JACC: ADVANCES VOL. 3, NO.

7, 2024

ª 2024 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY LICENSE (http://creativecommons.org/licenses/by/4.0/).

STATE-OF-THE-ART REVIEW

Use of Sodium–Glucose Cotransporter 2

Inhibitors in Hospitalized Patients
Ozan Unlu, MD,a,b,c,d Ankeet S. Bhatt, MD, MBA, SCM,e,f Alexander J. Blood, MD, MSCa,b,d

ABSTRACT

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have noted benefits in the treatment of type 2 diabetes, cardio-
vascular disease, heart failure, and chronic kidney disease. Despite these benefits, the adoption of SGLT2i in clinical
practice has been slow. Early initiation of SGLT2i during hospitalization has been proposed to address this gap for two
important reasons: 1) it provides early clinical benefit in multiple disease states; and 2) hospitalization presents an op-
portunity for medication optimization and patient education, thereby overcoming clinical inertia. Challenges in SGLT2i
adoption necessitate innovative strategies for integration into clinical practice. Ongoing trials and novel care delivery
models are anticipated to further elucidate effective strategies for SGLT2i implementation and adherence. This review
synthesizes the accrued evidence of SGLT2i across various chronic diseases. It emphasizes the rationale for early in-
hospital initiation and discusses barriers and potential solutions for widespread implementation of SGLT2i in hospitalized
patients. (JACC Adv 2024;3:101024) © 2024 The Authors. Published by Elsevier on behalf of the American College of
Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/
4.0/).

S odium–glucose cotransporter
(SGLT2i) prevent glucose reabsorption in the
2

proximal renal tubule and emerged as effective

treatments in modestly improving glycemic control
inhibitors
for type 2 diabetes (T2D).1 More recently, these thera-
pies have been shown to improve clinical outcomes
across a much wider range of conditions including
cardiovascular (CV) disease and heart failure (HF)
across the spectrum of left ventricular ejection frac-
tion (LVEF) with or without T2D and chronic kidney
disease (CKD).
Despite these benefits, the uptake of SGLT2i has
been slow leading to significant gaps in care for pa-
tients who would benefit.2 Early initiation of SGLT2i
during a hospital stay has been proposed as an
implementation strategy to help close this care gap
and to fully realize the potential population level
benefits of the medication seen after a hospitaliza-
tion.3 In hospital, implementation affords many po-
tential benefits, including disease and symptom
monitoring, availability of hemodynamic and lab as-
sessments, and time for reinforming, medication ed-
ucation, and provider-patient dialog. To capitalize on
this opportunity, it is paramount to educate clinicians
and develop and evaluate strategies for in-hospital
initiation of SGLT2i and subsequent maintenance af-
ter discharge. In this review, we aim to present the
evidence for the effectiveness and safety of SGLT2i in
the treatment of a variety of chronic diseases, estab-
lish the rationale for early, in-hospital initiation, and

From the aAccelerator for Clinical Transformation, Brigham and Women’s Hospital, Boston, Massachusetts, USA; bDivision of
Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA; cDepartment of Biomedical Informatics,
Harvard Medical School, Boston, Massachusetts, USA; dHarvard Medical School, Boston, Massachusetts, USA; eDepartment of
Cardiology and Division of Research, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA; and the
f
Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received December 18, 2023; revised manuscript received March 29, 2024, accepted April 16, 2024.

