DELIVER Primary Manuscript. N Engl J Med. 2022 - With VEEVA

The n e w e ng l a n d j o u r na l of 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 T
BACKGROUND
Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitaliza- The authors’ full names, academic de-
tion for heart failure and cardiovascular death among patients with chronic heart grees, and affiliations are listed in the
Appendix. Dr. Solomon can be contacted
failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 in- at ssolomon@bwh.harvard.edu or at the
hibitors are effective in patients with a higher left ventricular ejection fraction Cardiovascular Division, Brigham and
remains less certain. Women’s Hospital, 75 Francis St., Boston,
MA 02115.
METHODS * A complete list of the DELIVER trial in-
We randomly assigned 6263 patients with heart failure and a left ventricular ejec- vestigators is provided in the Supplemen-
tary Appendix, available at NEJM.org.
tion 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 was This article was published on August 27,
2022, at NEJM.org.
a composite of worsening heart failure (which was defined as either an unplanned
hospitalization for heart failure or an urgent visit for heart failure) or cardiovas- N Engl J Med 2022;387:1089-98.
DOI: 10.1056/NEJMoa2206286
cular death, as assessed in a time-to-event analysis. Copyright © 2022 Massachusetts Medical Society.
RESULTS Veeva ID: Z4-54232

Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients Date of preparation: April 2023
(16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the pla- Date of expiration: April 2024
cebo 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 dapagliflozin
group 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 events
and symptom burden were lower in the dapagliflozin group than in the placebo
group. Results were similar among patients with a left ventricular ejection fraction
of 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 or
without diabetes. The incidence of adverse events was similar in the two groups.
CONCLUSIONS
Dapagliflozin reduced the combined risk of worsening heart failure or cardiovas-
cular 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 387;12 nejm.org september 22, 2022 1089

The New England Journal of Medicine
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S
odium–glucose cotransporter 2 blind, randomized, controlled trial in which pa-
(SGLT2) inhibitors, which were originally tients with chronic heart failure and a left ven-
developed as glucose-lowering agents for tricular ejection fraction of more than 40%
the treatment of type 2 diabetes mellitus, reduce received dapagliflozin or matching placebo, in
the risk of death and other adverse outcomes addition to their usual therapy. The steering com-
A Quick Take is
available at among patients with chronic heart failure and mittee designed and oversaw the conduct of the
NEJM.org a reduced ejection fraction (i.e., a left ventricu- trial and the analysis of the data in collaboration
lar ejection fraction of ≤40%) and in those with with the sponsor (AstraZeneca). The trial proto-
chronic kidney disease, regardless of the pres- col was approved by a local or central institu-
ence or absence of type 2 diabetes mellitus.1-3 tional review board at each trial center. The au-
Current clinical guidelines strongly recommend thors who had access to the data vouch for the
the use of SGLT2 inhibitors in patients with accuracy and completeness of the data, and all
chronic heart failure and a reduced ejection the authors vouch for the fidelity of the trial to
fraction.4 the protocol. Details regarding the design of the
Few pharmacologic treatment options exist trial are provided in the protocol and in the Sup-
for patients with heart failure and a mildly re- plementary Appendix, both of which are avail-
duced or preserved left ventricular ejection frac- able with the full text of this article at NEJM.org.
tion.5,6 Recently, treatment with the SGLT2 in-
hibitor empagliflozin was shown to reduce the Trial Patients
combined risk of hospitalization for heart fail- Patients were eligible for enrollment if they were
ure or cardiovascular death among patients with at least 40 years of age; had stabilized heart
heart failure and a left ventricular ejection frac- failure, with or without type 2 diabetes mellitus;
tion of more than 40%, a finding that suggests had a left ventricular ejection fraction of more
that the benefits of SGLT2 inhibition may extend than 40%; had evidence of structural heart dis-
to all patients with heart failure, regardless of ease; and had an elevated natriuretic peptide
the left ventricular ejection fraction.7 The bene- level. Patients who had had a previous left ven-
fit, which was driven by a reduction in hospital- tricular ejection fraction of 40% or less were
ization for heart failure, appeared to be attenu- eligible provided that they had an ejection frac-
ated in patients with ejection fractions in the tion of more than 40% at the time of enroll-
highest part (≥65%) of the range.8 ment. Patients could have been enrolled either as
Several gaps in evidence remain regarding outpatients or during hospitalization for heart
the benefits of SGLT2 inhibitors in patients with failure. Detailed inclusion and exclusion criteria
heart failure, including whether these benefits have been published previously9 and are provid-
are conserved in patients with an ejection frac- ed in Table S1 in the Supplementary Appendix.
tion at the highest end of the ejection fraction
spectrum, in patients who start the treatment Trial Procedures and Outcomes
during or soon after hospitalization, and in pa- All the patients provided written informed con-
tients with a previously reduced ejection fraction sent. Those who met the inclusion and exclusion
that has since improved to more than 40%. We criteria were randomly assigned to receive dapa-
designed the Dapagliflozin Evaluation to Im- gliflozin at a dose of 10 mg once daily or match-
prove the Lives of Patients with Preserved Ejec- ing placebo, in addition to their usual therapy.
tion Fraction Heart Failure (DELIVER) trial to The primary outcome was a composite of
test the hypothesis that the SGLT2 inhibitor worsening heart failure, which was defined as
dapagliflozin would reduce the risk of worsen- either an unplanned hospitalization for heart
ing heart failure or cardiovascular death among failure or an urgent visit for heart failure, or
patients with a mildly reduced or preserved ejec- cardiovascular death. Secondary outcomes were
tion fraction. 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 physical
multicenter, parallel-group, event-driven, double- limitations) at month 8, cardiovascular death,
1090 n engl j med 387;12 nejm.org september 22, 2022

