CLINICAL RESEARCH www.jasn.

org

Treatment Effect of the SGLT2 Inhibitor Empagliflozin on

Chronic Syndrome of Inappropriate Antidiuresis: Results
of a Randomized, Double-Blind, Placebo-Controlled,
Crossover Trial
Julie Refardt ,1,2 Cornelia Imber,1,2 Rianne Nobbenhuis,1,2 Clara O. Sailer ,1,2
Aaron Haslbauer,3 Sophie Monnerat ,1,2 Cemile Bathelt,1,2 Deborah R. Vogt ,2
Manfred Berres,4 Bettina Winzeler,1,2 Stephanie A. Bridenbaugh,3 and Mirjam Christ-Crain 1,2

1
Department of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland
2
Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
3
University Department of Geriatric Medicine, Felix Platter Hospital, Basel, Switzerland
4
Department of Mathematics and Technology, University of Applied Sciences, Koblenz, Germany

ABSTRACT
Background The syndrome of inappropriate antidiuresis (SIAD) is characterized by a reduction of free
water excretion with consecutive hypotonic hyponatremia and is therefore challenging to treat. The
sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glu-
cose excretion, likely leading to increased electrolyte free water clearance.
Methods In this randomized, double-blind, placebo-controlled, crossover trial, we compared 4-week treat-
ment with empagliflozin 25 mg/d to placebo in outpatients with chronic SIAD-induced hyponatremia. At
baseline and after both treatment cycles, patients underwent different assessments including neurocogni-
tive testing (Montreal Cognitive Assessment [MoCA]). The primary end point was the difference in serum
sodium levels between treatments.
Results Fourteen patients, 50% female, with a median age of 72 years (interquartile range [IQR], 65–77),
completed the trial. Median serum sodium level at baseline was 131 mmol/L (IQR, 130–132). After treat-
ment with empagliflozin, median serum sodium level rose to 134 mmol/L (IQR, 132–136), whereas no
increase was seen with placebo (130 mmol/L; IQR, 128–132), corresponding to a serum sodium increase of
4.1 mmol/L (95% confidence interval [CI], 1.7 to 6.5; P50.004). Exploratory analyses showed that treat-
ment with empagliflozin led to improved neurocognitive function with an increase of 1.16 (95% CI, 0.05 to
2.26) in the MoCA score. Treatment was well tolerated; no serious adverse events were reported.
Conclusion The SGLT2 inhibitor empagliflozin is a promising new treatment option for chronic SIAD-
induced hyponatremia, possibly improving neurocognitive function. Larger studies are needed to confirm
the observed treatment effects.
Clinical Trial registration number: ClinicalTrials.gov NCT03202667.

JASN 34: –, 2022. doi: https://doi.org/10.1681/ASN.2022050623

The syndrome of inappropriate antidiuresis Received May 27, 2022. Accepted October 13, 2022.
(SIAD) leads to a reduction of free water Published online ahead of print. Publication date available at
excretion with consecutive hypotonic hypona- www.jasn.org.
tremia.1,2 There are diverse causes of SIAD, Correspondence: Dr. Julie Refardt, Department of Endocrinology,
including various organ dysfunctions, but also Diabetes, and Metabolism, University Hospital Basel, Petersgraben
4, 4031 Basel, Switzerland. Email: [email protected]
stress, such as chronic pain, or secondary to
medications.3 Copyright ß 2022 by the American Society of Nephrology

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Treatment options for SIAD, in addition to treating the

