{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:10:58Z","timestamp":1792023058557,"version":"4.4.0"},"reference-count":33,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Type 1 diabetes mellitus (T1DM) is a rare, irreversible immune-related adverse event reported in patients receiving treatment with immune checkpoint inhibitors (ICI). However, clinical risk factors for ICI-induced T1DM (ICI-T1DM) and its impact on survival in patients remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We used Optum\u2019s Clinformatics Data Mart database for assessment of the incidence and characteristics of T1DM in a large de-identified cohort of patients treated with ICI between 2017 and 2020. We applied Fine-Gray and cause-specific hazard models to study associations between patient\/treatment characteristics and ICI-T1DM and applied the Cox model with ICI-T1DM as a time-varying covariate to assess the impact of ICI-T1DM on survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>ICI-T1DM was observed in 261 of 30,337 (0.86%) patients. Dual use of antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) was associated with increasing risk of ICI-T1DM (hazard ratio [HR] 1.62; 95% CI 1.15\u20132.26) vs. anti\u2013PD-L1 or anti\u2013PD-1 alone. Younger age (HR 1.19 for every 5-year decrease; 95% CI 1.13\u20131.25) and preexisting non-T1DM diabetes (HR 4.48; 95% CI 3.45\u20135.83) were also associated with higher risk of ICI-T1DM. Conversely, prior use of immunosuppressive medications (HR 0.57; 95% CI 0.34\u20130.95) was associated with lower incidence of ICI-T1DM, but part of its protective effect may be due to the increased mortality rate. Development of ICI-T1DM does not seem to significantly impact patient survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>The risk of ICI-T1DM is associated with the type of ICI therapy, patient age, and preexisting non-T1DM diabetes. These data may help guide risk assessment and screening practices for patients during ICI therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc21-2213","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T10:56:40Z","timestamp":1646305000000},"page":"1170-1176","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":90,"title":["Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes"],"prefix":"10.2337","volume":"45","author":[{"given":"Xuan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison H.","family":"Affinati","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yungchun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina F.","family":"Turcu","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norah Lynn","family":"Henry","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Schiopu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Othus","sequence":"additional","affiliation":[{"name":"Biostatistics and Biomathematics Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Clauw","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nithya","family":"Ramnath","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, MI"},{"name":"Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-8206","authenticated-orcid":false,"given":"Lili","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"2022051317414149500_B1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1001\/jamaoncol.2017.3064","article-title":"Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis","volume":"4","author":"Barroso-Sousa","year":"2018","journal-title":"JAMA Oncol"},{"key":"2022051317414149500_B2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-related adverse events associated with immune checkpoint blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N Engl J Med"},{"key":"2022051317414149500_B3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front Oncol"},{"key":"2022051317414149500_B4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ctrv.2017.06.002","article-title":"Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management","volume":"58","author":"Sznol","year":"2017","journal-title":"Cancer Treat Rev"},{"key":"2022051317414149500_B5","doi-asserted-by":"crossref","first-page":"e000591","DOI":"10.1136\/bmjdrc-2018-000591","article-title":"Immune checkpoint inhibitors: an emerging cause of insulin-dependent diabetes","volume":"7","author":"Kotwal","year":"2019","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2022051317414149500_B6","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S2213-8587(19)30072-5","article-title":"Checkpoint inhibitor-induced insulin-dependent diabetes: an emerging syndrome","volume":"7","author":"Perdigoto","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2022051317414149500_B7","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.eprac.2020.12.009","article-title":"Real-world evidence of the incidence of and risk factors for type 1 diabetes mellitus and hypothyroidism as immune-related adverse events associated with programmed cell death-1 inhibitors","volume":"27","author":"Shimada","year":"2021","journal-title":"Endocr Pract"},{"key":"2022051317414149500_B8","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1111\/dme.14050","article-title":"Immune checkpoint inhibitor-induced type 1 diabetes: a systematic review and meta-analysis","volume":"36","author":"Akturk","year":"2019","journal-title":"Diabet Med"},{"key":"2022051317414149500_B9","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.2337\/dbi18-0002","article-title":"Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors","volume":"67","author":"Stamatouli","year":"2018","journal-title":"Diabetes"},{"key":"2022051317414149500_B10","doi-asserted-by":"crossref","first-page":"5499","DOI":"10.1210\/jc.2019-00423","article-title":"Checkpoint inhibitor-associated autoimmune diabetes is distinct from type 1 diabetes","volume":"104","author":"Tsang","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2022051317414149500_B11","doi-asserted-by":"crossref","first-page":"e150","DOI":"10.2337\/dc18-1465","article-title":"Increased reporting of immune checkpoint inhibitor-associated diabetes","volume":"41","author":"Wright","year":"2018","journal-title":"Diabetes Care"},{"key":"2022051317414149500_B12","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1172\/JCI131194","article-title":"Time to dissect the autoimmune etiology of cancer antibody immunotherapy","volume":"130","author":"Dougan","year":"2020","journal-title":"J Clin