European Heart Journal (2023) 00, 1–12 STATE OF THE ART REVIEW

https://doi.org/10.1093/eurheartj/ehad389 Heart failure and cardiomyopathies

Mechanisms of benefits of sodium-glucose

cotransporter 2 inhibitors in heart failure with
preserved ejection fraction
Arjun K. Pandey1, Deepak L. Bhatt 2, Avinash Pandey3, Nikolaus Marx 4
,
Francesco Cosentino 5,6, Ambarish Pandey7, and Subodh Verma 8*
1
Michael G. DeGroote School of Medicine, McMaster University, 90 Main Street West, Hamilton, Ontario L8P 1H6, Canada; 2Mount Sinai Heart, Icahn School of Medicine at Mount Sinai
Health System, 1 Gustave L. Levy Place, New York, NY 10029, USA; 3Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada;
4
Department of Internal Medicine, University Hospital Aachen, RWTH Aachen University, Templergraben 55, 52062 Aachen, Germany; 5Division of Cardiology, Department of Medicine,
Solna, Karolinska Institutet, Norrbacka S1:02, Stockholm, SE 17177, Sweden; 6Heart, Vascular and Neuro Theme, Department of Cardiology, Karolinska University Hospital, Anna Steckséns
gata 41, 171 64 Solna, Sweden; 7Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; and
8
Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, ON, Canada

Received 9 December 2022; revised 7 March 2023; accepted 29 May 2023

Abstract

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) in-
hibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the
landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease pro-
gression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors
have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and
autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce
epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with
SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through in-
direct mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been
shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 in-
hibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will
likely become foundational in the therapy of HFpEF.

* Corresponding author. Tel: +4168645997, Fax: +4168645881, Email: subodh.verma@unityhealth.to

© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
2 Pandey et al.
Graphical Abstract
HFpEF and diastolic
dysfunction
Oxidative stress, inflammation, fibrosis
Cardiac remodelling and hypertrophy
Myofilament stiffness
Impaired energetics
Ionic imbalances
Pathophysiology of heart failure with preserved ejection fraction (HFpEF) and mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
cGMP, cyclic guanosine monophosphate; NO, nitric oxide; PKG, protein kinase G; sGC, soluble guanylate cyclase.
.............................................................................................................................................................................................
Keywords Heart Failure • SGLT2 Inhibitor • HFpEF • Diabetes Mellitus
Heart failure is associated with an impaired quality of life, frequent hos-
pitalizations, and increased mortality.1 Disease-modifying therapies for
heart failure have traditionally consisted of neurohormonal modulators,
which inhibit the renin–angiotensin–aldosterone (RAAS) or adrenergic
systems.2,3 In patients with heart failure and a reduced ejection fraction
(HFrEF), these therapies have proved unambiguously beneficial, result-
ing in striking reductions in mortality.3 The benefit of such therapies in
patients who have heart failure and a preserved ejection fraction
(HFpEF) has been less robust.3,4 Prognosis in these patients has re-
mained poor and effective; disease-modifying therapies have remained
elusive.3,4 Over the past decade, sodium-glucose cotransporter 2
(SGLT2) inhibitors have shown clinical benefit in patients with heart fail-
ure across the entire spectrum of ejection fraction, and among patients
with worsening heart failure and acute heart failure.5–10 Several land-
mark trials, DELIVER, EMPEROR-Preserved, and SOLOIST-WHF,
showed significant reductions in the composite of heart failure hospital-
ization/cardiovascular death with these agents in patients with
HFpEF.6,8,9 In this state-of-the-art review, we will summarize the recent
results of SGLT2 inhibitors, discuss mechanisms of these agents in
HFpEF, as well as future directions.
Mechanisms of heart failure with
preserved ejection fraction
The mechanisms and pathophysiology underlying HFpEF have been
reviewed in detail previously and will only be briefly summarized
here.4,11–13 HFpEF traditionally described patients with an ejection frac-
tion greater than 40%, although heart failure with mildly reduced
(∼40%–49%) and improved ejection have recently been characterized
Mechanisms of SGLT2 inhibitors
in HFpEF
Improved NO-sGC-cGMP-PKG signaling
Improved metabolism and energetics
Reduced renal deterioration
Increased autophagic flux
Improved diastolic function
Reduced oxidative stress and inflammation
as clinically distinct phenotypes.14 Some patients with an ejection frac-
tion >40% have clinical signs and symptoms of heart failure secondary
to another disorder such as infiltrative cardiomyopathies (including
hemochromatosis or amyloidosis) or other cardiac conditions such
as valvular heart disease, hypertrophic cardiomyopathy, or pericardial
disease.15 In patients with such conditions, the mechanisms described
below may not be applicable.
There are a variety of pathophysiological processes, which contrib-
ute to the syndrome of HFpEF (Figure 1); there is likely heterogeneity
in the degree to which specific mechanisms contribute to disease in in-
dividual patients. Diastolic dysfunction is a hallmark of HFpEF; the land-
mark invasive study of Zile et al.16 showed impaired active relaxation
and increased passive stiffness in patients with HFpEF. Adverse remod-
elling and dysfunction are not just seen in the left ventricle but also in
the atria and vasculature.4,11,12,17,18 This may be accompanied by other
processes, which contribute to the progression of HFpEF including neu-
rohormonal activation, chronotropic incompetence, atrial arrythmias,
and renal dysfunction.4,11–13,18,19
Cellular and molecular mechanisms underlying HFpEF have been
thoroughly reviewed in the past.11,13,20–22 Adverse changes to cardio-
myocyte structure, function, and energetics in addition to changes in the
extracellular matrix contribute to diastolic dysfunction in HFpEF.23 One
key mediator of intrinsic cardiomyocyte stiffness in HFpEF is the giant elas-
tic, cytoskeletal protein titin; dysregulation of the NO-sGC-cGMP-PKG
pathway contributes to titin hypophosphorylation and isoform switching
between the compliant N2BA and stiff N2B states.13,22 Increased collagen-
dependent stiffness secondary to inflammatory and fibrotic processes
also contribute to diastolic dysfunction in HFpEF.13,22 Finally, alterations
in cardiomyocyte energetics and ionic homeostasis are other key mechan-
isms that may also contribute to HFpEF.13,24
Mechanisms of benefits of SGLT2 inhibitors in heart failure with preserved ejection fraction 3

