Circulation

ORIGINAL RESEARCH ARTICLE

Effects of Early Empagliflozin Initiation on Diuresis

and Kidney Function in Patients With Acute
Decompensated Heart Failure (EMPAG-HF)
P. Christian Schulze , MD, PhD; Jürgen Bogoviku, MD; Julian Westphal , MD; Pawel Aftanski, MD; Franz Haertel, MD;
Sissy Grund, MS; Stephan von Haehling, MD, PhD; Ulrike Schumacher, PhD; Sven Möbius-Winkler , MD, PhD; Martin Busch, MD

BACKGROUND: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often
limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and
sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated
heart failure is unclear.

METHODS: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients
with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments
that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included
diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide).

RESULTS: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of
empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative
urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6];
P=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent
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[95% CI, 0.6–27.7]; P=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus
54±17 mL/min per 1.73 m²; P=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975;
and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P=0.066) with more pronounced decrease in NT-
proBNP in the empagliflozin group compared with placebo (−1861 versus −727.2 pg/mL after 5 days; quotient in slope, 0.89
[95% CI, 0.83–0.95]; P<0.001). There were no differences in the incidence of safety events between groups.

CONCLUSIONS: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal
function in patients with acute decompensated heart failure.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04049045.

Key Words: diuretics ◼ heart failure ◼ kidney

Editorial, see p 299

H
eart failure (HF) has increased in incidence and impaired kidney function and diuretic resistance.3 The
prevalence worldwide and has high morbidity and only pharmacologic treatments available to augment
mortality.1,2 Acute decompensated HF (ADHF) diuresis are various combinations of diuretics added to
is a severe presentation of HF characterized by vol- loop diuretics or the addition of inotropes or vasodila-
ume retention and congestion, often accompanied by tors when decompensation is severe.2–4 The inability to
 
Correspondence to: P. Christian Schulze, MD, PhD, Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, Am Klinikum 1, 07743 Jena,
Germany. Email christian.schulze@med.uni-jena.de
Supplemental Material, the podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.059038.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
For Sources of Funding and Disclosures, see page 297.
© 2022 American Heart Association, Inc.
Circulation is available at www.ahajournals.org/journal/circ

Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038 July 26, 2022 289

 Schulze et al
Clinical Perspective
ORIGINAL RESEARCH
What Is New?
ARTICLE
• The addition of synthetic natriuretic peptides, vaso-
pressin antagonism, or ultrafiltration to standard
diuretic regimens has failed to improve outcomes in
chronic or acute decompensated heart failure.
• No new therapies for acute decompensated heart
failure, including diuretic drugs, have been intro-
duced in decades.
• The EMPAG-HF study (Empagliflozin in Acute
Decompensated Heart Failure) was designed
to test the hypothesis that early sodium-glucose
cotransporter-2 inhibition with empagliflozin added
to standard medical therapy enhances diuresis
without furthering kidney injury in patients with
acute decompensated heart failure.
What Are the Clinical Implications?
• Our study shows that in patients with acute decom-
pensated heart failure, early initiation of the sodium-
glucose cotransporter-2 inhibitor empagliflozin
within 12 hours of hospital presentation in addition
to standard treatment is safe and increases urine
output without affecting kidney function or injury
patterns.
• EMPAG-HF is the first randomized study to show
primary clinical benefits of a drug regimen added to
diuretic regimens in patients with acute decompen-
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sated heart failure.
• These observations suggest that addition of
sodium-glucose cotransporter-2 inhibition to stan-
dard diuretic therapy is a promising strategy to
assist with conventional decongestive treatment in
patients with acute decompensated heart failure.
Nonstandard Abbreviations and Acronyms
ADHF acute decompensated heart failure
AE adverse event
BNP brain natriuretic peptide
CKD-EPI Chronic Kidney Disease Epidemiology
Collaboration
eGFR estimated glomerular filtration rate
EMPAG-HF Empagliflozin in Acute Decompen-
sated Heart Failure
HF heart failure
NT-proBNP N-terminal probrain natriuretic peptide
SAE serious adverse event
SGLT2 sodium-glucose cotransporter-2
achieve decongestion is associated with a worse prog-
nosis and a higher rate of rehospitalization for ADHF.2,3
Several randomized controlled trials testing novel
pharmacotherapies in patients with ADHF failed to show
290 July 26, 2022 Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038
Empagliflozin in ADHF
benefit of these agents on outcomes after discharge,
highlighting a critical unmet need.5–8 The addition of
natriuretic peptides (nesiritide or ularitide),6,8 vasopres-
sin antagonism,7,9 or ultrafiltration10,11to standard diuretic
regimens have not shown consistent clinical benefit in
patients with chronic HF or ADHF. Therefore, novel strat-
egies with the potential to improve diuresis in ADHF rep-
resent a major therapeutic need.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors
reduce the risk of cardiovascular death and hospitaliza-
tion in ambulatory patients with stable chronic HF regard-
less of ejection fraction.12–15 However, the clinical effects
of an early start of SGLT2 inhibition within the first 12
hours after clinical presentation in addition to standard
loop diuretic–based decongestion strategies have not
been studied in patients with ADHF. The EMPAG-HF
study (Empagliflozin in Acute Decompensated Heart
Failure) was designed to test the hypothesis that early
SGLT2 inhibition using empagliflozin plus standard medi-
cal therapy enhances diuresis without furthering kidney
injury in patients with ADHF.
METHODS
Study Design and Oversight
The EMPAG-HF study (URL: https://www.clinicaltrials.gov;
Unique identifier: NCT04049045) randomly assigned patients
with ADHF to receive empagliflozin or placebo in a double-blind,
placebo-controlled trial. The SGLT2 inhibitor empagliflozin at a
dose of 25 mg daily was administered within 12 hours of hospi-
talization for 5 days compared with placebo added to standard
decongestive treatment.
The local ethics committee of the University of Jena
approved the protocol. All patients gave written informed
consent. All authors had full access to the trial data and take
responsibility for its integrity and the data analysis. The data
that support the findings of the current study are available from
the corresponding author on reasonable request.
Patient Cohort
Patients with ADHF (18 to 85 years of age) with BNP (brain
natriuretic peptide) >100 pg/mL or NT-proBNP (N-terminal
pro-BNP) >300 pg/mL were included. Patients with or
without type 2 diabetes or impaired glucose tolerance were
included. Patients did not have cognitive impairment. For
women of childbearing potential, a negative pregnancy test or
documentation of the correct use of a highly effective contra-
ceptive method was required.
Patients were excluded for the following: type 1 diabetes,
chronic kidney disease with estimated glomerular filtration
rate (eGFR) <30 mL/min per 1.73 m² or end-stage kidney
failure with the need for chronic dialysis treatment, acute kid-
ney injury (Acute Kidney Injury Network stage ≥2 or requiring
dialysis treatment), current medication with SGLT2 inhibitors,
known intolerance or hypersensitivity to the active substance
empagliflozin or a contraindication or intolerance to furosemide,
acute HF without signs of congestion (“dry” case), indication
for urgent coronary angiography or any planned administration
 Schulze et al
of an iodine-based contrast agent within the next 6 days, need
for hemofiltration or any other form of extracorporeal therapy,
planned surgery, or recent participation in another clinical trial
(within the 3 months before inclusion). Any cause of HF leading
to decompensation that needed urgent management (eg, acute
coronary syndrome, unstable arrhythmias, mechanical causes,
acute pulmonary embolism), inability to understand or provide
written informed consent, or documented alcohol abuse (daily
alcohol intake of >12 g in women or >24 g in men) also led to
exclusion from the study.
Primary and Secondary Outcomes
The primary outcome of EMPAG-HF was the total urine
output measured and summed over 5 days. Secondary end
points included markers of kidney function under treatment
(increase in creatinine of >0.3 mg/dL, doubling of serum cre-
atinine, need for renal replacement therapy) and the trajectory