Significance Statement
underlying cause, are limited.4,5 The first-line treatment option
is fluid restriction,6–8 which is burdensome and unlikely to be The syndrome of inappropriate antidiuresis (SIAD) is a major
sustained over an extended period, especially in chronic cause of hypotonic hyponatremia. Despite its prevalence, treat-
ment options are sparse, and data on their effect on
SIAD-induced hyponatremia. Urea effectively treats hypona-
hyponatremia-associated morbidity such as neurocognitive
tremia through the induction of osmotic diuresis.9,10 Although impairment are largely lacking. New treatment options are
a recent study showed its safety also over an extended treat- needed. The sodium-glucose cotransporter 2 (SGLT2) inhibitor
ment period,11 its poor palatability affects compliance.10 Vap- empagliflozin promotes osmotic diuresis via urinary glucose
tans correct hyponatremia through the induction of aquaresis, excretion and could be used as a treatment for chronic SIAD.
This randomized, double-blind, placebo-controlled, crossover
but they are costly and bear the risk of serum sodium overcor-
trial with 14 participants revealed that empagliflozin is well toler-
rection.5,12,13 As a result, treatment often remains inade- ated and effective compared with placebo. In addition, treat-
quate.14 This is concerning given the reported adverse effects ment with empagliflozin possibly led to an improvement in
of hyponatremia, particularly neurocognitive deficits and gait neurocognitive function. The results set the stage for further
disturbances.15–17 Despite these associations, intervention studies evaluating empagliflozin as a treatment option in
patients with SIAD-induced hyponatremia.
studies showing reversibility of these symptoms are largely
lacking, with only one study indicating improvement of a sub-
domain of neurocognition upon treatment with vaptans.7 hyponatremia, severe symptomatic hyponatremia in need of
We recently reported the efficacy of a 4-day treatment with hospital treatment, diabetes mellitus type 1, renal insuffi-
the sodium-glucose cotransporter 2 (SGLT2) inhibitor empa- ciency (GFR ,45 ml/min), heart failure, or known liver cir-
gliflozin in correcting hyponatremia in hospitalized patients rhosis or acute hepatic impairment (alanine amino
with SIAD-induced hyponatremia.18 The therapeutic effect of transferase/aspartate amino transferase .33 upper limit);-
empagliflozin is the induction of marked glucosuria leading to who were pregnant or breastfeeding; or who were under
osmotic diuresis, likely causing increased electrolyte free water treatment with SGLT2 inhibitors, lithium chloride, urea, or
clearance.19,20 Given its good tolerability and positive effects glitazone were excluded.
on cardiovascular and renal outcomes,21,22 empagliflozin could
be an ideal treatment for outpatients with chronic SIAD.
However, its efficacy in these patients is unknown. Trial Procedures and Assessments
The aim of this randomized, double-blind, placebo-con- Outpatients with hyponatremia due to chronic SIAD from
trolled, crossover trial was to investigate whether 4 weeks our institution and patients referred from endocrinologists
of treatment with the SGLT2 inhibitor empagliflozin leads in practice were asked to participate. After fulfilling eligibil-
to a greater increase in serum sodium levels than placebo ity criteria and providing informed consent, a medical ques-
in outpatients with chronic SIAD. As secondary objectives, tionnaire including evaluation of general well-being and
we investigated whether hyponatremia correction by treat- possible symptoms and effects of hyponatremia was com-
ment with empagliflozin leads to improvement in neuro- piled. Routine physical examination and baseline diagnos-
cognitive deficits and gait disturbances. tics were conducted including blood and urine sampling,
which were processed according to standardized operating
procedures. Participants then completed the following tests:
METHODS  EQ-5D-5L test24,25: a standardized test assessing quality of
life consisting of two parts. The first part was a visual analog
Trial Design and Participants scale (VAS) ranging from 0 (5worst health) to 100 (5best
This prospective randomized, double-blind, placebo-con- health) on which the patients rated their current health. In
trolled, crossover trial was performed at the University the second part, the patients were asked to attribute a level
Hospital Basel, Switzerland from December 2017 to August (no problems51 point, slight problems52 points, moderate
2021. The local ethics committee (EKNZ 2017-00701) and problems53 points, severe problems54 points, extreme
the national agency for the authorization and supervision of problems/unable to55 points) to each of the following
therapeutic products (Swissmedic 2017DR2127) approved five dimensions: mobility, self-care, usual activities,
the study protocol and study medication. The trial was reg- pain/discomfort, and anxiety/depression.
 Montreal Cognitive Assessment (MoCA)26: The MoCA is a
istered at ClinicalTrials.gov (NCT03202667). Written in-
30-point test ($26 defined as normal) used to assess the
formed consent was obtained from all participants. cognitive domains visuospatial, executive function, naming,
Eligible patients were 18 years of age or older and had memory, attention, language, abstraction, delayed recall, and
chronic SIAD-induced hyponatremia ,135 mmol/L, defined orientation (to time and place). The MoCA was chosen
as euvolemia according to clinical assessment, serum osmo- because it is a sensitive screening test for the detection of
lality ,275 mmol/kg, urine osmolality .100 mmol/L, urine mild cognitive impairment and was superior to the Mini-
sodium .30 mmol/L, exclusion of hypothyroidism, and Mental State Examination.27 A special focus was set on the
hypocortisolism.23 Patients with acute or transient subtest executive function, ranging from zero to five points.

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 Grip strength test: This was measured using a hand Diagnostics). Serum and urinary osmolality were measured
dynamometer.28 The best score of three trials of the domi- using the freezing point depression osmometer method. To
nant hand was reported. ensure the double-blind design of the study, results from
 Gait analysis: A quantitative analysis of spatiotemporal the urinary diagnostics after administration of the first
gait parameters using the GAITRite electronic walkway
study drug were blinded until the end of the study.
system29 was performed at the Basel Mobility Center of
the University Department of Geriatric Medicine, Felix
Platter Hospital. Gait was assessed from one trial of self- Sample Size Estimation
paced, habitual walking and included the variables walk- Assuming a baseline value of 127 mmol/L (SD, 3 mmol/L)
ing speed, step width, single support time (indirect marker and a within-patient correlation of r50.70, we estimated
of dynamic balance), and gait regularity (measured by that a sample of 13 evaluable patients would provide the
cycle time variability). trial with 90% power to detect a difference of 3 mmol/L in
Participants were randomly assigned to undergo the first serum sodium levels after 4 weeks of treatment at a signifi-
treatment period in the empagliflozin or, with equal cance level of 5%. The hypothesis test was based on a linear
chance, the placebo group. Treatment involved one capsule model with treatment as categorical predictor and the base-
per day (empagliflozin 25 mg or placebo, respectively) for line value as covariate. Considering a dropout rate of 20%,
28 days. Further treatment included limitation of daily fluid we planned to recruit three additional patients.
intake to #1.5 L/d. Participants were asked to maintain
their fluid intake during the observation period and to Patient Flow and Analysis Sets
record their daily fluid intake. A total of 17 patients were included in the study and random-
After baseline, weekly examinations were performed, ized (full analysis set) to the sequence empagliflozin–placebo
including a medical questionnaire, clinical parameters, and (n58) or placebo–empagliflozin (n59) (Figure 1). Of these,
blood and urine sampling. At the end of each treatment three patients were excluded from the analyses: two patients
cycle (i.e., 4 weeks after starting study medication) partici- withdrew their consent within/after the first week of treatment
pants additionally performed the above described quality of during the first treatment phase (one randomized to
life, neurocognition, grip strength, and gait assessments. A empagliflozin–placebo and one randomized to placebo–empa-
washout period of at least 2 weeks between the treatment gliflozin), and one patient (randomized to placebo–empagliflo-
cycles and a follow-up visit 30 days after completion of the zin) was excluded after the first treatment phase due to initial
second treatment phase were scheduled. incorrect diagnosis (transient hyponatremia).
The remaining 14 patients defined the modified intention-
Trial Outcomes to-treat analysis set (ITTS). All patients in the ITTS took at
The primary outcome was the difference in serum sodium least one dose of study medication for both empagliflozin
levels (in millimoles per liter) after 4 weeks of treatment and placebo treatments and received the treatments in the
with empagliflozin 25 mg compared with placebo. Second- sequence as randomized. Of these, one patient (place-
ary end points included serum sodium levels after 1, 2, and bo–empagliflozin) took only 18 pills of a total of 28 pills
3 weeks of treatment; derived serum sodium area under the and was not adherent to the treatment as defined per
curve (AUC), serum and urinary electrolytes, osmolality, protocol (predefined as 75% of pills taken, i.e., 21 of 28).
and glucose after 1, 2, 3, and 4 weeks of treatment; course The remaining 13 patients defined the per protocol analysis
of hyponatremia symptoms as assessed in the medical ques- set (PPS).
tionnaire and clinical parameters after 1, 2, 3, and 4 weeks
of treatment; and change from baseline to end of treatment Statistical Analyses
in EQ-5D-5L test, MoCA, grip strength test, and gait analy- We used linear mixed regression models to analyze the pri-
sis. In addition, adverse events, defined as any new medical mary outcome serum sodium levels at the end of treatment,
issue or exacerbation of an existing medical issue according with treatment (empagliflozin–placebo) and baseline levels
to Common Terminology Criteria for Adverse Events v4.0, (visit 0) as fixed effects. In order to account for the cross-
were recorded. Seriousness and severity of each event was over design, patient was included as random effect (random
documented and its relation to the study intervention intercept). Because preceding analyses revealed no evidence
assessed. for either carryover or sequence effect, treatment sequence
and study phase were not included in the primary analysis
Laboratory Measurements model (see Supplemental Statistical Analyses).
Serum and urine concentrations of sodium, glucose, creati- The primary analysis was performed on the modified
nine, urea, uric acid, and osmolality were measured by the ITTS and repeated on the PPS. We performed adjusted
central laboratory of the University Hospital Basel. Serum analyses by adding serum and urinary sodium and osmolal-
sodium levels were analyzed by indirect ion selective ity, and the fractional excretions of urinary sodium, urea,
electrode method (cobas 8000 modular analyzer; Roche and uric acid as additional covariates (separate models, also