Figure 1 Risk factors and pathophysiological mechanisms of heart failure with preserved ejection fraction. DM, diabetes mellitus; HFpEF, heart failure
with preserved ejection fraction; MI, myocardial infarction; OSA, obstructive sleep apnea; RAAS, renin–angiotensin–aldosterone system

Sodium-glucose cotransporter 2 to be consistent across the spectrum of mildly reduced or preserved

inhibitors in HFpEF: a serendipitous
discovery
The SGLT2 inhibitors were originally investigated in patients with type
2 diabetes mellitus. These agents were found to improve key outcomes
including cardiovascular death, and unexpectedly reduced hospitaliza-
tions for heart failure as well.25,26 Subgroup analyses of patients with
heart failure, including HFpEF specifically, suggested that these agents
may improve outcomes in these settings.27,28 Clinical evaluation of
these agents proceeded to patients with HFrEF as well as those with
chronic kidney disease (CKD). The SGLT2 inhibitors proved beneficial
in HFrEF, reducing the composite of heart failure hospitalization/cardio-
vascular death in the EMPEROR-Reduced and DAPA-HF trials.5,7 These
agents also slowed the rate of kidney function deterioration as well as
improved heart failure outcomes in patients with CKD.29–31 In the
SOLOIST-WHF and EMPULSE trials, which included patients across
the spectrum of ejection fraction, SGLT2 inhibitors improved out-
comes in patients with worsening heart failure or acute heart failure,
respectively.9,10 Finally, the landmark EMPEROR-Preserved and
DELIVER trials both demonstrated significant reductions in their pri-
mary outcomes (cardiovascular death or hospitalization [+/− urgent
visit] for heart failure) with SGLT2 inhibitors in HFpEF in addition to
modest improvements in symptom burden measured by the Kansas
City Cardiomyopathy Questionnaire score.6,8 These results appear
ejection fraction (41%–49%, 50%–60%, and >60%) as well as in a var-
iety of sub-groups based on sex, race, and presence of comorbidities
such as diabetes mellitus or atrial fibrillation.6,8,32
While a five-trial meta-analysis of patients with heart failure across
the entire ejection fraction spectrum did show a reduction in all-cause
mortality with SGLT2 inhibitors, in a two-trial meta-analysis of only pa-
tients with HFpEF (EMPEROR-Preserved and DELIVER), no significant
reduction in all-cause mortality and only a statistically borderline effect
on cardiovascular death was observed.32 The magnitude of effect and
absolute reduction in heart failure event rates with SGLT2 inhibitors
was lower than that seen in trials of RAAS inhibitors or beta-blockers
in HFrEF patients, many of which were stopped early due to clear evi-
dence of benefit with treatment.33–35 The clinical benefits with SGLT2
inhibitors in heart failure were notably, however, observed in trials in
which the vast majority of patients were already being treated with
both an angiotensin-converting enzyme inhibitor/angiotensin receptor
blocker/angiotensin receptor–neprilysin inhibitor (∼80%–95%) and a
beta-blocker (∼80%–95%) with a significant proportion of patients
treated with a mineralocorticoid receptor antagonist (∼35%–70%) as
well.32 Heart failure hospitalization/cardiovascular death or a similar
composite has been the primary outcome of many large trials evaluating
other classes of heart failure therapies in HFpEF (including
CHARM-Preserved, TOPCAT, and PARAGON-HF).36–38
Hospitalization due to heart failure was, however, only one cause for
hospital admission in patients with HFpEF, a population of patients
4 Pandey et al.
often with many comorbidities and risk factors for other cardiac and
non-cardiac events.39
In summary, over the past decade, SGLT2 inhibitors have emerged un-
expectedly as a therapy for heart failure. These drugs were subsequently
prospectively evaluated in over 12 000 patients with HFpEF in two land-
mark Phase III trials where they proved efficacious. As these trial results
are incorporated into clinical guidelines around the world, SGLT2 inhibi-
tors are likely to become important mainstays of therapy in HFpEF.
Mechanisms of sodium-glucose
cotransporter 2 inhibitors in heart
failure with preserved ejection
fraction
The mechanisms underlying clinical benefit with SGLT2 inhibitors in
HFpEF are complex and likely multifactorial (Graphical Abstract).
Attempts to tease apart the mechanisms of these agents have involved
investigations in preclinical models, mechanistic trials including evalu-
ation of proteomics and cardiac remodelling in human patients, in add-
ition to extrapolation from trials conducted in other populations (such
as HFrEF and diabetes mellitus/cardiovascular disease). Given the re-
markable consistency in benefits of SGLT2 inhibitors observed in pa-
tients with heart failure across the entire spectrum of reduced to
preserved ejection fraction, there is likely significant overlap in the
underlying mechanisms of SGLT2 inhibitors in patients with HFrEF
and those with HFpEF.32,40 These two entities share many common
risk factors (including hypertension, diabetes mellitus, and CKD), and
while amelioration of these traditional risk factors may play some
role in the robust effect of these medications, translational research
as well as the rapid time course of clinical benefit and remodelling
seen with these drugs suggest there are additional mechanisms at play.
Here, we will summarize mechanisms, which may contribute to the
benefit of SGLT2 inhibitors in HFpEF with a focus on direct and indirect
