A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

Abstract

Background Primary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide-1 (GLP-1) reduces appetite and food intake. In experimental models, they also play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia. MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover-trial, 34 patients with primary polydipsia received weekly dulaglutide (Trulicity®) 1.5mg and placebo (0.9% sodium chloride). During the last treatment week, patients attended an 8-hour evaluation visit with free water access. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI. Findings Patients on dulaglutide reduced fluid intake by 490ml [95%-CI -780, -199], p=0.002, from 2950ml [95% CI 2435, 3465] on placebo to 2460ml [95% CI 1946, 2475] on dulaglutide (model estimates), corresponding to a relative reduction of 17%. 24-hour urinary output was reduced by -943ml [95%-CI -1473, -413], p=0.001. Thirst perception in response to beverage pictures was higher in patients with primary polydipsia versus controls and lower on dulaglutide versus placebo, but functional activity was similar between groups and treatments.Interpretation GLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.

Approach to the Patient: “Utility of the Copeptin Assay”

“…Primary polydipsia has traditionally been linked to psychiatric disease, such as schizophrenia spectrum disorder ( 125 ), but is increasingly reported in healthy people without psychiatric comorbidities ( 40 , 126 , 127 ), as it was the case for our patient. In clinical practice, cognitive behavioral therapy is used to treat primary polydipsia and was successful in our patient.…”

“…However, guidelines for the management of this syndrome are lacking and medical treatment options are scarce ( 128 ). We have recently shown that a 3-week treatment with the glucacon-like peptide-1 receptor agonist dulaglutide reduces thirst, daily fluid intake, and 24-hour urine output in primary polydipsia ( 126 ). This proof of concept study provides a novel therapeutic approach and the GLP-1 receptor agonist may in the future become an interesting treatment option for these patients.…”

Hypothalamic–pituitary–adrenal axis activity in patients with primary polydipsia compared to healthy controls

“…This study combined data from two prospective studies conducted at the University Hospital Basel, Switzerland. The methodology of both studies was similar with the aim to elucidate the effect of GLP-1 receptor agonists on drinking behavior in 34 patients with primary polydipsia [14] and in 20 healthy volunteers [15] in a randomized placebo-controlled crossover design. For the present exploratory analysis, only data of participants during the placebo phase were evaluated.…”

“…For the present exploratory analysis, only data of participants during the placebo phase were evaluated. Full details of the studies' rationale, design, and statistical analysis have been published elsewhere [14,15]. Inclusion criteria for patients with primary polydipsia were age ≥ 18 years, polyuria of > 50 ml/kg/day, and polydipsia of > 3000 ml/day.…”

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

“…On the other hand, in addition to the brain effects described above, GLP-1R agonists could also act on intestinal hyperpermeability and gut microbiota diversity, probably in a way that protects against the harmful effects of chronic drug use. Dulaglutide might thus be of extra interest as a clinical study with dulaglutide reporting a low number of aversive effects (Winzeler et al, 2021 ). Finally, GLP-1 also increases anti-inflammatory cytokines, providing another beneficial effect relevant for certain types of addictions.…”