T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Original Article

Dapagliflozin in Heart Failure with Mildly
Reduced or Preserved Ejection Fraction
S.D. Solomon, J.J.V. McMurray, B. Claggett, R.A. de Boer, D. DeMets,
A.F. Hernandez, S.E. Inzucchi, M.N. Kosiborod, C.S.P. Lam, F. Martinez,
S.J. Shah, A.S. Desai, P.S. Jhund, J. Belohlavek, C.-E. Chiang, C.J.W. Borleffs,
J. Comin‑Colet, D. Dobreanu, J. Drozdz, J.C. Fang, M.A. Alcocer‑Gamba,
W. Al Habeeb, Y. Han, J.W. Cabrera Honorio, S.P. Janssens, T. Katova,
M. Kitakaze, B. Merkely, E. O’Meara, J.F.K. Saraiva, S.N. Tereshchenko, J. Thierer,
M. Vaduganathan, O. Vardeny, S. Verma, V.N. Pham, U. Wilderäng,
N. Zaozerska, E. Bachus, D. Lindholm, M. Petersson, and A.M. Langkilde,
for the DELIVER Trial Committees and Investigators*​​

A BS T R AC TBACKGROUND

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart
failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction
remains less certain.

The authors’ full names, academic degrees, and affiliations are listed in the
Appendix. Dr. Solomon can be contacted
at ­ssolomon@​­bwh​.­harvard​.­edu or at theCardiovascular Division, Brigham and
Women’s Hospital, 75 Francis St., Boston,
MA 02115.

METHODS* A complete list of the DELIVER trial investigators is provided in the Supplementary Appendix, available at NEJM.org.

We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once
daily) or matching placebo, in addition to usual therapy. The primary outcome wasa composite of worsening heart failure (which was defined as either an unplanned
hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.

This article was published on August 27,
2022, at NEJM.org.
DOI: 10.1056/NEJMoa2206286
Copyright © 2022 Massachusetts Medical Society.

RESULTSOver a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients(16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001).
Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozingroup and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95%
CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261
patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total eventsand symptom burden were lower in the dapagliflozin group than in the placebogroup. Results were similar among patients with a left ventricular ejection fractionof 60% or more and those with a left ventricular ejection fraction of less than 60%,
and results were similar in prespecified subgroups, including patients with orwithout diabetes. The incidence of adverse events was similar in the two groups.
CONCLUSIONS

Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved
ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number,
NCT03619213.)n engl j med﻿﻿  nejm.org﻿

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Sodium–glucose cotransporter 2(SGLT2) inhibitors, which were originallydeveloped as glucose-lowering agents forthe treatment of type 2 diabetes mellitus, reduce
the risk of death and other adverse outcomesamong patients with chronic heart failure anda reduced ejection fraction (i.e., a left ventricular ejection fraction of ≤40%) and in those withchronic kidney disease, regardless of the presence or absence of type 2 diabetes mellitus.1-3
Current clinical guidelines strongly recommend
the use of SGLT2 inhibitors in patients withchronic heart failure and a reduced ejection
fraction.4
Few pharmacologic treatment options exist
for patients with heart failure and a mildly reduced or preserved left ventricular ejection fraction.5,6 Recently, treatment with the SGLT2 inhibitor empagliflozin was shown to reduce the
combined risk of hospitalization for heart failure or cardiovascular death among patients withheart failure and a left ventricular ejection fraction of more than 40%, a finding that suggeststhat the benefits of SGLT2 inhibition may extend
to all patients with heart failure, regardless of
the left ventricular ejection fraction.7 The benefit, which was driven by a reduction in hospitalization for heart failure, appeared to be attenuated in patients with ejection fractions in thehighest part (≥65%) of the range.8
Several gaps in evidence remain regarding
the benefits of SGLT2 inhibitors in patients withheart failure, including whether these benefits
are conserved in patients with an ejection fraction at the highest end of the ejection fraction
spectrum, in patients who start the treatment
during or soon after hospitalization, and in patients with a previously reduced ejection fractionthat has since improved to more than 40%. We
designed the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial totest the hypothesis that the SGLT2 inhibitor
dapagliflozin would reduce the risk of worsening heart failure or cardiovascular death among
patients with a mildly reduced or preserved ejection fraction.