Dapagliflozin in Heart Failure with Preserved EF
and death from any cause. All potential worsen- (Covid-19) diagnosis, and death from noncardio-
ing heart failure events and all deaths were ad- vascular causes was taken into account as a
judicated according to prespecified criteria10 by competing risk.14
an independent clinical events committee whose
members were unaware of the trial-group as- R e sult s
signments. In light of the extensive data on the
safety of dapagliflozin, only data on serious Patients
adverse events, adverse events that led to discon- Between August 27, 2018, and December 30,
tinuation of dapagliflozin or placebo, and select 2020, a total of 10,418 patients were screened at
other adverse events were collected. 353 centers in 20 countries; of these patients,
6263 were randomly assigned to receive dapa-
Statistical Analysis gliflozin or matching placebo (Fig. S2). The
The primary outcome, the occurrence of worsen- reasons for exclusion from randomization are
ing heart failure or cardiovascular death, was provided in Table S3. The demographic and
assessed in a time-to-event analysis with the use clinical characteristics of the two groups were
of a Cox proportional-hazards model, stratified well balanced at baseline (Table 1 and Table S4).
according to diabetes status. This analysis was Dapagliflozin was discontinued for reasons other
performed concurrently in the overall population than death in 444 patients (14.2%), and placebo
and in patients with a left ventricular ejection was discontinued for reasons other than death
fraction of less than 60%, with an alpha level of in 442 patients (14.1%). The vital status was
0.024 used in the former analysis and an alpha known at the end of the trial in all but 2 patients
level of 0.038 used in the latter analysis (see the in the dapagliflozin group and 2 patients in the
Supplementary Methods section and Fig. S1 and placebo group. The median duration of follow-
Table S2). We estimated that enrollment of 6100 up was 2.3 years (interquartile range, 1.7 to 2.8).
patients followed for at least 13.5 months (and
up to 39 months) would result in the occurrence Efficacy
of at least 1117 events and would provide the In the overall population, the primary outcome
trial with 93% power to detect a hazard ratio of occurred in 512 patients (16.4%) in the dapa-
0.80 for the comparison of dapagliflozin and gliflozin group and in 610 patients (19.5%) in
placebo with respect to the primary outcome in the placebo group (hazard ratio, 0.82; 95% con-
the overall population, at a two-sided alpha level fidence interval [CI], 0.73 to 0.92; P<0.001) (Ta-
of 0.024. All the analyses were performed ac- ble 2 and Fig. 1A). The results of the analysis of
cording to the intention-to-treat principle. Second- the primary outcome in the patients with a left
ary analyses were performed with the use of a ventricular ejection fraction of less than 60%
closed-testing procedure that included a pre- were similar to those of the overall population
specified hierarchical ordering of the primary (hazard ratio, 0.83; 95% CI, 0.73 to 0.95;
and secondary outcomes; these outcomes in- P = 0.009) (Table S5).
cluded (in hierarchical order) the total number The number of cardiovascular deaths and
of worsening heart failure events and cardiovas- first and recurrent worsening heart failure events
cular deaths, a decrease in symptom burden as was lower in the dapagliflozin group than in the
measured by an increase in the KCCQ total placebo group in the overall population (rate
symptom score, and cardiovascular death and ratio, 0.77; 95% CI, 0.67 to 0.89; P<0.001) and
death from any cause (both of which were as- among the patients with a left ventricular ejec-
sessed in a time-to-event analysis). We analyzed tion fraction of less than 60% (rate ratio, 0.77;
the KCCQ total symptom score as a composite 95% CI, 0.65 to 0.90; P = 0.002). The incidence of
outcome based on the rank of the change in the components of the primary outcome favored
score from baseline to month 8, with a corre- the dapagliflozin group both in the overall popu-
sponding win ratio used to estimate the magni- lation and among those with a left ventricular
tude of the treatment effect.11-13 We assessed the ejection fraction of less than 60%, including
consistency of the treatment effect on the pri- worsening heart failure (hazard ratio in the
mary outcome in prespecified subgroups. In overall population, 0.79; 95% CI, 0.69 to 0.91)
separate sensitivity analyses, patient data were and cardiovascular death (hazard ratio, 0.88;
censored at the time of coronavirus disease 2019 95% CI, 0.74 to 1.05) (Fig. 1B and 1C), as well as

