Circulation

ORIGINAL RESEARCH ARTICLE

Dapagliflozin Effects on Biomarkers, Symptoms,

and Functional Status in Patients With Heart
Failure With Reduced Ejection Fraction
The DEFINE-HF Trial

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have Michael E. Nassif, MD
demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose et al
co-transporter-2 inhibitors. However, few of these patients had HF, and those that
did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2
inhibitors in patients with established HF with reduced ejection fraction, including
those with and without type 2 diabetes mellitus, remain unknown.

METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and

Functional Status in Patients with HF with Reduced Ejection Fraction) was an
investigator-initiated, multi-center, randomized controlled trial of HF patients with
left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class
II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic
peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or
placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal
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pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase
in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire
overall summary score, or a ≥20% decrease in NT-proBNP.

RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection

fraction with high use of optimal medical therapy. There was no significant difference
in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo
(1133 pg/dL (95% CI 1036–1238) vs 1191 pg/dL (95% CI 1089–1304), P=0.43).
For the second dual-primary outcome of a meaningful improvement in Kansas City
Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of
dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted
OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher
proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy
Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI
0.98–3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9,
95% CI 1.1–3.3) by 12 weeks. Results were consistent among patients with or
without type 2 diabetes mellitus, and other prespecified subgroups (all P values for
interaction=NS).

CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use
of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the
proportion of patients experiencing clinically meaningful improvements in HF-related
health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful
Key Words: biomarkers ◼ health
HF measures appear to extend to patients without type 2 diabetes mellitus. status ◼ heart failure ◼ outcomes
◼ SGLT2 inhibitors
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique
identifier: NCT 02653482. Sources of Funding, see page XXX

© 2019 American Heart Association, Inc.

