Efficacy and Safety of Tirzepatide in Refractory Hypoglycemia Associated with Esophagojejunostomy

We present the case of a 40-year-old woman with severe recurrent hypoglycemia, unresponsive to dietary glucose intake and occurring in the context of chronic intestinal pseudo-obstruction, esophagojejunostomy, and long-term parenteral nutrition. Extensive endocrine and imaging evaluations excluded insulinoma, autoimmune hypoglycemia, and counterregulatory hormone deficiencies, suggesting impaired incretin function as the likely mechanism. Conventional treatments-including acarbose, glucocorticoids, somatostatin analogues, and a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA)-failed to provide adequate glycemic control. Given the exclusion of the proximal duodenum from nutrient transit and its key role in glucose-dependent insulinotropic polypeptide (GIP) secretion, therapy with tirzepatide, a dual GIP/GLP-1 receptor agonist, was initiated. Tirzepatide led to near-complete remission of hypoglycemic episodes and substantial improvement in glycemic variability and quality of life. Due to recurrence of symptoms before the next scheduled dose, the interval was shortened from 7 to 5 days, maintaining therapeutic efficacy. This case highlights the potential of tirzepatide in treating refractory hypoglycemia related to altered incretin signaling, particularly in patients with complex gastrointestinal surgical histories and parenteral nutrition. While currently approved for type 2 diabetes and obesity, tirzepatide may offer a novel off-label approach in select hypoglycemic syndromes in which GIP deficiency plays a central role.