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60 outpatients with chronic hyponatremia (s-sodium <135 mmol/l) were assessed for eligibility

13 patients did not meet eligibility criteria, of which:

• 5 did not have SIAD-induced hyponatremia
• 6 had resolution of hyponatremia after stop of triggering medication
• 2 were under treatment with an SGLT2-inhibitor or urea

30 met eligibility criteria but were not included:

• 22 declined to participate
• 1 participated already in another study
• 1 was not able to consent
• 3 received end of life care
• 3 died before inclusion

17 patients underwent randomization

Placebo-Empagliflozin: 9 patients Empagliflozin-Placebo: 8 patients

2 blinded post-randomization exclusions: 1 blinded post-randomization exclusion due to

• 1 withdrawal of informed consent withdrawal of informed consent
• 1 due to wrong diagnosis

7 patients intention to treat analysis 7 patients intention to treat analysis

1 protocol violator
• intake less than 75% of study medication

6 patients treated per protocol 7 patients treated per protocol

Figure 1. Study flow diagram.

including the interaction term covariate 3 treatment). The All analyses were predefined and conducted using the
adjusted mean treatment effect is presented with 95% confi- statistical software package R versions 3.6.3 (February 29,
dence interval (CI). 2020) and 4.1.2 (November 1, 2021).30 No adjustment was
Secondary end points were analyzed analogously, using made for multiple testing.
mixed linear (continuous outcomes) or logistic regression
models (binary outcomes). To evaluate the effect of reaching
normonatremia (serum sodium level at end of treatment $135 RESULTS
mmol/L), separate mixed-effects linear regression models were
fitted with the change in MoCA, grip strength, and gait param- Baseline Characteristics
eters, from baseline to end of treatment as dependent variable, Fourteen patients completed both treatment cycles and
baseline value (covariate) and sodium status at the end of treat- were included into the analysis (see the study flow chart in
ment as fixed effects, and patient as random effect. Figure 1). Median age was 71.5 years (interquartile range
Secondary analyses were performed on the ITTS. Adverse [IQR], 64.5–76.8), with 50% of the participants being
events are reported for the full analysis set. female. Main comorbidities were arterial hypertension
Sodium measurements for baseline and week 4 were (79%), and cerebrovascular and psychiatric disorders (both
available for all patients for both treatment phases; how- 36%) (Table 1).
ever, several patients missed visits in between, due to Median serum sodium level at baseline was 131 mmol/L
comorbidities and the ongoing coronavirus disease 2019 (IQR, 130–132) (Table 2). The etiology of chronic SIADs
(COVID-19) pandemic. To derive the serum sodium AUC, ranged from drug-induced (antiepileptic [n53] and anti-
missing values were imputed by multiple imputation using depressants [n51] that could not be stopped) to pulmo-
chained equations (see Supplemental Statistical Analyses). nary (n53) or central nervous system disorders (n52) to
For all other secondary end points the analyses were based stress-induced due to chronic pain (n51). In four patients,
on the available data. the etiology remained idiopathic. Hyponatremia duration

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Table 1. Baseline characteristics Under treatment with empagliflozin, 36% (5 of 14) of