blind, randomized, controlled trial in which patients with chronic heart failure and a left ventricular ejection fraction of more than 40%
received dapagliflozin or matching placebo, in
addition to their usual therapy. The steering committee designed and oversaw the conduct of thetrial and the analysis of the data in collaboration
with the sponsor (AstraZeneca). The trial protocol was approved by a local or central institutional review board at each trial center. The authors who had access to the data vouch for theaccuracy and completeness of the data, and all
the authors vouch for the fidelity of the trial tothe protocol. Details regarding the design of thetrial are provided in the protocol and in the Supplementary Appendix, both of which are available with the full text of this article at NEJM.org.
Trial Patients

Patients were eligible for enrollment if they wereat least 40 years of age; had stabilized heart
failure, with or without type 2 diabetes mellitus;
had a left ventricular ejection fraction of morethan 40%; had evidence of structural heart disease; and had an elevated natriuretic peptide
level. Patients who had had a previous left ventricular ejection fraction of 40% or less were
eligible provided that they had an ejection fraction of more than 40% at the time of enrollment. Patients could have been enrolled either as
outpatients or during hospitalization for heart
failure. Detailed inclusion and exclusion criteria
have been published previously9 and are provided in Table S1 in the Supplementary Appendix.
Trial Procedures and Outcomes

All the patients provided written informed consent. Those who met the inclusion and exclusion
criteria were randomly assigned to receive dapagliflozin at a dose of 10 mg once daily or matching placebo, in addition to their usual therapy.
The primary outcome was a composite ofworsening heart failure, which was defined aseither an unplanned hospitalization for heart
failure or an urgent visit for heart failure, or
cardiovascular death. Secondary outcomes were
the total number of worsening heart failure
events and cardiovascular deaths, the change
from baseline in the total symptom score on the
Me thods
Kansas City Cardiomyopathy Questionnaire
Trial Design and Oversight(KCCQ; scores range from 0 to 100, with higher
The DELIVER trial was a phase 3, international, scores indicating fewer symptoms and physicalmulticenter, parallel-group, event-driven, double- limitations) at month 8, cardiovascular death,2n engl j med﻿﻿  nejm.org﻿

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Dapagliflozin in Heart Failure with Preserved EF

and death from any cause. All potential worsening heart failure events and all deaths were adjudicated according to prespecified criteria10 byan independent clinical events committee whose
members were unaware of the trial-group assignments. In light of the extensive data on thesafety of dapagliflozin, only data on serious
adverse events, adverse events that led to discontinuation of dapagliflozin or placebo, and selectother adverse events were collected.
Statistical Analysis

The primary outcome, the occurrence of worsening heart failure or cardiovascular death, wasassessed in a time-to-event analysis with the useof a Cox proportional-hazards model, stratified
according to diabetes status. This analysis was
performed concurrently in the overall populationand in patients with a left ventricular ejection
fraction of less than 60%, with an alpha level of
0.024 used in the former analysis and an alphalevel of 0.038 used in the latter analysis (see theSupplementary Methods section and Fig. S1 andTable S2). We estimated that enrollment of 6100
patients followed for at least 13.5 months (andup to 39 months) would result in the occurrenceof at least 1117 events and would provide thetrial with 93% power to detect a hazard ratio of0.80 for the comparison of dapagliflozin andplacebo with respect to the primary outcome inthe overall population, at a two-sided alpha levelof 0.024. All the analyses were performed according to the intention-to-treat principle. Secondary analyses were performed with the use of aclosed-testing procedure that included a prespecified hierarchical ordering of the primaryand secondary outcomes; these outcomes included (in hierarchical order) the total numberof worsening heart failure events and cardiovascular deaths, a decrease in symptom burden as
measured by an increase in the KCCQ total
symptom score, and cardiovascular death anddeath from any cause (both of which were assessed in a time-to-event analysis). We analyzed
the KCCQ total symptom score as a composite
outcome based on the rank of the change inscore from baseline to month 8, with a corresponding win ratio used to estimate the magnitude of the treatment effect.11-13 We assessed theconsistency of the treatment effect on the primary outcome in prespecified subgroups. In
separate sensitivity analyses, patient data were
censored at the time of coronavirus disease 2019

(Covid-19) diagnosis, and death from noncardiovascular causes was taken into account as acompeting risk.14