Table 1. Characteristics of the Patients at Baseline.*
Dapagliflozin Placebo
Characteristic (N = 3131) (N = 3132)
Age — yr 71.8±9.6 71.5±9.5
Female sex — no. (%) 1364 (43.6) 1383 (44.2)
Race — no. (%)†
Asian 630 (20.1) 644 (20.6)
Black 81 (2.6) 78 (2.5)
White 2214 (70.7) 2225 (71.0)
Other 206 (6.6) 185 (5.9)
Geographic region — no. (%)
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)
NYHA class — no. (%)‡
II 2314 (73.9) 2399 (76.6)
III 807 (25.8) 724 (23.1)
IV 10 (0.3) 8 (0.3)
Left ventricular ejection fraction
Mean — % 54.0±8.6 54.3±8.9
Distribution — no. (%)
≤49% 1067 (34.1) 1049 (33.5)
50–59% 1133 (36.2) 1123 (35.9)
≥60% 931 (29.7) 960 (30.7)
Medical history — no. (%)
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)
Estimated GFR — ml/min/1.73 m 2
61±19 61±19
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. GFR denotes glomerular filtra-
tion 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 not
included in the analysis of this variable.
death from any cause (hazard ratio, 0.94; 95% groups. These included the subgroups that were
CI, 0.83 to 1.07) (Fig. 1D). The change from defined according to the presence or absence of
baseline to month 8 in the KCCQ total symptom type 2 diabetes mellitus; enrollment that oc-
score indicated a benefit with dapagliflozin as curred during or within 30 days after hospital-
compared with placebo with respect to symp- ization for heart failure or enrollment that did
toms of heart failure (win ratio, 1.11; 95% CI, not occur during or within 30 days after hospi-
1.03 to 1.21; P = 0.009; mean placebo-corrected talization for heart failure; and the presence or
difference between baseline and month 8 among absence of a previous left ventricular ejection
survivors, 2.4 points; 95% CI, 1.5 to 3.4). fraction of 40% or less that improved to more
The effect of dapagliflozin on the primary out- than 40% by the time of enrollment (Fig. 2). A
come was consistent across all prespecified sub- prespecified Covid-19 sensitivity analysis in which

Table 2. Primary and Secondary Cardiovascular Outcomes and Safety Outcomes in the Overall Population.*
Hazard or Rate Ratio

Dapagliflozin Placebo or Win Ratio
Variable (N = 3131) (N = 3132) (95% CI) P Value
values events/ values events/
100 patient-yr 100 patient-yr
Efficacy outcomes
Primary composite outcome — no. (%) 512 (16.4) 7.8 610 (19.5) 9.6 0.82 (0.73–0.92) <0.001
Hospitalization for heart failure or an urgent visit for heart failure 368 (11.8) 5.6 455 (14.5) 7.2 0.79 (0.69–0.91) NA
Hospitalization for heart failure 329 (10.5) 5.0 418 (13.3) 6.5 0.77 (0.67–0.89) NA
Urgent visit for heart failure 60 (1.9) 0.9 78 (2.5) 1.1 0.76 (0.55–1.07) NA
Cardiovascular death† 231 (7.4) 3.3 261 (8.3) 3.8 0.88 (0.74–1.05) NA
Secondary outcomes
Total no. of worsening heart failure events and cardiovascular deaths‡ 815 11.8 1057 15.3 0.77 (0.67–0.89) <0.001
Change in KCCQ total symptom score at mo 8§ — — — — 1.11 (1.03–1.21) 0.009
Mean change in KCCQ total symptom score at mo 8 among survivors — — — — 2.4 (1.5–3.4) NA
n engl j med 387;12