myocardial effects related to metabolism, energetics, autophagic flux,
ionic homeostasis, inflammation, oxidative stress, and cardiac remodel-
ling (Figure 2).
Blood pressure, blood sugar, and
kidney function
The SGLT2 inhibitors improve many traditional risk factors for HFpEF
including blood pressure and blood sugar.41 However, these properties
alone likely do not explain the benefits of this class of drugs in HFpEF.42
The SGLT2 inhibitors have been shown to reduce systolic blood pressure
by an average 4 mmHg as assessed using 24-h ambulatory monitoring.43 In
the EMPEROR-Preserved trial, empagliflozin had similar benefits in pa-
tients with baseline systolic blood pressure below and above the median.8
With regard to blood sugar, other agents that lower glucose to a similar or
even greater degree do not have such potent benefits in heart failure.42
Relative effects of SGLT2 inhibitors in HFpEF in EMPEROR-Preserved
and DELIVER were near identical in patients with and without diabetes
mellitus.6,8
The cardiorenal effects of these drugs are an important consider-
ation given the strong association between CKD and HFpEF. In Phase
III trials, SGLT2 inhibitors have been shown to reduce the rate of de-
cline in kidney function as well as to reduce kidney failure/death in pa-
tients with CKD with or without diabetes; the underlying mechanisms
here are believed to be a reduction in trans-glomerular pressure and
regulation of tubule-glomerular feedback to protect kidney func-
tion.29,31,44–47 This is distinct and may be synergistic with the mechan-
ism of RAAS inhibitors, which reduce hyperfiltration through efferent
vasodilation.45,48 Cardiorenal effects play a major role in heart failure:
kidney dysfunction worsens heart failure, and impaired cardiovascular
function impairs kidney perfusion and function.47,49 This interplay is
mediated through several important factors, many of which are key mar-
kers and therapeutic targets in heart failure including natriuretic peptides
and the adrenergic and RAAS systems.49 Improvement of kidney function
is likely both a contributory mechanism and beneficial by-product of these
drugs in heart failure but does not solely explain their benefits in HFpEF.
The SGLT2 inhibitors were equally beneficial in patients with estimated
glomerular filtration rate below and above 60 mL/min/1.73 m2 in
EMPEROR-Preserved and DELIVER, and have been shown to improve
cardiovascular outcomes throughout the spectrum of kidney function.5,8
Natriuresis/diuresis
Natriuresis/diuresis may be an important contributor to the clinical im-
provement observed with SGLT2 inhibitors in patients with acute heart
failure.50–52 In the EMPA-RESPONSE-AHF trial, empagliflozin signifi-
cantly increased urine output and net fluids loss in patients with acutely
decompensated heart failure over the first 4 days of hospital admission
compared with placebo.53 In the EMPULSE trial of patients admitted to
hospital for acute heart failure, empagliflozin was associated with signifi-
cant weight loss by Day 15, which was sustained to Day 90 (including
after adjustment for daily loop diuretic dose).54 Significant improve-
ments compared with placebo in both clinical scores and markers
(haematocrit and N-terminal pro-B-type natriuretic peptide) of con-
gestion were also observed with empagliflozin by Day 15.54 The acute
decongestion observed with SGLT2 inhibitors has led to proposed fra-
meworks for incorporating SGLT2 inhibitors into the management of
patients presenting with acutely decompensated heart failure alongside
other diuretics like furosemide and acetazolamide.51
While natriuresis/diuresis may explain the effect of SGLT2 inhibitors
in patients with acute heart failure and may contribute to the rapid
time-course benefit observed with these agents, the available evidence
suggests against diuresis as the primary driving mechanism by SGLT2
inhibitors improves outcomes in chronic heart failure. In the
EMPEROR-Reduced trial, empagliflozin was not more effective in patients
initially identified as having clinical evidence of volume overload (n = 1477)
compared with those initially characterized as euvolemic, and decline in
weight with empagliflozin was similar in patients with and without volume
overload.42,55 In the DELIVER trial, which evaluated dapagliflozin, there was
a similar relative reduction (but greater absolute reduction) in the primary
outcome of worsening heart failure event/cardiovascular death in patients
with recent heart failure hospitalization compared with those without.56
There was no relation between changes in body weight and natriuretic
peptides in EMPEROR-Reduced suggesting against diuresis-induced reduc-
tion in volume overload as the underlying cause of weight loss.55 Sustained
weight reduction with SGLT2 inhibitors may instead be related to loss of
calories through glycosuria and reduction in visceral fat.55,57,58
Metabolism, energetics, and
autophagic flux
The SGLT2 membrane protein resides in the proximal convoluted tu-
bule and is responsible for 90% of glucose reabsorption from the filtrate
Mechanisms of benefits of SGLT2 inhibitors in heart failure with preserved ejection fraction
Figure 2 Mechanisms of SGLT2 inhibitors in heart failure with preserved ejection fraction. HFpEF, heart failure with preserved ejection fraction.
under physiological conditions.59 Renal glycosuria through SGLT2 in-
hibition represents a net loss of calories from the body, and some
have suggested that the SGLT2 protein may also function as a physio-