Participants the patients reached normonatremia compared with 14% (2
Characteristic of 14) of the patients under placebo. One patient reached
n514
Age, yr 71.5 [64.5–76.8] normonatremia under both treatments. Six patients had
Sex: female, n (%) 7 (50) moderate hyponatremia (serum sodium ,130 mmol/L) at
BMI, kg/m2 24.4 [21.6–27.6] the start of treatment with empagliflozin, with two of these
Comorbidities, n (%) patients also having moderate hyponatremia at the start of
Arterial hypertension 11 (79)
Cerebrovascular disorder 5 (36)
placebo treatment. At the end of the treatment period,
Pulmonary disease 4 (29) no patients on empagliflozin had moderate hyponatremia
Psychiatric disorder 5 (36) compared with six patients on placebo. Empagliflozin was
Diabetes mellitus type 2 2 (14) effective in increasing serum sodium levels independently
Central nervous system disorders 2 (14)
of the randomization sequence, there was no carryover
Malignancy 1 (7)
Chronic infectious disorders 1 (7) effect (Supplemental Figure 1). At the 30-day follow-up
Drugs, n (%) visit, 79% (11 of 14) of the patients showed persistent
Antihypertensive 9 (64) hyponatremia.
Statins 4 (29) Fluid intake remained stable during the active study
Antiepileptic/multiple sclerosis treatment 4 (29)
phase with no relevant difference between the treatment
Asthma/COPD inhalants 4 (29)
Proton pump inhibitors 4 (29) cycles (median [IQR]: fluid intake at week 1 was 1.5 L
Hormonal replacement 4 (29) [1.3–1.6] for empagliflozin versus 1.6 L [1.4–1.9] for pla-
Anti-inflammatory 4 (29) cebo; and at week 4 was 1.5 L [1.2–1.5] for empagliflozin
Metformin 3 (21) versus 1.5 L [1.1–1.5] for placebo).
Antipsychotic/antidepressants 2 (14)
Diuretics 2 (14)
Patients with a higher fractional excretion of urea at
Pain medication 2 (14) baseline tended to have a higher increase in serum sodium
Antiretroviral 1 (7) at the end of the treatment period, irrespective of the treat-
Other 9 (64) ment (estimate: 0.122 mmol/L; 95% CI, 0.007 to 0.236;
Causes of SIAD, n (%) P50.059). No evidence of an association was found for out-
Central nervous system disorders 2 (14)
Stress (chronic pain) 1 (7) come or treatment effect with serum or urine osmolality, or
Drug-induced 4 (29) urine sodium, or fractional excretion of sodium, or uric
Pulmonary disease 3 (21) acid (Supplemental Figure 2) and for age (data not shown).
Idiopathic 4 (29)
Duration of hyponatremia, mo 45.5 [15.8–57.3]
Secondary Outcomes
Summary statistics of patient characteristics according to the intention-to-
treat analysis set. Categorical variables are shown as frequencies (%), The course of clinical and laboratory parameters and the
numerical variables as median [interquartile range]. BMI, body mass index; different assessments are summarized in Table 2.
COPD, chronic obstructive pulmonary disease.

Clinical and Laboratory Parameters

ranged from a minimum of 4 months to a maximum of As expected, a strong increase in urine glucose and
90 months. osmolality was observed after 4 weeks of treatment with
empagliflozin compared with placebo (Figure 3 and
Supplemental Figure 3). Additionally, treatment with empa-
Efficacy gliflozin compared with placebo led to an increase in serum
After 4 weeks of treatment with empagliflozin, serum osmolality and mild decrease in serum glucose and body
sodium levels rose to a median of 134 mmol/L (IQR, weight. Our data further showed a slight increase in serum
132–136), whereas no improvement was seen under pla- creatinine under treatment with empagliflozin. Changes
cebo (130 mmol/L; IQR, 127.5–132) (Table 2). This resulted during the treatment phase occurred within the first week
in an estimated increase of 4.09 mmol/L (95% CI, 1.68 and were maintained until the end of treatment (Figure 3).
to 6.49) under empagliflozin as compared with placebo, No effect of empagliflozin was seen for the other clinical or
(ITTS, P50.004; Figure 2). This finding was confirmed by laboratory parameters.
the PPS: 4.44 mmol/L (95% CI, 1.87 to 7.00; P50.004).
While serum sodium levels rose already within the first Assessments
week of treatment with empagliflozin and stayed constantly The patients rated their general health state as rather good
increased for the remaining treatment period, no notable according to the EQ-5D-5L questionnaire. Compared with
change was seen under placebo (Figure 2); the difference in baseline, the majority of patients indicated an improved
AUC weeks 1–4 was 9.08 mmol/L per three weeks (95% CI, overall health after both treatment cycles, with no relevant
2.78 to 15.39; P50.01). difference between treatments.