R e sult s
Patients

Between August 27, 2018, and December 30,
2020, a total of 10,418 patients were screened at
353 centers in 20 countries; of these patients,
6263 were randomly assigned to receive dapagliflozin or matching placebo (Fig. S2). The
reasons for exclusion from randomization areprovided in Table S3. The demographic andclinical characteristics of the two groups were
well balanced at baseline (Table 1 and Table S4).
Dapagliflozin was discontinued for reasons otherthan death in 444 patients (14.2%), and placebo
was discontinued for reasons other than deathin 442 patients (14.1%). The vital status was
known at the end of the trial in all but 2 patientsin the dapagliflozin group and 2 patients in theplacebo group. The median duration of followup was 2.3 years (interquartile range, 1.7 to 2.8).
Efficacy

In the overall population, the primary outcome
occurred in 512 patients (16.4%) in the dapagliflozin group and in 610 patients (19.5%) in
the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001) (Table 2 and Fig. 1A). The results of the analysis of
the primary outcome in the patients with a left
ventricular ejection fraction of less than 60%
were similar to those of the overall population(hazard ratio, 0.83; 95% CI, 0.73 to 0.95;
P = 0.009) (Table S5).
The number of cardiovascular deaths andfirst and recurrent worsening heart failure eventswas lower in the dapagliflozin group than in theplacebo group in the overall population (rateratio, 0.77; 95% CI, 0.67 to 0.89; P<0.001) andamong the patients with a left ventricular ejection fraction of less than 60% (rate ratio, 0.77;
95% CI, 0.65 to 0.90; P = 0.002). The incidence ofthe components of the primary outcome favoredthe dapagliflozin group both in the overall population and among those with a left ventricularejection fraction of less than 60%, including
worsening heart failure (hazard ratio in theoverall population, 0.79; 95% CI, 0.69 to 0.91)
and cardiovascular death (hazard ratio, 0.88;
95% CI, 0.74 to 1.05) (Fig. 1B and 1C), as well asn engl j med﻿﻿  nejm.org﻿

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T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Characteristics of the Patients at Baseline.*
Dapagliflozin(N = 3131)

Characteristic

Placebo(N = 3132)

Age — yr71.8±9.671.5±9.5

Female sex — no. (%)

1364 (43.6)

1383 (44.2)

630 (20.1)

644 (20.6)

Race — no. (%)†
Asian
Black

81 (2.6)

78 (2.5)

White2214 (70.7)2225 (71.0)

Other

206 (6.6)

185 (5.9)

North America

428 (13.7)

423 (13.5)

Latin America

602 (19.2)

579 (18.5)

Europe or Saudi Arabia

1494 (47.7)

1511 (48.2)

Asia

607 (19.4)

619 (19.8)

II2314 (73.9)

2399 (76.6)

III

807 (25.8)

724 (23.1)

IV

10 (0.3)

8 (0.3)54.0±8.654.3±8.9≤49%1067 (34.1)

1049 (33.5)

50–59%

1133 (36.2)

1123 (35.9)≥60%

931 (29.7)

960 (30.7)

Type 2 diabetes mellitus

1401 (44.7)

1405 (44.9)

Hypertension

2755 (88.0)

2798 (89.3)

Previous left ventricular ejection fraction ≤40%

572 (18.3)

579 (18.5)

61±19

61±19

Geographic region — no. (%)

NYHA class — no. (%)‡

Left ventricular ejection fraction
Mean — %Distribution — no. (%)

Medical history — no. (%)

Estimated GFR — ml/min/1.73 m

2*	Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. GFR denotes glomerular filtration rate.
†	Race was reported by the investigators.
‡	One patient in the placebo group who had New York Heart Association (NYHA) class I disease at baseline was notincluded in the analysis of this variable.

death from any cause (hazard ratio, 0.94; 95%
CI, 0.83 to 1.07) (Fig. 1D). The change frombaseline to month 8 in the KCCQ total symptomscore indicated a benefit with dapagliflozin ascompared with placebo with respect to symptoms of heart failure (win ratio, 1.11; 95% CI,
1.03 to 1.21; P = 0.009; mean placebo-correcteddifference between baseline and month 8 among
survivors, 2.4 points; 95% CI, 1.5 to 3.4).
The effect of dapagliflozin on the primary outcome was consistent across all prespecified sub4groups. These included the subgroups that were
defined according to the presence or absence oftype 2 diabetes mellitus; enrollment that occurred during or within 30 days after hospitalization for heart failure or enrollment that did
not occur during or within 30 days after hospitalization for heart failure; and the presence orabsence of a previous left ventricular ejection
fraction of 40% or less that improved to morethan 40% by the time of enrollment (Fig. 2). A
prespecified Covid-19 sensitivity analysis in whichn engl j med﻿﻿  nejm.org﻿