logical sensor of nutrient surplus.42,60–62 Inhibition of SGLT2 is there-
fore proposed to induce a state of perceived starvation and hypoxia,
up-regulating signals to induce a ‘fasting’ and ‘hypoxic’-like transcrip-
tional paradigm.42,60–65 This results in adaptions such as increased
erythropoietin (EPO) levels and ketogenesis.42,60–62 The majority of
cardiac energy is normally generated from fatty acid oxidation; in the
failing heart, fatty acid oxidation is reduced, and alternative pathways
including glucose metabolism and anaerobic glycolysis are relied
upon.66,67 The SGLT2 inhibitors increase serum ketone bodies, which
represent additional source of energy for the failing heart.66,68 Ketone
bodies have been shown to increase cardiac contractility and have im-
portant signalling roles as well, triggering cellular processes like
autophagy.66,68
The downstream effects of the fasting and hypoxic-like transcription-
al paradigms have been suggested to be a key aspect of SGLT2 inhibi-
tors, which may be mediated at a cellular level through autophagic
flux.60,62,63 This is a cellular degradation process mediated by lysosomes
by which cells recycle organelles, proteins, and debris to generate en-
ergy, and is triggered in response to cellular stress including perceived
nutritional depletion and hypoxia. Induction of autophagy can also con-
tribute to degradation of dysfunctional mitochondria and subsequent
5
reduction in oxidative stress.60,62,63 This cellular process is impaired
in the failing myocardium, and induction of autophagy by SGLT2 inhibi-
tors may contribute to the improvements in cardiac function observed
with these drugs.69–71 Several of the most widely discussed cellular
mediators thought to mediate this effect are the nutrient-deprivation
sensors AMPK and sirtuins (SIRT1, SIRT3, and SIRT6) as well as
hypoxia-inducible factors (HIF) and mammalian target of rapamycin
(mTOR). Regulation of these mediators, which are all involved in maintain-
ing homeostasis of energy, metabolism, and oxygen, is dysfunctional in
heart failure, which contributes to the development of cardiomyop-
athy.65,69 Mechanistic studies demonstrate that SGLT2 inhibitors increase
the activities of AMPK, sirtuins, and HIFs and decrease phosphorylation/ac-
tivation of mTOR in the myocardium as well as in other tissues, which may
at least partially underlie their benefit on organ function.72–80 The totality
of evidence on this topic has recently been reviewed in great detail.80 The
mechanisms by which SGLT2 inhibitors promote autophagy in tissues that
do not express the SGLT2 protein have yet to definitively established; pro-
posed but unproven mechanisms include nutrient-deprivation signalling
secondary to caloric loss, or direct effects of these drugs on other cellular
transporters/proteins such as glucose transporters or sirtuins.80 In sum-
mary, the proposed paradigm is as follows: SGLT2 inhibition enhances au-
tophagic flux and induces a fasting/hypoxic mimicry state resulting in
activation of mediators including AMPK, sirtuins, and HIF, which promote
ketosis and erythropoiesis that lead to reductions in oxidative stress and
6 Pandey et al.
inflammation as well as improved cellular function. This emerging mechan-
ism may explain the beneficial effects of SGLT2 inhibitors on metabolism
and cellular function in tissues/organs (such as the heart) that do not ex-
press the SGLT2 protein and could be a contributing factor to the reduc-
tion in oxidative stress and inflammation observed with these agents.
Recent proteomics analysis from the EMPEROR-Pooled analysis,
which included 535 patients from the EMPEROR-Preserved trial, as-
sessed differential levels of circulating proteins in patients randomized
to empagliflozin compared with placebo at baseline, Week 12 and
Week 52.81 This analysis showed that empagliflozin had substantial ef-
fects on circulating levels of proteins previously shown to be mediators
of cardiac autophagy and apoptosis (including IGFBP1, TfRI, FST, RBP2,
and Mdk) in addition to EPO and other circulating proteins related to
fibrosis, oxidative stress, hypertrophy, and energetics.81
The effect of SGLT2 inhibitors on iron homeostasis and erythrocy-
tosis has proved to be an intriguing development and has recently
been reviewed in detail.82 Iron deficiency is a common comorbidity
among patients with heart failure and is associated with reduced func-
tional status and poor outcomes.83,84 Increasingly, evidence suggests
that iron deficiency in patients with heart failure may be more likely
to be functional (i.e. related to inflammatory-mediated increases in hep-
cidin, resulting in suppression of duodenal iron absorption and release
from hepatocytes and the reticulocyte-endothelial system) rather than
absolute in nature.82 In either case, reduced circulating and bioreactive
cytosolic iron contributes to both anaemia and may impair synthesis of
iron-containing proteins involved in ATP production in cardiomyo-
cytes.82,85 In a preclinical study, iron deficiency has been directly shown
to impair contractility, cellular ATP levels, and ATP-linked respiration in
isolated human cardiomyocytes.85 In several placebo-controlled trials
including analyses from DAPA-HF and the EMPEROR programme,
SGLT2 inhibitors have been consistently shown to decrease circulating
levels of both hepcidin and ferritin, while increasing levels of transferrin
receptor protein 1.81,82,86–89 This combination of findings suggests
SGLT2 inhibitors may alleviate functional iron deficiency, enabling in-
