Long-term Empagliflozin Use in Chronic Syndrome of Inappropriate Antidiuresis Due to Traumatic Subarachnoid Hemorrhage

Abstract

Syndrome of inappropriate antidiuresis (SIAD), the leading cause of hyponatremia, poses treatment challenges. Fluid restriction often proves insufficient. Alternative therapies such as demeclocycline, tolvaptan, and urea are limited to selected cases due to frequent side effects, high cost, and low availability, respectively. This case report explores the potential of empagliflozin as a novel treatment option. A 32-year-old female with SIAD following a traumatic subarachnoid hemorrhage experienced persistent hyponatremia despite fluid restriction and initial treatment with hypertonic saline and tolvaptan. Treatment with severe fluid restriction of 800 milliliters/day (mL/day) for almost a year led to significant impairment in her quality of life. Empagliflozin 25 milligrams/day was then initiated, resulting in sustained normonatremia for 16 months, the longest reported duration to date. This allowed increased fluid intake (1750 mL/day) and improved quality of life. Empagliflozin shows potential for managing chronic SIAD; prospective studies are needed to validate its efficacy and safety.

Introduction

The syndrome of inappropriate antidiuresis (SIAD), the most common cause of hyponatremia, is characterized by increased arginine vasopressin (AVP) action without hemodynamic and osmotic stimuli, leading to a state of excess extracellular water and subsequent dilutional hyponatremia [1]. Chronic hyponatremia causes significant morbidity, including neurocognitive deficits, reduced bone mineral density, and gait instability with increased risk of falls [2, 3]. SIAD is a diagnosis of exclusion, requiring euvolemia, the combination of inappropriately concentrated urine and elevated urinary sodium excretion with plasma hypo-osmolality, normal renal function, absence of hypocortisolemia, hypothyroidism, or diuretic use [1]. The etiology of SIAD varies, including pathologies of the central nervous system and drug-induced causes [1].

Fluid restriction, the first-line therapy, is effective in only 30% to 50% of patients [4]. Individuals with limited electrolyte-free water clearance, ie, high urinary osmolality and sodium concentration, are least likely to respond [5, 6]. Due to scarcity of evidence, recommendations regarding second-line treatment options diverge between tolvaptan and urea [6, 7]. Tolvaptan, an oral selective antagonist of AVP receptors on the renal collecting ducts, promotes aquaresis and the clearance of water without increasing electrolyte excretion [8]. Tolvaptan remains the only approved medication for SIAD [9]. However, its prohibitive cost, high risk of overly rapid hyponatremia correction and risk for osmotic demyelination limit its use [10, 11]. Oral urea promotes osmotic diuresis and free water clearance, increasing serum sodium levels [12, 13]. However, the absence of randomized controlled trials (RCTs) and poor palatability hinder its use [10]. Demeclocycline, a tetracycline derivative inducing AVP resistance, is not recommended because of variable efficacy and adverse events [6, 7].

Considering the unmet clinical need for optimal SIAD management, 2 RCTs suggest empagliflozin, an oral sodium-glucose cotransporter-2 inhibitor, as a promising treatment option [14, 15] We report a patient with refractory chronic SIAD treated successfully with empagliflozin for 16 months.

Case Presentation

A 32-year-old woman with no prior medical history and a healthy lifestyle presented to the emergency department with headache and vomiting following a mechanical fall from 1-meter height, resulting in occipital head impact on the ground, transient loss of consciousness, and retrograde amnesia for events preceding the fall. Her only medication was the combined oral contraceptive pill (COCP) (ethinylestradiol/levonorgestrel). Physical examination was unremarkable with no focal neurological deficit, normal Glasgow Coma Score, and clinical euvolemia.

Diagnostic Assessment

An initial noncontrast head computerized tomography scan revealed a small traumatic subarachnoid hemorrhage (SAH) with frontal lobe contusion injury. Computed tomography angiography and magnetic resonance imaging of the head did not show any anatomical defects. On admission, serum sodium concentration was 109 millimoles/liter (mmol/L) (reference range: 135-145 mmol/L), consistent with severe acute-onset hyponatremia, given evidence of recent normonatremia (143 mmol/L). Biochemical evaluation (Table 1) demonstrated a combination of serum hypo-osmolality with inappropriately elevated urine osmolality and sodium concentration. Hypocortisolism and hypothyroidism were excluded—fulfilling criteria for SIAD diagnosis [6, 7]. Cerebral salt-wasting syndrome was considered due to polyuria (up to 2.5 liters/day) with elevated urinary sodium concentration (117 mmol/L). Fractional excretion of urate was not measured to differentiate between SIAD and cerebral salt-wasting syndrome. However, the combination of clinical euvolemia, lack of improvement with initial trial of isotonic 0.9% sodium chloride, and resolution of the polyuric phase collectively favored a unifying diagnosis of SIAD due to traumatic SAH [16].

