Endocrine Abstracts

Background/Introduction: Today, GLP-1 receptor agonists have great clinical importance in the treatment of type 2 diabetes and obesity. Beside their known mechanisms to lower blood sugar and enhance satiety signals, GLP-1 also seems to play a significant role in sodium and water balance. This can be supported by the finding of GLP-1 receptor expression in various locations of the kidney, the enteric system and key brain structures. Recent findings investigating long-term effects of treatment with GLP-1 receptor agonists showed a significant reduction of fluid intake and 24-h-urine volume compared to placebo. There were no changes in serum sodium, urinary sodium excretion or in hormones of the RAAS system as a possible physiological explanation. To our knowledge data are inconclusive regarding physiological mechanisms that could explain these observations. Furthermore, no direct effect of GLP-1 on Vasopressin has been observed to date. The aim of this secondary analysis was to investigate changes of Copeptin levels in euvolemic participants treated with dulaglutide vs placebo. We hypothesize that dulaglutide effects a stimulation in Vasopressin due to reduced water intake, lowered blood pressure and nausea which are known side effects of GLP-1 receptor agonists.

Methods: A secondary analysis of randomized, double-blind, placebo-controlled, crossover-trials in 20 healthy participants (GATE trial) and 34 patients with primary polydipsia (GOLD trial) was performed at the University Hospital of Basel between 2016 and 2019. In both studies participants received either Dulaglutide (Trulicity®) 1.5 mg or placebo, in random order, subcutaneously once weekly over a three-week treatment phase and attended an 8-hour evaluation visit during the last treatment week. After a wash-out period of at least three weeks, patients received the complementary intervention.

Results: All 54 participants of the two cross-over trials were included. Median age was 27 (IQR 24 to 37) years and 63% were female. Median plasma sodium concentration, plasma osmolality and GFR were all in the mid-normal range. To estimate the treatment effect of Dulaglutide, we derived the absolute within-subject differences of Copeptin between Dulaglutide and placebo and used the wilcoxon rank test for statistical analysis. After a three-week treatment phase, Dulaglutide showed a significant suppression of Copeptin in both trials (P=0.04) compared to placebo [GOLD: treatment effect: -0.67 pmol/l vs GATE: treatment effect: -1 pmol/l].

Conclusion: This analysis provides further insights into the direct effects of GLP-1 on Vasopressin and reveals physiological mechanisms that could explain the role of GLP-1 in sodium and water balance.