creased iron mobilization and augmenting bioreactive cytosolic iron le-
vels in erythroid precursors and cardiomyocytes.82 While further
research is needed to clarify the mechanisms by which SGLT2 inhibitors
alter iron homeostasis, possible contributors include the reductions in
inflammatory mediators (which may impact ferritin and hepcidin levels)
as well as downstream effects of nutrient-deprivation signalling (includ-
ing SIRT1) induced by SGLT2 inhibition.82 The SGLT2 inhibitors have
also been consistently shown to increase EPO levels, doing so in as little
as 1 month of treatment initiation in the EMPA-HEART CardioLink-6
trial.90 In the DAPA-HF trial, treatment with dapagliflozin led to rises
in haematocrit to the point of correction into the non-anemic range
in 62.2% of patients with anaemia at baseline (compared with 41.1%
in the placebo arm).86 Intriguingly, while treatment with EPO analogues
has not been shown to improve outcomes in heart failure or patients
with diabetes mellitus and CKD, the degree of erythrocytosis/increase
in haematocrit has been strongly associated with improved heart fail-
ure outcomes in the CANVAS program as well as the VERTIS-CV and
EMPA-REG OUTCOME trials.91–95 While correction of anaemia may
result in improved oxygen delivery to the failing myocardium, the as-
sociation between changes in haematocrit and improved outcomes
could also stem from common underlying pathways (i.e. autophagy
signalling pathways and increased cytosolic bioreactive iron available
for iron-dependent proteins in cardiomyocytes) as opposed to repre-
senting a direct causal mechanism.
Other metabolic pathways may contribute to the effects of SGLT2
inhibitors as well. The SGLT2 inhibitors attenuate insulin resistance, which
is associated with poor cardiac function and future risk of HFpEF.96–100 The
SGLT2 inhibitors are also associated with reductions in serum uric acid, al-
though the degree to which this has any clinical significance is unclear.41,101
Uric acid may increase oxidative stress, inflammation, and endothelial dys-
function and is associated with a poor prognosis in heart failure.41,101
Adipose tissue
Epicardial adipose tissue (EAT) is a form of white, visceral adipose tissue
around the heart with important paracrine/vasocrine signalling proper-
ties.102,103 Expansion of this tissue in patients with diabetes mellitus and/
or obesity induces states of insulin resistance, oxidative stress, inflamma-
tion, and fibrosis and alters calcium homeostasis, all of which may contrib-
ute to diastolic dysfunction.102,103 Expansion of EAT has been associated
with a poor prognosis and worse haemodynamic profiles in patients
with HFpEF.104,105 In meta-analyses, SGLT2 inhibitors have been asso-
ciated with reductions in EAT despite having no significant effects on total
body mass index.57,106 The reduction in EAT may contribute to the attenu-
ation of myocardial inflammation and fibrosis observed with SGLT2 inhi-
bitors. In addition to reducing visceral fat, SGLT2 inhibitors also
modulate adipokines levels, increasing levels of adiponectin, an insulin-
sensitizing and anti-inflammatory hormone, and reducing levels of leptin,
a hormone released by adipose tissue in states of nutritional excess.107
Paracrine leptin release from epicardial tissue impairs calcium homeostasis
and induces cardiac fibrosis and microcirculatory dysfunction.108
Inflammation and oxidative stress
The SGLT2 inhibitors are known to decrease oxidative stress and inflamma-
tion.109,110 The SGLT2 inhibitors reduce levels of circulating pro-inflammatory
factors such as C-reactive protein, tumour necrosis factor-α, and
interleukin-6.111 They also reduce markers of oxidative stress and reactive
oxygen species including hydrogen peroxide in the myocardium.112,113 The at-
tenuation of oxidative stress and inflammation associated with SGLT2 inhibi-
tors is likely multifactorial, and a number of mechanisms including decreased
uric acid, reduced epicardial fat, alterations in adipokine levels and up-regulation
of autophagy all may play a role.114 Another important dimension is the
NLRP3 inflammasome, a multimeric cytoplasmic protein complex in macro-
phages, which plays an important role in the chronic inflammation of heart fail-
ure and atherosclerosis.115–117 Treatment with SGLT2 inhibitors inhibits
activation of the NLRP3 inflammasome, an effect which may be in part
mediated by the increased ketosis and decreased uric acid associated with
these agents.91,92 Reduced NLRP3 activity results in decreased macrophage
infiltration and pro-inflammatory cytokine release.115–117 This effect may
not be limited to the heart, with data showing inhibition of the NLRP3 inflam-
masome by SGLT2 inhibitors in the kidney, liver, and vasculature.117–119
Within the vasculature, SGLT2 inhibitors have been shown to increase nitric
oxide bioavailability, attenuate endothelial dysfunction, and increase circulating
levels of pro-angiogenic progenitor cells.120,121 In a head-to-head comparison,
treatment with empagliflozin compared with insulin or metformin was recent-
ly shown to be associated with with improvement in microRNA profiles as-
sociated with endothelial dysfunction in patients with HFpEF and diabetes
mellitus.122
Ion handling/homeostasis: Na+
and Ca2+
Features of ionic imbalance in heart failure include a state of calcium
overload as well as increased intracellular sodium.123,124 The SGLT2
Mechanisms of benefits of SGLT2 inhibitors in heart failure with preserved ejection fraction 7