Table 1.

Laboratory work-up of hyponatremia at initial presentation

Biochemical parameter	Result (RR)
Serum Na+	109 mmol/L (135-145 mmol/L)
Serum osmolality	230 mOsmol/kg H2O [SI: 230 mmol/kg] (275-295 mOsmol/kg H2O [SI: 275-295 mmol/kg])
Urine Na+	117 mmol/L [SI: 117 mmol/L]
Urine osmolality	502 mOsmol/kg H2O [SI: 502 mmol/kg]
Urine K+	37 mmol/L [SI: 37 mmol/L]
9 Am cortisol (on COCP)	28.2 µg/dL [SI: 778 nmol/L] (5.0-25.0 µg/dL [SI: 140-690 nmol/L])
TSH	1.2 μIU/mL [SI: 1.2 mIU/L] (0.3-4.2 μIU/mL [SI: 0.3-4.2 mIU/L])
Free T4	1.3 ng/dL [SI: 16.9 pmol/L] (0.9-1.7 ng/dL [SI: 12.0-22.0 pmol/L])
Urea	10.8 mg/dL [SI: 1.8 mmol/L] (5.0-20.0 mg/dL [SI: 2.5-7.8 mmol/L])
Creatinine	0.47 mg/dL [SI: 42.0 µmol/L] (0.70-1.30 mg/dL [61.9-114.9 µmol/L])

Abbreviations: COCP, combined oral contraceptive pill; mg/dL, milligrams/deciliter; mIU/L, milli-international units/liter; mmol/kg, millimoles/kilogram; mmol/L, millimoles/liter; mOsmol/kg H₂O, milliosmoles/kilogram of water; µg/dL, micrograms/deciliter; μIU/mL, micro-international units/milliliter; µmol/L, micromoles/liter; Na⁺, sodium concentration; ng/dL, nanograms/deciliter; nmol/L, nanomoles/liter; pmol/L, picomoles/liter; RR, reference range.

Treatment

First-line therapy for SIAD was initiated with fluid restriction to 750 mL/day with minimal effect. In view of this and considering the high risk of deterioration, she was admitted to intensive care unit for hypertonic saline administration under close monitoring. IV 1.8% hypertonic saline was commenced and maintained as an infusion. Fluid restriction was discontinued to mitigate the risk of overly rapid sodium correction.

Although this treatment achieved modest increases in serum sodium, persistently suboptimal and fluctuating sodium concentrations—occasionally reaching dangerously low levels—in an otherwise healthy individual were concerning. Additional therapeutic modalities were trialed, namely sodium chloride tablets [1200 milligrams (mg) thrice daily] and a short course of fludrocortisone, both with limited efficacy. Serum sodium decreased to 119 mmol/L despite triple therapy with hypertonic saline, fludrocortisone, and sodium chloride tablets, prompting a second intensive care unit admission. Following 48 hours of intensified hypertonic saline infusion and persistence of severe hyponatremia, a single 7.5 mg oral dose of tolvaptan was administered after cessation of hypertonic saline, resulting in a marked but transient increase in serum sodium (132 to 141 to 131 mmol/L). A second 7.5 mg tolvaptan dose reproduced a similar effect (131 to 140 to 133 mmol/L). As serum sodium approached the normal range, fluid restriction was reinstated and titrated to 800 mL/day. The patient was discharged with a serum sodium concentration of 134 mmol/L.

The inpatient trend in serum sodium concentration and corresponding interventions are illustrated in Fig. 1.

Figure 1.

Schematic of serum Na⁺ over time throughout patient's admission to hospital and associated hyponatremia treatment. Time (days) following admission is shown on the horizontal axis. Serum Na⁺ is displayed by the left vertical axis, with the normal reference range indicated by horizontal orange dotted lines. Fluid restriction (mL/day) is plotted on the right vertical axis. Yellow bars denote fluid restriction at corresponding time points. ⁺Intensive care unit admissions. *1.8% NaCl IV fluid administered initially as a bolus injection of 400 mL and subsequently as an infusion at a rate of 50 to 150 mL/hour. ^†5 doses of fludrocortisone given in total (100/100/100/200/300 micrograms). ^‡1200 milligrams NaCl tablets 3 times a day.

