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

Abstract

BackgroundPrimary 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, GLP-1 has also been shown to 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 (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. 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 an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Keywords: Addiction; Endocrinology; Homeostasis; Neuroimaging; Neuroscience.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Consort flow diagram.

Reconstructed CONSORT diagram for the randomized, controlled trial.

Figure 2. Observed total fluid intake during the evaluation visit for participants on dulaglutide or placebo.

(A) Thick line indicates the median; box indicates the IQR; whiskers include all points within the range of 1.5 times the IQR; dots represent all points outside 1.5 times the IQR. Note that the figure shows descriptive summary statistics of the data (“raw data”), whereas we report the estimated means and the mean difference from statistical models in the results (linear mixed-effect model with trial arm as a single fixed effect and patient as a random effect). (B) Within-patients differences in total fluid/water intake (within 8 hours) during the evaluation visit between treatment with dulaglutide versus placebo. Differences were calculated as the value in patients on dulaglutide minus the value when on placebo, hence, negative differences indicate a reduced fluid/water intake on dulaglutide, while positive values indicate an increased fluid/water intake on dulaglutide.

Figure 3. Time course of self-reported average daily fluid intake, daytime voiding frequency, and nocturia.

(A) Self-reported average daily fluid intake during the preceding week for each study injection visit and both treatment arms. (B) Daytime voiding frequency per day during the preceding weeks for each study injection visit and both treatment arms. Thick line indicates the median; box indicates the IQR; whiskers include all points within the range of 1.5 times the IQR; dots represent all points outside 1.5 times the IQR. (C) Patients reporting nocturia during the preceding week for each study injection visit and both treatment arms.

Figure 4. Thirst perception during the functional paradigm of the MRI visit.

Self-reported thirst perception on a 7-point NRS for matched controls and patients on dulaglutide or placebo during the functional paradigm of the MRI visit. Thick line indicates the median; box indicates the IQR; whiskers include all points within the range of 1.5 times the IQR; dots represent all points outside 1.5 times the IQR.