inhibitors reduce intracellular sodium and cytosolic calcium, although

the mechanism underlying these changes has not been definitively es-
tablished.125–127 Sodium–hydrogen antiporters (NHE) are expressed
in various sites including the heart and the kidneys.128,129 The SGLT2
protein in the kidney interacts closely with NHE-3, which is a transport-
er primarily responsible for sodium reabsorption from the filtrate.62
Increased NHE-3 activity increases oxidative stress and adrenergic ac-
tivation, and increased sodium reabsorption by this transporter de-
creases distal sodium delivery to the macula densa, leading to
glomerular hyperfiltration and destruction of nephrons.62 The NHE-3
is functionally intertwined with SGLT2 in the nephron, and knockout/
inhibition of one impairs the activity of the other.62 This may in part ex-
plain the nephroprotective effects of SGLT2 inhibitors. The NHE-1 is
expressed in cardiomyocytes and is up-regulated in the failing heart, in-
creasing intracellular sodium and calcium.130,131 The SGLT2 inhibitors
reduce intracellular sodium despite the SGLT2 protein not being ex-
pressed in the heart.62,132 It has been postulated that direct, off-target
inhibition of NHE-1 by SGLT2 inhibitors could be responsible for im-
proved cardiac remodelling and reduced fibrosis with these agents.
There is conflicting evidence about whether SGLT2 inhibitors can dir-
ectly inhibit the NHE-1 transporter in cardiomyocytes.62,133,134 The re-
duction in intracellular sodium with SGLT2 inhibitors observed could
instead be a downstream effect of other signalling pathways, and there
is some evidence that SGLT2 inhibitor may reduce NHE-1 mRNA ex-
pression, which may be mediated through an AMPK-dependent path-
way.62,135 Another potential off-target effect of SGLT2 inhibitors is
interaction with the cardiac sodium channel Nav1.5 (also known as
SCN5A), which mediates late sodium current.136,137 A molecular study
showed that SGLT2 inhibitors may bind to the same site on Nav1.5 as
known Class 1 antiarrhythmics such as lidocaine and inhibit late sodium
current; whether this interaction has any clinical significance has yet to
be determined.137 These effects on ionic homeostasis could in part ex-
plain the rapid time course of benefits observed with SGLT2 inhibitors.
Diastolic function and remodelling
Treatment with empagliflozin has been shown to improve diastolic
function after only 3 months in a small cohort of patients with diabetes
and high cardiovascular risk.138 The IDDIA trial of patients with type 2
diabetes mellitus and at least grade 1 left ventricular diastolic dysfunc-
tion showed improvements in left ventricular diastolic function, includ-
ing diastolic reserve, assessed by diastolic stress echocardiography after
24 weeks of treatment with dapagliflozin compared with placebo.139 As
discussed above, diastolic dysfunction in HFpEF has several compo-
nents including intrinsic myofilament stiffness (related to titin regulation
and NO-sGC-cGMP-PKG signalling) as well as extracellular matrix-
related stiffness/myocardial fibrosis.23 It may be here where the various
pathways involved in SGLT2-mediated reductions in oxidative stress
and inflammation converge. In animal models, SGLT2 inhibitors in-
crease NO bioavailability, and restore the pathologically altered
phosphorylation of titin mediated through downstream cGMP-PKG
signalling; this translates to improved diastolic function.140 In a mechan-
istic analysis of isolated human and murine myocardial tissue, SGLT2 in-
hibitors were shown to reduce diastolic tension and passive
myofilament stiffness as well as alter phosphorylation of myofilament
proteins including titin.141,142 Beyond direct cardiomyocyte effects,
SGLT2 inhibitors have been shown to reduce macrophage infiltration,
regulate macrophage polarization, inhibit cardiac fibroblast differenti-
ation, and suppress fibrotic markers such as type 1 collagen, resulting
in attenuated fibrosis and adverse extracellular remodelling in the
heart.66,78,109,113,118,143–145 In addition to reducing myofilament stiff-
ness and fibrosis, SGLT2 inhibitors have been shown to reduce
hypertrophy measured by left ventricular mass index within only 6
months in patients with type 2 diabetes mellitus and coronary artery
disease in the EMPA-HEART CardioLink-6 trial.146 A systematic review
of five randomized controlled trials showed that SGLT2 inhibitors were
associated with left ventricular mass regression compared with