of eGFR, cystatin-C, and changes in baseline kidney function.
Net urine output was assessed daily and urine output was
also controlled for diuretic dosage according to Clark et al.16
and Oh and Han.4 Additional end points included worsening or
persistent HF defined by New York Heart Association class;
patient-reported outcomes assessed by a visual analog scale
for health status and a quality of life questionnaire (EQ-5D
index)17; intermediate care, intensive care unit, and hospi-
tal length of stay; markers of liver function (bilirubin, serum
aminotransferases, and relevant change in coagulation sta-
tus); NT-proBNP; oxygen saturation without oxygen therapy
or need for oxygen, in liters per minute; presence of rales;
changes in chest X-ray; and number of patients alive at dis-
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charge and out of hospital after 30 days.
Safety End Points
Prespecified safety end points included serious adverse events
(SAEs), events related to study drug discontinuation, and
adverse events (AEs) related to deteriorating kidney function.
Other outcome measures included the number of AEs and
SAEs including MedDRA SAE preferred terms and system and
organization controls in both groups within 30 days. All AEs
and SAEs including laboratory measures were documented
except for efficacy measures.
The clinical event adjudication committee consisted of
3 independent clinicians blinded to study arm assignment
(Supplemental Material). The committee reviewed abstracted
clinical data to determine whether major events occurred.
Monitoring and Follow-Up
Blood and spot urine samples were taken daily from day 1 to
5, at hospital discharge, and at day 30 after hospital discharge
(safety end point). All laboratory values were measured at the
central laboratory of the institution. eGFR was on the basis
of serum creatinine and calculated using the Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equation.
Statistical Analysis
All treated patients were included in the full analysis set and
were analyzed as randomized with regard to demographic
characteristics, protocol deviations, baseline characteristics,
Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038
Empagliflozin in ADHF
drug exposure, and safety, laboratory, and efficacy measures
according to the intention-to-treat principle.
ORIGINAL RESEARCH
Patients without major protocol deviations were included
in the per-protocol analysis. A sensitivity analysis was per-
ARTICLE
formed for selected demographic and baseline characteris-
tics (ie, age, sex), primary efficacy, and selected secondary
efficacy measures (ie, daily urine volume and the diuretics-
corrected urine volume).
A per-protocol analysis of the primary variable was per-
formed for patients without major protocol deviations as a
sensitivity analysis. Results of this analysis were in line with
the analysis on the basis of the intention-to-treat popula-
tion. To keep the definition of the per-protocol analysis as
unaffected as possible, predictable protocol deviations (eg,
time window deviations) were classified a priori as minor
or major.
The safety analysis set included all patients included in
the full analysis. For safety purposes, patients were analyzed
as treated.
For all data assessed, descriptive statistics including mean,
SD, minimum, quartiles with median and maximum for metric
data, and frequency analysis for nonmetric data were evaluated.
For selected end points, change from baseline was evaluated.
Volume assessments sum values over the complete day 1 (ie,
reflect effect of first treatment). Therefore, for these values, no
baseline is available. Comparison of treatment groups is on the
basis of time point values. Analysis was performed by treatment
group and in total.
Sample Size and Power Considerations
A sample size of 52 participants (26 per treatment arm) was
estimated to provide a power of 80% at a 2-sided α level of
0.05 to detect a difference in urine volume between the 2
groups if the effect size is 0.8 assuming normal distribution
of means. To account for an attrition rate of ≈10% to 15%, 4
participants per group were added, resulting in a total sample
size of 60 patients (30 per treatment arm).
Calculation of sample size and 80% power analysis was
performed with nQuery Advisor 7.0.
Analysis of the Primary End Point
V5 denotes the total urine volume over the study days 1 to 5:
V5E for the empagliflozin treatment group and V5P for the pla-
cebo treatment group.
The null hypothesis H0: V5E=V5P was tested against the
alternative H0: V5E≠V5P by means of a nonparametric Mann-
Whitney U test, α=0.05, 2-sided. The data distribution was
checked by graphical means.
Results of 2 patients with missing information on urine vol-
ume at day 5 were regarded as missing data.
Analysis of Secondary End Points
The diuretics-corrected daily urine volume (V1D) was evaluated
for every patient and day according to the following formula,
where V1 denotes the daily urine volume, Vnorm the standard
output of urine in the given patient population, D the daily body
weight–adopted dose of furosemide, and Dmin the minimal daily
body weight–adopted dose of furosemide:
V1D=(V−Vnorm)/D at the respective day
July 26, 2022 291
 Schulze et al
We assumed Vnorm=1.8 L according to Clark et al.16 and
Dmin=10 mg/70 kg body weight according to Oh and Han.4 In
ORIGINAL RESEARCH
a case when no diuretics were administered, Dmin/2 was used
as denominator.
ARTICLE
The daily urine volume V1 and the diuretics-corrected urine
volume V1D as well as weight, NT-proBNP (after logarithmic
transformation), and eGFR were analyzed by means of a mixed
model with the treatment, time, and treatment–time interaction
as fixed effects and the patient as random effect.
All tests of secondary measures are regarded as sensi-
tivity analyses and are exploratory. For this reason, the sig-
nificance level was set to α=0.05 and no α correction for
multiple testing was done.
RESULTS
Baseline Demographics
A total of 87 patients were screened between June
2019 and May 2021 at the University Hospital Jena,
Germany, of whom 30 were randomized to empa-
gliflozin and 30 to placebo (Figure 1). One patient
had to be excluded after randomization before the first
dose of trial medication was administered because of
