Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM

Front Endocrinol (Lausanne). 2023 Jan 4:13:1084441. doi: 10.3389/fendo.2022.1084441. eCollection 2022.


Background: 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.

Methods: 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.

Results: 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 ± 102.5 vs 686.7 ± 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.

Conclusions: 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' clinical characteristics and outcomes.

Keywords: combined DKA-HHS; diabetes mellitus; hyperosmolar hyperglycemic state; immune checkpoint inhibitor; programmed cell death-1.

Publication types

  • Systematic Review
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 1* / complications
  • Diabetes Mellitus, Type 1* / drug therapy
  • Diabetic Ketoacidosis* / complications
  • Humans
  • Hyperglycemia* / chemically induced
  • Hyperglycemia* / complications
  • Hyperglycemic Hyperosmolar Nonketotic Coma* / chemically induced
  • Hyperglycemic Hyperosmolar Nonketotic Coma* / complications
  • Hyperglycemic Hyperosmolar Nonketotic Coma* / diagnosis
  • Immune Checkpoint Inhibitors / adverse effects
  • Retrospective Studies


  • Immune Checkpoint Inhibitors