Figure 3 Ongoing and completed trials of SGLT2 inhibitors in patients with cardiovascular or renal disease. CKD, chronic kidney disease; CV, car-
diovascular; CVD, cardiovascular disease; DM, diabetes mellitus; HFH, heart failure hospitalization; HFpEF, heart failure with preserved ejection fraction;
HFrEF, heart failure with reduced ejection fraction, HR, hazard ratio; nsMRA, non-steroidal mineralocorticoid receptor antagonist.
8 Pandey et al.

placebo, although none of the included trials were conducted in pa- which contribute to reduced adverse remodelling and diastolic dysfunc-
tients with HFpEF.147 tion. As recent trial results are incorporated into clinical guidelines,
SGLT2 inhibitors will become foundational in the therapy of HFpEF.

Future directions
Acknowledgements
While SGLT2 inhibitors have already proved to improve outcomes in
patients with HFpEF, there are several avenues of research that are on- The authors would like to thank Sana Khan for assistance with prepar-
going (Figure 3). ation of the figures.
The DAPA ACT HF-TIMI 68 trial is evaluating the effects of in-
hospital initiation of dapagliflozin on cardiovascular death or worsening
heart in patients hospitalized for acute heart failure, irrespective of ejec-
Declarations
tion fraction.148 This trial will help inform the most appropriate time Disclosure of Interest
point for initiation of these agents in patients with HFpEF. Atrial fibrillation
A.P. has no disclosures.
is known to be associated with HFpEF: each condition independently in-
D.L.B. discloses the following relationships—advisory board:
creases the risk factor for the other.15 The relative benefit of SGLT2 inhi-
AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno
bitors in patients with HFpEF is similar in those with and without atrial
Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level
fibrillation; however, given that patients with atrial fibrillation suffer from
Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed,
a higher rate of adverse heart failure events at baseline, the absolute benefit
Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; board
may likely be greater.149 The SGLT2 inhibitors have also been shown to
of directors: AngioWave (stock options), Boston VA Research Institute,
reduce the rate of atrial fibrillation events in analyses of adverse event re-
Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll
porting from randomized controlled trials.149 DAPA-AF and EMPA-AF are
(stock), Society of Cardiovascular Patient Care, TobeSoft; chair:
two ongoing randomized trials, which will quantify the effects of SGLT2
Inaugural Chair, American Heart Association Quality Oversight Committee;
inhibitors on atrial fibrillation burden.150,151 Finally, there are also ongoing
consultant: Broadview Ventures; data monitoring committees:
trials (DAPA-MI and EMPACT-MI) evaluating the effects of SGLT2 inhibi-
Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim
tors following myocardial infarction.152,153
Institute for Clinical Research (formerly Harvard Clinical Research
Two other classes of medications, which have emerged over the past
Institute, for the PORTICO trial, funded by St. Jude Medical, now
decade and have also shown benefit in patients with diabetes and/or kidney
Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (in-
disease, are glucagon-like peptide-1 receptor agonists and non-steroidal
cluding for the ExCEED trial, funded by Edwards), Contego Medical
mineralocorticoid receptor antagonists.154,155 Evaluation of potential syn-
(chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo
ergy of these classes of agents with SGLT2 inhibitors is an area of interest.
Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded
Two trials, MIRACLE and CONFIDENCE, will evaluate the effects of the
by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept
combination of SGLT2 inhibitors with non-steroidal mineralocorticoid re-
Medical), Novartis, Population Health Research Institute; Rutgers
ceptor antagonists in patients with cardiorenal disease.156,157
University (for the NIH-funded MINT Trial); honoraria: American
Finally, SGLT1 inhibition, through molecules such as the SGLT1/2 in-
College of Cardiology (senior associate editor, Clinical Trials and
hibitor sotagliflozin, has been hypothesized to also have possible supple-
News, ACC.org; chair, ACC Accreditation Oversight Committee),
mentary benefits in heart failure as well.158 The SGLT1 is expressed in
Arnold and Porter law firm (work related to Sanofi/Bristol Myers
the small intestine where it contributes to glucose absorption, as well as
Squibb clopidogrel litigation), Baim Institute for Clinical Research (for-
in other sites including the kidney.158 Decreases in SGLT1-mediated glu-
merly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial
cose absorption increase serum glucagon-like peptide-1 levels, and
steering committee funded by Boehringer Ingelheim; AEGIS-II execu-
SGLT1 inhibition may also inhibit hypertrophy and fibrosis within the myo-
tive committee funded by CSL Behring), Belvoir Publications (editor
cardium.158,159 The SGLT1/2 inhibitor sotagliflozin reduced myocardial in-