acute ECG changes and need for urgent cardiac cath-
eterization. Thus, only 29 patients were included in the
placebo group for analysis.
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Figure 1. Consolidated Standards of Reporting Trials diagram.
292 July 26, 2022 Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038
Empagliflozin in ADHF
Baseline demographic characteristics of random-
ized study participants are described in Table 1.
Mean age was 74.7±9.9 years and 38% were
female. A total of 53.3% of patients had de novo
HF and 68.3% of all patients had ischemic cardio-
myopathy. Median NT-proBNP concentrations were
3386 (interquartile range, 2122–5344) pg/mL and
mean systolic blood pressure was 135±23 mm Hg.
The mean eGFR at baseline was 60.2±18.7 mL/min
per 1.73 m2. A total of 21.1% had a left ventricular
ejection fraction <30%.
A total of 63% of patients in the empagliflozin group
and 59% of patients in the placebo group had previous
treatment with loop diuretic medication (Table 1). No
significant differences in baseline characteristics were
noted between the 2 groups.
Primary Outcome
Cumulative urine output over 5 days was higher in the
empagliflozin group compared with the placebo group
(median, 10 775 versus 8650 mL in placebo; group dif-
ference, 2125 mL [95% CI 840–3550]; Figure 2). Thus,
patients in the empagliflozin group showed a 25% in-
crease in urine output over 5 days compared with pa-
tients in the placebo group (P=0.003).
 Schulze et al
Table 1.  Baseline Characteristics
Characteristics
Age, y
Female sex
Type 2 diabetes
NYHA functional class
 II
 III
 IV
Body mass index, kg/m2
Heart rate, bpm
Systolic blood pressure,
mm Hg
Atrial fibrillation
Hypertension
Left ventricular ejection
fraction, %
  ≤30%
Pathogenesis of heart failure
 Ischemic
 Nonischemic
De novo heart failure
Heart failure medication
 Renin–angiotensin
inhibitor
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 Sacubitril/valsartan
 Mineralocorticoid re-
ceptor antagonist
  β-blocker
 Previous treatment with
loop diuretics
Laboratory values
  Sodium, mmol/L
  Potassium, mmol/L
  Creatinine, µmol/L
 eGFR, mL/min per
1.73 m2
  Hemoglobin A1c, %
 Fasting glucose,
mmol/L
  Uric acid, µmol/L
  Urea, mmol/L
  Bilirubin, µmol/L
 Alanine aminotransfer-
ase, µmol/L×s
 Aspartate aminotrans-
ferase, µmol/L×s
  MELD-XI score
 Lactate dehydroge-
nase, µmol/L×s
Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038
Empagliflozin in ADHF
Table 1. Continued
ORIGINAL RESEARCH
Empagliflozin (n=30) Placebo (n=29) Characteristics Empagliflozin (n=30) Placebo (n=29)
72.9±11.2 76.5±8.3  Creatine kinase, µmol/ 1.9±2.2 (1.1–2.8) 1.6±1.0 (1.2–2.0)
ARTICLE
(68.8–77.1) (73.4–79.7) L×s
11/30 (36.7) 12/29 (41.4)   Lactate, mmol/L 1.7±0.7 (1.4–2) 1.7±0.7 (1.4–2)
13/30 (43.3) 10/29 (34.5)   Leukocytes, Gpt/L 8.6±2 (7.8–9.3) 8.8±3.9 (7.3–10.3)
  Hemoglobin, mmol/L 7.7±1.4 (7.2–8.2) 7.8±1.5 (7.2–8.3)
3 (10) 5 (17.2)   Hematocrit, % 37.7±5.9 (35.5–39.9) 38.1±6.8 (35.4–40.7)
20 (66.7) 13 (44.8)   Platelets, Gpt/L 218±61 (195–240) 226±66 (200–252)
7 (23.3) 11 (37.9)   NT-proBNP, pg/mL 4726±4516 4823±4995
(2939–6513) (2923–6724)
31.1±9.6 (27.5–34.7) 29.9±6.5 (27.1–32.6)
80±17 (73–87) 79±23 (70–88) Values are mean±SD (95% CI) or n/total N (%). eGFR indicates estimated
glomerular filtration rate; MELD-XI, Model for End-Stage Liver Disease Exclud-
139±25 (129–148) 132±21 (124–140) ing International Normalized Ratio; NT-proBNP, N-terminal probrain natriuretic
peptide; and NYHA, New York Heart Association.
13/27 (48.1) 14/27 (51.9)
27/30 (90) 25/29 (86.2) Secondary Outcomes
45±16 (39–51) 44±14 (30–50) Patients in the empagliflozin group showed no signifi-
cant difference in body weight reduction compared
6/29 (20.7) 6/28 (21.4) with patients in the placebo group over 5 days (mean
−4.2 versus −3.0 kg; difference, −1.2 kg [95% CI
8/30 (27) 10/29 (34) −2.99 to 0.63]; P=0.198), which persisted until hos-
22/30 (73) 19/29 (66)
pital discharge with a trend toward lower levels at
follow-up on day 30 (difference in slope, −0.07 kg/d
18/30 (60) 14/29 (48)
[95% CI, −0.131 to 0.001]; P=0.054; Figure 3A).
This was accompanied by a greater reduction in mean
23/30 (76.7) 20/29 (69) NT-proBNP from baseline in the empagliflozin group
compared with placebo (−1861 versus −727.2 pg/mL
5/30 (16.7) 5/29 (17.2) after 5 days; quotient in slope, 0.89 [95% CI 0.83–
7/30 (23.3) 4/29 (13.8) 0.95]; P<0.001; Figure 2B). The treatment effect on
NT-proBNP remains similar when the mixed model
22/30 (73.3) 25/29 (86.2) analysis is adjusted for de novo HF and previous use
19/30 (63) 17/29 (59) of loop diuretics (P=0.0006).
Both total and net urine output over 5 days were
higher in the empagliflozin group compared with the pla-
139±4 (138–141) 138±5 (136–140) cebo group (Table 2). Daily furosemide equivalent dose
4.1±0.5 (3.9–4.3) 3.9±0.6 (3.7–4.2) and the cumulative dose of loop diuretics were lower and
107±29 (96–118) 98±28 (87–109)
diuretic efficiency expressed as milliliters urine produc-
tion per milligram furosemide equivalent was higher in
58.2±19.3 (51–66) 62.2±18.2 (55–69)
the empagliflozin group compared with placebo (14.1
6.6±1.5 (6.0–7.2) 6.4±0.9 (6.0–6.7)
mL urine per milligram furosemide equivalent [95% CI,
0.6–27.7]; P<0.041; Table 2, Figure 2C, and Tables S2
8±1.5 (6.7–9.3) 7.8±2.3 (6.0–9.5)
and S3; Hodges-Lehmann estimate of group difference
43.7 mL urine per milligram furosemide equivalent [95%
458±111 (411–505) 488±151 (421–555)
CI, 0.1–93]). Urine output and diuretic efficiency are
7.9±3.7 (6.5–9.3) 7.7±3.7 (6.3–9.2)
independent of de novo HF or previous loop diuretic use
13.3±9.4 (9.8–16.8) 16.8±9.6 (13–20.6) (Tables S2 and S3).
0.83±1.8 0.45±0.43 No differences in changes in eGFR during the treat-
(0.15–1.51) (0.28–0.61)
ment period were observed between the 2 groups
0.92±1.6 (0.3–1.54) 0.50±0.2 (0.41–0.58) (eGFR, 51±19 versus 54±17 mL/min per 1.73 m²;
P=598). Previous use of loop diuretics or de novo HF
12.3±2.5 (11.4–13.3) 11.9±2.5 (11.0–12.9) had no effect on eGFR levels (Table S3). At the 30-day
4.6±0.9 (4.3–5) 5.7±4.2 (3.8–7.3) follow-up visit, patients in the placebo group had lower
eGFR compared with patients in the empagliflozin
(Continued ) group (Figure 3B). Additional serum markers of kidney
July 26, 2022 293
 Schulze et al Empagliflozin in ADHF