Abbreviations: Na⁺, sodium concentration; NaCl, sodium chloride.

As an outpatient, she remained adherent to a strict fluid restriction of 800 milliliters/day (mL/day), which was gradually liberalized to 1000 mL/day. Repeat biochemistry confirmed persistent SIAD, with normocortisolemia 2 months after discontinuation of COCP, alongside stable body mass index and blood pressure. Unfortunately, severe hyponatremia recurred 2 months after the initial presentation, with serum sodium of 118 mmol/L. This responded to a third 7.5 mg dose of tolvaptan. Subsequently, following a 2.5-month period of relative stability on a 1000 mL/day fluid allowance, sodium concentration gradually declined to a new trough of 123 mmol/L. Reintensification of fluid restriction to 750 mL/day resulted in prompt biochemical improvement. Serial cranial imaging demonstrated resolution of the SAH. Given the persistence of chronic hyponatremia, limited response to conventional therapy, and significant impairment of quality of life, a therapeutic trial of empagliflozin was proposed.

The patient's outpatient serum sodium trajectory prior to empagliflozin is illustrated in Fig. 2.

Figure 2.

Schematic of serum Na⁺ over time following hospitalization and associated hyponatremia treatment. Time (days) following admission is shown on the horizontal axis. Serum Na⁺ is displayed by the left vertical axis, with the normal reference range indicated by horizontal orange dotted lines. Fluid restriction is plotted on the right vertical axis. Yellow bars denote fluid restriction at corresponding time points. Single tolvaptan dose (7.5 milligrams) and lowest serum sodium concentration reached following fluid restriction relaxation are denoted by the black arrows. Liberalization of fluid restriction from 800 mL/day to 1000 mL/day was associated with the development of severe hyponatremia (circled in red). Of note is that serum sodium was below normal range for most of the time despite aggressive fluid restriction.

Abbreviation: Na⁺, sodium concentration.

Outcome and Follow-up

Serum sodium increased by 3 mmol/L within 3 weeks of initiating empagliflozin 25 mg once daily under an 800 mL/day fluid restriction. Over the subsequent year, gradual liberalization of fluid intake was achieved, maintaining normonatremia within the range of 136 to 142 mmol/L while progressively increasing the fluid allowance to 1750 mL/day. Serum sodium concentrations have since remained stable (138-141 mmol/L). Within 2 months of empagliflozin initiation, a reduction in urine osmolality to 287 milliosmoles per kilogram of water (mOsmol/kg H₂O) (SI: 287 mmol/kg) and spot urinary sodium concentration to 81 mmol/L was observed, with concurrent maintenance of serum osmolality within the normal range (282 mOsm/kg H₂O [SI: 282 mmol/kg]) (reference range: 275-295 mOsmol/kg H₂O; mmol/kg). Biochemical parameters on admission are summarized in Table 1. Throughout the follow-up period, the patient's weight and blood pressure remained stable. Figure 3 illustrates serum sodium concentrations following empagliflozin initiation.

Figure 3.

Schematic of serum Na⁺ concentration over time following initiation of empagliflozin. Time (days) following admission is shown on the horizontal axis. Serum sodium concentration (Na+) is displayed by the left vertical axis, with the normal reference range indicated by horizontal orange dotted lines. Fluid restriction is plotted on the right vertical axis. Yellow bars denote fluid restriction at corresponding time points. Following empagliflozin initiation, serum sodium has been maintained in range despite progressive relaxation of fluid restriction. *Empagliflozin was initiated on day 552 following admission and initial injury.

Abbreviation: Na⁺, sodium concentration.

Empagliflozin was well tolerated, with no significant side effects. Overall, the patient achieved a 16-month period of sustained normonatremia, accompanied by a marked improvement in quality of life, attributed to relaxation of fluid restriction. Data beyond this point are unavailable owing to the patient's relocation to another geographical region; however, follow-up telephone contact confirmed continued clinical benefit from empagliflozin up to 27 months after treatment initiation.

Discussion

This report describes successful treatment of chronic, refractory SIAD with empagliflozin for an unprecedentedly long period of 16 months. The sole case report to date describes a 6-month treatment period with empagliflozin for chronic SIAD [17]. Available outpatient data derive from an RCT including only 14 patients for a 4-week duration of empagliflozin therapy, highlighting the dearth of evidence [15].