Death from any cause — no. (%) 497 (15.9) 7.2 526 (16.8) 7.6 0.94 (0.83–1.07) NA
Safety outcomes — no./total no. (%)¶
Any serious adverse event 1361/3126 (43.5) — 1423/3127 (45.5) — — —
nejm.org
Any adverse event that led to discontinuation of dapagliflozin or placebo 182/3126 (5.8) — 181/3127 (5.8) — — —
Any adverse event that led to interruption of dapagliflozin or placebo 436/3126 (13.9) — 494/3127 (15.8) — — —
Any amputation 19/3126 (0.6) — 25/3127 (0.8) — — —
Any adverse event that potentially placed a patient at risk for a lower-limb 188/3126 (6.0) — 199/3127 (6.4) — — —
amputation

Any definite or probable diabetic ketoacidosis 2/3126 (0.1) — 0 — — —
september 22, 2022

Any major hypoglycemic event‖ 6/3126 (0.2) — 7/3127 (0.2) — — —
Any serious adverse event or adverse event that led to discontinuation of 42/3126 (1.3) — 32/3127 (1.0) — — —
dapagliflozin or placebo that was suggestive of volume depletion

Any renal serious adverse event or adverse event that led to discontinua- 73/3126 (2.3) — 79/3127 (2.5) — — —

tion of dapagliflozin or placebo
Fournier’s gangrene 0 — 0 — — —
* 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, with
higher 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 and
recurrent 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.
1093
A Primary Outcome B Worsening Heart Failure Event
1094
30 30
Hazard ratio, 0.82 (95% CI, 0.73–0.92) Hazard ratio, 0.79 (95% CI, 0.69–0.91)
P<0.001
100 25 Placebo 100 25
90 20 90 20 Placebo
80 80
15 Dapagliflozin 15
70 70
10 10 Dapagliflozin
60 60
50 5 50 5
40 40
0 0
30 0 90 180 270 360 450 540 630 720 810 900 990 1080 30 0 90 180 270 360 450 540 630 720 810 900 990 1080
Cumulative Incidence (%)

20 20
10 10
0 0
0 90 180 270 360 450 540 630 720 810 900 990 1080 0 90 180 270 360 450 540 630 720 810 900 990 1080
The
Days since Randomization Days since Randomization

No. at Risk No. at Risk
Placebo 3132 3007 2896 2799 2710 2608 2318 2080 1923 1554 1140 772 383 Placebo 3132 3007 2896 2799 2710 2608 2318 2080 1923 1554 1140 772 383
Dapagliflozin 3131 3040 2949 2885 2807 2716 2401 2147 1982 1603 1181 801 389 Dapagliflozin 3131 3040 2949 2885 2807 2716 2401 2147 1982 1603 1181 801 389
C Death from Cardiovascular Causes D Death from Any Cause
n engl j med 387;12

30 30
Hazard ratio, 0.88 (95% CI, 0.74–1.05) Hazard ratio, 0.94 (95% CI, 0.83–1.07)
100 25 100 25
Placebo
90 90
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20 20
80 80
15 15
n e w e ng l a n d j o u r na l
Dapagliflozin
70 Placebo 70

of
60 10 60 10
50 Dapagliflozin 50
5 5
40 40
0 0
september 22, 2022

30 0 90 180 270 360 450 540 630 720 810 900 990 1080 30 0 90 180 270 360 450 540 630 720 810 900 990 1080