ISSN 2772-963X https://doi.org/10.1016/j.jacadv.2024.101024

2 Unlu et al
Inpatient SGLT2i Initiation
ABBREVIATIONS discuss potential barriers and solutions for
AND ACRONYMS
widespread in-hospital implementation of
SGLT2i.
CKD = chronic kidney disease
CV = cardiovascular
SGLT2i IN THE TREATMENT AND
eGFR = estimated glomerular
PREVENTION OF CHRONIC DISEASES
filtration rate
GDMT = guideline-directed
medical therapy
SGLT2i have demonstrated improved out-
comes for patients with HF across the spec-
HF = heart failure
trum of LVEF in a number of pivotal clinical
HFpEF = HF with preserved
ejection fraction trials. For patients with HF with reduced
HFrEF = HF with reduced
ejection fraction (HFrEF), EMPEROR-
ejection fraction reduced,4 DAPA-HF, 5 SOLOIST-WHF, 6 and
LVEF = left ventricular ejection DEFINE 7 provided the evidence that ulti-
fraction mately led to inclusion of SGLT2i as a class I
OOP = ou-of-pocket recommendation for HFrEF in the contem-
QALY = quality-adjusted life porary HF guidelines. 4-9 Similar to those with
year HFrEF, pivotal trials for patients with HF
SGLT2i = sodium–glucose with preserved ejection fraction (HFpEF)
cotransporter 2 inhibitor
including EMPEROR-Preserved, 10 DELIVER,11
T2D = type 2 diabetes
PRESERVED-HF, 12 and some participants
from SOLOIST-WHF 6 established the efficacy of
SGLT2i.6,10-14 These studies provided the first evi-
dence of benefit from the addition of HF therapy for
patients with improved ejection fraction, adding to
evidence surrounding initiation and continuation of
guideline-directed medical therapy (GDMT).15
Several major trials established the efficacy of
SGLT2i in patients with T2DM and established CV
disease. These included the CANVAS Program, 16
DECLARE-TIMI 58 trial, 17 EMPA-REG OUTCOME,18
SCORED trial19 which not only established the CVD
benefit of SGLT2i in patients with T2D but also laid
the groundwork for further studies to illustrate their
benefits in patients with HF and CKD. These trials not
only established the CVD benefit of SGLT2i in patients
with T2D but also laid the groundwork for further
studies to illustrate their benefits in patients with HF
and CKD.
Finally, three major trials evaluated the efficacy of
SGLT2i in patients with CKD with and without T2DM
including the CREDENCE trial 20 , DAPA-CKD trial 21
, urgent
and the EMPA-Kidney trial.22 These trials demon-
strated in patients with both reduced estimated
glomerular filtration rate (eGFR) and albuminuria
with SGLT2i, leading to reductions in kidney disease
progression and kidney and CV-associated death.
The aforementioned pivotal trials and their key
components are listed in Table 1. On the basis of these
trials, the US Food and Drug Administration approved
the following: 1) in 2016, empagliflozin to reduce the
risk of CV death in adults with T2D and established
CV disease; 2) in September 2019, canagliflozin to
treat diabetic kidney disease; 3) in May 2020,
JACC: ADVANCES, VOL. 3, NO. 7, 2024
JULY 2024:101024
HIGHLIGHTS

SGLT2 inhibitors are effective in man-
aging type 2 diabetes, cardiovascular
diseases, heart failure, and chronic
kidney disease.

Initiating SGLT2 inhibitors early during a
hospital stay offers a strategic approach
to optimize patient care and overcome
barriers to initiation.

Advancements in care delivery methods
will focus on addressing barriers to
adoption and integrating innovative care
models for wider implementation.
dapagliflozin for HFrEF; 4) in May 2021, dapagliflozin
to treat patients with CKD at risk of disease progres-
sion, regardless of diabetes and albuminuria status;
and 5) in September 2022, empagliflozin for HFpEF,
and September 2023, empagliflozin for CKD without
DM or HF.
INITIATION OF SGLT2i IN HOSPITALIZED PATIENTS
The initiation of SGLT2i in hospitalized patients has
been a point of discussion on the basis of two
important arguments: 1) potential benefits of early
initiation of SGLT2i; and 2) hospitalizations providing
an additional touch point for medication optimization
and monitorization of potential adverse events
(Central Illustration).
BENEFIT OF EARLY INITIATION OF SGLT2i. The
SOLOIST-WHF and EMPULSE trials have underscored
the advantages of commencing SGLT2i treatment
early. In the SOLOIST-WHF study which included
patients hospitalized due to worsening HF, the
administration of sotagliflozin, which is a both SGLT2
and 1 inhibitor, either immediately prior to or shortly
following discharge, resulted in a significant decrease
in death from CV causes and hospitalizations and
visits for HF (HR 0.67; 95% CI 0.52-
0.85; P < 0.001).6
Similarly, the EMPULSE trial included patients
hospitalized with a diagnosis of acute de novo or
decompensated chronic HF and initiated empagli-
flozin when the patients were clinically stable in the
hospital. The primary outcome was clinical benefit
that was assessed using a win ratio and was defined as
a hierarchical composite of death from any cause,
number of HF events and time to first HF event, or a 5
point or greater change in KCCQ Total Symptoms
Score at 90 days. Patients in the empagliflozin group
had a higher rate of clinical benefit than the placebo
JACC: ADVANCES, VOL. 3, NO. 7, 2024 Unlu et al 3
JULY 2024:101024 Inpatient SGLT2i Initiation

T A B L E 1 Pivotal Trials for Sodium–Glucose Cotransporter 2 Inhibitor

Trial Name Patient Population Drug Tested Comparison Primary Endpoints Key Findings