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231 (7.4)

Cardiovascular death†—

Mean change in KCCQ total symptom score at mo 8 among survivors

42/3126 (1.3)
73/3126 (2.3)

Any serious adverse event or adverse event that led to discontinuation of
dapagliflozin or placebo that was suggestive of volume depletion

Any renal serious adverse event or adverse event that led to discontinuation of dapagliflozin or placebo

—

—

—

—

—

—

—

—

—

—

7.2

—

—

11.8

3.3

0.9

5.0

5.6

7.8

events/100 patient-yr

079/3127 (2.5)

32/3127 (1.0)

7/3127 (0.2)

0199/3127 (6.4)

25/3127 (0.8)

494/3127 (15.8)

181/3127 (5.8)

1423/3127 (45.5)

526 (16.8)

—

—

1057

261 (8.3)

78 (2.5)418 (13.3)

455 (14.5)

610 (19.5)

values

—

—

—

—

—

—

—

—

—

—

7.6

—

—

15.3

3.8

1.1

6.5

7.2

9.6

events/100 patient-yr

Placebo(N = 3132)

—

—

—

—

—

—

—

—

—

—

0.94 (0.83–1.07)

2.4 (1.5–3.4)

1.11 (1.03–1.21)

0.77 (0.67–0.89)

0.88 (0.74–1.05)

0.76 (0.55–1.07)

0.77 (0.67–0.89)

0.79 (0.69–0.91)

0.82 (0.73–0.92)

Hazard or Rate Ratio
or Win Ratio(95% CI)

—

—

—

—

—

—

—

—

—

—

NA

NA

0.009

<0.001

NA

NA

NA

NA

<0.001

P Value*	All treatment effects are shown as hazard ratios, except for the total number of hospitalizations for heart failure and cardiovascular deaths, which is reported as a rate ratio, and the change
in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at month 8, which is reported as a win ratio. The total symptom scores on the KCCQ range from 0 to 100, withhigher scores indicating fewer symptoms and physical limitations. NA denotes not applicable because P values for efficacy outcomes are reported only for outcomes that were included in
the hierarchical-testing strategy.
†	Cardiovascular death was also a prespecified secondary outcome.
‡	Worsening heart failure events were defined as hospitalization for heart failure or an urgent visit for heart failure. The total number of worsening heart failure events included first andrecurrent events.
§	The results of the assessment of the KCCQ total symptom score in a sensitivity analysis in which data were not censored after March 11, 2020, were similar to those shown (win ratio,
1.11; 95% CI, 1.05 to 1.18).
¶	A total of 10 patients (5 in the dapagliflozin group and 5 in the placebo group) were excluded from the safety analyses because they did not receive any dose of dapagliflozin or placebo.
Safety outcomes were events with an onset date on or after the date of the first dose and up to and including 30 days after the last dose of dapagliflozin or placebo.
‖	Major hypoglycemic events are defined in the Supplementary Methods section in the Supplementary Appendix.

0

6/3126 (0.2)

Any major hypoglycemic event‖

Fournier’s gangrene

2/3126 (0.1)

Any definite or probable diabetic ketoacidosis

188/3126 (6.0)

Any adverse event that potentially placed a patient at risk for a lower-limb
amputation

436/3126 (13.9)

Any adverse event that led to interruption of dapagliflozin or placebo
19/3126 (0.6)

182/3126 (5.8)

Any adverse event that led to discontinuation of dapagliflozin or placebo

Any amputation

1361/3126 (43.5)

Any serious adverse event

Safety outcomes — no./total no. (%)¶

497 (15.9)—

Change in KCCQ total symptom score at mo 8§

Death from any cause — no. (%)

815

Total no. of worsening heart failure events and cardiovascular deaths‡

Secondary outcomes60 (1.9)329 (10.5)

Hospitalization for heart failure

Urgent visit for heart failure368 (11.8)512 (16.4)

valuesHospitalization for heart failure or an urgent visit for heart failure

Primary composite outcome — no. (%)

Efficacy outcomes

Variable

Dapagliflozin(N = 3131)