m e dic i n e

20 20
10 10
0 0
0 90 180 270 360 450 540 630 720 810 900 990 1080 0 90 180 270 360 450 540 630 720 810 900 990 1080
Days since Randomization Days since Randomization
No. at Risk No. at Risk
Placebo 3132 3096 3054 3008 2957 2872 2570 2314 2157 1759 1306 910 451 Placebo 3132 3097 3058 3012 2962 2877 2575 2319 2161 1762 1309 910 451
Dapagliflozin 3131 3091 3046 3006 2960 2892 2584 2339 2171 1775 1312 903 441 Dapagliflozin 3131 3093 3048 3009 2962 2895 2587 2342 2174 1778 1314 905 443
Figure 1 (facing page). Efficacy Outcomes in the Overall among patients with heart failure and a left
Population. ventricular ejection fraction of 40% or less.1 The
Shown are time-to-event curves for the primary outcome results of the DELIVER trial extend those of the
(Panel A), individual components of the primary outcome DAPA-HF trial to patients with heart failure and
(worsening heart failure [Panel B] and cardiovascular a left ventricular ejection fraction of more than
death [Panel C]), and death from any cause (Panel D).
40% and are consistent with the overall results
The insets show the same data on an expanded y axis.
of the EMPEROR-Preserved trial (Empagliflozin
Outcome Trial in Patients with Chronic Heart
patient data were censored at the time of Failure with Preserved Ejection Fraction), which
Covid-19 diagnosis showed similar results (Ta- assessed the effects of empagliflozin in patients
ble S6). Overall results were similar when death with a left ventricular ejection fraction of more
from noncardiovascular causes was taken into than 40%.10 The rationale for the dual primary
account as a competing risk (subdistribution analyses in our trial (i.e., evaluation of the pri-
hazard ratio, 0.82; 95% CI, 0.73 to 0.92). The mary outcome in patients with a left ventricular
results of the assessment of the proportional- ejection fraction of less than 60% in addition to
hazards assumption are provided in the Supple- the overall patient population) was based on
mentary Appendix. concern about a potential declining benefit in
patients with an ejection fraction in the normal
Safety range that had been observed in several previous
Overall, serious adverse events, including death, trials of neurohormonal modulators.6,15 Although
were reported in 1361 patients (43.5%) in the the EMPEROR-Preserved trial suggested some
dapagliflozin group and in 1423 patients (45.5%) potential attenuation of benefit in the highest part
in the placebo group (Table 2). Adverse events of the range of ejection fraction,8 we observed no
that led to discontinuation of dapagliflozin or evidence of heterogeneity with respect to left
placebo were reported in 182 patients (5.8%) in ventricular ejection fraction in the DELIVER trial,
the dapagliflozin group and in 181 patients with similar overall treatment effects among
(5.8%) in the placebo group (Table S7). patients with a left ventricular ejection fraction
of 60% or more and those with a left ventricular
ejection fraction of less than 60%. This finding
Discussion
suggests that the benefit of SGLT2 inhibition is
In this randomized, placebo-controlled trial in- likely to extend throughout the full range of
volving patients with heart failure and a mildly ejection fraction.
reduced or preserved ejection fraction, dapa- The DELIVER trial was designed with broader
gliflozin resulted in a lower risk of the primary inclusion criteria than those used in previous
composite outcome, worsening heart failure or trials involving similar populations in that we en-
cardiovascular death, than placebo, with no ap- rolled patients who were hospitalized or recently
preciable difference in benefit among patients hospitalized, for whom evidence-based therapy
with a left ventricular ejection fraction of 60% or is limited, as well as those with heart failure and
more and those with a left ventricular ejection a left ventricular ejection fraction that had im-
fraction of less than 60%, or in other subgroups. proved to more than 40% at the time of enroll-
Each of the three components of this composite ment.4 Our data suggest that these understudied
outcome was less common in the dapagliflozin groups also benefit from dapagliflozin.
group than in the placebo group. In addition, The most recent guidelines of the American
dapagliflozin resulted in fewer total worsening Heart Association, American College of Cardiol-
heart failure events and cardiovascular deaths ogy, and Heart Failure Society of America desig-
and a lower symptom burden than placebo. The nated SGLT2 inhibitors as class IIA, level B, for
incidence of adverse events was similar to that in the treatment of heart failure with a mildly re-
the placebo group. duced or preserved left ventricular ejection frac-
In a previous trial (DAPA-HF; Dapagliflozin tion.4 The results of the DELIVER trial may in-
and Prevention of Adverse Outcomes in Heart form future guidelines and provide further
Failure), dapagliflozin reduced the risk of wors- guidance for their broader use in clinical prac-
ening heart failure or cardiovascular death tice. Although the risk of cardiovascular death