https://www.ahajournals.org/journal/circ

Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929 xxx xxx, 2019 1

 Nassif et al
Clinical Perspective
ORIGINAL RESEARCH
What Is New?
ARTICLE
• This the first randomized, double-blind, placebo-
controlled trial examining the early effects of SGLT-
2i on clinically important end points in patients
with heart failure and reduced ejection fraction.
• In this trial of 263 patients, dapagliflozin did not
have a significant effect on mean NT-proBNP levels
over 12 weeks of therapy.
• Significantly greater proportion of patients treated
with dapagliflozin experienced clinically meaningful
improvements in heart failure–related symptoms,
functional status and quality of life, or natriuretic
peptides, as compared with placebo—which was
observed in patients with and without type 2 dia-
betes mellitus.
• No imbalance was seen across safety events,
although the number of events was small.
What Are the Clinical Implications?
• These findings suggest that dapagliflozin may have
a favorable effect on improving disease-specific
health status (symptoms, function, and quality of
life) after 12 weeks of treatment in patients with
heart failure and reduced ejection fraction.
• These beneficial effects of dapagliflozin in heart
failure with reduced ejection fraction may poten-
tially extend to patients with or without type 2 dia-
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betes mellitus.
H
eart failure (HF) remains a leading cause of hos-
pitalization in the United States and Western Eu-
rope.1,2 Patients who have HF with reduced ejec-
tion fraction (HFrEF) have a high burden of debilitating
symptoms, and are at especially high risk of disease pro-
gression, including frequent hospitalizations, require-
ment for advanced therapies, and death.3 Despite ther-
apeutic advances developed over the past 2 decades,4
outcomes for patients with HFrEF remain poor, and
many interventions demonstrating benefit on hard out-
comes (such as mortality) may not improve health sta-
tus (symptoms, function and quality of life).5 Improving
symptom burden in HFrEF is a key goal of management,
highly predictive of lower risk of future HF hospitaliza-
tion, and increasingly recognized by practice guidelines
and regulators as an important therapeutic target.6,7
Notably, the recent Food and Drug Administration draft
guidance to industry on drug development in HF has
endorsed measures of patients’ symptoms and physical
function as acceptable (and important) end points.8
Sodium-glucose co-transporter-2 inhibitors (SGLT-
2i) are a class of medications developed for treatment
of type 2 diabetes mellitus (T2D), which lower plasma
glucose concentrations via increased urinary excretion
2 xxx xxx, 2019
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
of glucose.9 Three large cardiovascular outcomes trials,
and one kidney outcome trial, all conducted in patients
with T2D at increased cardiovascular risk, have dem-
onstrated robust and consistent reductions in the risk
of hospitalization for HF with 3 different agents in the
SGLT-2i class.9–13 However, the overwhelming majority
of patients in these trials did not have established HF,
and those who did were not well-characterized in terms
of left ventricular ejection fraction (LVEF), cause, symp-
tom burden, biomarkers, or use of optimal guideline-
directed medical therapies for HFrEF.14–16 Thus, while
SGLT-2i appear to be effective at preventing HF-related
hospitalizations in patients with T2D at high cardiovas-
cular risk, whether they are beneficial for treatment of
established HF in general, and HFrEF specifically, par-
ticularly on top of optimal medical and device therapy,
has not been definitively established. Moreover, wheth-
er such benefits may extend to HF patients without T2D
remains speculative. Although several large outcome
trials examining the effects of SGLT-2i in patients with
prevalent HF with and without T2D are currently under
way, to date, no trial has examined the early effects of
SGLT-2i on HF disease-specific health status, function
and quality of life, or natriuretic peptides.17
To address this important knowledge gap, we de-
signed the DEFINE-HF (Dapagliflozin Effects on Bio-
markers, Symptoms and Functional Status in Patients
with HF with Reduced Ejection Fraction) trial, to test
the hypothesis that treatment with the SGLT-2i dapa-
gliflozin will improve natriuretic peptides and health
status in well-phenotyped and optimally treated HFrEF
patients, both with and without T2D.
METHODS
The authors declare that all supporting data are available
within the article (and its online-only Data Supplement).
DEFINE-HF was a randomized, double-blind, placebo con-
trolled, multi-center trial that enrolled patients with HFrEF,
defined as an established diagnosis of HF for at least 16
weeks, left ventricular ejection fraction ≤40%, NYHA class
II-III symptoms, and an elevated NT-proBNP (N-terminal pro
b-type natriuretic peptide) or BNP (B-type natriuretic peptide).
Patients were randomized to treatment with dapagliflozin
10 mg daily or matching placebo in addition to guideline
directed standard of care therapy for 12 weeks (Appendix SI
in the online-only Data Supplement). The trial was conducted
across 26 sites in the United States (US). The list of participat-
ing sites and investigators can be found in Appendix SII in
the online-only Data Supplement. The primary objectives of
the trial were to evaluate the effects of dapagliflozin on HF
disease-specific biomarkers (NT-proBNP) and health status, as
assessed by the Kansas City Cardiomyopathy Questionnaire
(KCCQ).18
DEFINE-HF was an investigator-initiated trial, with the
concept developed, and trial sponsored and executed by
the national coordinating center at Saint Luke’s Mid America
Heart Institute in collaboration with the academic Executive
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
 Nassif et al
Committee, independent of the funding source (Astra
Zeneca). The study was monitored by an independent data
safety and monitoring committee. Institutional review boards
approved the study for all sites, and all patients provided
informed consent for research participation. The trial was
conducted in accordance with the ICH E6(R1) Guidelines of
Good Clinical Practice and the Declaration of Helsinki.
Patient Selection
Full inclusion and exclusion criteria can be found in Appendix
SIII in the online-only Data Supplement. Adult ambulatory
patients with or without T2D, established HF for at least 16
weeks, LVEF ≤40%, and NYHA class II-III HF were recruited
from 26 sites in the US, and screened for participation. Key
exclusion criteria were recent hospitalization (within 30 days)
for decompensated HF, eGFR <30 mL/min/1.73m2 at the
screening visit (using modified MDRD equation), and history
of type 1 diabetes mellitus.19
Trial Design
Patients considered potentially eligible who agreed to par-
ticipate and provided informed consent entered a 2-week
screening phase, during which their eligibility was confirmed
based on central core laboratory evaluation (NT-proBNP ≥400
pg/mL, or BNP ≥100 pg/ml), eGFR ≥30 mL/min/1.73m2, and
clinical stability was ensured. Patients confirmed eligible were
randomized 1:1 to oral dapagliflozin 10 mg or matching pla-
cebo once daily (Figure I in the online-only Data Supplement).
Before administration of the first dose of dapagliflozin or pla-
cebo, patients underwent a physical exam, trial-related labo-
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ratory assessments, completion of the KCCQ questionnaire
and a 6-minute walk test. Patients then entered a 12-week
treatment period, during which they were followed via 4
phone call visits, as well as 2 in-person study visits (at 6 and
12 weeks), at which time repeat physical exams, laboratory
assessments, KCCQ questionnaires, and 6-minute walk tests
were completed. At week 12, study medication was discon-
tinued, and patients were followed for 1 additional week, at
the end of which another in-person study visit was conducted
to assess for any intercurrent safety events, and to collect
additional laboratory samples.
Study Measurements
Levels of NT-proBNP and BNP, and all other study laboratory
assessments were analyzed at a Quest Diagnostics central
laboratory, blinded to treatment assignment (NT-ProBNP assay
Roche electrochemiluminescent method on Elecsys© plat-
form, Pro-BNP II reagent by Roche/Cobas; BNP assay chemi-
luminescent method on Siemens ADVIA Centaur® platform).
The KCCQ questionnaire was completed at each time
point by patients without assistance by site study staff (as
validated). The KCCQ is a 23-item, self-administered instru-
ment that quantifies physical function, symptoms (frequency,
severity and recent change), quality of life, and social func-
tion. In the KCCQ, an overall summary score (KCCQ-OS) can
be derived from the physical function, symptoms, quality
of life and social function domains. KCCQ clinical summary
score (KCCQ-CS) includes the physical function and symp-
toms domains. For each domain, the validity, reproducibility,
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
responsiveness and interpretability have been independently
ORIGINAL RESEARCH
established. Scores are transformed to a range of 0 to 100, in
which higher scores reflect better health status.18
Six-minute walk tests were conducted by site study per-
ARTICLE
sonnel, based on protocol instructions.
Concomitant Medications
The trial was designed to enroll patients on optimal doses of
guideline-directed medical therapy for HFrEF, though adjust-
ment of standard therapies, including attempted up-titration
of neurohormonal antagonists was permitted if clinically
indicated. In patients with T2D, plans for risk reduction of
hypoglycemia included suggested 20% reduction in the total
daily dose of insulin or insulin secretagogues (ie, sulfonyl-
urea, metiglinides) for patients with baseline hemoglobin A1c
(HbA1c) of ≤7%. All participants were counseled on the signs
and symptoms of hypoglycemia and the appropriate treat-
ment and were monitored for recent hypoglycemic events at
each study visit.
Trial End Points
Dual primary end points were (1) the average of 6- and
12-week mean NT-proBNP and (2) a composite of the propor-
tion of patients that achieved a meaningful improvement in
health status (≥5-point increase in average of 6- and 12-week
KCCQ-OS) or NT-proBNP (≥20% decrease in average of 6- and
12-week NT-proBNP).20,21 Key secondary end points included
proportion of patients with meaningful change in KCCQ,
and NT-proBNP at each time point, mean BNP and propor-
tion of patients with meaningful change in BNP, functional
status based on 6-minute walk test, change in weight, systolic
blood pressure and HbA1c. Exploratory end points included
a composite of hospitalization for HF or urgent HF visits (see
Appendix SI in the online-only Data Supplement).
All serious adverse events were reported by investigators.
A blinded Clinical Events Committee adjudicated all deaths,
hospitalizations for heart failure, urgent heart failure visits,
myocardial infraction and transient ischemic attack/stroke
events. In addition, investigator reported adverse events of
special interest included acute kidney injury (defined as dou-
bling of serum creatinine), diabetic ketoacidosis, volume
depletion, severe hypoglycemia (defined as blood glucose
<54 mg/dL (<3.0 mmol/L) and requiring assistance), and
lower limb amputations.
Statistical Analysis
Patient disposition is reported including all patients who
signed the informed consent. All primary and secondary effi-
cacy end points were evaluated using the modified intention
to treat data set, which included all randomized patients who
received at least 1 dose of study medication and had at least
1 evaluable end point. Patients with no evaluable follow-up
data for a particular outcome (eg, NT-proBNP) were excluded
from these analyses. The on-treatment data set includes all
patients in the modified intention to treat data set; however,
efficacy end point measurements in the on-treatment data
set were excluded for follow-up time point(s) during which
patients were off the study medication at the time the cor-
responding measurements were obtained. The on-treatment
xxx xxx, 2019 3
 Nassif et al
data set was used for sensitivity analyses. The safety analysis
ORIGINAL RESEARCH
set included all patients who received at least 1 dose of study
medication and was used for all safety analyses.
Baseline characteristics were evaluated overall and by
ARTICLE
treatment group. Continuous measures were summarized
by mean±standard deviation and compared using Students
t tests. Categorical variables were summarized by frequency
and percent and compared using Chi square or Fisher’s exact
tests, as appropriate.
For the first dual primary end point, a generalized linear
mixed model was used to estimate the effect of treatment
on the average of 6- and 12-week mean NT-proBNP values,
adjusting for log baseline NT-proBNP, history of T2D, eGFR, and
age. A gamma distribution and log link function were used to
account for the skewed nature of NT-proBNP. For the second
dual primary end point that includes both health status mea-
sures and biomarker measurement, the proportion of patients
achieving meaningful change in KCCQ (a ≥5-point increase in
average of 6- and 12-week KCCQ-OS) or NT-proBNP (≥20%
decrease in average of 6- and 12-week NT-proBNP), were
calculated by treatment group. A logistic regression model
was used to assess the effect of dapagliflozin versus placebo.
Models were adjusted for log baseline NT-proBNP, baseline
KCCQ, history of T2D, eGFR, and age.
For the primary end points, several subgroup analyses
were prespecified, including T2D status, age (<65, ≥65 years),
sex (male, female), race, baseline NT-proBNP (< median, ≥
median), baseline LVEF (≤30%, >30%), atrial fibrillation,
baseline KCCQ-OS (<70, ≥70), baseline eGFR (<60, ≥60 mL/
min/1.73 m2), cause of cardiomyopathy (ischemic, non-isch-
emic), baseline renin angiotensin aldosterone system inhibi-
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tor type (angiotensin receptor neprilysin inhibitor (ARNI),
angiotensin-converting enzyme inhibitors, angiotensin recep-
tor blockers, neither), baseline loop diuretic dose (furosemide
equivalent mean daily dose: ≤ 40 mg, >40 mg).
Both primary hypotheses were tested at the 2-sided
5% significance level. The statistical analysis plan prespeci-
fied that in the case of non-significant findings for the first
dual primary end point, the second dual primary end point
would be tested at the 2-sided 5% significance level but will
be regarded as an exploratory end point, and a nominal P
value will be produced. No adjustments for multiplicity were
made for secondary or exploratory end points. Prespecified
responder analyses were conducted examining proportions
of patients with significant worsening, no change, and clini-
cally important improvement in NT-proBNP and KCCQ at the
end of the treatment period. These analyses used clinically
meaningful threshold for NT-proBNP (as well as BNP) of 20%
or greater change, based on previous studies demonstrating
that change in the excess of 20% demonstrates more than
random or physiologic variation in NT-proBNP, correlates with
echocardiographic markers of adverse left ventricular remod-
eling, and is associated with clinical events in patients with
established HF.22–24 We also used previously established mean-
ingful thresholds for change in KCCQ (5 to <10 point (small–
moderate), 10 to <20 point (moderate-large), and ≥20 point
(very large) change).20,21
Sensitivity analysis was performed, including per protocol
evaluation using the on-treatment data set, in which only the
end points ascertained while patients were receiving dapa-
gliflozin or placebo were included.
4 xxx xxx, 2019
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
Prespecified supportive analyses were also performed that
included KCCQ-CS, which specifically evaluates patients’
symptom burden and physical function, instead of KCCQ-OS,
within a similar composite end point of clinically meaningful
change in NT-proBNP and KCCQ over 12 weeks.
For secondary end points, binary outcomes were ana-
lyzed in a manner analogous to that of the second dual
primary outcome, and continuous outcomes were analyzed
in a manner analogous to that of the first dual primary out-
come, although appropriate distributions and link functions
were chosen for the given outcomes. Models also provided
separate effect estimates for the 6 and 12-week time points.
Additional prespecified supportive analyses assessed the sub-
domains of KCCQ-OS separately.
For the exploratory outcome of time to first adjudicated
HF event (HF hospitalization or urgent HF visit) a Cox propor-
tional hazard model was used to assess the effect of treatment
versus placebo on the time to first occurrence of adjudicated
HF event, adjusting for history of T2D, eGFR, and age. Safety
outcomes were assessed using descriptive statistics only, and
no P values were calculated.
Sample Size Calculations
For the dual primary biomarker end point, a sample size of
110 for each group was projected to achieve 80% power with
α=0.05 to detect a difference in mean adjusted NT-proBNP
between the 2 groups of at least 302 pg/mL from baseline to
12 weeks. The assumptions for this calculation were derived
from a previous trial where the estimated standard deviation
for NT-proBNP was 1250 pg/mL.25 For the dual primary health
status and biomarker end point, a sample size of 110 for each
group was projected to achieve 80% power with α=0.05 to
detect an absolute difference in the proportions between the
2 groups of 18% from baseline to 12 weeks. There was an
anticipated non-completion rate of approximately 13%, so
the final sample size per group was estimated at 125 patients
per treatment group.
RESULTS
Patients and Treatment
A total of 510 patients were screened, of which 263
qualified and were subsequently randomized: 131 to
dapagliflozin and 132 to placebo (Figure 1). Baseline
characteristics were not different between the 2 groups
(Table 1). Across the entire cohort, the mean age was
61.3 years, 73% were male, and 40% African American.
The mean duration of HF was 7.1 years and more than
85% had been hospitalized for HF at least once before
study enrolment. Overall, 62% (166 patients) had T2D,
and 40% had atrial fibrillation; median body mass index
was 30.6 (interquartile range (IQR), 27.5–36.3). NYHA
class II symptoms were present in 66%, with class III
symptoms in 34%. The frequency of guideline-directed
optimal medical therapy for HFrEF was high: 97% of
patients were on beta blockers, 61% on mineralocorti-
coid antagonists, 59% of patients were on angiotensin-
converting enzyme inhibitors or angiotensin receptor
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
 Nassif et al
blockers, 33% ARNI, 62% had implanted cardiac defi-
brillators, including 35% with cardiac resynchronization
therapy. The majority (86%) were on a loop diuretic.
Mean eGFR was 69 mL/min/1.73m2, and median urine
albumin creatinine ratio was 37 mg/gm. The median
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NT-proBNP level at randomization was 1136pg/mL (IQR,
615–2267 pg/mL) and mean LVEF was 26%.
Every randomized patient received at least 1 dose
of dapagliflozin or placebo. One patient in each of the
dapagliflozin and placebo groups died during the study.
Premature permanent treatment discontinuation oc-
curred in 11 patients in the dapagliflozin group, and 12
in the placebo group (see Table I in the online-only Data
Supplement which outlines detailed reasons for dis-
continuation), resulting in 119 patients in each group
completing the trial on treatment. Safety follow-up was
competed in all patients; no patients withdrew consent
or were lost to follow-up.
Primary End Points
In the intent-to-treat analysis, there was no between-
group difference in the biomarker dual primary out-
come, the average 6 and 12 week adjusted mean NT-
proBNP between patients treated with dapagliflozin
versus placebo (1133 pg/dL (95% CI, 1036–1238) vs
1191 pg/dL (95% CI 1089–1304), adjusted ratio 0.95;
95% CI 0.84–1.08, P=0.43; Figure 2A). For the second
dual primary outcome, a greater proportion of patients
treated with dapagliflozin had a clinically meaningful
improvement of ≥5 points in KCCQ-OS or at least a
20% reduction in NT-proBNP, as compared with pla-
cebo (61.5% vs 50.4%, adjusted OR 1.8, 95% CI
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
ORIGINAL RESEARCH
ARTICLE
Figure 1. Trial flow chart.
1.03–3.06, nominal P value=0.039; Figure 2B). The re-
sults were consistent within subgroups of patients with
and without T2D, as well as across all other prespeci-
fied subgroups (Figure  2B; all P values for interaction
were non-significant). The results were also consistent
when KCCQ-CS was analyzed instead of KCCQ-OS
(Figure 2B), and in the on-treatment sensitivity analyses
(Table II in the online-only Data Supplement).
Secondary End Points
A numerically greater proportion of patients treated with
dapagliflozin versus placebo had a clinically meaningful
≥5 point improvement in KCCQ-OS at 6 weeks (47% vs
36%), and 12 weeks (43% vs 33%); with adjusted odds
ratios favoring dapagliflozin both at 6 and 12 weeks
(OR 1.8, 95% CI: 1.04–3.12, P=0.03; OR 1.7, 95% CI
0.98–3.1, P=0.06, respectively). Results were similar
when using KCCQ-CS, with improvements in physical
limitations and symptoms diverging over time (KCCQ-
CS improvement of ≥5 points with dapagliflozin versus
placebo: 6 weeks, 44% vs 38%; 12 weeks: 47% vs
32%), with adjusted odds ratios favoring dapagliflozin
both at 6 and 12 weeks (OR 1.5, 95% CI 0.86–2.70,
P=0.14; OR 2.4, 95% CI 1.31–4.2, P<0.01, respective-
ly). In the supportive analyses, mean KCCQ-OS was 3.7
points higher (P=0.037), and mean KCCQ-CS was 4.6
points higher (P=0.007) at 12 weeks in patients treated
with dapagliflozin versus placebo. Three of 4 domains of
KCCQ improved significantly with dapagliflozin versus
placebo at 12 weeks (total symptoms, physical limita-
tions, quality of life), with the benefits increasing over
time (Figure 3). The only domain that did not show a sig-
xxx xxx, 2019 5
 Nassif et al Dapagliflozin in Heart Failure With Reduced Ejection Fraction