Table 2. Primary and Secondary Cardiovascular Outcomes and Safety Outcomes in the Overall Population.*

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0

40

540

630

720

810

900

990

1080

383
389

90

180

0

450

540

630

720

Days since Randomization

360

810

900

540

630

720

810

900

990

1080

270

450

540

630

720

Days since Randomization

360

810

900

910
905

990

451
443

1080

180 270 360 450 540 630 720 810 900 990 1080

Placebo3132 3097 3058 3012 2962 2877 2575 2319 2161 1762 1309
Dapagliflozin 3131 3093 3048 3009 2962 2895 2587 2342 2174 1778 1314

180

90

No. at Risk
451
441

90

0

Placebo

383
389

1080

Dapagliflozin

Placebo3132 3096 3054 3008 2957 2872 2570 2314 2157 1759 1306
Dapagliflozin 3131 3091 3046 3006 2960 2892 2584 2339 2171 1775 1312

910
903

0

0

5

10

15

Hazard ratio, 0.94 (95% CI, 0.83–1.07)

No. at Risk

Days since Randomization

0

450

20

30

40

50

60

70

80

20

90

10
360

180 270 360 450 540 630 720 810 900 990 1080

270

90

Dapagliflozin

Placebo

25

30
100

0

180

0

Hazard ratio, 0.88 (95% CI, 0.74–1.05)

D Death from Any Cause

10

20

90

0

40

0

5

50

30

10

60

70

15

20

90

80

25

100

30

C Death from Cardiovascular Causes

772
801

990

180 270 360 450 540 630 720 810 900 990 1080

270

90

Placebo3132 3007 2896 2799 2710 2608 2318 2080 1923 1554 1140
Dapagliflozin 3131 3040 2949 2885 2807 2716 2401 2147 1982 1603 1181

Cumulative Incidence (%)

Placebo

Dapagliflozin

No. at Risk
772
801

0

0

5

10

Hazard ratio, 0.79 (95% CI, 0.69–0.91)

Placebo3132 3007 2896 2799 2710 2608 2318 2080 1923 1554 1140
Dapagliflozin 3131 3040 2949 2885 2807 2716 2401 2147 1982 1603 1181

Days since Randomization

0

450

20

30

10
360

180 270 360 450 540 630 720 810 900 990 1080

270

90

40

50

60

70

15

20

90
80

100

30
25

0

180

0

Dapagliflozin

Placebo

10

20

90

5

50

30

10

60

70

0

90

15

20

100

80

25

Hazard ratio, 0.82 (95% CI, 0.73–0.92)
P<0.001

B Worsening Heart Failure Event

No. at Risk

Cumulative Incidence (%)

30

Cumulative Incidence (%)

6
Cumulative Incidence (%)

A Primary Outcome

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Dapagliflozin in Heart Failure with Preserved EF

Figure 1 (facing page). Efficacy Outcomes in the Overall
Population.
Shown are time-to-event curves for the primary outcome(Panel A), individual components of the primary outcome(worsening heart failure [Panel B] and cardiovasculardeath [Panel C]), and death from any cause (Panel D).
The insets show the same data on an expanded y axis.

patient data were censored at the time of­Covid-19 diagnosis showed similar results (Table S6). Overall results were similar when deathfrom noncardiovascular causes was taken into
account as a competing risk (subdistribution
hazard ratio, 0.82; 95% CI, 0.73 to 0.92). The
results of the assessment of the proportionalhazards assumption are provided in the Supplementary Appendix.
SafetyOverall, serious adverse events, including death,
were reported in 1361 patients (43.5%) in the
dapagliflozin group and in 1423 patients (45.5%)in the placebo group (Table 2). Adverse events
that led to discontinuation of dapagliflozin orplacebo were reported in 182 patients (5.8%) in
the dapagliflozin group and in 181 patients(5.8%) in the placebo group (Table S7).

