Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy
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We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy.
We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search.
Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile–third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4–9.4) μg/day, and 0.46 (0.20–0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive.
Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.
KeywordsNivolumab Pembrolizumab Anti-PD-1 antibody Fulminant type 1 diabetes Type 1 diabetes Immune-checkpoint inhibitors
The other member of the Japan Diabetes Society Committee on Type 1 Diabetes Mellitus Research is Seiho Nagafuchi (Faculty of Medicine, Saga University). The authors express their sincere gratitude to the authors of the referenced cases, attending doctors, and diabetes specialists affiliated with the JDS for answering the questionnaire: Drs. Masahide Okamoto (Oita University), Osamu Ogawa (Kameda Medical Center), Emi Itateyama (Oita Red Cross Hospital), Hiroyuki Ohtake (Saitama Medical Center), Yushi Hirota (Kobe University), Masako Tomoyasu (Tokyu Hospital), Yasushi Nakajima (Nippon Medical School Hospital), Seiichi Yano (Kyushu University), Kenji Ashida (Kyushu University), Ryo Kumagai (Mito Kyodo General Hospital), Hiroaki Yagyu (Mito Kyodo General Hospital), Nobuyuki Koriyama (Kagoshima Medical Center), Michiaki Fukui (Kyoto Prefectural University of Medicine), Harumi Daikoku (Showa General Hospital), Shiko Asai (Kawasaki Municipal Tama Hospital), Akihiro Mochida (Juntendo University Urayasu Hospital), Fumitaka Okajima (Nippon Medical School Chiba Hokusoh Hospital), Satoshi Takagi (Tokyo Women’s Medical University), Kaoru Nagasawa (Toranomon Hospital), and Yasunori Taketomo (Kindai University). The authors also sincerely thank the doctors at Osaka University for their assistance with this study: Drs. Chisaki Ishibashi, Kenji Fukui, Hiromi Iwahashi, and Iichiro Shimomura.
Compliance with ethical standards
Conflict of interest
Akihisa Imagawa received scholarship donations from Ono Pharmaceutical Co., Ltd. and MSD and honoraria for lectures from Ono Pharmaceutical Co., Ltd. Norio Abiru received research grants from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Hiroshi Ikegami received a scholarship grant from Ono Pharmaceutical Co., Ltd. Yumiko Kawabata received a scholarship grant from Ono Pharmaceutical Co., Ltd. Other authors declare that they have no conflicts of interest.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (The Ethics Committees of the JDS, date of approval: 26 August 2016, approval number: 28-003-(2), Osaka University Hospital, date of approval: 27 April 2016, approval number: 15589, and Osaka Medical College, date of approval: 10 January 2017, approval number: 2098) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
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