SAT-064 Copeptin Levels at Baseline and in Response to Short-Acting GLP-1 Receptor Agonists in Patients with Endogenous Hyperinsulinemic Hypoglycemia and Healthy Controls - A Secondary Analysis

Abstract Disclosure: S. Leibnitz: None. S. Baumann: None. C. Atila: None. C. Romberg: None. M. Hepprich: None. K. Antwi: None. E.R. Christ: None. M. Christ-Crain: None. Background: Acute hypoglycemia is a recognized non-osmotic trigger for copeptin release, a surrogate marker for vasopressin. However, data on copeptin levels in individuals at risk of chronic hypoglycemia remain scarce. Endogenous hyperinsulinemic hypoglycemia (EHH), characterized by inappropriate insulin secretion and intermittent chronic hypoglycemia, provides a useful model for investigating copeptin dynamics in the context of chronic hypoglycemia. Therefore, this study aimed at evaluating baseline copeptin levels and copeptin responses to acute hypoglycemia induced by short-acting GLP-1 receptor agonists, comparing patients with confirmed EHH to healthy controls. Methods: This is a secondary analysis of the previously completed, randomized, double-blind, cross-over, proof of principle FAST study (NCT04909333) in patients with confirmed EHH and age-, sex- and BMI-matched healthy controls at the University Hospital Basel. The primary objective was to investigate baseline copeptin levels and to assess the acute effect of exenatide-induced decrease in glucose on copeptin levels in both groups. Patients were randomly assigned to first receive a single dose of exenatide (10µg) or placebo (0.9% sodium chloride) intravenously, followed by the alternate treatment on a subsequent day. Healthy controls only received exenatide. Plasma copeptin levels were measured at baseline and 60 minutes after the infusion. Individuals reporting nausea were excluded from the analysis. Results: This analysis included eight patients and eight healthy controls. The median [IQR] age was 40 [34, 45] years, 75% were male, and the BMI was 28.4 kg/m2 [26.0, 30.4]. Baseline copeptin levels were significantly higher in patients with EHH (7.28 pmol/l [4.27, 10.05]) compared to healthy controls (3.21 pmol/l [2.69, 4.55]) (p=0.03). Fifty percent of patients experienced hypoglycemia within 30 to 45 minutes after exenatide, accompanied by a glucose nadir of 2.71 mmol/l [2.68, 2.75], resulting in a copeptin increase of +2.13 pmol/l [0.40, 3.72] in this subgroup. Compared to placebo, no hypoglycemic episodes occurred and copeptin levels decreased by -1.42 pmol/l [-2.11, -0.71]). Healthy controls reached a glucose nadir of 3.45 mmol/L [3.17, 3.53] within 30 to 45 minutes after exenatide, resulting in no relevant copeptin increase of +0.34 pmol/l [-0.01, 0.86], and only one participant experienced hypoglycemia. Conclusions: Patients with risk of chronic intermittent hypoglycemia exhibit significantly elevated baseline copeptin levels compared to healthy controls. Exenatide induced a more pronounced blood glucose decrease in patients, triggering a stronger copeptin response compared to healthy controls, without downregulation from chronic hypoglycemic stress. These findings provide further insights into copeptin dynamics in both chronic and acute hypoglycemic states. Presentation: Saturday, July 12, 2025