Discussion
In this randomized, placebo-controlled trial involving patients with heart failure and a mildlyreduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of the primary
composite outcome, worsening heart failure or
cardiovascular death, than placebo, with no appreciable difference in benefit among patientswith a left ventricular ejection fraction of 60% ormore and those with a left ventricular ejection
fraction of less than 60%, or in other subgroups.
Each of the three components of this composite
outcome was less common in the dapagliflozingroup than in the placebo group. In addition,
dapagliflozin resulted in fewer total worsening
heart failure events and cardiovascular deaths
and a lower symptom burden than placebo. The
incidence of adverse events was similar to that in
the placebo group.
In a previous trial (DAPA-HF; Dapagliflozin
and Prevention of Adverse Outcomes in Heart
Failure), dapagliflozin reduced the risk of worsening heart failure or cardiovascular deathamong patients with heart failure and a left
ventricular ejection fraction of 40% or less.1 The
results of the DELIVER trial extend those of the
DAPA-HF trial to patients with heart failure anda left ventricular ejection fraction of more than
40% and are consistent with the overall resultsof the EMPEROR-Preserved trial (Empagliflozin
Outcome Trial in Patients with Chronic Heart
Failure with Preserved Ejection Fraction), whichassessed the effects of empagliflozin in patientswith a left ventricular ejection fraction of morethan 40%.10 The rationale for the dual primary
analyses in our trial (i.e., evaluation of the primary outcome in patients with a left ventricularejection fraction of less than 60% in addition tothe overall patient population) was based on
concern about a potential declining benefit inpatients with an ejection fraction in the normal
range that had been observed in several previous
trials of neurohormonal modulators.6,15 Although
the EMPEROR-Preserved trial suggested somepotential attenuation of benefit in the highest partof the range of ejection fraction,8 we observed noevidence of heterogeneity with respect to left
ventricular ejection fraction in the DELIVER trial,with similar overall treatment effects among
patients with a left ventricular ejection fractionof 60% or more and those with a left ventricularejection fraction of less than 60%. This finding
suggests that the benefit of SGLT2 inhibition is
likely to extend throughout the full range ofejection fraction.
The DELIVER trial was designed with broader
inclusion criteria than those used in previous
trials involving similar populations in that we enrolled patients who were hospitalized or recently
hospitalized, for whom evidence-based therapy
is limited, as well as those with heart failure anda left ventricular ejection fraction that had improved to more than 40% at the time of enrollment.4 Our data suggest that these understudiedgroups also benefit from dapagliflozin.
The most recent guidelines of the American
Heart Association, American College of Cardiology, and Heart Failure Society of America designated SGLT2 inhibitors as class IIA, level B, forthe treatment of heart failure with a mildly reduced or preserved left ventricular ejection fraction.4 The results of the DELIVER trial may inform future guidelines and provide further
guidance for their broader use in clinical practice. Although the risk of cardiovascular deathn engl j med﻿﻿  nejm.org﻿

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Subgroup

Dapagliflozin

Placebo

Hazard Ratio (95% CI)

no. of patients with events/total no.
All patientsAge≤72 yr>72 yrSex
Female
Male
Race
Asian
Black
White
Other
Geographic region
Europe or Saudi Arabia
Asia
Latin America
North America
NYHA class at enrollment
IIIII or IV
LVEF at enrollment≤49%
50–59%≥60%
NT-proBNP at enrollment≤1011 pg/ml>1011 pg/ml
Enrollment during or within 30 days after
hospitalization for heart failure
No
Yes
Type 2 diabetes mellitus at enrollment
No
Yes
Atrial fibrillation or flutter at enrollment ECG
No
Yes
Body-mass index at enrollment<30≥30
Estimated GFR at enrollment<60 ml/min/1.73 m2≥60 ml/min/1.73 m2
Systolic blood pressure at randomization≤128 mm Hg>128 mm Hg
Previous LVEF ≤40%
No
Yes

512/3131

610/3132

0.82 (0.73–0.92)

247/1545
265/1586

306/1604
304/1528

0.82 (0.69–0.97)
0.81 (0.69–0.96)

195/1364
317/1767

243/1383
367/1749

0.81 (0.67–0.97)
0.82 (0.71–0.96)

97/63021/81
372/2214
22/206

106/64419/78
461/2225
24/1850.91 (0.69–1.21)
1.08 (0.58–2.01)
0.79 (0.69–0.90)
0.83 (0.46–1.48)

261/1494
92/60770/602
89/428309/1511
103/61987/579111/4230.83 (0.70–0.98)
0.89 (0.67–1.18)
0.78 (0.57–1.07)
0.75 (0.57–1.00)

331/2314
181/817411/2399
198/732

0.81 (0.70–0.94)
0.80 (0.65–0.98)

207/1067
174/1133
131/931229/1049
211/1123
170/960

0.87 (0.72–1.04)
0.79 (0.65–0.97)
0.78 (0.62–0.98)

