SAT-065 Comparison of Long-Acting and Short-Acting GLP-1 Receptor Agonists on Copeptin in Euvolemic Participants - A Secondary Analysis of Three Prospective Trials

Abstract Disclosure: S. Leibnitz: None. S. Baumann: None. C. Atila: None. C. Romberg: None. M. Hepprich: None. K. Antwi: None. B. Winzeler: None. E.R. Christ: None. C. Mirjam: None. Introduction: Glucagon-like peptide-1 (GLP-1) plays an important role in regulating sodium and water balance. Long-acting GLP-1 receptor agonist (RA) treatment reduces fluid intake, diuresis, and copeptin levels, a surrogate marker for vasopressin. In contrast, short-acting GLP-1 RA induces natriuresis, but their effects on copeptin remain unknown. The aim of this analysis was to compare the effects of long-acting and short-acting GLP-1 RA on copeptin levels. Methods: This analysis combined data from three prospective trials conducted at the University Hospital Basel, Switzerland. The primary objective was to compare the effect of a three-week treatment with dulaglutide (GOLD & GATE trials) to a single dose of exenatide (FAST trial) on plasma copeptin release in euvolemic adults. In the GOLD & GATE trials, 34 and 20 participants were randomly assigned, respectively, to first receive a three-week treatment with either dulaglutide (1.5 mg) or placebo (0,9% sodium chloride) subcutaneously once a week. After a wash-out period of at least three weeks, participants received the opposite intervention. In the FAST trial, 10 participants received a single dose of Exenatide (10ug) intravenously. Results: In total, 64 participants in the three trials were included. The median age was 27 (IQR, 24 to 37) years in the GOLD & GATE cohorts, whereas participants in the FAST cohort were modestly older with 38 [33 to 41] years. The body mass index (BMI) was 23 (IQR 20.8-24.8) in the GOLD & GATE cohorts, compared to 27(IQR 24.8-30.4) in the FAST cohort. Participants in the FAST cohort were predominantly male (72%), whereas gender distribution was more balanced in the GOLD & GATE cohorts. Long-term treatment with dulaglutide resulted in a significant suppression of copeptin in both GOLD & GATE trials (p=0.04) compared to placebo [GATE: treatment effect: -1.4 pmol/L and GOLD: treatment effect: -0.4 pmol/L]. In contrast, short-term treatment with exenatide in the FAST trial resulted in an increase of copeptin (p=0.06) compared to baseline [FAST: treatment effect: + 0.34 pmol/L]. Conclusion: Long- and short-acting GLP-1 RA differ in their effects on copeptin regulation. Long-acting GLP-1 agonists significantly suppress copeptin, likely through a synergistic mechanism, while short-acting GLP-1 RAs appear to stimulate copeptin release. These differing effects may also extend to other GLP-1-related mechanisms with potential high clinical relevance. Presentation: Saturday, July 12, 2025