Table 1.  Baseline Characteristics

ORIGINAL RESEARCH

Baseline Characteristics Dapagliflozin (n=131) Placebo (n=132) P Value

Demographics
ARTICLE

  Age, y 62.2±11.0 60.4±12.0 0.21

  Male 95 (72.5%) 98 (74.2%) 0.75
  White 74 (59.7%) 70 (55.6%) 0.76
  African American 47 (37.9%) 52 (41.3%)
Medical history
  Duration of heart failure, y 7.1±5.8 7.2±6.8 0.94
  Previous hospitalization for heart failure 101 (77.1%) 108 (81.8%) 0.34
  Time since last hospitalization for heart failure, y 1.4±2.3 1.9±3.1 0.22
  Ejection fraction, % 27.2±8.0% 25.7±8.2% 0.11
  Ischemic heart disease 70 (53.4%) 69 (52.3%) 0.85
  Type 2 diabetes mellitus 81 (61.8%) 85 (64.4%) 0.67
  Atrial Fibrillation 57 (43.5%) 49 (37.1%) 0.29
  ICD 88 (67.2%) 75 (56.8%) 0.08
  CRT 43 (32.8%) 25 (18.9%)
Baseline HF/CV medications
  ACEI/ARB 76 (58.0%) 80 (60.6%) 0.67
  ARNI 47 (35.9%) 38 (28.8%) 0.22
  β-blockers 130 (99.2%) 124 (93.9%) 0.04
  Hydralazine 19 (14.5%) 26 (19.7%) 0.26
  Long-acting nitrates 17 (13.0%) 22 (16.7%) 0.40
  MRA 76 (58.0%) 84 (63.6%) 0.35
  Loop diuretics 114 (87.0%) 111 (84.1%) 0.50
  Digoxin 25 (19.1%) 21 (15.9%) 0.50
  Lipid-lowering agents 107 (81.7%) 104 (78.8%) 0.56
  Anticoagulant agent 58 (44.3%) 42 (31.8%) 0.04
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Glucose lowering medications among patients with type 2 diabetes mellitus

  Insulin 42 (51.9%) 45 (52.9%) 0.89
  GLP-1RA 4 (4.9%) 1 (1.2%) 0.20
  DPP4-inhibitor 11 (13.6%) 10 (11.8%) 0.72
  Sulfonylurea 20 (24.7%) 15 (17.6%) 0.27
  Metformin 29 (35.8%) 33 (38.8%) 0.69
Physical exam
  Body mass index, median (Q1, Q3) 30.7 (27.3, 35.9) 30.6 (27.6, 36.4) 0.49
  Heart rate* 72.2±12.4 71.8±11.3 0.76
  Systolic blood pressure* 122.3±20.1 124.8±21.6 0.28
Baseline laboratory studies
  NT-proBNP, pg/mL (median Q1, Q3) 1136 (668, 2465) 1136 (545, 2049) 0.94
  BNP, pg/mL(median Q1, Q3) 288 (158, 592) 242 (138, 542) 0.99
  eGFR, mL/min/1.73m2 66.9±21.1 71.2±23.1 0.12
  Urine albumin/creatinine ratio, mg/g (median, Q1, Q3) 19.0 (7.0, 87.0) 25.0 (6.5, 103.0) 0.29
  Hemoglobin A1c, % 7.0±1.8 7.3±2.0 0.25
  Hemoglobin, g/dL 13.5±1.9 13.3±1.7 0.42
Functional measures
  NYHA Class II 91 (69.5%) 82 (62.1%) 0.21
  NYHA Class III 40 (30.5%) 50 (37.9%)
  KCCQ-OS 67.4±22.0 67.0±21.1 0.89
  KCCQ-CS 70.8±21.9 69.9±21.4 0.76
  6-minute walk distance, meters (median (Q1, Q3) 306 (243, 368) 305 (227, 372) 0.98

Values are shown as absolute numbers (percentages) and mean±SD. ACE-I indicates angiotensin converting enzyme-inhibitor; ARB, angiotensin II receptor blocker; ARNI,
angiotensin receptor-neprilysin inhibitor; BNP, B-type natriuretic peptide; CRT, creatinine; CV, cardiovascular; DPP, Dipetidyl Pepdidase; eGFR, estimated glomerular filtration
rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; ICD, internal cardiac defibrillator; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire–Overall
Summary Score; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; and NT-proBNP, N-terminal pro B-type natriuretic peptide.
*Blood pressure and heart rate measured from noninvasive cuff measurements for patients in sinus rhythm and manual pulse and blood pressure for patients in atrial fibrillation.

