{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:20:24Z","timestamp":1768321224694,"version":"3.49.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Combined diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) secondary to immune checkpoint inhibitors (ICIs) is extremely rarely reported among ICIs- diabetes mellitus (DM) cases and is always ignored by physicians. This study aimed to conduct a systematic review to recognize better the rare adverse event of combined DKA-HHS associated with immune checkpoints.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A electronic search in Pubmed\/Cochrane\/Web of Science, complemented by manual searches in article references, was conducted to identify clinical features of ICIs-combined DKA-HHS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>we identified 106 patients with ICIs- type 1 diabetes mellitus (T1DM) from 82 publications: 9 patients presented a coexistence of metabolic acidosis, severe hyperglycemia, and\/or DKA; All patients were not diagnosed as combined DKA-HHS. Compared with ICIs-DKA patients, combined DKA-HHS cases were prone to higher hyperglycemia (1020 \u00b1 102.5 vs 686.7 \u00b1 252.6mg\/dL). Moreover, acute kidney injury (87.5% vs 28.6%) and prior chemotherapy (66.7% vs 31.6%) showed higher occurrences with the onset of ICIs-HHS or combined DKA-HHS.B<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Combined DKA-HHS portends a poor diagnosis in patients with coexistence features of DKA and HHS, which healthcare professionals and patients should be aware of due to differences in treatment. Our observational retrospective case series shows that patients with more risk factors were more likely to develop combined DKA-HHS. We are the first to report this group of patients\u2019 clinical characteristics and outcomes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.1084441","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T14:45:33Z","timestamp":1672843533000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM"],"prefix":"10.3389","volume":"13","author":[{"given":"Wenjing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiexiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Bi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","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":"Diabetes Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1801663","article-title":"Adverse events associated with immune checkpoint blockade","volume":"378","author":"Akturk","year":"2018","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1001\/jama.2018.22119","article-title":"Adverse events associated with immune checkpoint inhibitors","volume":"321","author":"Akturk","year":"2019","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.7861\/clinmed.2020-0054","article-title":"Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus","volume":"20","author":"Kyriacou","year":"2020","journal-title":"Clin Med (Lond)"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","DOI":"10.12890\/2021_002756","article-title":"Hyperosmolar hyperglycaemic state and diabetic ketoacidosis in nivolumab-induced insulin-dependent diabetes mellitus","volume":"8","author":"Saleh","year":"2021","journal-title":"Eur J Case Rep Intern Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2016.15","article-title":"Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia","volume":"12","author":"Umpierrez","year":"2016","journal-title":"Nat Rev Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4158\/EP-2018-0120","article-title":"Pediatric diabetic ketoacidosis with hyperosmolarity: Clinical characteristics and outcomes","volume":"24","author":"Agrawal","year":"2018","journal-title":"Endocr Pract"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabet.2019.04.005","article-title":"Variability in clinical presentation of diabetes mellitus during anti-PD-1 immunotherapy","volume":"46","author":"Bastin","year":"2020","journal-title":"Diabetes Metab"},{"key":"B11","doi-asserted-by":"publisher","first-page":"bcr2017220999","DOI":"10.1136\/bcr-2017-220999","article-title":"New onset diabetes after nivolumab treatment","volume":"2018","author":"Capitao","year":"2018","journal-title":"BMJ Case Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/1078155219841116","article-title":"Nivolumab-induced type 1 diabetes mellitus as an immune-related adverse event","volume":"26","author":"Yilmaz","year":"2020","journal-title":"J Oncol Pharm Pract"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8981375","article-title":"Fulminant diabetes in a patient with advanced melanoma on nivolumab","volume":"2018","author":"Chokr","year":"2018","journal-title":"Case Rep Oncol Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1530\/EDM-18-0153","article-title":"A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma","volume":"2019","author":"Hakami","year":"2019","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-20-408","article-title":"Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report","volume":"9","author":"Lopes","year":"2020","journal-title":"Transl Lung Cancer Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/8781347","article-title":"Immune checkpoint inhibitor induced diabetes mellitus treated with insulin and metformin: Evolution of diabetes management in the era of immunotherapy","volume":"2019","author":"Alrifai","year":"2019","journal-title":"Case Rep Oncol Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00014","article-title":"Immune checkpoint inhibitor-induced diabetic