We present three patients with a history of AVP-D and stable desmopressin treatment who initiated GLP-1 RA therapy for type 2 diabetes mellitus or obesity. Following weight loss and a self-reported decrease in thirst, all three patients were able to reduce their desmopressin dosage while maintaining normal thirst and urine output. None of the patients were taking diuretics, lithium, or following a low-sodium diet. Although all patients experienced weight loss after starting GLP-1 RAs, this 6–7% reduction in weight is insufficient to explain the 40–50% decrease in desmopressin dosage. These cases suggest a potential impact of GLP-1 RAs on desmopressin requirements in AVP-D. Herein, we discuss the possible interactions between these medications and propose a hypothesis to explain the enhanced antidiuretic effect of desmopressin when combined with GLP-1 RA.

GLP-1 plays a complex role in regulating sodium and water homeostasis. It acts on the brain to decrease thirst and potentially suppress AVP production. GLP-1 has been shown to significantly reduce water intake by 36% in healthy subjects after a salty meal, without affecting their blood sodium levels [1]. This effect is thought to be mediated by a direct influence on drinking behavior, as supported by evidence in rats demonstrating reduced fluid intake with GLP-1 RAs independent of food intake [6]. Interestingly, a recent study utilizing Brattleboro rats, a model of hereditary hypothalamic diabetes insipidus, revealed an augmented response to centrally administered GLP-1 RAs, leading to a greater reduction in fluid intake compared to wildtype rats [7]. However, both wildtype and Brattleboro rats exhibited similar reductions in food intake following GLP-1 RA treatment. This suggests that Brattleboro rats may have a specific dysfunction in the GLP-1 pathway that regulates water intake [7].

In rats, GLP-1 receptor signaling in hypothalamic neurons can directly inhibit the production of AVP [2]. Furthermore, GLP-1 could decrease water consumption by reducing sodium absorption in the gut via inhibition of the intestinal sodium-hydrogen exchanger-3 (NHE3) [1].

The GLP-1 receptor is expressed in various renal locations, including preglomerular vascular smooth muscle cells and juxtaglomerular cells [8]. Multiple studies on experimental models, healthy volunteers, overweight individuals, and diabetic patients have shown that GLP-1 RAs stimulate natriuresis and diuresis [9,10,11,12]. This effect is likely mediated by NHE3 inhibition in the proximal renal tubule. When GLP-1 binds to its receptor, it activates protein kinase A (PKA). This activation leads to the phosphorylation of NHE3, which ultimately results in the inhibition of sodium reabsorption in the proximal tubule leading to less fluid reabsorption at this site and increased distal delivery [12, 13].

In the kidney, AVP binds to vasopressin V2 receptors, regulating urine concentration by increasing sodium reabsorption in the thick ascending limb of the loop of Henle and enhancing aquaporin 2 (AQP-2) expression in the apical membrane of collecting duct principal cells, thereby increasing their osmotic permeability [14].

In individuals with intact AVP system, GLP-1 RA treatment is thought to reduce AVP secretion and induce natriuresis, increasing fluid delivery to the distal nephron and collecting ducts. The GLP-1 RA-induced decrease in AVP should reduce the osmotic permeability of collecting duct, allowing excretion of sodium-free water and restoring osmotic homeostasis (Fig. 1A).

Proposed mechanism of GLP-1 RA impact on sodium and water homeostasis in the kidney. A In individuals with normal AVP production, administration of GLP-1 RAs decreases AVP secretion and induces natriuresis. Reduced endogenous AVP levels result in decreased V2 receptor-mediated sodium reabsorption in the distal nephron. Additionally, reduced endogenous AVP levels decrease the osmotic permeability of collecting ducts, leading to increased water excretion. B GLP-1 RAs promote natriuresis and increased fluid delivery to the distal nephron. In patients with AVP-D receiving desmopressin replacement, V2 receptor-mediated sodium reabsorption and collecting duct water permeability are primarily regulated by exogenous desmopressin dosage, not endogenous AVP levels. This may account for the observed amplification of desmopressin effects

We propose that GLP-1 RAs will also induce natriuresis and increased distal fluid delivery in patients with AVP-D. However, as these individuals receive exogenous desmopressin to replace AVP, the osmotic permeability of the collecting ducts is primarily influenced by desmopressin dosage, not endogenous AVP levels. This may account for the observed amplification of desmopressin effects and subsequent reduction in desmopressin dosages in our cases (Fig. 1B). In other words, the increased distal fluid delivery caused by GLP-1 RAs may allow for lower desmopressin doses to maintain water balance.

This hypothesis is supported by observations of increased hyponatremia risk when desmopressin is combined with other medications that increase distal fluid delivery in the nephron, such as thiazides [15].

GLP-1 RAs may interact directly with the renin–angiotensin–aldosterone system (RAAS) by inhibiting angiotensin II formation, although their effect on renin release remains unclear. Two potential mechanisms have been proposed: indirect inhibition of renin release through tubuloglomerular feedback activation secondary to natriuresis (induced by NHE3 in the proximal tubule), and direct inhibition of angiotensin II production in tissues [16]. Nevertheless, this interaction does not appear to undermine our hypothesis.

In the case of patient 3, who is treated with valsartan, an angiotensin II type 1 receptor (AT1R) antagonist, an additional interaction may exist. AT1R antagonists inhibit sodium reabsorption in the proximal tubule leading to natriuresis via activation of unblocked angiotensin II type 2 receptors by angiotensin III [17]. This could theoretically attenuate the natriuretic effect of GLP-1 RAs. Despite this, patient 3 was able to decrease her desmopressin dosage by 50% after initiating GLP-1 RA.

In the kidneys, the angiotensin-converting enzyme (ACE) maintains a balance between the vasodilatory and natriuretic actions of bradykinin and the vasoconstrictive and salt-retentive effects of angiotensin II. By disrupting this balance, ACE inhibitors promote natriuresis [18]. This could theoretically weaken the natriuretic effect of GLP-1 RAs in patients taking ACE inhibitors. However, patient 1, who was on enalapril, still achieved a 50% reduction in desmopressin dose after starting GLP-1 RA treatment.

While desmopressin can increase hyponatremia risk in older adults [19], this does not explain the 50% dosage decrease in patients 1 and 3, who had stable doses and normal serum sodium levels before GLP-1 RA initiation.

Another factor to consider in patients 2 and 3 is their secondary hypothyroidism. If chronically uncontrolled, it may be associated with a decreased capacity for free water excretion and hyponatremia. This is due to elevated AVP levels, mainly attributed to the hypothyroidism-induced decrease in cardiac output [20]. This interaction seems less relevant in patients 2 and 3, who have AVP-D and were well-controlled with levothyroxine.

An additional factor to consider in patient 3 is secondary hypoadrenalism. Glucocorticoid deficiency can lead to impaired renal free water clearance, causing water retention and dilutional hyponatremia [21]. Additionally, cortisol deficiency stimulates the hypothalamus to increase production of corticotropin-releasing hormone (CRH), which in turn promotes the secretion of AVP [21]. However, our patient has AVP-D and her hypoadrenalism was controlled with prednisolone. Therefore, these interactions are unlikely to be relevant in this case.

This report is limited by its small sample size, observational design, reliance on self-reported data, and lack of specific measurements such as urinary sodium, which precluded assessment of fractional excretion of sodium.

Nonetheless, existing evidence supports our hypothesis and provides a plausible explanation for the observed decrease in desmopressin requirements in patients with AVP-D treated with GLP-1 RAs. However, further research is needed to confirm this hypothesis and elucidate the underlying mechanisms.