The n e w e ng l a n d j o u r na l of m e dic i n e

cular outcomes in the low-risk trial population, 3. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines
on diabetes, pre-diabetes, and cardiovascular diseases developed
so there are unanswered questions beyond those in collaboration with the EASD. Eur Heart J 2020;​41:​255-323.
related to microvascular outcomes. With respect 4. Standl E, Schnell O, McGuire DK, Ceriello A, Rydén L. Inte-
to the metabolic outcomes, the fact that all four gration of recent evidence into management of patients with
atherosclerotic cardiovascular disease and type 2 diabetes. Lan-
randomly assigned glucose-lowering agents ap- cet Diabetes Endocrinol 2017;​5:​391-402.
peared to be equivalent in their effects, including 5. UK Prospective Diabetes Study (UKPDS) Group. Effect of in-
their effects on the risk of hypoglycemia, is of tensive blood-glucose control with metformin on complications
in overweight patients with type 2 diabetes (UKPDS 34). Lancet
great clinical importance. The data confirm that 1998;​352:​854-65.
older generic or biosimilar low-cost agents still 6. Ahlqvist E, Storm P, Käräjämäki A, et al. Novel subgroups of
have a role in the treatment of persons with adult-onset diabetes and their association with outcomes: a da-
ta-driven cluster analysis of six variables. Lancet Diabetes Endo-
early type 2 diabetes who are at low cardiovas- crinol 2018;​6:​361-9.
cular risk. 7. D’Alessio D, Häring H-U, Charbonnel B, et al. Comparison
Disclosure forms provided by the authors are available with of insulin glargine and liraglutide added to oral agents in pa-
the full text of this editorial at NEJM.org. tients with poorly controlled type 2 diabetes. Diabetes Obes
Metab 2015;​17:​170-8.
From the Department of Medicine, Solna, Karolinska Institutet, 8. Monnier L, Lapinski H, Colette C. Contributions of fasting
Stockholm (L.R.), and the Diabetes Research Group at Munich, and postprandial plasma glucose increments to the overall diur-
Helmholtz Center, Neuherberg, Germany (E.S.). nal hyperglycemia of type 2 diabetic patients: variations with
increasing levels of HbA(1c). Diabetes Care 2003;​26:​881-5.
1. The GRADE Study Research Group. Glycemia reduction in 9. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide
type 2 diabetes — glycemic outcomes. N Engl J Med 2022;​387:​ and renal outcomes in type 2 diabetes: an exploratory analysis of
1063-74. the REWIND randomised, placebo-controlled trial. Lancet 2019;​
2. The GRADE Study Research Group. Glycemia reduction in 394:​131-8.
type 2 diabetes — microvascular and cardiovascular outcomes. DOI: 10.1056/NEJMe2210531
N Engl J Med 2022;​387:​1075-88. Copyright © 2022 Massachusetts Medical Society.

DELIVERing Progress in Heart Failure

with Preserved Ejection Fraction
Kenneth B. Margulies, M.D.

More than 6 million adults in the United States
have heart failure, accounting for at least 800,000
hospitalizations annually.1 More than half of
these persons have heart failure with a preserved
left ventricular ejection fraction.1 As the popula-
tion ages, the overall prevalence of patients with
heart failure and a preserved ejection fraction is
increasing.1,2 Heart failure with a preserved ejec-
tion fraction is associated with substantial func-
tional and quality-of-life impairments that are at
least equivalent to those of patients with heart
failure and a reduced ejection fraction.2 One-year
mortality among patients with heart failure and
a preserved ejection fraction is between 20% and
29%.2 Until recently, several agents that were
known to improve outcomes among patients with
heart failure and a reduced ejection fraction failed
to establish clear benefit among patients with
heart failure and a preserved ejection fraction.3
In contrast, sodium–glucose cotransporter 2
(SGLT2) inhibitors, which were initially developed
for the treatment of type 2 diabetes mellitus,
have produced remarkable benefits among pa-
tients with heart failure and a reduced ejection
fraction, as well as among those with heart
failure and a preserved ejection fraction, with or
without diabetes.4 Specifically, multiple trials in
which empagliflozin, dapagliflozin, or cana-
gliflozin was evaluated in patients with heart
failure and a reduced ejection fraction showed
positive results. Subsequently, the EMPEROR-
Preserved trial (Empagliflozin Outcome Trial in
Patients with Chronic Heart Failure with Pre-
served Ejection Fraction) showed that empa-
gliflozin reduced the combined risk of cardio-
vascular death or hospitalization for heart failure
in patients with a mildly reduced ejection frac-
tion (left ventricular ejection fraction of >40%)
or a preserved ejection fraction (left ventricular
ejection fraction of ≥50%).5
In an article now published in the Journal,
Solomon and colleagues6 report the key findings

