Abstract Disclosure: A. Musleh: None. M.T. Rauf: None. E. Afroze: None. S. Al-Bacha: None. A 75-year-old male with Type 2 Diabetes was brought to the emergency department (ED) by emergency medical services (EMS) due to altered mentation. The patient’s wife found him unresponsive with seizure-like activity. EMS was called to the scene and obtained a capillary blood glucose reading of 31 mg/dL. Despite initial treatment with 50% dextrose the patient’s capillary blood glucose came down to 21 mg/dL in the ED and was confirmed by venous glucose. Workup including Computed Tomography (CT) imaging was inconsistent with a cerebrovascular accident. Given refractory hypoglycemia and delirium, the patient was started on a dextrose 10% infusion at 150 milliliters per hour. He was admitted to the intensive care unit for closer monitoring. His wife states that the patient had a few episodes of mild hypoglycemia overnight for the past several weeks, which improved after eating. His home medications included NPH insulin 46 units twice daily, empagliflozin 25 mg once daily, and injectable semaglutide 2 mg once weekly. The last dose of NPH insulin was the night before the presentation and the last dose of semaglutide was 5 days prior to admission. Serum creatinine levels were stable at 1.3-1.5 mg/dL throughout the hospitalization, which was below his baseline creatinine of 1.7 mg/dL. Laboratory results were as follows: hemoglobin A1c 5.9%, c-peptide level was 0.3 ng/mL (normal range 0.8-3.9 ng/mL) with a glucose of 68 mg/dL (normal range 70-100 mg/dL), insulin 203.8 mcIU/mL (normal range less than 24 mcIU/mL), proinsulin 3.2 pmol/L (normal range less than or equal to 8 pmol/L), beta-hydroxybutyrate 0.06 mmol/L (normal range 0.02-0.27), cortisol 66.6 mcg/dL (normal range 6.7-22.6 mcg/dL), insulin-like growth factor 1 123 ng/mL (normal range 53-222), and hypoglycemic agent panel was negative. On ICU Day 2, his mentation improved, he was allowed to eat but continued to require dextrose infusion to prevent hypoglycemia. Repeat fasting insulin levels even four days from prior showed an incremental decrease to 59.4 mcIU/mL with a glucose of 77 mg/dL. It took 7 days before the patient was able to maintain glucose above 70 mg/dL off of dextrose infusion. After which he had hyperglycemia requiring gradual reintroduction of his diabetes medicines other than insulin. It is rare to see such prolonged refractory hypoglycemia from an exogenous source of insulin as exhibited in this case. Notably, the patient was on semaglutide and had stable chronic kidney disease without acute kidney injury. Although multiple mechanisms explain the prolonged insulin duration of action in kidney disease, the effects of semaglutide on insulin action are unknown. Presentation: 6/3/2024