Invest"},{"key":"2022051317414149500_B13","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1056\/NEJM200002033420501","article-title":"A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies","volume":"342","author":"Imagawa","year":"2000","journal-title":"N Engl J Med"},{"key":"2022051317414149500_B14","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.2169\/internalmedicine.9518-17","article-title":"Fulminant type 1 diabetes mellitus accompanied by positive conversion of anti-insulin antibody after the administration of anti-CTLA-4 antibody following the discontinuation of anti-PD-1 antibody","volume":"57","author":"Shiba","year":"2018","journal-title":"Intern Med"},{"key":"2022051317414149500_B15","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00592-018-1234-8","article-title":"Diabetes mellitus induced by PD-1 and PD-L1 inhibitors: description of pancreatic endocrine and exocrine phenotype","volume":"56","author":"Marchand","year":"2019","journal-title":"Acta Diabetol"},{"key":"2022051317414149500_B16","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.3389\/fphar.2019.01453","article-title":"Incidence of immune checkpoint inhibitor-associated diabetes: a meta-analysis of randomized controlled studies","volume":"10","author":"Lu","year":"2019","journal-title":"Front Pharmacol"},{"key":"2022051317414149500_B17","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00262-019-02321-z","article-title":"Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer","volume":"68","author":"Kehl","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"2022051317414149500_B18","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1097\/MLR.0000000000000735","article-title":"Identifying increased risk of readmission and in-hospital mortality using hospital administrative data: the AHRQ Elixhauser Comorbidity Index","volume":"55","author":"Moore","year":"2017","journal-title":"Med Care"},{"key":"2022051317414149500_B19","article-title":"Glucocorticoid therapy and adrenal suppression","volume-title":"Endoxtext","author":"Nicolaides","year":"2015"},{"key":"2022051317414149500_B20","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A proportional hazards model for the subdistribution of a competing risk","volume":"94","author":"Fine","year":"1999","journal-title":"J Am Stat Assoc"},{"key":"2022051317414149500_B21","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1200\/JCO.2008.16.1000","article-title":"Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables","volume":"26","author":"Anderson","year":"2008","journal-title":"J Clin Oncol"},{"key":"2022051317414149500_B22","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s12902-019-0467-z","article-title":"Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports","volume":"19","author":"Zezza","year":"2019","journal-title":"BMC Endocr Disord"},{"key":"2022051317414149500_B23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1084\/jem.20022125","article-title":"The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice","volume":"198","author":"Ansari","year":"2003","journal-title":"J Exp Med"},{"key":"2022051317414149500_B24","first-page":"e1164","article-title":"PD-1 pathway-mediated regulation of islet-specific CD4+ T cell subsets in autoimmune diabetes","volume":"3","author":"Martinov","year":"2016","journal-title":"Immunoendocrinology (Houst)"},{"key":"2022051317414149500_B25","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/COC.0000000000000239","article-title":"CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition","volume":"39","author":"Buchbinder","year":"2016","journal-title":"Am J Clin Oncol"},{"key":"2022051317414149500_B26","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.cmet.2017.01.005","article-title":"\u03b2 cells that resist immunological attack develop during progression of autoimmune diabetes in NOD mice","volume":"25","author":"Rui","year":"2017","journal-title":"Cell Metab"},{"key":"2022051317414149500_B27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2337\/diabetes.52.1.102","article-title":"\u03b2-Cell deficit and increased \u03b2-cell apoptosis in humans with type 2 diabetes","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"2022051317414149500_B28","first-page":"151","article-title":"Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes","volume":"9","author":"Clark","year":"1988","journal-title":"Diabetes Res"},{"key":"2022051317414149500_B29","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1463-1326.2008.00969.x","article-title":"Pancreatic \u03b2-cell mass in European subjects with type 2 diabetes","volume":"10","author":"Rahier","year":"2008","journal-title":"Diabetes Obes Metab"},{"key":"2022051317414149500_B30","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1210\/jc.2018-01430","article-title":"PD-1 inhibitor immune-related adverse events in patients with preexisting endocrine autoimmunity","volume":"103","author":"Akturk","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"2022051317414149500_B31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cei.13424","article-title":"Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes","volume":"200","author":"Quandt","year":"2020","journal-title":"Clin Exp Immunol"},{"key":"2022051317414149500_B32","unstructured":"Centers for Disease Control and Prevention\n          . National Diabetes Statistics Report. Accessed 12 October 2021. Available from https:\/\/www.cdc.gov\/diabetes\/library\/features\/diabetes-stat-report.html"},{"key":"2022051317414149500_B33","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.2337\/dc09-0373","article-title":"Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside","volume":"32","author":"Bresson","year":"2009","journal-title":"Diabetes Care"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/5\/1170\/678636\/dc212213.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/5\/1170\/678636\/dc212213.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T13:42:05Z","timestamp":1652449325000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/45\/5\/1170\/144640\/Immune-Checkpoint-Inhibitors-and-Risk-of-Type-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3,3]]},"published-print":{"date-parts":[[2022,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc21-2213","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.19165250.v1","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.19165250","asserted-by":"object"}]},"ISSN":["0149-5992"],"issn-type":[{"value":"0149-5992","type":"print"}],"subject":[],"published":{"date-parts":[[2022,3,3]]}}}