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 Nassif et al
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nificant difference between dapagliflozin and placebo
was the social limitations score. In the responder analy-
sis, fewer patients treated with dapagliflozin versus
placebo had deterioration, or experienced no change,
whereas greater proportion of patients treated with
dapagliflozin experienced small-moderate, moderate-
large, and very large improvements in KCCQ-OS and
KCCQ-CS (Figure 4A and 4B).
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
ORIGINAL RESEARCH
ARTICLE
Figure 2. Effects of dapagliflozin versus
placebo on the primary end points.
A, Effects of dapagliflozin vs placebo on
NT-proBNP (N-terminal pro b-type natriuretic
peptide) levels over 12 weeks. Adjusted mean
NT-proBNP values with whiskers equal to 1.5×
interquartile range. B, Proportion of patients
achieving clinically meaningful improvement in
heart failure disease-specific health status or
natriuretic peptides (overall, and within prespec-
ified subgroups).
Although there was no difference between dapagliflozin
and placebo in the proportion of patients with 20% reduc-
tion in NT-proBNP at 6 weeks (34.4 vs 33.3%; adjusted OR
1.1, 95% CI: 0.6–1.9, P=0.74), a greater proportion of pa-
tients treated with dapagliflozin experienced ≥20% reduc-
tion in NT-proBNP at 12 weeks (44.0 vs 29.4%; adjusted
OR 1.9, 95% CI: 1.1–3.3, P=0.02; Table 2). Patients treated
with dapagliflozin had greater reduction in average of 6
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 Nassif et al Dapagliflozin in Heart Failure With Reduced Ejection Fraction
ORIGINAL RESEARCH
ARTICLE
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Figure 3. Effects of dapagliflozin versus placebo on KCCQ (overall, and within specific domains).
A, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score (KCCQ-OS) over 12 weeks. B, KCCQ clinical summary score (KCCQ-CS) over 12
weeks. C, KCCQ total symptom score over 12 weeks. D, KCCQ quality of life score over 12 weeks, E, KCCQ physical limitation score over 12 weeks, F, KCCQ
social limitation score over 12 weeks.

and 12 week adjusted mean BNP versus placebo (232 pg/
dL (95% CI: 210–256) vs 268 pg/dL (95% CI: 243–296),
P=0.04; Figure II in the online-only Data Supplement). As
with NT-proBNP, while there was no difference between
dapagliflozin and placebo in the proportion of patients
with 20% decline in BNP at 6 weeks (43.5% vs 35.4%;
adjusted OR 1.5, 95% CI: 0.9–2.7, P=0.15), a greater pro-
portion of patients treated with dapagliflozin experienced
≥20% reduction in BNP at 12 weeks (50.0% vs 33.9%;
adjusted OR 2.0, 95% CI: 1.1–3.4, P=0.01; Table  2). In
the responder analysis, fewer patients treated with dapa-
gliflozin versus placebo had moderate-large increase or no
change, whereas a greater proportion of patients treated
with dapagliflozin experienced moderate-large reduction
in NT-proBNP and BNP (Figure 4C and 4D).
There was no difference in 6-minute walk distance
between dapagliflozin and placebo (adjusted mean
walk distance at week 12: 304 meters vs 301 meters;
P=0.79). There were no significant between-group dif-
ferences in weight, hemoglobin A1c, or systolic blood
pressure, although most values were numerically lower
with dapagliflozin versus placebo (Table 3). Virtually all
results were consistent within subgroups of patients
with and without T2D, and across all other subgroups
(data not shown) for all secondary end points, with all
P values for interaction being non-significant, except
for weight. Patients without T2D experienced a mean
weight reduction of -1.33 kg (95% CI -2.41 to -0.23
kg, P=0.018) with dapagliflozin versus placebo; while
patients with T2D had a mean change in weight of 0.24
kg (95% CI -0.76 to 1.25 kg, P=0.64) with dapagliflozin
versus placebo (P for interaction =0.08). The per-proto-
col sensitivity analyses demonstrated consistent results
(Table III in the online-only Data Supplement).

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 Nassif et al
Figure 4. Responder analyses of clinically meaningful changes in KCCQ and natriuretic peptides.
 A, Clinically meaningful changes in Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) with dapagliflozin vs placebo at 12 weeks. B,
Clinically meaningful changes in KCCQ clinical summary score (KCCQ-CS) with dapagliflozin vs placebo at 12 weeks. C, Clinically meaningful changes in NT-proB-
NP (N-terminal pro b-type natriuretic peptide) levels with dapagliflozin vs placebo at 12 weeks. D, Clinically meaningful changes in BNP levels with dapagliflozin vs
placebo at 12 weeks.
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Exploratory Clinical End Points
In total, there were 25 patients with adjudicated HF
events (18 hospitalizations for HF, and 7 urgent HF vis-
its) during the study period.
In the time to first event analysis, there was no sig-
nificant difference in adjudicated HF events with dapa-
gliflozin versus placebo, including hospitalization for
HF or urgent HF visits (HR 0.84, 95% CI: 0.35–1.97,
P=0.62; Table IV in the online-only Data Supplement).
Safety Outcomes
Serious adverse events and adverse events of special
interest observed with dapagliflozin and placebo are
reported in Table  4. In total, there were 85 reported
adverse events with dapagliflozin versus 82 with pla-
cebo. Adverse events leading to treatment discontinu-
ation occurred in 11 patients with dapagliflozin and
12 patients with placebo. There was 1 death in the
dapagliflozin group (<1%) caused by worsening HF,
and 1 death in the placebo group (<1%) caused by
sudden cardiac death. There were 2 transient ischemic
attacks, no myocardial infarctions, and no strokes in
the dapagliflozin group and no transient ischemic at-
tacks, 1 stroke, and 4 myocardial infarctions in the pla-
cebo group. There was 1 (<1%) event of acute kidney
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
ORIGINAL RESEARCH
ARTICLE
injury in the dapagliflozin group and 1 (<1%) in the
placebo group. The number of severe hypoglycemic
events was 1 (<1%) in the dapagliflozin group versus 1
(<1%) with placebo; both events occurred in patients
with T2D. There were no episodes of diabetic ketoaci-
dosis or amputations.
DISCUSSION
In this investigator-initiated, multi-center, double blind,
placebo-controlled trial in patients with HFrEF, with or
without T2D, treatment with dapagliflozin did not sig-
nificantly reduce the adjusted mean NT-proBNP levels
over 12 weeks as compared with placebo. However,
a greater proportion of patients treated with dapa-
gliflozin versus placebo experienced a clinically mean-
ingful improvement in health status (KCCQ-OS) or a
clinically meaningful reduction in NT-proBNP over the
treatment period, which was the second dual primary
outcome. Moreover, in secondary analyses directly as-
sessing the impact of treatment on patient reported
outcomes, dapagliflozin had favorable effects on health
status at the end of the study, especially on the KCCQ
clinical summary score (symptoms and physical func-
tion). The proportions of patients with ≥20% decrease
in NT-proBNP and BNP were also higher, and mean BNP
xxx xxx, 2019 9
 Nassif et al Dapagliflozin in Heart Failure With Reduced Ejection Fraction

Table 2.  Binary Secondary End Points at 6 and 12 Weeks for Patients Treated With Dapagliflozin Versus Placebo
ORIGINAL RESEARCH

Adjusted Odds
Binary Secondary End Points Dapagliflozin Placebo Ratio* 95% CI P Value
ARTICLE