the empagliflozin group had lower levels of serum uric

A Cumulative urine volume
acid during the 5-day study period.
ORIGINAL RESEARCH

12500
Mixed model analysis of daily urine volume sum
Difference of least square means (treatment effect):
387 mL (95% CI 50 to 724) Empagliflozin
ARTICLE

P=0.025
Urine volume sum cumulative [mL]

10000
Placebo
Quality of Life Questionnaires
Patients in the empagliflozin group had a greater abso-
7500
lute change in New York Heart Association class from
baseline to day 5 and until hospital discharge (Figure
5000
S1). The absolute improvement in EQ-5D index and vi-
sual analogue scale health status was numerically higher
2500
in the empagliflozin group compared with placebo but
day 1 day 2 day 3 day 4 day 5
not statistically significant (Figure 4).17
Number of patients
Empagliflozin 30 30 30 30 28
Placebo 29 29 29 29 29

Safety and Adverse Events

B Dynamics in NT-proBNP by day
No statistically significant differences in the occurrence
120 Mixed model analysis after logarithmic transformation
Quotient of slopes (treatment-time interaction)
0.888 (95% CI 0.830 to 0.950)
of safety events were observed between the 2 groups
P<0.001
during the study period or during follow-up of 30 days
NT-proBNP relative to baseline [%]

100
after randomization (Table 4). No early discontinuation of
trial drug was registered. No patient was lost to follow-
80 up. Two patients died in the placebo group and 1 patient
Placebo
died in the empagliflozin arm.
60

Empagliflozin
DISCUSSION
40
Baseline day 2 day 3 day 4 day 5 In patients with ADHF, early initiation of empagliflozin
Number of patients
Empagliflozin
Placebo
27
29
26
26
24
23
25
25
24
24
added to standard decongestive treatments led to a
25% increase in cumulative urine output over 5 days
of treatment. Empagliflozin also led to an increase in
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C Diuretic efficency

diuretic efficiency as well as greater reduction in NT-

Net urine output per mg furosemide [mL/mg]

20
Empagliflozin
proBNP and a trend toward lower body weight (Fig-
Placebo ures 2 and 3). These effects were not accompanied by
0 increased kidney dysfunction compared with placebo
(Figure 3B and Tables 2 and 3).
-20
The findings of the current study add to the increas-
ing evidence on effects of SGLT2 inhibition in patients
-40
Mixed model analysis of net urine output per mg furosemide equivalent
with cardiovascular diseases.12–15,18–21 The effects of
Difference of least square means (treatment effect):
14.1 mL/mg furosemide IV (95% CI 0.6 to 27.7)
empagliflozin in patients with ADHF are consistent with
-60 P=0.041
findings of previous studies in patients with kidney dys-
day 1
Number of patients
day 2 day 3 day 4 day 5
function and HF with preserved and reduced ejection
Empagliflozin
Placebo
30
29
30
29
30
29
30
29
28
29 fraction regardless of diabetes status that consistently
showed the clinical benefits of SGLT2 inhibition.12–15,19
Figure 2. Primary and secondary outcomes. First introduced as antihyperglycemic drugs, SGLT2
A, Cumulative urine output over 5 days (primary outcome). B, inhibitors have shown benefits in cardiovascular risk pre-
Dynamics in NT-proBNP levels in relation to baseline (mean and
SEM values evaluated under logarithmic transformation). C, Diuretic
vention and in patients with chronic stable HF.12–15,18,19
efficiency over 5 days. Error bars represent SEM. SGLT2 inhibitors reduce renal glucose reabsorption
and thus increase urinary glucose excretion. In addi-
function and injury including creatinine, urea, and cys- tion to glucosuric effects, empagliflozin is also associ-
tatin-C as well as urine markers of kidney injury includ- ated with osmotic diuresis and natriuresis.22 Chronic
ing urinary total protein, albumin, and α1-microglobulin use decreases body weight and blood pressure with-
(corrected for urine creatinine) were not different out increases in heart rate and has favorable effects on
between the 2 groups (total urinary protein, 492±845 markers of arterial stiffness and vascular resistance.21 In
versus 503±847 mg/g creatinine; P=0.975; and uri- patients with HF with reduced and preserved ejection
nary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 fraction, SGLT2 inhibition prevented the decline in eGFR
mg/g creatinine; both P=0.066; Table 3). Patients in over time.14,15,18,21

294 July 26, 2022 Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038

 Schulze et al Empagliflozin in ADHF

A Change from baseline in body weight by day B Change from baseline in eGFR by day

ORIGINAL RESEARCH
0 Mixed model analysis
Mixed model analysis
Change from baseline in actual body weight [kg]