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Table 2. Summary statistics and treatment effect for clinical parameters, laboratory values, and assessment outcomes
End of Treatment
Treatment
Characteristic Baseline Placebo Empagliflozin P Value
Effect [95% CI]
Clinical parameters
Body weight, kg 72.0 [69.0–80.4] 73.5 [70.1–79.6] 72.8 [66.4–78.4] 21.65 [22.75 to 20.55] 0.009
Systolic BP, mm Hg 149.0 [134.5–160.2] 141 [135.3–152.5] 140.5 [132–146.5] 25.34 [214.05 to 3.38] 0.23
Diastolic BP, mm Hg 80.0 [68.8–86.0] 79 [75–93] 80.5 [72.3–88] 21.74 [26.94 to 3.47] 0.51
Heart rate, bpm 66.0 [60.8–72.2] 64 [60.3–66] 64.5 [60–68] 0.03 [26.27 to 6.32] 0.99
Laboratory values
S-sodium, mmol/L 131 [130–132] 130 [127.5–132] 134 [132–136] 4.09 [1.68 to 6.49] 0.004
S-glucose, mmol/L 5.0 [4.8–5.8] 5 [4.73–5.88] 5.1 [4.8–5.8] 20.41 [20.81 to 20.02] 0.05
S-creatinine, mmol/L 61.0 [57.5–64.5] 61 [53.3–70.3] 72.5 [59–78.3] 7.76 [3.88 to 11.64] 0.001
GFR, ml/min 87.0 [85.0–101] 88 [82.3–100.5] 81.5 [68.3–95] 27.09 [210.97 to 23.21] 0.003
S-urea, mmol/L 3.70a [3.40–4.40] 3.75 [3.3–4.92] 4.75 [3.73–5.68] 0.50 [20.24 to 1.24] 0.19
S-uric acid, mmol/L 213.0a [160.2–332.8] 200.5 [149.5–304.75] 192 [134.75–271] 220.09 [252.39 to 12.21] 0.22
S-osmolality, mosm/kg 271.5 [264.0–281.0] 268.5 [261.75–280.75] 281 [274.5–284.75] 17.16 [0.38 to 33.93] 0.06
U-sodium, mmol/L 97.5 [77.0–130.0] 81.5 [70–101.25] 94 [57.75–107.5] 3.26 [216.08 to 22.61] 0.73
U-glucose, mmol/L 0.2 [0.2–0.27] 0.25 [0.2–0.38] 131.7 [90.58–155.88] 6.19 [5.79 to 6.59] ,0.001
U-urea, mmol/L 143.0 [109.8–187.8] 155.5 [97.25–208.5] 160 [123–216] 21.82 [236.51 to 32.88] 0.92
U-uric acid, mmol/L 2072 [1532–2393] 1989 [1332.25–2583.5] 2009.5 [1578.5–2640.75] 78.31 [2563.97 to 720.59] 0.80
U-osmolality, mosm/kg 468.0 [361.2–567.0] 494 [337.75–592.75] 601 [502.5–676.3] 131.11 [70.61 to 191.62] ,0.001
Assessments
EQ-5D-5L score
EQ-5D-5L (VAS score) 70a [60–85] 75a [60–80] 65a [60–87] 20.38 [29.02 to 8.26] 0.93
EQ-5D-5L (unit score) 0.87a [0.72–0.94] 0.8a [0.72–0.86] 0.87a [0.72–1] n.d. n.d.
MoCA score n512 n512 n512
MoCA total score 22.7b (5.1) 24.6b (4.4) 25.8b (4.2) 1.16 [0.05 to 2.26] 0.04
MoCA executive 3.0b (1.5) 3.0b (1.4) 3.4b (1.7) 0.36 [20.02 to 0.74] 0.06
function
Grip strength
Grip strength, kg 25.5b [17.4–34.8] 25b [16.5–33.5] 21.5b [18–34] 20.57 [24.14 to 2.99] 0.68
Gait tests
Gait speed normal 99.7b (35.5) 100.6b (32.3) 106.0c (25.9) 20.8 [25.9 to 4.3] 0.77
walk, cm/s
Step width normal 9.9b (4.2) 10.9b (4.1) 10.0c (5.0) 20.8 [22.2 to 0.5] 0.28
walk, cm
Cycle time variability 3.0b (1.3) 3.0b (1.6) 2.3c (0.6) 20.21 [20.78 to 0.35] 0.48
normal walk, %
Single support time 0.45b (0.11) 0.44b (0.06) 0.41c (0.03) 20.0062 [20.0138 to 0.0015] 0.16
normal walk, s
These data are from 14 patients (unless otherwise indicated). Summary statistics are shown as median [interquartile range] or mean (standard deviation) for
descriptive purposes. For inferential purposes, the treatment effect is indicated by the estimated difference in the outcome (estimate [95% CI]:
empagliflozin–placebo), derived from linear mixed-effects models fit by maximum likelihood. Models included the baseline levels as covariate and patient as
random effect. Each outcome was analyzed by a separate statistical model. The treatment effect is calculated from the individual, within-patient differences
empagliflozin–placebo and is adjusted for baseline levels; the treatment effect cannot be derived directly from the summary statistics. S, serum; U, urinary; VAS,
visual analog scale; n.d., not done.
a
13 patients.
b
12 patients.
c
10 patients.

The mean (SD) score in the MoCA at baseline was 22.7 Test scores after both treatment phases of patients
(5.1). After 4 weeks of treatment with empagliflozin, the reaching normonatremia (seven observations) were com-
mean (SD) score rose to 25.8 (4.2) compared with 24.6 pared with those of patients with persistent hyponatremia
(4.4) under placebo. This resulted in a difference of 1.16 (17 observations). Although no effect of sodium normaliza-
(95% CI, 0.05 to 2.26) under empagliflozin compared with tion on MoCA total score was seen (0.29; 95% CI, 21.45 to
placebo. A similar observation was made for the MoCA 2.02), a beneficial effect was seen for the MoCA executive
executive function subscore with a difference of 0.36 function subscore (0.77; 95% CI, 0.16 to 1.38).
(95% CI, 20.02 to 0.74). Visualization and evaluation of No notable change from baseline or difference between
the data showed no signs of a possible learning effect empagliflozin and placebo was seen in grip strength
(P50.29) or sequence effect (P50.21), (Supplemental (Table 2), independently of whether treatment led to nor-
Figure 4). monatremia or not (data not shown).

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ASerum sodium (mmol/l) Treatment Empagliflozin Placebo B Treatment Empagliflozin Placebo

Serum sodium (mmol/l)

135 135

130 130

125 125

baseline end of treatment 0 1 2 3 4

Measurement time Weeks since treatment start

Figure 2. Course of serum sodium levels from baseline to end of treatment. (A) Serum sodium levels before (baseline) and after
(week 4) treatment with empagliflozin or placebo. (B) Course of serum sodium from baseline to end of treatment according to treat-
ment phase. Boxes contain the 25% and 75% quartiles (spanning the interquartile range); the thick horizontal line is the median.
Whiskers indicate the most extreme values lying within the box edge and 1.5 times the interquartile range. All eventual further values
are plotted as individual points (outliers).