173/1555
339/1576

208/1578
402/1553

0.84 (0.68–1.02)
0.79 (0.69–0.92)

419/2803
93/328497/2806
113/3260.82 (0.72–0.94)
0.78 (0.60–1.03)

242/1730
270/1401

293/1727
317/1405

0.81 (0.68–0.96)
0.83 (0.70–0.97)

285/1803
227/1327

339/1814271/1317

0.82 (0.70–0.96)
0.81 (0.68–0.97)

275/1734
236/1395

302/1736
308/1392

0.89 (0.75–1.04)
0.74 (0.63–0.88)

289/1516
223/1615

355/1554
255/1577

0.81 (0.69–0.94)
0.84 (0.70–1.00)

280/1568
232/1563

300/1590
310/1542

0.93 (0.79–1.10)
0.71 (0.60–0.85)

420/2559
92/572491/2553
119/579

0.84 (0.73–0.95)
0.74 (0.56–0.97)
0.50

0.75

1.00

Dapagliflozin Better

was not significantly lower with dapagliflozin
than with placebo, the rate of cardiovasculardeath among patients who received placebo wassubstantially lower among patients with a left
8

1.50

2.00

Placebo Better

ventricular ejection fraction of more than 40%
than among those in the DAPA-HF trial with areduced ejection fraction (3.8 events per 100
patient-years in DELIVER vs. 7.9 events per 100

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Dapagliflozin in Heart Failure with Preserved EF

Figure 2 (facing page). Primary Outcome in Prespecified
Subgroups.
The primary outcome was a composite of worsening
heart failure, which was defined as either an unplanned
hospitalization for heart failure or an urgent visit forheart failure, or cardiovascular death. Race was reportedby the investigators. The body-mass index is the weightin kilograms divided by the square of the height in meters.
The size of the boxes is proportional to the number ofpatients in the subgroup, and arrows on the confidence
interval bars indicate that the upper or lower boundaryof the confidence interval is off the scale. One patientin the placebo group who had New York Heart Association (NYHA) class I disease at baseline was not includedin the analysis of NYHA class at enrollment. ECG denotes
electrocardiography, GFR glomerular filtration rate, LVEF
left ventricular ejection fraction, and NT-proBNP N-terminal pro–B-type natriuretic peptide.

patient-years in DAPA-HF), and DELIVER was
not powered to assess the effect of dapagliflozin
on cardiovascular death alone. Trials in higherrisk populations, or of longer duration, or
pooled analyses of several trials would be needed for robust evaluation of benefits with respect
to mortality.
This trial has some limitations. The use of
specific inclusion and exclusion criteria may have
limited the generalizability of our findings. Less
than 5% of the patients enrolled were Black, although this percentage was proportional to the