in chief, Harvard Heart Letter), Canadian Medical and Surgical
farction and stroke in the SCORED trial, a finding that has not been seen
Knowledge Translation Research Group (clinical trial steering commit-
with traditional SGLT2 inhibitors, and which has been postulated to be
tees), Cowen and Company, Duke Clinical Research Institute (clinical
mediated in part through increased endogenous incretin levels.31 There
trial steering committees, including the PRONOUNCE trial, funded
are no direct data comparing dual SGLT1/2 inhibitors with SGLT2 inhibi-
by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of
tors, but this may prove to be an area of interest in the future.
Invasive Cardiology), Journal of the American College of Cardiology
(guest editor; associate editor), K2P (co-chair, interdisciplinary curric-
ulum), Level Ex, Medtelligence/ReachMD (CME steering committees),
Conclusion MJH Life Sciences, Oakstone CME (course director, Comprehensive
In summary, HFpEF has proved an elusive entity to treat. With the re- Review of Interventional Cardiology), Piper Sandler, Population
sults of DELIVER, SOLOIST-WHF, and EMPEROR-Preserved, SGLT2 Health Research Institute (for the COMPASS operations committee,
inhibitors have solidified themselves as robust therapies to improve publications committee, steering committee, and USA national co-
outcomes in patients with HFpEF. The underlying mechanism of these leader, funded by Bayer), Slack Publications (chief medical editor,
agents cannot be wholly ascribed to improvements in traditional risk Cardiology Today’s Intervention), Society of Cardiovascular Patient
factors such as blood pressure, blood sugar, volume status, and renal Care (secretary/treasurer), WebMD (CME steering committees),
function. Rather, the rapid time course of improvement as well as ex- Wiley (steering committee); Other: Clinical Cardiology (deputy editor),
perimental evidence suggests that a combination of mechanisms for NCDR-ACTION Registry Steering Committee (chair), VA CART
SGLT2 inhibitors in HFpEF including induction of autophagy improved Research and Publications Committee (chair); Patent: Sotagliflozin
ionic homeostasis and reduced inflammation and oxidative stress, (named on a patent for sotagliflozin assigned to Brigham and Women’s
Mechanisms of benefits of SGLT2 inhibitors in heart failure with preserved ejection fraction
Hospital who assigned to Lexicon; neither I nor Brigham and Women’s
Hospital receive any income from this patent); Research Funding:
Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen,
AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific,
Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi,
CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring
Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics,
Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck,
Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer,
PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation,
Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio;
Royalties: Elsevier (editor, Braunwald’s Heart Disease); site co-investigator:
Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical
(now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee:
American College of Cardiology; Unfunded Research: FlowCo, Takeda.
A.P. has no disclosures.
N.M. has received support for clinical trial leadership from
Boehringer Ingelheim, Novo Nordisk, served as a consultant to
Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, re-
ceived grant support from Boehringer Ingelheim, Merck, Novo
Nordisk, and served as a speaker for Boehringer Ingelheim, Merck,
Novo Nordisk, Lilly, BMS, and AstraZeneca. He declines all personal
compensation from pharma or device companies.
F.C. has served as a speaker and advisory board members for
AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Lilly,
Merck Sharp & Dohme, Novo Nordisk, and Pfizer; and has received re-
search grants from the City Pharmacy, Abu Dhabi, UAE, King Gustav V
and Queen Victoria Foundation, the Swedish Heart & Lung Foundation,
and the Swedish Research Council.
A.P. has received research grant support from the Gilead Sciences
Research Scholar Program and Applied Therapeutics; honoraria out-
side the present study as an advisor/consultant for Tricog Health Inc
and Lilly, USA, Rivus, and Roche Diagnostics, and nonfinancial support
from Pfizer and Merck.
S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery,
and has received research grants and/or speaking honoraria from
Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol
Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics,
Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun
Pharmaceuticals, and the Toronto Knowledge Translation Working
Group. He is the President of the Canadian Medical and Surgical
Knowledge Translation Research Group, a federally incorporated
not-for-profit physician organization.
Data Availability
All data described were obtained from published sources that are cited
within the manuscript.
Funding
All authors declare no funding for this contribution.
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