Difference in slope (treatment-time interaction) Difference in slope (treatment-time interaction):

-0.066 kg per day (95% CI -0.131 to 0.001) 0.29 mL/min per day (95% CI 0.07 to 0.51)

Change from baseline in eGFR [mL/min]

ARTICLE
Empagliflozin
P=0.054 P=0.010
0
-2

-4
Placebo
-10

-6 Empagliflozin
Placebo

-20

Baseline day 2 day 3 day 4 day 5 Discharge day 30 Baseline day 2 day 3 day 4 day 5 Discharge day 30
Number of patients Number of patients
Empagliflozin 30 28 30 29 28 26 19 Empagliflozin 29 29 28 28 27 25 17
Placebo 26 24 26 23 25 25 15 Placebo 29 27 26 28 28 26 18

Figure 3. Secondary outcomes with extended 30-day follow-up.

A, Change in body weight from baseline in both groups. B, Dynamics in estimated glomerular filtration rate (eGFR) as change from baseline in
both groups. Error bars represent SEM.

The current study is distinct from previous clinical tri- urine output compared with 10 mg. We aimed to explore
als of SGLT2 inhibition in HF in several aspects. First, potentially negative effects of empagliflozin in ADHF in com-
no previous trial has recruited patients at such an early bination with high-dose loop diuretics and other HF drugs.
time period (<12 hours) after hospital admission with- Previous studies on the role of ultrafiltration in decom-
out hemodynamic stabilization. Second, this trial was pensated HF, such as UNLOAD (Ultrafiltration Versus
designed to monitor early effects of SGLT2 inhibition Intravenous Diuretics for Patients Hospitalized for Acute
including risks and benefits during the acute phase of Decompensated Congestive HF) and AVOID-HF (Aqua-
decongestive treatment in decompensated HF. Third, pheresis Versus Intravenous Diuretics and Hospitaliza-
patients were monitored during the most vulnerable tion for HF), have demonstrated that these therapies
Downloaded from http://ahajournals.org by on July 8, 2023

phase of acute HF treatment from admission to clinical may cause incremental weight loss comparable with the
stabilization (full study observation time was 5 days). effects of SGLT2 inhibition as shown in EMPAG-HF.10,11
The dosage of 25 mg empagliflozin in EMPAG-HF was Results from AQUAMARINE (Answering the Question
chosen to maximize potential diuretic effects in ADHF. We of Tolvaptan’s Efficacy for Patients With ADHF and Kid-
hypothesized that the higher dose would result in increased ney Failure) demonstrated that tolvaptan was associated

Table 2.  Primary and Secondary End Points

Estimation of group
Outcomes Empagliflozin Placebo difference* (95% CI)
Total urine output over 5 days, mL 10 775 (9100 to 12 925) 8650 (6450 to 10 350) 2125 (840 to 3550)†
Secondary outcomes
  Net urine output over 5 days, mL 3725 (2622 to 5830) 1480 (650 to 3826) 1950 (674 to 3250)
  Net fluid output over 5 days, mL 3925 (2825 to 6505) 1680 (850 to 4026) 2005 (700 to 3300)
  Change in body weight, kg (day 5) – 4.19±3.5 –3.02±2.9 –1.18 (–2.99 to 0.63)
  Cumulative dose of diuretics (in milligrams furosemide equivalent) 313±194.6 351.4±220.7 –38.4 (–176.7 to 70.0)
  Diuretic efficiency (mL/mg furosemide equivalent) 8.3 (–32.9 to 58.8) –25.9 (–80.3 to 16.8) 43.7 (0.1 to 93)
Renal function measures under treatment (day 5)
  Increase in serum creatinine of ≥26.5 µmol/L (0.3 mg/dL) 3/26 (11.5) 9/28 (32.1)
  Doubling of serum creatinine 0 of 26 0 of 28
  Need for renal replacement therapy 0 of 29 0 of 29
  Total urinary sodium excretion, mmol/L (day 5) 93±36.8 99.4±30.6 –6.4 (–27.6 to 14.8)
  Fractional excretion of sodium (day 5) 3170±2802.2 2439.1±2134.6 731 (–939 to 2400)

Values are mean±SD (95% CI), median (interquartile range), or n/total N (%).
*Hodges-Lehman estimation for median.
†Wilcoxon 2-sample test; P=0.003.

Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038 July 26, 2022 295

 Schulze et al Empagliflozin in ADHF

Table 3.  Dynamics in Renal Function

ORIGINAL RESEARCH

Empagliflozin Placebo

Renal function measure Day 1 Day 3 Day 5 Day 30 Day 1 Day 3 Day 5 Day 30
ARTICLE

Daily urine output, mL 1688±972 2241±629 2555±1192 — 1580±1524 1963±871 1929±889 —