ketoacidosis: A report of four cases and literature review","volume":"11","author":"Hong","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fcdhc.2021.723855","article-title":"Female sex and obesity are risk factors for inadequate calcium intake in youth with type 1 diabetes","volume":"2","author":"Rahmani","year":"2021","journal-title":"Front Clin Diabetes Healthc"},{"key":"B19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/S0140-6736(13)60591-7","article-title":"Type 1 diabetes","volume":"383","author":"Atkinson","year":"2014","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1177\/0897190019850929","article-title":"Programmed cell death-1 monoclonal antibody therapy and type 1 diabetes mellitus: A review of the literature","volume":"34","author":"Farina","year":"2021","journal-title":"J Pharm Pract"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.649863","article-title":"Immune checkpoint inhibitors-related thyroid dysfunction: Epidemiology, clinical presentation, possible pathogenesis, and management","volume":"12","author":"Zhan","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1010279","article-title":"Thyroid-related adverse events induced by immune checkpoint inhibitors","volume":"13","author":"Chera","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.598836","article-title":"The role of thyroid hormones and autoantibodies in metabolic dysfunction associated fatty liver disease: TgAb may be a potential protective factor","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.620522","article-title":"Coexistence of immune checkpoint inhibitor-induced autoimmune diabetes and pancreatitis","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B26","doi-asserted-by":"publisher","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":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.764138","article-title":"Unravelling checkpoint inhibitor associated autoimmune diabetes: From bench to bedside","volume":"12","author":"Wu","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B28","doi-asserted-by":"publisher","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":"B29","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3390\/ijms22042093","article-title":"Immune checkpoint inhibitor-induced diabetes mellitus: Potential role of T cells in the underlying mechanism","volume":"22","author":"Mourad","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1475","article-title":"PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during type 1 diabetes","volume":"62","author":"Pauken","year":"2013","journal-title":"Diabetes"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900679","article-title":"Transgenic expression of single-chain anti-CTLA-4 fv on beta cells protects nonobese diabetic mice from autoimmune diabetes","volume":"183","author":"Shieh","year":"2009","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-020-09618-w","article-title":"Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? review of the literature","volume":"22","author":"Lo Preiato","year":"2021","journal-title":"Rev Endocr Metab Disord"},{"key":"B33","article-title":"A case of hyperosmolar nonketotic coma occurring during chemotherapy using cisplatin for gallbladder cancer","volume":"46","author":"Sakakura","year":"1999","journal-title":"Hepatogastroenterology"},{"key":"B34","article-title":"Cisplatin-induced hyperglycemic hyperosmolar coma","volume":"65","author":"Komdeur","year":"2007","journal-title":"Neth J Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2020-241109","article-title":"Capecitabine-induced hyperosmolar hyperglycaemic state","volume":"14","author":"Yim","year":"2021","journal-title":"BMJ Case Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2010.148221","article-title":"Genetics of type 1 diabetes","volume":"57","author":"Steck","year":"2011","journal-title":"Clin Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-19-0291","article-title":"Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review","volume":"181","author":"de Filette","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00728","article-title":"Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus","volume":"103","author":"Clotman","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2300","article-title":"Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab","volume":"101","author":"de Filette","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-1168","article-title":"Clinical outcomes in patients with isolated or combined diabetic ketoacidosis and hyperosmolar hyperglycemic state: A retrospective, hospital-based cohort study","volume":"43","author":"Pasquel","year":"2020","journal-title":"Diabetes Care"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J Clin Oncol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jpeds.2010.09.048","article-title":"Drugs, and therapeutics committee of the Lawson Wilkins pediatric endocrine s, hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment","volume":"158","author":"Zeitler","year":"2011","journal-title":"J Pediatr"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1084441\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T14:45:39Z","timestamp":1672843539000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.1084441\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":42,"alternative-id":["10.3389\/fendo.2022.1084441"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.1084441","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]},"article-number":"1084441"}}