1138 n engl j med 387;12  nejm.org  September 22, 2022

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 Editorials
of the DELIVER trial (Dapagliflozin Evaluation
to Improve the Lives of Patients with Preserved
Ejection Fraction Heart Failure). This was a large,
international, multicenter, randomized trial in
which dapagliflozin was compared with placebo
in patients with heart failure and a mildly re-
duced or preserved left ventricular ejection frac-
tion. Randomization of 6263 patients enrolled
across 350 sites in 20 countries produced well-
matched cohorts. At the end of the trial, the vital
status was known in all but 4 patients. Treat-
ment with dapagliflozin resulted in a lower risk
of the primary composite outcome — worsening
heart failure (defined as hospitalization for heart
failure or an urgent visit for heart failure) or
cardiovascular death — than placebo in the
overall cohort and in several subgroups.
Because the design of the DELIVER trial was
similar to that of the EMPEROR-Preserved trial,
it is important to clarify similarities and distinc-
tions. Both trials examined a selective oral SGLT2
inhibitor in patients with heart failure and a left
ventricular ejection fraction of more than 40%,
with similar inclusion and exclusion criteria and
a similar primary composite outcome. The main
features of the DELIVER trial that distinguished
it from the EMPEROR-Preserved trial were the
use of dapagliflozin in the DELIVER trial rather
than empagliflozin and the inclusion of patients
who previously had a left ventricular ejection
fraction of 40% or less that subsequently improved
to more than 40% (i.e., patients with heart fail-
ure and an improved left ventricular ejection frac-
tion). Beyond affirming several findings from the
EMPEROR-Preserved trial, the prespecified sub-
group analyses in the DELIVER trial showed
new findings of benefit among patients with a
left ventricular ejection fraction of 60% or more
and among those with a left ventricular ejection
fraction that had improved to more than 40%.
In additional prespecified subgroup analyses,
the DELIVER trial extended the results of the
EMPEROR-Preserved trial by showing a clear
benefit among patients with a body-mass index
(the weight in kilograms divided by the square
of the height in meters) of 30 or higher and
among those with more severe symptoms (New
York Heart Association class III or IV).
The observed benefit of dapagliflozin among
patients with symptomatic heart failure and an
improved left ventricular ejection fraction merits
particular attention. Owing to the success of the
n engl j med 387;12  nejm.org  September 22, 2022
The New England Journal of Medicine
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
several proven treatments for patients with heart
failure and a reduced ejection fraction — includ-
ing medications, devices, and revascularization,
when appropriate — those with a left ventricular
ejection fraction that has improved by at least
10%, to 40% or more, represent a growing co-
hort of patients with heart failure.7 Such patients
are typically excluded from clinical trials of treat-
ments for heart failure and a preserved ejection
fraction. However, recent reviews and guidelines
highlight the fact that patients with heart failure
and an improved left ventricular ejection fraction
have worse outcomes than patients with no his-
tory of heart failure, even when the left ventricu-
lar ejection fraction has improved to within the
normal range.7,8 Building on trials that show
that outcomes worsen when disease-modifying
therapy is discontinued in patients with heart
failure and an improved left ventricular ejection
fraction,9 the DELIVER trial shows that the addi-
tion of an SGLT2 inhibitor provides further
benefit among those with residual symptoms of
heart failure. In this context, the DELIVER trial
should inspire future trials of promising thera-
peutics for heart failure with a preserved ejec-
tion fraction that would include the important
and growing contingent of patients with heart
failure and an improved left ventricular ejection
fraction.
Despite progress to date, more work is need-
ed to fully define the role of SGLT2 inhibitors in
patients with heart failure and a preserved ejec-
tion fraction. Owing to the very low enrollment
of patients who identified as Black in both the
DELIVER trial and the EMPEROR-Preserved trial,
it is still not known whether this patient sub-
group benefits from treatment with SGLT2 in-
hibitors. It is also unknown whether the benefits
of SGLT2 inhibitors extend to patients with heart
failure and a preserved ejection fraction due to
cardiomyopathies (e.g., hypertrophic cardiomy-
opathy and restrictive cardiomyopathies due to
amyloidosis, sarcoidosis, or other causes), since
patients with these cardiomyopathies were ex-
cluded from both trials. Finally, there is a need
to better define the mechanisms by which SGLT2
inhibitors provide therapeutic benefit among
patients with heart failure and a preserved ejec-
tion fraction. Because SGLT2 inhibitors were
developed as hypoglycemic agents and were
fortuitously found to improve cardiovascular
outcomes during postmarketing safety trials,
1139
 Editorials

trials that are designed to define the mecha-
nisms that result in cardiovascular benefits have
lagged behind those designed to show improved
clinical outcomes. From this perspective, the
impressive and accumulating clinical successes
with SGLT2 inhibitors are both inspiring and
humbling.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Cardiovascular Institute, Perelman School of Medi- with recovered left ventricular ejection fraction: JACC scientific
cine, University of Pennsylvania, Philadelphia.
This editorial was published on August 27, 2022, at NEJM.org.
1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and
stroke statistics — 2020 update: a report from the American
Heart Association. Circulation 2020;​141(9):​e139-e596.
2. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart
failure with preserved ejection fraction. Nat Rev Cardiol 2017;​14:​
591-602.
3. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guide- DOI: 10.1056/NEJMe2210177
lines for the diagnosis and treatment of acute and chronic heart Copyright © 2022 Massachusetts Medical Society.
failure: the task force for the diagnosis and treatment of acute
and chronic heart failure of the European Society of Cardiology
(ESC) developed with the special contribution of the Heart Fail-
ure Association (HFA) of the ESC. Eur Heart J 2016;​37:​2129-200.
4. Braunwald E. Gliflozins in the management of cardiovascu-
lar disease. N Engl J Med 2022;​386:​2024-34.
5. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart
failure with a preserved ejection fraction. N Engl J Med 2021;​
385:​1451-61.
6. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin
in heart failure with mildly reduced or preserved ejection frac-
tion. N Engl J Med 2022;​387:​1089-98.
7. Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart failure
expert panel. J Am Coll Cardiol 2020;​76:​719-34.
8. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/
HFSA guideline for the management of heart failure: executive
summary: a report of the American College of Cardiology/Amer-
ican Heart Association Joint Committee on Clinical Practice
Guidelines. Circulation 2022;​145(18):​e876-e894.
9. Halliday BP, Wassall R, Lota AS, et al. Withdrawal of phar-
macological treatment for heart failure in patients with recov-
ered dilated cardiomyopathy (TRED-HF): an open-label, pilot,
randomised trial. Lancet 2019;​393:​61-73.

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