KCCQ OS increase ≥5 points (6w) 59 (46.8%) 46 (35.9%) 1.83 1.04, 3.21 0.03
KCCQ OS increase ≥5 points (12w) 54 (42.9%) 41 (32.5%) 1.73 0.98, 3.05 0.06
KCCQ CS increase ≥5 points (6w) 56 (44.4%) 49 (38.3%) 1.53 0.86, 2.72 0.15
KCCQ CS increase ≥5 points (12w) 59 (46.8%) 40 (31.7%) 2.35 1.31, 4.22 <0.01
NT-proBNP decrease ≥20% (6w) 43 (34.4%) 42 (33.3%) 1.10 0.63, 1.92 0.74
NT-proBNP decrease ≥20% (12w) 55 (44.0%) 37 (29.4%) 1.90 1.09, 3.31 0.02
BNP decrease ≥20% (6w) 54 (43.5%) 45 (34.5%) 1.52 0.86, 2.67 0.15
BNP decrease ≥20% (12w) 62 (50.0%) 42 (33.9%) 1.99 1.15, 3.45 0.01

Values are shown as absolute numbers (percentages) for the binary outcomes, with odds ratios and 95 percent confidence intervals; *adjusted for corresponding
baseline value, history of type 2 diabetes mellitus, age and baseline estimated glomerular filtration rate. BNP indicates B-type natriuretic peptide; KCCQ CS, Kansas
City Cardiomyopathy Questionnaire clinical summary score; KCCQ OS, Kansas City Cardiomyopathy Questionnaire overall summary score; and NT-proBNP, N-terminal
pro B-type natriuretic peptide.

levels were lower, in patients treated with dapagliflozin
by the end of the treatment period.
Responder analyses, especially when using KCCQ-
CS, which quantifies both symptoms and physical limi-
tations, indicated that a higher proportion of patients
treated with dapagliflozin experienced small-moder-
ate, moderate-large, and very large improvements, and
fewer patients treated with dapagliflozin experienced
deterioration or no change in health status. Health sta-
tus improvements with dapagliflozin versus placebo
were seen across all KCCQ domains, except for the
social limitations score. Similar effects of dapagliflozin
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treated patients experiencing substantial increase or
no change, and greater proportions of dapagliflozin-
treated patients experiencing substantial reductions
in natriuretic peptides versus placebo. These analyses
used a threshold of 20% or greater change; based on
previous studies which demonstrated that change in
the excess of 20% demonstrates more than random
or physiologic variation in NT-proBNP, correlates with
echocardiographic markers of adverse left ventricular
remodeling, and is associated with clinical events in
patients with established HF.22–24 Notably, these results
were achieved in the context of high rates of back-

versus placebo were seen in the responder analyses ex- ground guideline-directed optimal medical therapy
amining NT-proBNP and BNP with fewer dapagliflozin- for HFrEF, including >95% patients treated with beta

Table 3.  Continuous Secondary End Points at 6 and 12 Weeks for Patients Treated With Dapagliflozin Versus Placebo

Continuous Secondary End Points Dapagliflozin Placebo P Value

NT-proBNP, adjusted mean, pg/ml (6w)* 1159 (1050, 1279) 1180 (1068, 1304) 0.80
NT-proBNPm adjusted mean, pg/ml (12w)* 1108 (1003, 1223) 1203 (1088, 1329) 0.25
BNP, adjusted mean, pg/ml (6w)* 236 (212, 263) 265 (238, 296) 0.14
BNP, adjusted mean, pg/ml (12w)* 228 (204, 254) 272 (243, 303) 0.03
KCCQ OS, adjusted mean (6w)* 71.1 (68.7, 73.5) 70.1 (67.7, 72.5) 0.58
KCCQ OS, adjusted mean (12w)* 72.6 (70.2, 75.0) 68.9 (66.5, 71.4) 0.04
KCCQ CS, adjusted mean (6w)* 75.2 (72.8, 77.5) 72.8 (70.5, 75.2) 0.17
KCCQ CS, adjusted mean (12w)* 75.0 (72.6, 77.3) 70.4 (68.0, 72.7) <0.01
Six-minute walk distance, adjusted mean m (6w)* 297.1 (285.1, 309.6) 289.6 (278.0, 301.7) 0.39
Six-minute walk distance, adjusted mean m (12w)* 303.7 (291.2, 316.7) 301.3 (289.1, 313.9) 0.79
Hemoglobin A1c, adjusted mean % (6w)* 6.9 (6.8, 7.1) 7.1 (7.0, 7.2) 0.09
Hemoglobin A1c, adjusted mean % (12w)* 6.9 (6.8, 7.1) 7.1 (7.0, 7.2) 0.13
Systolic blood pressure, adjusted mean mm Hg (6w)* 119.2 (116.6, 121.9) 121.1 (118.5, 123.7) 0.32
Systolic blood pressure, adjusted mean mm Hg (12w)* 120.9 (118.2, 123.5) 119.8 (117.2, 122.4) 0.59
Weight, adjusted mean kg (6w)* 96.0 (95.4, 96.5) 96.4 (95.8, 96.9) 0.33
Weight, adjusted mean kg (12w)* 96.3 (95.7, 96.8) 96.6 (96.0, 97.1) 0.46

Values are shown as adjusted means (95 percent confidence intervals) for continuous variables. BNP indicates B-Type Natriuretic Peptide; KCCQ CS, Kansas City
Cardiomyopathy Questionnaire clinical summary score; KCCQ OS, Kansas City Cardiomyopathy Questionnaire overall summary score; and NT-proBNP, N-Terminal
Pro B-Type Natriuretic Peptide.
*Adjusted for corresponding baseline value, history of type 2 diabetes mellitus, age, and baseline estimated glomerular filtration rate.

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 Nassif et al Dapagliflozin in Heart Failure With Reduced Ejection Fraction

Table 4.  Safety Analyses the ability to prevent HF hospitalizations in high-risk

ORIGINAL RESEARCH
Dapagliflozin patients with T2D, with these cardiovascular benefits
(n=131) Placebo (n=132) having little to do with their effect on plasma glucose

ARTICLE
All-cause death 1 (0.8%) 1 (0.8%) or HbA1c. Whether this class of medications can also
Cardiovascular death 1 (0.8%) 1 (0.8%) effectively improve prognosis and symptom burden in
Nonfatal MI 0 (0.0%) 4 (3.0%)
patients with established HF (specifically HFrEF) was not
previously explored. Moreover, whether they would be
Stroke 0 (0.0%) 1 (0.8%)
helpful in patients without T2D was also not established.
Acute kidney injury 1 (0.8%) 1 (0.8%)
While large HF outcomes trials are currently underway
Diabetic ketoacidosis 0 (0.0%) 0 (0.0%) with several agents in the class, DEFINE-HF is the first
Volume depletion event 12 (9.2%) 7 (5.3%) randomized controlled trial to explore the early effects
Severe hypoglycemic event 1 (0.8%) 1 (0.8%) of an SGLT-2i on natriuretic peptides and health status.
Lower limb amputation 0 (0.0%) 0 (0.0%) The 3.7 point mean improvement in KCCQ-OS and
4.6 point mean improvement in KCCQ-CS with dapa-
Drug adverse event 3 (2.3%) 3 (2.3%)
gliflozin versus placebo after 12 weeks of treatment
AE leading to study drug 11 (8.4%) 12 (9.1%)
discontinuation
compare favorably with the 2 most recently approved
therapies for HFrEF. Specifically, ivabradine demon-
Serious adverse event 30 (22.9%) 24 (18.2%)
strated a 2.6 point mean improvement in KCCQ-OS,
Values are shown as absolute numbers (percentages) for patients with and 1.9 point mean improvement in KCCQ-CS over 22
events. AE indicates adverse event; and MI, myocardial infarction.
months of treatment, and ARNI demonstrated 1.3 and
0.9 point improvements in KCCQ-OS and KCCQ-CS,
blockers, 33% on ARNI, 59% on angiotensin-convert- respectively, after 8 months of treatment.27,28
ing enzyme inhibitors/angiotensin receptor blockers, There are several reasons that may explain why
and over 60% on mineralocorticoid antagonists, as dapagliflozin did not significantly reduce the first dual
well as frequent use of devices, including cardiac resyn- primary outcome (mean adjusted NT-proBNP) while
chronization therapy. There were modest numeric im- it did improve the second primary outcome (clinically
provements in weight, HbA1c, systolic blood pressure, meaningful changes in NT-proBNP and health status).
and 6-minute walk distance in patients treated with SGLT-2i exert modest osmotic diuretic effect by prevent-
ing glucose reabsorption in the proximal tubule, and
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dapagliflozin versus placebo, but none of these were

