Potential Effect of the Short-Acting GLP-1 Agonist Exenatide on Copeptin in Healthy Adults

Abstract Objective Glucagon-like peptide-1 (GLP-1) plays an emerging role in regulating sodium and water balance. Long-acting GLP-1 receptor agonist (RA) treatment reduces fluid intake and diuresis. In contrast, short-acting GLP-1 RAs induces natriuresis, but its effects on copeptin, a surrogate marker for arginine vasopressin, remain unknown. We therefore investigated the effect of short-acting GLP-1 RAs on copeptin levels. Design This is a secondary analysis of a double-blind, placebo-controlled trial in 13 healthy euvolemic adults. Methods Our primary objective was to investigate the effect of a single 10 µg exenatide injection on copeptin levels. The treatment effect was assessed using the Wilcoxon rank test comparing baseline and 60 minutes post-injection. Results Thirteen healthy participants were included (median age 38 years (IQR, 33-42), 69% male, BMI 26.1 kg/m2 (24.6-29.2)). Copeptin levels were 3.54 pmol/L (2.69-8.53), 4.39 pmol/L (2.69-6.50), and 4.01 pmol/L (2.73-5.74) at baseline, 60, and 90 minutes post- injection, resulting in a mild increase of +0.60 pmol/L, which did not reach statistical significance (95%CI: -0.46-2.07, p=0.23). Excluding participants who experienced nausea (n=3 of 13), the treatment effect was more pronounced (+1.06 pmol/L; 95%CI: -0.06-2.95, p=0.06). Repeated measures correlation revealed a weak non-significant negative correlation between GLP-1-induced decreases in blood glucose and copeptin (r=-0.293, p=0.138). Conclusion This first investigation of a short-acting GLP-1 RA on copeptin suggests a potential modulatory role of GLP-1 on arginine vasopressin regulation, providing preliminary evidence for a direct effect independent of non-osmotic stimuli such as nausea or low glucose levels.