Subgroup Dapagliflozin Placebo Hazard Ratio (95% CI)

no. of patients with events/total no.
All patients 512/3131 610/3132 0.82 (0.73–0.92)
Age
≤72 yr 247/1545 306/1604 0.82 (0.69–0.97)
>72 yr 265/1586 304/1528 0.81 (0.69–0.96)
Sex
Female 195/1364 243/1383 0.81 (0.67–0.97)
Male 317/1767 367/1749 0.82 (0.71–0.96)
Race
Asian 97/630 106/644 0.91 (0.69–1.21)
Black 21/81 19/78 1.08 (0.58–2.01)
White 372/2214 461/2225 0.79 (0.69–0.90)
Other 22/206 24/185 0.83 (0.46–1.48)
Geographic region
Europe or Saudi Arabia 261/1494 309/1511 0.83 (0.70–0.98)
Asia 92/607 103/619 0.89 (0.67–1.18)
Latin America 70/602 87/579 0.78 (0.57–1.07)
North America 89/428 111/423 0.75 (0.57–1.00)
NYHA class at enrollment
II 331/2314 411/2399 0.81 (0.70–0.94)
III or IV 181/817 198/732 0.80 (0.65–0.98)
LVEF at enrollment
≤49% 207/1067 229/1049 0.87 (0.72–1.04)
50–59% 174/1133 211/1123 0.79 (0.65–0.97)
≥60% 131/931 170/960 0.78 (0.62–0.98)
NT-proBNP at enrollment
≤1011 pg/ml 173/1555 208/1578 0.84 (0.68–1.02)
>1011 pg/ml 339/1576 402/1553 0.79 (0.69–0.92)
Enrollment during or within 30 days after
hospitalization for heart failure
No 419/2803 497/2806 0.82 (0.72–0.94)
Yes 93/328 113/326 0.78 (0.60–1.03)
Type 2 diabetes mellitus at enrollment
No 242/1730 293/1727 0.81 (0.68–0.96)
Yes 270/1401 317/1405 0.83 (0.70–0.97)
Atrial fibrillation or flutter at enrollment ECG
No 285/1803 339/1814 0.82 (0.70–0.96)
Yes 227/1327 271/1317 0.81 (0.68–0.97)
Body-mass index at enrollment
<30 275/1734 302/1736 0.89 (0.75–1.04)
≥30 236/1395 308/1392 0.74 (0.63–0.88)
Estimated GFR at enrollment
<60 ml/min/1.73 m2 289/1516 355/1554 0.81 (0.69–0.94)
≥60 ml/min/1.73 m2 223/1615 255/1577 0.84 (0.70–1.00)
Systolic blood pressure at randomization
≤128 mm Hg 280/1568 300/1590 0.93 (0.79–1.10)
>128 mm Hg 232/1563 310/1542 0.71 (0.60–0.85)
Previous LVEF ≤40%
No 420/2559 491/2553 0.84 (0.73–0.95)
Yes 92/572 119/579 0.74 (0.56–0.97)
0.50 0.75 1.00 1.50 2.00
Dapagliflozin Better Placebo Better
was not significantly lower with dapagliflozin ventricular ejection fraction of more than 40%
than with placebo, the rate of cardiovascular than among those in the DAPA-HF trial with a
death among patients who received placebo was reduced ejection fraction (3.8 events per 100
substantially lower among patients with a left patient-years in DELIVER vs. 7.9 events per 100

