A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia
Open accessAbstract
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.
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Patients on any obesity medication, but particularly incretin medications, are at risk for a low oral intake of fluids and solid food, predisposing to dehydration.
“Often, patients on any obesity medication, but particularly incretin medications, are at risk for a low oral intake of fluids and solid food, predisposing to dehydration, and patients, particularly those engaging in vigorous or intense physical activity, should be encouraged to hydrate and eat water-rich foods [104,105].”
From Lifestyle Medicine for Obesity in the Era of Highly Effective Anti-Obesity Treatment (2025) · cites this paper as [105]
The Results report that dulaglutide reduced fluid intake in patients with primary polydipsia, and the Introduction says GLP-1 affects appetite and food intake. The trial does not establish reduced solid-food intake in its participants, dehydration risk, or the same effects for patients taking any obesity medication. Food intake during the evaluation visit was standardized (Trial procedures). (LLM, conf=0.87)
Experimental — accuracy not yet measuredIndividuals with obesity frequently have biochemical evidence of deficiencies of micronutrients including vitamin D, vitamin B12, folate, thiamine, iron, and zinc.
“For example, individuals with obesity are frequently found to have biochemical evidence of deficiencies of micronutrients, including vitamin D, vitamin B12, folate, thiamine, iron, and zinc [80][81][82][83].”
From Nutritional considerations with antiobesity medications (2024) · cites this paper as [80]
The Introduction (page unavailable) discusses primary polydipsia and mentions weight gain as a medication side effect, but does not address micronutrient deficiencies in people with obesity. Searches for biochemical micronutrient deficiencies and for obesity with vitamin D, zinc, iron, and folate found no passage supporting the claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredAvailable data from animal and clinical studies suggest that GLP-1 agonism may reduce thirst and water intake.
“Available data from animal and clinical studies also suggest that GLP-1 agonism may reduce thirst and water intake [Fig. 3] [70,71].”
From Application of nutrition interventions with GLP-1 based therapies: A narrative review of the challenges and solutions (2025) · cites this paper as [71]
Treatment of patients with primary polydipsia with dulaglutide for three weeks was associated with a 17% reduction in fluid intake (p=0.002) and a reduction in acute thirst perception compared with placebo.
“Treatment of patients with primary polydipsia with the GLP-1 based therapy dulaglutide for three weeks was associated with a 17 % reduction in fluid intake (p = 0.002) and a reduction in acute thirst perception compared with placebo [71].”
From Application of nutrition interventions with GLP-1 based therapies: A narrative review of the challenges and solutions (2025) · cites this paper as [71]
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“Esiste, inoltre, un’evidenza spe-rimentale che gli analoghi del peptide glucagone-simile di tipo 1 ( glucagon-like peptide-1 , GLP1) influenzino il bilan-cio idroelettrolitico tanto che la dulaglutide viene suggerita per il trattamento della polidipsia psicogena [11].”
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A clinical and experimental investigation of liraglutide effects on the brain-kidney axis
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“These agonists decrease both thirst sensation and appetite in rodents and humans, the outcome being that less fluid enters the body ( 11 – 13 ).”
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“…behavior characterized by excessive liquid intake which is related to dysfunctions of reward and compulsivity and which is typically identified in people with mental and/or neurodevelopmental disorders [ 44 ], has shown symptoms’ improvement in a controlled trial involving dulaglutide [ 86].”
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“Dulaglutide treatment in primary polydipsia did not significantly alter resting-state connectivity despite improvements in thirst, fluid intake, and quality of life (Winzeler et al., 2021).”
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- Authors
- Winzeler, B., Sailer, C. O., Coynel, D., Zanchi, D., Vogt, D. R., Urwyler, S. A., Refardt, J., & Christ-Crain, M.
- Affiliations
- University of Basel (CH)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Winzeler, Bettina
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-10-15
- Volume
- 131
- Issue
- 20
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8516458
- OpenAlex
- W3198007080
- Cited by
- 37
- References
- 47
- Citations by year
- 2026: 13 · 2025: 6 · 2024: 12 · 2023: 1 · 2022: 4 · 2021: 1
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Swiss National Science Foundation (-)
- , University Hospital and University of Basel (-)
- Swiss Academy of Medical Sciences (-)
- G.& J. Bangerter-Rhyner Foundation (-)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Electrolyte and hormonal disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- dulaglutide, GLP-1 receptor agonists, primary polydipsia, fluid intake, thirst perception, water intoxication, hyponatremia, urine output, drinking behavior, appetite regulation
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Adult, Double-Blind Method, Drinking, Glucagon-Like Peptides, Female, Humans, Immunoglobulin Fc Fragments, Magnetic Resonance Imaging, Male, Quality of Life, Recombinant Fusion Proteins, Thirst, Polydipsia, Psychogenic
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