statistically significant. No statistical heterogeneity in
the effects of dapagliflozin was observed among pa-
tients with or without T2D, or across other subgroups.
Finally, no imbalance was seen across safety events, al-
though the number of events was small.
Patients with HFrEF represent a vulnerable popula-
tion with high symptom burden, reduced quality of life,
and high event rates, including HF hospitalizations and
death. Despite advances in therapeutic options, these
patients remain at high risk for symptomatic progres-
sion and clinical deterioration. While several treatments
have been shown to improve death or rehospitalization
rates in patients with HFrEF, most have shown neutral
effects on (beta blockers),26 or modest improvements in
(angiotensin-converting enzyme inhibitors),27 health sta-
tus, resulting in a large unmet clinical need for agents
that not only improve prognosis but also have a favor-
able effect on symptoms, physical function, and quality
of life. Notably, patient health status has been increas-
ingly recognized by practice guidelines and regulators
as an important therapeutic target, and the recently re-
leased Food and Drug Administration draft guidance on
drug development in heart failure has formally endorsed
measures of patients’ symptoms and physical function
as acceptable, and important, end points.8 SGLT-2i are a
promising class of agents in HF, that were initially devel-
oped as glucose-lowering medications but have shown
may have several other potential mechanisms through
which HF-related benefits may be mediated.29 While
this could decrease intra-cardiac pressures and lower
NT-proBNP, the variability of this biomarker in patients
with established HFrEF and high NT-proBNP levels at
baseline, precluded the detection of anything less than
a very large change. Specifically, our observed baseline
NT-proBNP standard deviation of approximately 2300
pg/mL was much greater than our a priori estimate
(1250 pg/mL), with this greater variability likely increas-
ing noise-to-signal ratio and negatively impacting the
power for the mean NT-proBNP analyses. Further but-
tressing this explanation is our finding of a larger pro-
portion of patients having a clinically meaningful ≥20%
reduction in NT-proBNP (and BNP) levels at the end of
the study, results that were highly consistent in the NT-
proBNP and BNP responder analyses.20 More impor-
tantly, from the patients’ perspective, treatment with
dapagliflozin improved symptoms, physical limitations,
and quality of life, effects which were amplified over
time. In fact, given the pathophysiologic mechanisms
by which dapagliflozin would be expected to impact
patients’ experiences of HF, it is not surprising that
these measures improved more rapidly than the social
limitation scale (included in KCCQ-OS, but not KCCQ-
CS). Following these patients over a longer period may
have led to greater improvements in the latter domain,