population percentage on a regional basis (Table
S8). Owing to the Covid-19 pandemic, assessment of symptom burden was limited to patientsfor whom an 8-month assessment was plannedor performed before March 11, 2020, although
results were similar in all patients for whomdata were available. Because all the subgroups in
the DELIVER trial were underpowered, withinsubgroup results should be interpreted cautiously.
Among patients with heart failure and amildly reduced or preserved ejection fraction,
dapagliflozin resulted in a lower risk of the primary composite outcome (worsening heart failure or cardiovascular death), in fewer worsening
heart failure events and cardiovascular deaths,
and in a lower symptom burden, with no excess
of adverse events. Findings were consistentacross prespecified subgroups, including thosedefined according to left ventricular ejection
fraction. These data provide further evidence tosupport the use of an SGLT2 inhibitor as essential therapy in patients with heart failure,
regardless of the presence or absence of type 2
diabetes mellitus or left ventricular ejection
fraction.
Supported by AstraZeneca.
Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: Scott D. Solomon, M.D., John J.V. McMurray, M.D., Brian Claggett, Ph.D.,
Rudolf A. de Boer, M.D., David DeMets, Ph.D., Adrian F. Hernandez, M.D., Silvio E. Inzucchi, M.D., Mikhail N. Kosiborod, M.D.,
Carolyn S.P. Lam, M.D., Felipe Martinez, M.D., Sanjiv J. Shah, M.D., Akshay S. Desai, M.D., Pardeep S. Jhund, M.B., Ch.B., Ph.D., Jan
Belohlavek, M.D., Chern‑En Chiang, M.D., C. Jan Willem Borleffs, M.D., Josep Comin‑Colet, M.D., Ph.D., Dan Dobreanu, M.D., Jaroslaw Drozdz, M.D., Ph.D., James C. Fang, M.D., Marco Antonio Alcocer‑Gamba, M.D., Waleed Al Habeeb, M.D., Yaling Han, M.D.,
Jose Walter Cabrera Honorio, M.D., Stefan P. Janssens, M.D., Tzvetana Katova, M.D., Masafumi Kitakaze, M.D., Béla Merkely, M.D.,
Ph.D., Eileen O’Meara, M.D., Jose Francisco Kerr Saraiva, M.D., Ph.D., Sergey N. Tereshchenko, M.D., Jorge Thierer, M.D., Muthiah
Vaduganathan, M.D., M.P.H., Orly Vardeny, Pharm.D., Subodh Verma, M.D., Vinh Nguyen Pham, M.D., Ulrica Wilderäng, Ph.D., Natalia Zaozerska, M.D., Ph.D., Erasmus Bachus, M.D., Ph.D., Daniel Lindholm, M.D., Ph.D., Magnus Petersson, M.D., Ph.D., andAnna Maria Langkilde, M.D., Ph.D.
The authors’ affiliations are as follows: the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston (S.D.S., B.C., A.S.D., M.V.); the British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular andMetabolic Health, University of Glasgow, Glasgow, Scotland, United Kingdom (J.J.V.M., P.S.J.); the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen (R.A.B., C.S.P.L.), and Haga Teaching Hospital, the Hague(C.J.W.B.) — both in the Netherlands; the University of Wisconsin, Madison (D. DeMets); Duke University Medical Center, Durham,
NC (A.F.H.); Yale School of Medicine, New Haven, CT (S.E.I.); Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas
City, Kansas City (M.N.K.); National Heart Center Singapore and Duke–National University of Singapore, Singapore (C.S.P.L.); National University of Cordoba, Cordoba (F.M.), and Jefe de Unidad de Insuficiencia Cardíaca, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno, Buenos Aires (J.T.) — both in Argentina; Northwestern University Feinberg School of Medicine,
Chicago (S.J.S.); General University Hospital, Charles University, Prague, Czech Republic (J.B.); General Clinical Research Center andthe Division of Cardiology, Taipei Veterans General Hospital and National Yang Ming Chiao Tung University, Taipei, Taiwan (C.-E.C.);
the Department of Cardiology, Bellvitge University Hospital and Bellvitge Biomedical Research Institute, University of Barcelona,
L’Hospitalet de Llobregat, Barcelona (J.C.-C.); George Emil Palade University of Medicine, Pharmacy, Science, and Technology, TârguMureş, Romania (D. Dobreanu); the Department of Cardiology, Medical University Lodz, Lodz, Poland (J.D.); University of Utah Medical Center, Salt Lake City (J.C.F.); Centro de Estudios Clínicos de Querétaro, Querétaro, Mexico (M.A.A.-G.); the Cardiac Sciences Department, King Saud University, Riyadh, Saudi Arabia (W.A.H.); the Cardiovascular Research Institute and Department of Cardiology,n engl j med﻿﻿  nejm.org﻿

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9

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

General Hospital of Northern Theater Command, Shenyang, China (Y.H.); Clínica Vesalio, San Borja, Peru (J.W.C.H.); the Departmentof Cardiovascular Diseases, Cardiac Intensive Care, University Hospitals Leuven, Leuven, Belgium (S.P.J.); the Department of Noninvasive Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.); Kinshukai Hanwa Daini Senboku Hospital, Osaka, Japan (M.K.);
Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Institut de Cardiologie de Montréal, Université de Montréal, Montreal (E.O.), and the Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto (S.V.) — both in
Canada; the Cardiovascular Division, Instituto de Pesquisa Clínica de Campinas, Campinas, Brazil (J.F.K.S.); the Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow (S.N.T.); the Minneapolis Veterans AffairsCenter for Care Delivery and Outcomes Research, University of Minnesota, Minneapolis (O.V.); Cardiovascular Center, Tam Anh Hospital, Tan Tao University, Tan Duc, Vietnam (V.N.P.); and Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden (U.W., N.Z., E.B., D.L., M.P., A.M.L.).

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Copyright © 2022 Massachusetts Medical Society.

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