Effects of GLP-1 receptor agonists on copeptin in euvolemic participants.
This secondary analysis pooled data from two randomized, double-blind, placebo-controlled crossover trials to examine whether the GLP-1 receptor agonist (RA) dulaglutide affects copeptin — a stable surrogate marker for vasopressin (antidiuretic hormone) — in euvolemic individuals. A total of 54 participants were included: 34 with primary polydipsia and 20 healthy volunteers. Participants received three weeks of either subcutaneous dulaglutide or saline placebo once weekly before crossing over. Fasting blood samples for copeptin were collected after each treatment phase. The study found that dulaglutide was associated with a statistically significant suppression of copeptin levels, with a median within-subject difference of −0.7 pmol/L (p = .047), representing approximately a 12% reduction relative to placebo. This effect was not significantly correlated with dulaglutide-related changes in blood pressure, BMI, or nausea frequency. The authors suggest this finding may help explain GLP-1's known role in fluid and sodium homeostasis. Key limitations include the secondary-analysis design (not pre-specified as the primary outcome), modest sample size, a mixed population (healthy and polydipsic participants), and the reliance on copeptin as a proxy rather than directly measured vasopressin.
Why this grade: The finding comes from a pooled secondary analysis of two randomized double-blind crossover trials in humans (n=54), which provides controlled within-subject data but is limited by its post-hoc, secondary-analysis nature and modest sample size.
Objective Glucagon-like peptide-1 (GLP-1) plays an important modulatory role in sodium and water homeostasis. Recent studies demonstrated that long-term treatment with GLP-1 receptor agonists (RAs) reduces fluid intake and urine output. To the best of our knowledge, no direct effect of GLP-1 on vasopressin has been observed. This secondary analysis aimed to investigate changes in copeptin levels in euvolemic participants treated with the GLP-1 RA dulaglutide versus placebo. Design Secondary analysis of two randomized, double-blind, placebo-controlled, cross-over trials in 34 patients with primary polydipsia and 20 healthy participants. Methods Participants received a 3-week intervention with dulaglutide (Trulicity) 1.5 mg or placebo (.9% sodium chloride) subcutaneously once weekly. Blood for copeptin analysis was collected at 08:00 after each treatment phase. 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. Results All 54 participants of the two cross-over trials were included. Median age was 27 years [interquartile range (IQR), 24-37.5 years], and 63% were female. Median body mass index (BMI) was 23 kg/m2 (IQR, 20.8-24.8). After 3-week treatment, dulaglutide was associated with a significant suppression of copeptin with a median within-subject difference of -.7 pmol/L (p = .047), corresponding to a 12% reduction compared to placebo. Treatment-induced changes in copeptin were not significantly correlated with GLP-1-mediated reductions in blood pressure, BMI, or incidence of nausea. Conclusions Our analysis provides evidence that the GLP-1-RA dulaglutide inhibits the vasopressin system and proposes physiological mechanisms that may explain the role of GLP-1 in sodium and water balance.
Educational summary of published research — not medical advice. License: cc by. Full text is shown only where licensing permits.