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 Nassif et al
as the benefits of fewer symptoms, less physical limita-
ORIGINAL RESEARCH
tions, and better quality of life become more apparent
to patients in their social activities.
ARTICLE
Despite the large improvement in patient reported
physical limitations because of HF with dapagliflozin
versus placebo (based on KCCQ physical limitations do-
main), we did not observe a corresponding significant
improvement in 6-minute walking distance. There are
several potential explanations for this seeming discrep-
ancy. First (and most likely) reason is that the 6-minute
walk test is more heavily dependent on the effort of the
operator and the patient at 1 point in time (the day of
the clinic visit), which may potentially create significant
variability, and make it more difficult to standardize.
Second, comorbidities unrelated to heart failure (such
as orthopedic limitations) can affect 6-minute walking
distance even if HF-related physical limitations have im-
proved. In contrast, KCCQ is only dependent on the
patient (self-standardized), has a 2-week recall period,
and it is specific to HF-related physical limitations. Third,
while there is a correlation between change in 6-minute
walking distance and change in KCCQ, it is a relatively
modest correlation (r=0.28).30 Finally, it may take time
for the patient perception of less physical limitations
(KCCQ) to translate to a better objective measurement
of physical function (6-minute walking distance).
Dapagliflozin demonstrated a reassuring safety pro-
file, consistent with previous studies. Dapagliflozin was
well tolerated with only 11 of 131 patients stopping
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drug because of adverse events, which was similar to
the number of patients that stopped placebo. These
safety data are important, as DEFINE-HF is one of the
first rigorous studies to report on the tolerability of SGLT-
2i for patients without T2D. Indeed, there have been
potential concerns with volume depletion in patients
with HFrEF on high doses of loop diuretics; however,
we found only a small numerical increase in volume
depletion events with dapagliflozin (12 total events vs 7
with placebo). Likewise, we did not observe any imbal-
ance in severe hypoglycemic events in patients with or
without T2D, although investigators were encouraged
to consider a modest reduction in the dose of insulin
or sulfonylureas in those entering the trial with HbA1c
already tightly controlled (a strategy that may also be
adopted in clinical practice). It is also reassuring that
we did not observe any events of diabetic ketoacidosis
(although the duration of the study was short and pa-
tients with type-1 diabetes mellitus were excluded) or
lower limb amputations.
There are several key attributes of the DEFINE-HF
Trial that deserve to be highlighted. A substantial pro-
portion of the patients were African American, a popu-
lation traditionally under-represented in clinical trials.
We observed a high rate of optimal guideline directed
medical therapy, including a third of patients on ARNI,
and frequent use of cardiac resynchronization therapy,
12 xxx xxx, 2019
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
which allowed an appropriate interpretation of the ef-
fects SGLT-2i on HF-related health status and natriuretic
peptides on top of state-of-the art guideline-directed
medical and device therapy for HFrEF. Furthermore, we
ensured high adherence to study procedures, with a
small proportion of patients prematurely discontinuing
assigned treatments, and 100% completing the study,
with no withdrawals of consent or loss to follow-up.
Finally, and perhaps most importantly, this is the first
time that early clinical cardiovascular benefits from this
emerging class of medications have been observed in
HF patients without T2D.
Despite the strengths in study design and execution,
our findings should be interpreted in the context of sev-
eral potential limitations. DEFINE-HF was not powered
to evaluate effects on HF hospitalizations or mortality.
Second, its short duration of follow up precludes an
assessment on the durability of the observed benefit
on HF disease-specific health status. Third, all patients
were enrolled at sites in the US, and while this makes
the study applicable to the US population with HFrEF,
its generalizability outside the US is uncertain. Large
outcome trials, including DAPA-HF (Study to Evaluate
the Effect of Dapagliflozin on the Incidence of Wors-
ening Heart Failure or Cardiovascular Death in Patients
with Chronic Heart Failure; NCT03036124), EMPER-
OR-Reduced (Empagliflozin Outcome Trial in Patients
With Chronic Heart Failure With Reduced Ejection
Fraction; NCT 03057977) and SOLOIST-WHF (Effect of
Sotagliflozin on Cardiovascular Events in Patients With
Type 2 Diabetes Post Worsening Heart Failure; NCT
03521934) will ultimately address these limitations.
Conclusion
Among patients with HFrEF with and without T2D re-
ceiving optimal guideline directed medical therapy, the
addition of dapagliflozin for 12 weeks did not affect
the mean NT-proBNP but significantly increased the
proportion of patients experiencing clinically meaning-
ful improvements in HF disease-specific health status
and natriuretic peptides.
ARTICLE INFORMATION
Received July 25, 2019; accepted August 20, 2019.
The online-only Data Supplement is available with this article at https://
www.ahajournals.org/doi/suppl/10.1161/circulationaha.119.042929.
Authors
Michael E. Nassif, MD; Sheryl Windsor, BS; Fengming Tang, MS; Yevgeniy
Khariton, MD; Mansoor Husain, MD; Silvio Inzucchi, MD; Darren McGuire,
MD; Bertram Pitt, MD; Benjamin Scirica, MD; Bethany Austin, MD; Mark
Drazner, MD; Michael Fong, MD; Michael Givertz, MD; Robert Gordon, MD;
Rita Jermyn, MD; Stuart Katz, MD; Sumant Lamba, MD; David Lanfear, MD;
Shane LaRue, MD; JoAnn Lindenfeld, MD; Michael Malone, MD; Kenneth
Margulies, MD; Robert Mentz, MD; R. Kannan Mutharasan, MD; Michael
Pursley, MD; Guillermo Umpierrez, MD; Mikhail Kosiborod, MD; On behalf of
the DEFINE-HF Investigators
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
 Nassif et al
Correspondence
Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, 4401 Wornall
Rd, Kansas City, MO 64111. Email mkosiborod@saint-lukes.org
Affiliations
Saint Luke’s Mid America Heart Institute, Kansas City, MO (M.E.N., S.W., F.T.,
Y.K., B.A., M.K.). University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A.,
M.K.). Toronto General Hospital Research Institute, University Health Network,
Toronto, Canada (M.H.). Ted Rogers Centre for Heart Research, Toronto, Can-
ada (M.H.). University of Toronto, Canada (M.H.). Peter Munk Cardiac Centre,
Toronto, Canada (M.H). Yale University School of Medicine, New Haven, CT
(S.I.). University of Texas Southwestern Medical Center, Dallas (D.M., M.D.).
University of Michigan School of Medicine, Ann Arbor (B.P.). Brigham and
Women’s Hospital, Boston, MA (B.S., M.G.). University of Southern California,
Los Angeles (M.F.). NorthShore University, Evanston, IL (R.G.). St. Francis Hospi-
tal, New York, NY (R.J.). New York University Langone Health, New York (S.K.).
First Coast Cardiovascular Institute, Jacksonville, FL (S.L.). Henry Ford Hospital,
Detroit, MI (D.L.). Washington University School of Medicine, St. Louis, MO
(S.L.). Vanderbilt University, Nashville, TN (J.L.). Charlotte Heart Group Research
Center, Port Charlotte, FL (M.M.). University of Pennsylvania, Philadelphia
(K.M.). Duke University, Durham, NC (R.M.). Northwestern University, Chicago,
IL (R.K.M.). Heart Group of the Eastern Shore, Fairhope, AL (M.P.). Emory Uni-
versity, Atlanta, GA (G.U.). The George Institute for Global Health, Sydney, Aus-
tralia (M.K.). University of New South Wales, Sydney, Australia (M.K.).
Acknowledgments
We thank Hunter Brandt, Sharon Chavis, Cheryl Cangemi, Karry Calderon,
Stanley Cobos, Matthew Fink, Caroline Foster, Rosann Gans, Ellen Hathcock,
Patricia Hendershot, Mary Hudson, Jessica Huckleberry, Carolyn Kelly, Latreina
Koonce, Zack Malouf, Jennifer Marshall, Robinson Mendoza, Morgan Moore,
Karen Mullinax, Navdeep Nayyar, Kelsey Neaton, Ngozi Okafor, Kimberly Pap-
rockas, Diane Peterman, Linda Pierchala, Kirsten Quiles, Melissa Ramos, Mary
Reed, Michaela Ritz, Sindy Roche, Daniel Roshevsky, Sevinj Sasunova, Rosanne
Schenks, Virginia Schmidt, Mary Sheehan, Ruth Sorg, Marlo Sierra, Emily Tem-
poni, Bernardo Vargas, Pamela Williams, and Jennifer Wilson.
Downloaded from http://ahajournals.org by on October 7, 2019
Sources of Funding
The study was an investigator-initiated trial funded by AstraZeneca and con-
ducted by Saint Luke’s Mid America Heart Institute independent of the funding
source.
Disclosures
Dr Kosiborod: Grant/Research Support; Company Relationship; Astra Zeneca,
Boehringer Ingelheim. Honoraria; Company Relationship; Astra Zeneca, Boeh-
ringer Ingelheim, Novo Nordisk. Consultant; Company Relationship; Amarin,
Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Eisai,
Glaxo Smith Kline, Glytec, Intarcia, Janssen, Merck (diabetes), Novartis, Novo
Nordisk, Sanofi Aventis. Dr Nassif: Honoraria; Company Relationship; Abbott.
Dr Umpierrez: Grant/Research Support; Company Relationship; Dr Umpierrez is
partly supported by research grants from the Public Health Service Grant Number
UL1TR002378 from the Clinical and Translational Science Award program, and
1P30DK111024-01 from the National Inst, Dr Umpierrez has received unrestrict-
ed research support for inpatient studies (to Emory University) from Novo Nordisk,
Sanofi, and Dexcom. Dr Lamba: Speaker’s Bureau; Company Relationship; Ab-
bott Medical. Dr Katz: Grant/Research Support; Company Relationship; Astra Ze-
neca, Pfizer, Luitpold, Biocardia, Sanofi Aventis. Consultant; Company Relation-
ship; Merck. Dr Husain: Grant/Research Support; Company Relationship; Astra
Zeneca, Merck, Novo Nordisk. Consultant; Company Relationship; Astra Zeneca,
Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Roche. Patents; Company
Relationship; Dr Husain has a patent US61/721,819, United States pending, and
a patent US61/719,075, United States, and EP2911686A1, European Patent Of-
fice, pending. Dr Inzucchi: Grant/Research Support; Company Relationship; Dr
Inzucchi has participated on clinical trial steering, executive or publications com-
mittees including related lectures for Boehringer Ingelheim, Astra-Zeneca, Novo
Nordisk, Sanofi/Lexicon, Eisai. Honoraria; Company Relationship; Boehringer
Ingelheim, Astra Zeneca, Novo Nordisk, Sanofi/Lexicon, Easai. Consultant; Com-
pany Relationship; Astra Zeneca, vTv Therapeutics, Merck, Zafgen, Abbott. Dr
McGuire: Grant/Research Support; Company Relationship; Clinical trial leader-
ship: GlaxoSmithKline, Janssen, Lexicon, AstraZeneca, Sanofi Aventis, Boehringer
Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai Inc., Esperion, Lilly USA. Con-
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
sultant; Company Relationship; Astra Zeneca, Lilly USA, Boehringer Ingelheim,
Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi Aventis. Dr
ORIGINAL RESEARCH
Pitt: Consultant; Company Relationship; Astra Zeneca, Bayer, Sanofi Aventis,
Vifor, Sarfez, KBP pharmaceuticals, scPharmaceuticals, Cereno. Stock or Stock
ARTICLE
Options; Company Relationship; Vifor, Sarfez, KBP Pharmaceuticals, scPharma-