The second unusual feature is the 2.5-year duration of SIAD despite resolution of the underlying cause. In the acute phase after SAH, hyponatremia is frequent and affects almost half of patients [18]. However, SIAD is typically self-limiting after resolution of SAH [6]. In contrast, hyponatremia due to SIAD is less common with traumatic brain injury [19, 20].

Notably, our patient had been long-established on COCP prior to presentation. Although the evidence remains inconclusive, dynamic perfusion studies demonstrated microstructural hypothalamic alterations in COCP users, potentially reflecting changes in perfusion dynamics [21]. It is therefore plausible that, in this case, prolonged COCP use may have exacerbated subtle hypothalamic sequelae arising from the traumatic injury [22].

Both sodium chloride tablets and fludrocortisone have been trialed as adjunctive therapies, although current evidence is limited and conflicting [23, 24]. In our case, fludrocortisone coincided with worsened hyponatremic profile, though confounding factors cannot be excluded. Mechanistically, fludrocortisone's potent mineralocorticoid activity could exacerbate fluid retention and dilutional hyponatremia in the context of SIAD. The independent effect of oral sodium chloride supplementation remains difficult to isolate; however, no appreciable clinical benefit was observed, consistent with existing controversy regarding its role in SIAD [23, 24].

Empagliflozin is approved for type 2 diabetes mellitus, heart failure, and chronic kidney disease [25, 26]. Through potent inhibition of sodium-glucose cotransporter-2, it reduces glucose reabsorption in the proximal tubule, leading to glycosuria-induced osmotic diuresis, increasing electrolyte-free water excretion [27-29]. Other mechanisms, like a direct effect on sodium and water channels, may also contribute to its aquaretic effect [28].

In 2020, an RCT involving 87 inpatients with euvolemic hyponatremia showed that 4-day treatment with empagliflozin increased serum sodium concentration by 3 mmol/L compared to placebo in patients on a 1000 mL/day fluid restriction [14]. Subsequently, another RCT showed that empagliflozin increased serum sodium by 4.1 mmol/L compared to placebo in 14 outpatients with SIAD on a 1500 mL/day fluid restriction. There was also a small improvement in neurocognitive function [15]. Together, these highlight empagliflozin's potential as an effective, well-tolerated treatment option for SIAD.

For chronic SIAD, empagliflozin is an attractive treatment option; it is widely available, affordable and has cardio- and nephroprotective properties and a favorable safety profile. Prospective studies evaluating its efficacy in restoring normonatremia and improving clinical outcomes, such as cognitive function, bone turnover markers, and fracture occurrence, are needed. Empagliflozin's ability to safely correct hyponatremia of different severity should be explored. If empagliflozin is successfully repurposed, its modest effect in increasing serum sodium may be used to treat chronic SIAD and reduce the burden of fluid restriction. Alternatively, it could be used in the acute setting for hyponatremia refractory to fluid restriction. Future prospective studies could also investigate any modulating effects at the sites of action, such as receptor downregulation, which may allow sustained therapeutic benefit following drug withdrawal. Insights from such studies could inform clinical strategies for safe drug discontinuation following sustained normonatremia.

We temper our optimism with a word of caution: despite the widespread administration of empagliflozin for other indications, the available efficacy and safety data of empagliflozin for chronic SIAD are limited to only 14 patients. Therefore, we do not advocate for its routine use. We recommend that only clinicians with expertise in the field of water balance disorders should consider the off-label use of empagliflozin for SIAD in highly selected patients. In those cases, we encourage reporting of real-world outcomes, whether positive or negative.

Learning Points

• There is an unmet clinical need for an efficacious, safe, and widely available treatment option for chronic SIAD.

• Rarely, SIAD may persist after resolution of SAH.

• Empagliflozin as an add-on to fluid restriction may represent a promising treatment option for chronic SIAD.

• Empagliflozin may improve quality of life by reducing the burden of fluid restriction.

• Prospective studies are warranted to evaluate the long-term efficacy and safety of empagliflozin for the management of chronic SIAD.

Contributors

All authors made individual contributions to authorship. J.A.W., K.M.S., and P.T. were involved in the diagnosis and management of the patient. A.K. and K.M.S. drafted the manuscript and undertook literature review. P.T. provided expertise in hyponatremia management and empagliflozin use for SIAD. J.W. and P.T. conceptualized and A.K. produced the figures. All authors critically reviewed, edited, and approved the final manuscript.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Original data generated and analyzed during this study are included in this published article.