Daily net urine output, mL 737±971 784±636 1060±1027 — 616±1521 601±924 466±746 —
Diuretics-controlled urine output, −28.4±60.9 16.8±45.1 20.9±69 — −48.4±87.0 0.5±26.6 7.5±34.5 —
mL/mg furosemide
Serum markers of renal function
  Creatinine, µmol/L 107±28.8 115±34.8 119±33.9 120±42.1 97.8±28.2 107±24.7 111±29.4 118.4±29.4
  eGFR, mL/min per 1.73 m² 58.2±19.32 53.2±19.8 51.1±19.1 52.9±23.7 62.2±18.2 55.0±16.7 53.7±17.4 47.5±11.7
  Urea, mmol/L 7.9 C3.7 9.0±3.5 9.7±3.5 8.0±3.3 7.7±3.7 8.8±3.1 8.9±3.0 9.7±4.5
  Cystatin-C, mg/L 2±1.5 2.1±1.5 2.0±0.8 2.3±1.3 1.5±0.3 1.7±0.4 1.6±0.4 1.7±0.3
  Uric acid, µmol/L 458±111 436±117 423±121 482±146 488±151 512±138 509±152 501±147
Urine markers
  Urine total protein, mg/g creatinine 343±333 583±742 492±845 664±930 273±168 418±469 503±847 309±214
  Urine albumin, mg/g creatinine 112±153 250±543 233±682 309±812 80.6±93.1 127±177 164±408 86.7±82.2

 Urine α1- microglobulin, mg/g 95.1±91 105±159 55.4±38.6 76.7±75.8 141±258 141±496 31.3±33.6 20.6±15.7
creatinine
  Urine creatinine, mmol/L 5.8±5.3 4.48±3.11 4.6±3.5 6.3±3.0 6.78±4.32 6.45±4.66 6.5±7.3 7.92±6.77
  Urine uric acid, µmol/L 1460±1045 1852±1767 1635±1243 1820±1695 1460±1444 1635±1782 1595±1164 1537±1346
  Urine glucose, mmol/L 7.4±15.6 84.7±76.3 70.1±82.3 13.7±44.5 0.3±0.3 5.5±18.8 7.7±29.4 15.5±30.2

All data are expressed as mean±SD. eGFR indicates estimated glomerular filtration rate.

with incremental diuresis and no evidence for untoward Who Have Been Stabilized)])20 only after clinical stabiliza-
effects on kidney function in acute HF.9 However, early tion. A previous study using 10 mg of empagliflozin ver-
initiation of tolvaptan in patients with HF and reduced sus placebo initiated within 24 hours of hospitalization for
Downloaded from http://ahajournals.org by on July 8, 2023

ejection fraction did not improve outcomes in EVEREST ADHF (EMPA-RESPONSE [Randomized, Double Blind,
(Efficacy of Vasopressin Antagonism in Heart Failure Placebo Controlled, Multicenter Pilot Study on the Effects
Outcome Study With Tolvaptan).7 of Empagliflozin on Clinical Outcomes in Patients with Acute
Because of concerns about AEs, recent acute HF trials Decompensated Heart Failure]) failed to show a difference
have focused on initiation of medication (eg, sacubitril-val- in the primary end point of dyspnea score, diuretic response,
sartan [PIONEER-HF (Comparison of Sacubitril-Valsartan length of stay, or change in NT-proBNP.24 Here, we show for
Versus Enalapril on Effect on NT-proBNP in Patients Sta- the first time in a randomized study the safety and tolerabil-
bilized From an Acute Heart Failure Episode)]23 or empa- ity of an early initiation of the SGLT2 inhibitor empagliflozin
gliflozin [EMPULSE (Empagliflozin Compared to Placebo on top of diuretic regimens in patients with ADHF without
Initiated in Patients Hospitalized for Acute Heart Failure negative effects on kidney function or injury patterns.

A EQ-5D-3L sum score by day B EQ-5D-3L VAS by day

Mixed model analysis Mixed model analysis
Difference in slope (treatment-time interaction): 70 Difference in slope (treatment-time interaction):
0.85 0.003 per day (95% CI -0.002 to 0.008) 0.02 per day (95% CI -0.37 to 0.42)
P=NS P=NS
Index et al 2005

Empagliflozin Empagliflozin
Actual health state (VAS)

0.80 60
acc. Greiner

Placebo Placebo
EQ-5D IndexEQ-5D

0.75
50

0.70

40

0.65
Baseline day 5 Discharge day 30 Baseline day 5 Discharge day 30
Number of patients Number of patients
Empagliflozin 30 29 24 28 Empagliflozin 30 29 23 27
Placebo 28 29 25 25 Placebo 28 29 25 24

Figure 4. Clinical outcomes.

A, Change in EQ-5D. B, Change in health status visual analogue scale. Error bars represent SEM.