ceuticals, Cereno. Patents; Company Relationship; US patent # 9931412-site
specific delivery of eplerenone to the myocardium. Dr Scirica: Grant/Research
Support; Company Relationship; Dr Scirica reports research grants via Brigham
and Women’s Hospital from AstraZeneca, Eisai, Novartis, and Merck, member
of the TIMI Study Group which has received institutional research grant support
through Brigham and Women’s Hospital in the past 36 months from: Abbott,
Amgen, Aralez, AstraZeneca, Bayer Health, Pharmaceuticals, Inc., BRAHMS,
Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck,
Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines
Company, Zora B. Consultant; Company Relationship; AbbVie, Allergan, Astra
Zeneca, Boehringer Ingelheim, Covance, Eisai, Elsevier Practice Update Cardiol-
ogy, Glaxo Smith Kline, Lexicon, Medtronic, Merck, NovoNordisk, Sanofi Aventis,
Equity in Health [at] scale. Dr Mutharasan: Consultant; Company Relationship;
GE Healthcare. Dr Givertz: Consultant; Company Relationship; Merck. Dr Jer-
myn: Speaker’s Bureau; Company Relationship; Novartis. Dr Lindenfeld: Grant/
Research Support; Company Relationship; Astra Zeneca. Consultant; Company
Relationship; Abbott, Astra Zeneca, Boehringer Ingelheim, Edwards Lifesciences,
CVRx, Impulse Dynamics, Relypsa, VWave. Dr Margulies: Grant/Research Sup-
port; Company Relationship; GlaxoSmithKline, Merck Sharp and Dohme, Sanofi-
Aventis USA. Consultant; Company Relationship; American Reagent Pharmaceu-
ticals (formerly Luitipold), MyoKardia, Inc. Dr Mentz: Grant/Research Support;
Company Relationship; National Institutes of Health (U01HL125511-01A1 and
R01AG045551-01A1), Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline,
Gilead, InnoLife, Luitpold/American Regent, Medtronic, Merck, Novartis, Sanofi.
Honoraria; Company Relationship; Abbott, Amgen, AstraZeneca, Bayer, Boston
Scientific, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Sanofi.
Consultant; Company Relationship; Amgen, AstraZeneca, Luitpold, Merck, No-
vartis, Boehringer Ingelheim. The other authors report no conflicts.
APPENDIX
DEFINE-HF Investigators
Saint Luke’s Mid America Heart Institute: Ali Malik, MD
Emory University: Nannette Wenger, MD; Modele Ogunniyi, MD; Priyathama
Vellanki, MD
First Coast Cardiovascular Institute: Brenda Murphy, APRN-BC
New York University Langone Health: Jonathan Newman, MD
Washington University: Justin Hartupee, MD
NorthShore University: Charu Gupta, MD; Marcela Goldsmith, APN
Truman Medical Center: Paramdeep Baweja, MD
Eastern Nephrology Associates: Manuel Montero, MD
University of Maryland: Steve Gottlieb, MD
Chicago Advocate Health and Hospitals: Maria Rosa Costanzo, MD
Walter Reed National Military Medical Center: Thanh Hoang, MD; Alicia
Warnock, MD
University of Colorado: Larry Allen, MD
Cleveland Clinic Foundation: Wilson Tang, MD
Mayo Clinic (Rochester): Horng Chen, MD
Freeman Medical Center: John Cox, MD
REFERENCES
1. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW,
Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, et al; Ameri-
can Heart Association Council on Epidemiology and Prevention Statistics
Committee and Stroke Statistics Subcommittee. Heart disease and stroke
statistics-2019 update: a report from the American Heart Association. Cir-
culation. 2019;139:e56–e528. doi: 10.1161/CIR.0000000000000659
2. Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC,
Ikonomidis JS, Khavjou O, Konstam MA, Maddox TM, et al; American
Heart Association Advocacy Coordinating Committee; Council on Arte-
riosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascu-
lar Radiology and Intervention; Council on Clinical Cardiology; Council
on Epidemiology and Prevention; Stroke Council. Forecasting the im-
pact of heart failure in the United States: a policy statement from the
American Heart Association. Circ Heart Fail. 2013;6:606–619. doi:
10.1161/HHF.0b013e318291329a
xxx xxx, 2019 13
 Nassif et al
3. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart
failure. Nat Rev Cardiol. 2011;8:30–41. doi: 10.1038/nrcardio.2010.165
ORIGINAL RESEARCH
4. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
Shi VC, Solomon SD, Swedberg K, et al; PARADIGM-HF Investigators and
ARTICLE
Committees. Angiotensin-neprilysin inhibition versus enalapril in heart fail-
ure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077
5. Reddy P, Dunn AB. The effect of beta-blockers on health-related quality
of life in patients with heart failure. Pharmacotherapy. 2000;20:679–689.
doi:10.1592/phco.20.7.679.35178
6. Tsevat J, Weeks JC, Guadagnoli E, Tosteson AN, Mangione CM, Pliskin JS,
Weinstein MC, Cleary PD. Using health-related quality-of-life information:
clinical encounters, clinical trials, and health policy. J Gen Intern Med.
1994;9:576–582. doi: 10.1007/bf02599287
7. Lewis EF, Johnson PA, Johnson W, Collins C, Griffin L, Stevenson LW. Pref-
erences for quality of life or survival expressed by patients with heart fail-
ure. J Heart Lung Transplant. 2001;20:1016–1024. doi: 10.1016/S1053-
2498(01)00298-4
8. US FDA. Treatment for Heart Failure: Endpoints for Drug Development
Guidance for Industry. https://wwwfdagov/regulatory-information/search-
fda-guidance-documents/treatment-heart-failure-endpoints-drug-devel-
opment-guidance-industry. 2019.
9. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM,
Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular
risk: proposed pathways and review of ongoing outcome trials. Diab Vasc
Dis Res. 2015;12:90–100. doi: 10.1177/1479164114559852
10. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N,
Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative
Group. Canagliflozin and cardiovascular and renal events in type 2 diabe-
tes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925
11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S,
Mattheus M, Devins T, Johansen OE, Woerle HJ, et al; EMPA-REG OUT-
COME Investigators. Empagliflozin, cardiovascular outcomes, and mor-
tality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi:
10.1056/NEJMoa1504720
12. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG,
Zelniker TA, Kuder JF, Murphy SA, et al; DECLARE–TIMI 58 Investigators.
Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J
Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389
Downloaded from http://ahajournals.org by on October 7, 2019
13. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM,
Edwards R, Agarwal R, Bakris G, Bull S, et al; CREDENCE Trial Investiga-
tors. Canagliflozin and renal outcomes in type 2 diabetes and nephropa-
thy. N Engl J Med. 2019;380:2295–2306. doi: 10.1056/NEJMoa1811744
14. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE,
Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME® trial investiga-
tors. Heart failure outcomes with empagliflozin in patients with type 2
diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME®
trial. Eur Heart J. 2016;37:1526–1534. doi: 10.1093/eurheartj/ehv728
15. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M,
Schmoor C, Ohneberg K, Johansen OE, George JT, et al. How does empa-
gliflozin reduce cardiovascular mortality? Insights from a mediation analy-
sis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:356–363.
doi: 10.2337/dc17-1096
16. Januzzi JL Jr, Butler J, Jarolim P, Sattar N, Vijapurkar U, Desai M,
Davies MJ. Effects of canagliflozin on cardiovascular biomarkers in older
adults with type 2  diabetes. J Am Coll Cardiol. 2017;70:704–712. doi:
10.1016/j.jacc.2017.06.016
17. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN,
Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, et
14 xxx xxx, 2019
Dapagliflozin in Heart Failure With Reduced Ejection Fraction
al; DAPA-HF Committees and Investigators. A trial to evaluate the effect
of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbid-
ity and mortality in patients with heart failure and reduced left ventricu-
lar ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21:665–675. doi:
10.1002/ejhf.1432
18. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evalu-
ation of the Kansas City Cardiomyopathy Questionnaire: a new health
status measure for heart failure. J Am Coll Cardiol. 2000;35:1245–1255.
doi: 10.1016/s0735-1097(00)00531-3
19. Nair DR, Mehta S, Mikhailidis DP. Assessing renal function - searching
for the perfect marker continues! Arch Med Sci. 2011;7:565–567. doi:
10.5114/aoms.2011.24120
20. Araújo JP, Azevedo A, Lourenço P, Rocha-Gonçalves F, Ferreira A and
Bettencourt P. Intraindividual variation of amino-terminal pro-B-type na-
triuretic peptide levels in patients with stable heart failure. Am J Cardiol.
2006;98:1248-1250. doi: 10.1016/j.amjcard.2006.06.017
21. Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P,
McCullough PA, Pina I, Tooley J, Weintraub WS, et al; Cardiovascular Out-
comes Research Consortium. Monitoring clinical changes in patients with
heart failure: a comparison of methods. Am Heart J. 2005;150:707–715.
doi: 10.1016/j.ahj.2004.12.010
22. Schou M, Gustafsson F, Nielsen PH, Madsen LH, Kjaer A, Hildebrandt PR.
Unexplained week-to-week variation in BNP and NT-proBNP is low in chron-
ic heart failure patients during steady state. Eur J Heart Fail. 2007;9:68–
74. doi: 10.1016/j.ejheart.2006.05.001
23. Schou M, Gustafsson F, Kjaer A, Hildebrandt PR. Long-term clinical varia-
tion of NT-proBNP in stable chronic heart failure patients. Eur Heart J.
2007;28:177-182. doi:10.1093/eurheartj/ehl449
24. Miller WL, Hartman KA, Grill DE, Burnett JC, Jaffe AS. only large reductions
in concentrations of natriuretic peptides (BNP and NT-proBNP) are associ-
ated with improved outcome in ambulatory patients with chronic heart
failure. Clin Chem. 2009;55:78-84. doi:10.1373/clinchem.2008.108928
25. Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A,
Yandle TG, Hamid AK, Nicholls MG, Richards AM. N-terminal pro-B-type
natriuretic peptide-guided treatment for chronic heart failure: results from
the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Car-
diac Readmissions and Death) trial. J Am Coll Cardiol. 2009;55:53–60.
doi: 10.1016/j.jacc.2009.02.095
26. Dobre D, van Jaarsveld CH, deJongste MJ, Haaijer Ruskamp FM,
Ranchor AV. The effect of beta-blocker therapy on quality of life in heart
failure patients: a systematic review and meta-analysis. Pharmacoepide-
miol Drug Saf. 2007;16:152–159. doi: 10.1002/pds.1234
27. Lewis EF, Claggett BL, McMurray JJV, Packer M, Lefkowitz MP, Rouleau JL,
Liu J, Shi VC, Zile MR, Desai AS, et al. Health-related quality of life out-
comes in PARADIGM-HF. Circ Heart Fail. 2017;10:e003430. doi: 10.1161/
CIRCHEARTFAILURE.116.003430
28. Ekman I, Chassany O, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L,
Swedberg K. Heart rate reduction with ivabradine and health relat-
ed quality of life in patients with chronic heart failure: results from
the SHIFT study. Eur Heart J. 2011;32:2395–2404. doi: 10.1093/
eurheartj/ehr343
29. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascu-
lar benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–2117.
doi: 10.1007/s00125-018-4670-7
30. Flynn KE, Lin L, Moe GW, Howlett JG, Fine LJ, Spertus JA, McConnell TR,
Piña IL, Weinfurt KP. Relationships between changes in patient-reported
health status and functional capacity in outpatients with heart failure. Am
Heart J. 2012;163:88–94.e3. doi: 10.1016/j.ahj.2011.09.027
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929