Baseline gait analysis showed slightly slowed walking Tolerability and Safety
speed with a healthy step width, single support time, and Treatment with empagliflozin was generally well tolerated
regular gait, as measured by the cycle time variability. (Table 3). Of the evaluated symptoms, thirst was indicated
Although some improvements were observed under empa- in about half of all patients under both treatments and at
gliflozin resulting in faster gait, reduced cycle time variabil- any measurement time. Few patients reported headache
ity, and shorter single support time, no difference was seen and vertigo; nausea was only reported under placebo.
between treatments. Also, no effect of sodium normaliza- No events of sodium overcorrection, hypoglycemia,
tion could be shown. hypotension, or urinary tract or genital infection occurred

A Treatment Empagliflozin Placebo B Treatment Empagliflozin Placebo

9 120
creatinine (umol/l)

8
glucose (mmol/l)

100
7
80
6

5 60

4
0 1 2 3 4 0 1 2 3 4
Weeks since treatment start Weeks since treatment start

C Treatment Empagliflozin Placebo

D Treatment Empagliflozin Placebo
urine glucose (mmol/l)

urine sodium (mmol/l)

100.0 150

10.0 100

1.0
50

0.1
0 1 2 3 4 0 1 2 3 4
Weeks since treatment start Weeks since treatment start

Figure 3. Time course of different parameters under treatment with empagliflozin or placebo. Results are shown for (A) serum
glucose, (B) serum creatinine, (C) urine glucose, and (D) urine sodium. Boxes contain the 25% and 75% quartiles (spanning the inter-
quartile range); the thick horizontal line is the median. Whiskers indicate the most extreme values lying within the box edge and 1.5
times the interquartile range. All eventual further values are plotted as individual points (outliers).

JASN 34: –, 2022 SGLT2 Inhibitor Treatment for Chronic SIAD 7
 CLINICAL RESEARCH www.jasn.org

Table 3. Symptoms and adverse events occurring during However, such a pronounced fluid restriction is a burden-
observation phase some treatment that is unlikely to be sustained over an
Placebo Empagliflozin extended period. Meanwhile, the effect of empagliflozin was
Characteristic evident within one week of treatment with sodium levels
Week 0 Week 4 Week 0 Week 4
remaining consistently elevated until the end of the treat-
Symptoms: yes, n (%)
ment cycle, supporting the efficacy of a long-term treatment
Thirst 8 (57) 6 (43) 6 (43) 9 (64)
Vertigo 1 (7) 1 (7) 1 (7) 3 (21) effect. Possibly, the treatment effect of empagliflozin could
Headache 1 (7) 2 (14) 5 (39) 3 (21) be increased by a mild fluid restriction analogous to our
Nausea 0 (0) 2 (15) 0 (0) 0 (0) previous study.18
Adverse events, n Having a higher fractional excretion of urea was found
All adverse events 7 7
to be a predictive marker for empagliflozin treatment
Serious adverse events 0 0
Potentially study related 2 5 response in our study. Because this ratio is usually used to
Specific adverse events, n distinguish between SIAD and hypovolemic hyponatre-
Mild headache 1 1 mia,32 a higher value likely characterizes patients with
Potentially study related 1 1 more substantial water excess that therefore benefit from
Viral/bacterial/fungal 4 1
osmotic diuresis. Interestingly, all patients for which serum
infection
Potentially study related 0 0 sodium levels did not increase under placebo (change #0)
Gastrointestinal disorders 0 2 showed a clear increase in serum sodium levels after empa-
Potentially study related 0 2 gliflozin treatment. This observation further strengthens the
Dry mouth 0 1 role of empagliflozin as a new treatment option in patients
Potentially study related 0 1
with chronic SIAD.
Hypertensive episode 1 0
Potentially study related 0 0 One safety concern of the proof-of-concept study18
Tiredness 0 1 was the transient decrease in renal function observed in
Potentially study related 0 1 four patients in the empagliflozin group. A mild 6%
Gait insecurity (heavy legs) 0 1 decrease in glomerular function was again observed in
Potentially study related 0 0
this study. However, several large outcome studies inves-
Exanthema 1 0
Potentially study related 1 0 tigating SGLT2 inhibitors in diabetic and nondiabetic
n refers to number of patients. patients23,33,34 showed that a decrease in GFR of up to
30% of baseline after initiation of treatment is to be
during the observation period under empagliflozin. Of the expected and was associated with nephroprotective effects.
seven reported adverse events, five were potentially related Other factors associated with improved outcome were gluco-
to empagliflozin treatment. Under placebo, two of the suria and mild weight loss, which were also present in our
cohort. Accordingly, we consider treatment with empagliflo-
reported seven adverse events were judged to be potentially
zin to be safe in patients with chronic SIAD-induced hypo-
related to the study intervention. No adverse events were
natremia, as also reflected by the low number of only mild
recorded for the two participants who withdrew their con-
adverse events.
sent. There were no serious adverse events during the
In addition to being a novel, well-tolerated, and efficient
observation period.
treatment option for chronic SIAD-induced hyponatremia,
exploratory analyses also suggest a possible treatment-
induced improvement in neurocognitive function. Several
DISCUSSION studies report neurocognitive deficits in hyponatremic
patients, regardless of the severity of hyponatremia.15–17
We here show that treatment with the SGLT2 inhibitor This was confirmed in our cohort with mild to moderate
empagliflozin leads to a relevant increase in serum sodium hyponatremia, where patients achieved a median MoCA
levels compared with placebo in outpatients with chronic score of 22.7 (normal $26 points) indicating mild to mod-
SIAD. Exploratory analyses suggest a possible treatment- erate impairment. However, despite one tolvaptan trial
induced improvement in neurocognitive function. Treat- showing improvement in the psychomotor speed domain
ment was safe and well tolerated. (a subtest combining neurocognitive and gait function7) no
In addition to the findings of our proof-of-concept study interventional study has yet demonstrated reversibility of
consisting of a 4-day treatment period in hospitalized neurocognitive impairments after treatment of hyponatre-
patients with SIAD,18 we here show that empagliflozin is mia.35–38 The MoCA test is very sensitive for mild cognitive
efficient as a long-term treatment option for chronic SIAD- impairment, which could explain why we were able to
induced hyponatremia. The rise in serum sodium levels was detect an effect. We consider the observed improvement to
similar to the one of two recent intervention studies, evalu- be significant, because most intervention studies (even in
ating the efficacy of fluid restriction of ,0.5–1 L/d.8,31 other disorders outside the area of hyponatremia) showed