Figure 2 (facing page). Primary Outcome in Prespecified population percentage on a regional basis (Table
Subgroups. S8). Owing to the Covid-19 pandemic, assess-
The primary outcome was a composite of worsening ment of symptom burden was limited to patients
heart failure, which was defined as either an unplanned for whom an 8-month assessment was planned
hospitalization for heart failure or an urgent visit for or performed before March 11, 2020, although
heart failure, or cardiovascular death. Race was reported
results were similar in all patients for whom
by the investigators. The body-mass index is the weight
in kilograms divided by the square of the height in meters. data were available. Because all the subgroups in
The size of the boxes is proportional to the number of the DELIVER trial were underpowered, within-
patients in the subgroup, and arrows on the confidence subgroup results should be interpreted cau-
interval bars indicate that the upper or lower boundary tiously.
of the confidence interval is off the scale. One patient
Among patients with heart failure and a
in the placebo group who had New York Heart Associa-
tion (NYHA) class I disease at baseline was not included mildly reduced or preserved ejection fraction,
in the analysis of NYHA class at enrollment. ECG denotes dapagliflozin resulted in a lower risk of the pri-
electrocardiography, GFR glomerular filtration rate, LVEF mary composite outcome (worsening heart fail-
left ventricular ejection fraction, and NT-proBNP N-termi- ure or cardiovascular death), in fewer worsening
nal pro–B-type natriuretic peptide.
heart failure events and cardiovascular deaths,
and in a lower symptom burden, with no excess
of adverse events. Findings were consistent
patient-years in DAPA-HF), and DELIVER was across prespecified subgroups, including those
not powered to assess the effect of dapagliflozin defined according to left ventricular ejection
on cardiovascular death alone. Trials in higher- fraction. These data provide further evidence to
risk populations, or of longer duration, or support the use of an SGLT2 inhibitor as es-
pooled analyses of several trials would be need- sential therapy in patients with heart failure,
ed for robust evaluation of benefits with respect regardless of the presence or absence of type 2
to mortality. diabetes mellitus or left ventricular ejection
This trial has some limitations. The use of fraction.
specific inclusion and exclusion criteria may have Supported by AstraZeneca.
limited the generalizability of our findings. Less Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
than 5% of the patients enrolled were Black, al- A data sharing statement provided by the authors is available
though this percentage was proportional to the 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., Jaro-
slaw 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., Na-
talia Zaozerska, M.D., Ph.D., Erasmus Bachus, M.D., Ph.D., Daniel Lindholm, M.D., Ph.D., Magnus Petersson, M.D., Ph.D., and
Anna Maria Langkilde, M.D., Ph.D.
The authors’ affiliations are as follows: the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Bos-
ton (S.D.S., B.C., A.S.D., M.V.); the British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and
Metabolic Health, University of Glasgow, Glasgow, Scotland, United Kingdom (J.J.V.M., P.S.J.); the Department of Cardiology, Univer-
sity 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.); Na-
tional University of Cordoba, Cordoba (F.M.), and Jefe de Unidad de Insuficiencia Cardíaca, Centro de Educación Médica e Investiga-
ciones 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 and
the 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, Târgu
Mureş, Romania (D. Dobreanu); the Department of Cardiology, Medical University Lodz, Lodz, Poland (J.D.); University of Utah Medi-
cal Center, Salt Lake City (J.C.F.); Centro de Estudios Clínicos de Querétaro, Querétaro, Mexico (M.A.A.-G.); the Cardiac Sciences De-
partment, King Saud University, Riyadh, Saudi Arabia (W.A.H.); the Cardiovascular Research Institute and Department of Cardiology,

General Hospital of Northern Theater Command, Shenyang, China (Y.H.); Clínica Vesalio, San Borja, Peru (J.W.C.H.); the Department
of Cardiovascular Diseases, Cardiac Intensive Care, University Hospitals Leuven, Leuven, Belgium (S.P.J.); the Department of Noninva-
sive 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 Mon-
tréal, 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 Myo-
cardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow (S.N.T.); the Minneapolis Veterans Affairs
Center for Care Delivery and Outcomes Research, University of Minnesota, Minneapolis (O.V.); Cardiovascular Center, Tam Anh Hos-
pital, Tan Tao University, Tan Duc, Vietnam (V.N.P.); and Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharma-
ceuticals Research and Development, AstraZeneca, Gothenburg, Sweden (U.W., N.Z., E.B., D.L., M.P., A.M.L.).
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The n e w e ng l a n d j o u r na l of m e dic i n e

Dapagliflozin in Heart Failure with Mildly

RESULTS Veeva ID: Z4-54232

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Table 1. Characteristics of the Patients at Baseline.*

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Hazard or Rate Ratio

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dapagliflozin or placebo that was suggestive of volume depletion

Copyright © 2022 Massachusetts Medical Society. All rights reserved.

Cumulative Incidence (%)

Days since Randomization Days since Randomization

C Death from Cardiovascular Causes D Death from Any Cause

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september 22, 2022

Copyright © 2022 Massachusetts Medical Society. All rights reserved.

Cumulative Incidence (%)

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Subgroup Dapagliflozin Placebo Hazard Ratio (95% CI)

Dapagliflozin Better Placebo Better

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The New England Journal of Medicine

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