296 July 26, 2022 Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038

 Schulze et al
Table 4.  Safety Events
Event Empagliflozin
Worsening heart failure 1 (3.3)
Worsening renal function (increase in 3/26 (11.5)
serum creatinine ≥26.5 µmol/L [0.3
mg/dL])
Worsening liver function 0 0
Change in coagulation status at day 5 1/23 (4.3)
Urinary tract infection 1 (3.3)
Stroke or transient ischemic attack 1 (11.1)
30-day mortality 1 (3.3)
All data are expressed as n/total N (%).
Consistent with data from previous trials in ambulatory
patients with HF, an initial decrease of eGFR was noted
that was lower in the empagliflozin group compared with
placebo, followed by higher eGFR in the empagliflozin
group at 30 days.18 This suggests the possible absence
of a reduction in intraglomerular pressure attributable to
enhanced tubulo-glomerular feedback19,21,25 occurring dur-
ing the very early phase of SGLT-2 inhibition in patients with
ADHF. An intermittent reduction of glomerular filtration was
typically seen during the first 2 to 4 weeks of treatment
with SGLT2 inhibitors and subsequently increased within 2
to 3 months.19,26,27 This finding led to concerns about the
very early use of SGLT2 inhibitors in patients with acute HF,
especially in those with concurrent renal impairment. More-
over, this so-called eGFR dip caused by SGLT2 inhibition
Downloaded from http://ahajournals.org by on July 8, 2023
was more pronounced in patients having additional diuretic
therapy and more advanced kidney disease.27 Despite this
background, our study demonstrated that the early use of
empagliflozin in ADHF is safe and well-tolerated without
evidence of kidney dysfunction or injury.
No difference in renal or cardiovascular safety end
points was detected and no event of ketoacidosis
occurred in this study despite reduced eGFR and albu-
minuria at baseline. Of note, patients in the empagliflozin
group had lower levels of uric acid. This observation
supports the hypothesis that the use of SGLT2 inhibi-
tion in patients with ADHF may affect the incidence of
acute gout attacks, a common complication of intensive
diuretic regiments.
Our trial has some limitations. The short observation
period of only 5 days may not be sufficient to observe AEs
that occur after discharge and during longer use. The study
was not powered or designed for analysis of clinical end
points such as cardiovascular mortality and hospitalization.
The focus on early decongestion and inclusion of patients
within 12 hours of hospitalization also excluded patients
with a more prolonged course of cardiac decompensation.
Our study used New York Heart Association classification,
the EQ-5D index, and visual analogue scale health status
for clinical status and quality of life assessment instead of
visual assessment scales for assessment of dyspnea and
well-being and other conventional HF symptom assess-
Circulation. 2022;146:289–298. DOI: 10.1161/CIRCULATIONAHA.122.059038
Empagliflozin in ADHF
ment instruments such as the Kansas City Cardiomyopa-
thy Questionnaire. Because of the COVID-19 pandemic,
ORIGINAL RESEARCH
Placebo
4 (13.8)
we recruited patients at slower enrollment rates and over
a relatively long period (2019 through 2021). The use of
ARTICLE
9/28 (32.1)
sacubitril-valsartan was low and patients with previous
SGLT2 inhibition were excluded.
In patients with ADHF, early initiation of the SGLT2
2/25 (8)
inhibitor empagliflozin in addition to standard treatment
is safe and increases urine output without affecting kid-
4 (13.8)
ney function. Thus, addition of SGLT2 inhibition to stan-
0
dard diuretic therapy is a promising strategy to improve
2 (6.9) early decongestion in patients with ADHF.
ARTICLE INFORMATION
Received January 4, 2022; accepted May 25, 2022.
Affiliations
Department of Internal Medicine I, Division of Cardiology, Angiology and Intensive
Medical Care (P.C.S., J.B., J.W., P.A., F.H., S.G., S.M.-W.), Center for Clinical Stud-
ies (U.S.), and Department of Internal Medicine III, Division of Nephrology (M.B.),
Friedrich-Schiller-University, University Hospital Jena, Germany. Department of
Cardiology and Pneumology, Georg-August-University, University Medical Cen-
tre Göttingen, Germany (S.v.H.). German Center for Cardiovascular Research
(DZHK), partner site Göttingen, Germany (S.v.H.).
Sources of Funding
This study was supported through funding by Boehringer Ingelheim to the Uni-
versity Hospital Jena.
Disclosures
Dr Schulze received honoraria and travel support from Bayer, Astra Zeneca, Dai-
ichi Sankyo, Novartis, Actelion, Roche, Sanofi Aventis, Pharmacosmos, Medtronic,
Thoratec, Boehringer Ingelheim, HeartWare, Coronus, Abbott, Edwards Inc,
Boston Scientific, St Jude Medical, Abiomed, and the German Cardiac Society;
research support from the National Institutes of Health, the German Research
Foundation, the Else Kröner Fresenius Foundation, the German Heart Founda-
tion, the European Society of Cardiology, Actelion, Medtronic, BMBF, Abiomed,
Boehringer Ingelheim, and Boston Scientific; and served on advisory boards for
the German Research Council, Eurotransplant, Novartis, Bayer, Pharmacosmos,
Astra Zeneca, Boehringer Ingelheim Inc, the German Cardiac Society, and the
European Society of Cardiology. Dr Möbius-Winkler received honoraria and travel
support from Bayer, Daiichi Sankyo, Novartis, Boston Scientific, Abiomed, and
the German Society of Cardiology; and research support from Boston Scien-
tific and Abiomed. Dr von Haehling has been a paid consultant for or received
honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS,
Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche,
Servier, Sorin, and Vifor; and reports research support from Amgen, AstraZeneca,
Boehringer Ingelheim, IMI, and the German Center for Cardiovascular Research
(DZHK). Dr Busch has been a paid consultant for or received honoraria payments
or travel support from Novartis, AstraZeneca, Boehringer Ingelheim, Vifor Pharma,
OTSUKA, Bristol Myers Squibb, and Pfizer. The other authors report no conflicts.
Supplemental Material
Executive Committee and Data Safety Monitoring Board
Study Protocol and Statistical Analysis Plan
Figure S1
Tables S1–S3
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