8 JASN JASN 34: –, 2022

 www.jasn.org CLINICAL RESEARCH

no effect on MoCA scores or only in patients with severe In conclusion, this study shows that the SGLT2 inhibitor
neurocognitive impairment.39–42 One study evaluating empagliflozin is a promising treatment option for outpa-
physical exercise was able to show a two-point increase tients with chronic SIAD-induced hyponatremia, possibly
after 3 months of intensive training.43 Normonatremic leading to an improvement of neurocognitive function.
patients in our study reached a higher score on the execu- Larger studies in in- and outpatient settings are needed to
tive function subtest of the MoCA. This suggests the confirm the observed treatment effects.
increase in sodium levels as an underlying mechanism for
improvement of neurocognitive function. Although a drug-
specific effect of empagliflozin cannot be excluded, it seems DISCLOSURES
unlikely in view of several observational studies showing
improvement in neurocognitive function after treatment, All authors have nothing to disclose.
especially in those patients reaching normonatremia.15,17,44
Chronic hyponatremia has been associated with gait
instability leading to increased falls17,45,46 and two obser- FUNDING
vational studies have shown gait normalization after
hyponatremia correction.17,45 The baseline gait parameters This study was supported by the Swiss Endocrine Society (Young
Investigator grant to J. Refardt); by the University Hospital Basel and
of this study population showed only mild gait disturban- Gottfried and Julia Bangerter-Rhyner Stiftung (Young Talents in Clinical
ces, primarily manifested with reduced walking speed. Research grant to C. Imber); and by the Swiss National Science
Although some improvements in gait were noted after Foundation (SNF-162608 to M. Christ-Crain; SNF-199391 MD-PhD fel-
treatment, no differences were seen between the interven- lowship to S. Monnerat). The funders had no role in design and conduct
tions. The fact that no clinically relevant improvement was of the study; collection, management, analysis, and interpretation of the
data; preparation, review, and approval of the manuscript; and decision to
observed in our cohort could be due to the good baseline submit the manuscript for publication.
situation. Another explanation could be that, compared
with the two observational studies, only a minority of our
patients achieved normonatremia. Interestingly, however, ACKNOWLEDGMENTS
a post- versus pretreatment reduction in gait cycle time
variability was observed, suggesting improved gait regular- We thank all patients for their participation in our study. In addition, we
ity. Because deficits in executive function are associated thank the medical and laboratory personnel at the University Hospital
Basel for their contribution to the study. A special thanks goes to our
with increased gait cycle time variability,47 this finding is
study nurses Nina Hutter and Joyce Santos de Jesus for their invaluable
in line with the improvement in the MoCA executive support.
function subscore.
With daily treatment cost of empagliflozin being similar
to urea (approximately 2 USD versus 4 USD), but being AUTHOR CONTRIBUTIONS
1/40th of the daily cost of tolvaptan (approximately 80
USD), empagliflozin would also be a cost-effective treat- M. Christ-Crain, J. Refardt, D. Vogt, and B. Winzeler conceptualized
ment option. Considering the cardiovascular and renal the study; M. Christ-Crain was responsible for funding acquisition and
benefits of SGLT2 inhibitors, a chronic treatment with validation; S. Bridenbaugh and M. Christ-Crain were responsible for
supervision; C. Bathelt, S. Bridenbaugh, A. Haslbauer, C. Imber, R. Nob-
empagliflozin can be seen as a holistic approach in patients
benhuis, J. Refardt, and C. Sailer were responsible for investigation;
with chronic hyponatremia, who are usually older and have C. Bathelt, A. Haslbauer, C. Imber, R. Nobbenhuis, J. Refardt, and C.
a high burden of comorbidities. Sailer were responsible for data curation; C. Bathelt, M. Christ-Crain, and
The strength of our study lies in the prospective ran- J. Refardt were responsible for project administration; M. Christ-Crain,
domized, double-blind, crossover design and the novelty of J. Refardt, and B. Winzeler were responsible for methodology; M. Berres,
S. Monnerat, J. Refardt, and D. Vogt were responsible for formal analysis;
the treatment approach. The observed treatment effect of
S. Monnerat was responsible for resources; J. Refardt wrote the original
empagliflozin is convincing and should prompt further draft; and C. Bathelt, M. Berres, S. Bridenbaugh, M. Christ-Crain, A. Hasl-
evaluations of empagliflozin as an efficient treatment option bauer, C. Imber, S. Monnerat, R. Nobbenhuis, C. Sailer, D. Vogt, and B.
in SIAD-induced hyponatremia. Winzeler reviewed and edited the manuscript.
A limitation of our study includes the small patient popula-
tion and that not all patients were able to perform the planned
assessments (due to comorbidities and the ongoing COVID- DATA SHARING STATEMENT
19 pandemic), thereby inducing a possible power issue for
detecting a difference in test performance. Also, although our The following data will be shared upon publication to researchers who
provide a methodologically sound proposal to achieve the aims in the
data suggest an increase in electrolyte free water excretion as
approved proposal: deidentified individual participant data that underlie
an explanation for the therapeutic effect of empagliflozin on the results reported in this article; study protocol; and statistical analysis
serum sodium levels, this cannot be verified because urine plan. Proposals should be directed to the corresponding author. To gain
output and urine potassium were not measured. access, data requestors will need to sign a data access agreement.

