Case Presentation: A 44-year-old woman with type 2 diabetes and left renal cell carcinoma with partial left nephrectomy presented with three weeks of progressive anorexia, nausea, vomiting and diarrhea. She was on adjuvant pembrolizumab, an immune checkpoint inhibitor (ICI) for nine months. Her labs revealed significant hyperglycemia, elevated beta-hydroxybutyrate, elevated creatinine, an acidotic venous blood gas pH, and an anion gap. These demonstrated diabetic ketoacidosis (DKA), and acute kidney injury (AKI). Her hemoglobin A1c (HbA1c) was 7.7%. She was managed with standard hospital protocol for DKA. Though her keto acidosis subsequently resolved, her blood glucose remained between 300 and 400 mIU/L, despite intensive glycemic management. In contrast, her home blood sugars were under 150 mIU/L with metformin use. This prompted a work-up for ICI-induced diabetes (IID). The C-peptide level was low, indicating insulin deficiency. The patient was tested for other endocrine immune-related adverse events (irAEs). The free T4 was low at 0.84 mIU/L with an inappropriately normal TSH, confirming central hypothyroidism. The morning cortisol level was less than 0.5 mcg/dL. The patient had a positive ACTH stimulation test, confirming secondary adrenal insufficiency. She was discharged with basal insulin, prandial insulin, levothyroxine, and hydrocortisone.
Discussion: Immune-related endocrinopathies occur in 10% of patients using ICIs, the most common of which include thyroiditis and hypophysitis . In contrast, IID is an emerging, though less common, irAE of profound clinical significance, presenting within weeks to months of therapy initiation. Under normal conditions, checkpoints like PD-1, PD-L1, and CTLA-4 inhibit autoreactive T-cell activation. ICIs block these signals, permitting T-cells to target pancreatic islet cells and cause abrupt insulin deficiency. IID has a heterogenous clinical presentation that includes classic Checkpoint Inhibitor-Associated Auto-immune Diabetes Mellitus (CIADM), life-threatening DKA, or a marked exacerbation of hyperglycemia in patients with pre-existing type 2 diabetes. Retrospective studies have indicated incidence of 13-27% hyperglycemia in all ICI-treated patients among which 42%-72% were patients with known diabetes. IID should be suspected in any patient using an ICI who develops new-onset hyperglycemia in the absence of common risk factors for diabetes, such as obesity or steroid use. Diagnosis requires random blood glucose ≥ 200 mg/dL or HbA1c > 6.5%, plus a low or undetectable C-peptide level. DKA is a common initial presentation. Critically, the management of IID diverges from that of other irAEs which often responds to steroid use. However, the pancreatic beta-cell destruction in IID is typically irreversible, so it does not improve with steroid treatment. Therefore, the cornerstone of management is permanent hormonal replacement. Patients usually require lifelong insulin therapy.
Conclusions: This case illustrates the need for a low threshold to diagnose immune checkpoint inhibitor induced endocrinopathies. Given their potential for rapid and life-threatening decline, prompt recognition and appropriate management is critical to prevent acute metabolic crisis. Early involvement of endocrinology and oncology is essential to guide both acute care and future immunotherapy.