs. Anti-PD-1 antibodies can cause immune-related adverse events, including T1D. FT1D, a novel subtype of T1D, is characterized by the abrupt onset of hyperglycemia with ketoacidosis, a relatively low glycated hemoglobin level and depletion of C-peptide level at onset. In patients being treated with anti-PD-1 antibody, hyperglycemia with C-peptide level persistence should be monitored through regular blood tests. Because of C-peptide persistence and mild hyperglycemia, it is possible to miss a diagnosis of life-threatening FT1D induced by anti-PD-1 antibody. In particular, in patients who have no history of diabetes, hyperglycemia without DKA is likely to be the very beginning of anti-PD-1 antibody-induced T1D. Therefore, such patients must be considered for either hospitalization or frequent outpatient visits with insulin injections and self-monitoring of blood glucose.

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“…There was also a hyperglycemic patient with a normal C-peptide level at first. But his serum C-peptide level gradually decreased to <0.3 ng/dL in 8 days (26). This indicated that when hyperglycemic with normal C-peptide level occurred in patients with the anti PD-1/PD-L1 treatment, treatment induced diabetes should also be considered and monitored the C-peptide level was necessary.…”

Section: Discussionmentioning

confidence: 98%

Anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus: a case report and brief review

Li¹,

Wang²,

Chen³

et al. 2020

Transl Lung Cancer Res

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Nowadays, immune checkpoint inhibitor therapy has been used in more and more cancer patients. These agents were associated with immune-related adverse effects, and autoimmune diabetes mellitus is one of them. And it is not common but can be potentially fatal. Anti PD-1 monoclonal antibody is a humanized IgG4 antibody against PD-1, which has been applied in advanced non-small cell lung cancer (NSCLC) treatment. In this paper, we reported the case of autoimmune diabetes mellitus induced by anti PD-1 monoclonal antibody in NSCLC treatment. Here is a 73-year-old male patient with no diabetes history who had anti PD-1 monoclonal antibody 200 mg every 3 weeks for NSCLC treatment. After 10 cycles of the therapy, his blood glucose level elevated and he suffered diabetic ketoacidosis (DKA). And his C-peptide was significantly decreased with negative relative auto-antibodies. Combined with his medical history and the laboratory examination, anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus was diagnosed. After recovering from DKA and controlling his blood glucose, his anti PD-1 therapy was continued and he still got some benefit. This report suggested that glycemic monitoring is imperative during this anti PD-1 monoclonal antibody treatment. Moreover, after controlling the blood glucose level, continuing the immune therapy could still be benefit and safe for the patient.

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A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia

Cited by 15 publications

References 23 publications

Fulminant type 1 diabetes: recent research progress and future prospects

Fulminant type 1 diabetes: recent research progress and future prospects

Pembrolizumab-induced fulminant type 1 diabetes with C-peptide persistence at first referral

Anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus: a case report and brief review

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