JASN 34: –, 2022 SGLT2 Inhibitor Treatment for Chronic SIAD 9
 CLINICAL RESEARCH www.jasn.org

SUPPLEMENTAL MATERIAL 14. Greenberg A, Verbalis JG, Amin AN, Burst VR, Chiodo 3rd JA,
Chiong JR, et al.: Current treatment practice and outcomes. Report
of the hyponatremia registry. Kidney Int 88: 167–177, 2015
This article contains the following supplemental material online at http://jasn.
15. Suarez V, Norello D, Sen E, Todorova P, Hackl MJ, H€ user C, et al.:
asnjournals.org/lookup/suppl/doi:10.1681/ASN.2022050623/-/DCSupplemental.
Supplemental Statistical Analyses. Impairment of neurocognitive functioning, motor performance, and
Supplemental Figure 1. Individual serum sodium measurements at base- mood stability in hospitalized patients with euvolemic moderate and
line and at the end of treatment for each patient under each treatment, profound hyponatremia. Am J Med 133: 986–993.e5, 2020
grouped by the two randomization sequences. 16. Refardt J, Kling B, Krausert K, Fassnacht M, von Felten S, Christ-
Supplemental Figure 2. Time course of fractional excretion of sodium, Crain M, et al.: Impact of chronic hyponatremia on neurocognitive
urea, and uric acid under treatment with empagliflozin or placebo. and neuromuscular function. Eur J Clin Invest 48: e13022, 2018
Supplemental Figure 3. Time course of serum osmolality and urine 17. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G:
osmolality under treatment with empagliflozin or placebo. Mild chronic hyponatremia is associated with falls, unsteadiness, and
Supplemental Figure 4. Visualization of the MoCA total scores accord- attention deficits. Am J Med 119: 71.e1–71.e8, 2006
ing to the two treatment cycles. 18. Refardt J, Imber C, Sailer CO, Jeanloz N, Potasso L, Kutz A, et al.: A
randomized trial of empagliflozin to increase plasma sodium levels
in patients with the syndrome of inappropriate antidiuresis. J Am
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SUPPLEMENTARY APPENDIX of the manuscript:

Treatment Effect of the SGLT2-inhibitor Empagliflozin on chronic SIAD

TABLE OF CONTENTS

Statistical analyses:

Carry-over/sequence effect page 2

Missing data page 2

Supplementary Figure S1 page 3

Supplementary Figure S2 page 4

Supplementary Figure S3 page 5

Supplementary Figure S4 page 6

1
Statistical analyses

Carry-over/sequence effects: We assumed no carry-over effects and hence no differences in

the treatment effect between the two treatment sequences (placebo/verum vs. verum/placebo).

These assumptions were examined by a) fitting a model with sequence and the interaction term

treatment x sequence as additional fixed effects; and b) calculating for each patient the

difference between verum and placebo in the baseline levels and testing whether this difference

differs between the two sequences using a two-sample t-test. Since there was no evidence for a

sequence effect (primary endpoint: p-value interaction term = 0.666, p-value t-test = 0.435),

neither the main effect nor the interaction term of treatment-sequence was included in the

statistical analysis model.

Missing data: Serum sodium measurements for week 0 and 4 were complete for all patients for

both treatment phases. However, several patients skipped one or several in-between visits

(week 1–3) – mainly because of the COVID-19 pandemic. Thus, several serum sodium

measurements and other secondary outcomes are missing. In order to derive a serum sodium

AUC for all patients, the missing values were imputed by multiple imputation using chained

equations (R package mice van Buuren & Groothuis-Oudshoorn (2011)) creating 50 imputation

sets. All available serum sodium measurements and the treatment arm were included in the

imputation model. For each imputed data set, the serum sodium AUC was then derived.

Statistical analyses were performed on each imputed data set separately and results were

pooled according to Rubin’s rule.

Missing values in secondary endpoints were not imputed and all analyses are based on the

respective data available (indicated in the summary tables).

2
Supplementary Figure S1

Supplementary Figure S1 Individual serum sodium measurements at baseline and at the end

of treatment for each patient under each treatment, grouped by the two randomization

sequences.

3
Supplementary Figure S2

Supplementary Figure S2 Time course of fractional excretion of sodium, urea and uric acid

under treatment with empagliflozin or placebo.

Boxes contain the 25 through 75% quantiles (spanning the interquartile range), the thick

horizontal line is the median. Whiskers indicate the most extreme values lying within the box-

edge and 1.5 times the interquartile range. All eventual further values are plotted as individual

points (outliers).

4
Supplementary Figure S3

A B

Figure S3 Time course of serum osmolality (A) and urine osmolality (B) under treatment with

empagliflozin or placebo.

Boxes contain the 25 through 75% quantiles (spanning the interquartile range), the thick

horizontal line is the median. Whiskers indicate the most extreme values lying within the box-

edge and 1.5 times the interquartile range. All eventual further values are plotted as individual

points (outliers).

5
Supplementary Figure S4

Figure S4 Visualization of the MOCA total scores according to the two treatment cycles
bsl = baseline, Verum = Empagliflozin