HFrEF
EMPEROR-Reduced HFrEF; NYHA functional Empagliflozin Placebo Composite of CV death or Empagliflozin significantly reduced the risk of CV
class II, III, or IV hospitalization for HF death or hospitalization for HF in patients
with HFrEF compared to placebo, irrespective
of the presence or absence of diabetes.
DAPA-HF HFrEF; NYHA functional Dapagliflozin Placebo Composite of worsening HF or Dapagliflozin reduced the risk of worsening HF or
class II, III, or IV death from CV causes death from CV causes among patients with
HFrEF compared to placebo, regardless of
diabetes status. In patients without a previous
history of HF hospitalization, dapagliflozin
decreased the relative risk of the primary
outcome by 16%. For those who had been
hospitalized for HF more than a year before
joining the study, the reduction was 27%, and
for those who had an HF hospitalization within
the 12 mo prior to entering the trial, the risk
reduction was 36%.
DEFINE HFrEF; NYHA functional Dapagliflozin Placebo Composite of improvement in Dapagliflozin improved the composite outcome of
class II or III, KCCQ overall summary Kansas City Cardiomyopathy Questionnaire
eGFR $30 mL/ score or NT-proBNP level (KCCQ) overall summary score or NT-proBNP
min/1.73m2, elevated level in patients with HFrEF.
natriuretic peptide
SOLOIST-WHF T2D and worsening HF Sotagliflozin Placebo Composite of total number of Sotagliflozin led to a lower rate of primary-
across the EF deaths from CV causes, endpoint events than placebo in patients with
spectrum hospitalizations, and T2D and worsening HF across the EF
urgent visits for HF spectrum.
HFpEF
EMPEROR-Preserved HFpEF; NYHA functional Empagliflozin Placebo Composite of CV death or Compared to placebo, empagliflozin reduced the
class II, III, or IV hospitalization for HF in risk of CV death or hospitalization for HF in
patients with HFpEF patients with HFpEF, regardless of the
diabetes status.
DELIVER HFpEF or mildly reduced Dapagliflozin - Composite of worsening HF Dapagliflozin led to a lower rate of composite
EF; with or without and CV death; endpoint of worsening HF and CV death and
diabetes, with signs improvement in symptom improved symptom burden determined by
and symptoms of HF, burden measured by KCCQ KCCQ total symptom score. Dapagliflozin
elevated natriuretic total symptom score reduced the risk of worsening HF or CV death
peptide by 22% in recently hospitalized patients and
by 18% in nonhospitalized patients.
PRESERVED-HF HFpEF; NYHA functional Dapagliflozin - Improvement in health status, Dapagliflozin improved health status, functional
class II, III, or IV, functional ability, and ability, and quality of life in patients with
elevated natriuretic quality of life in patients HFpEF.
peptide, loop diuretic with HFpEF
use with HF
hospitalization within
the past 12 mo
Continued on the next page

group (stratified win ratio, 1.36; 95% CI: 1.09-1.68;
P ¼ 0.0054) regardless of the ejection fraction, acute
vs chronic HF, or the presence of diabetes. 23
In addition, secondary analyses of DAPA-HF, EM-
PEROR-Reduced, EMPEROR-Preserved, and DELIVER
were conducted to investigate time to clinical benefit
of SGLT2i in HF across the LVEF spectrum. DAPA-HF
showed that the composite of CV death or worsening
HF was lower with dapagliflozin. The statistical sig-
nificance of this benefit was sustained by 28 days
after randomization (HR at 28 days, 0.51 [95% CI:
0.28-0.94]; P ¼ 0.03). The upper confidence boundary
of the HR remained below unity for the remainder of
the trial. A similar pattern of early and consistent
benefit was observed for the individual components
of the primary efficacy outcome (worsening HF: HR at
28 days 0.48, 95% CI: 0.23-0.94; CV death: HR at
28 days 0.87, 95% CI: 0.31-2.41). EMPEROR Reduced
trial included patients with HFrEF to investigate the
effect of empagliflozin compared to placebo for a
primary endpoint of CV death or hospitalization for
HF. The study found that empagliflozin significantly
reduced the primary composite endpoint in empa-
gliflozin group compared to placebo (HR: 0.75;
95% CI: 0.65-0.86; P < 0.001). The benefit of empa-
gliflozin on this endpoint first reached statistical sig-
nificance at 12 days after randomization, and
statistical significance was sustained from day 34
onwards. Similarly, The EMPEROR-Preserved trial
studied the effects of empagliflozin in patients with
HFpEF and found that empagliflozin reduced the
composite outcome of CV death or HF hospitalization
4 Unlu et al JACC: ADVANCES, VOL. 3, NO. 7, 2024

Inpatient SGLT2i Initiation JULY 2024:101024

T A B L E 1 Continued

Trial Name Patient Population Drug Tested Comparison Primary Endpoints Key Findings

T2DM
CANVAS Program Patients with T2DM and
high CV risk; 65.6%
had a history of CV
disease at baseline
DECLARE-TIMI 58 Patients with T2DM and
established ASCVD or
multiple risk factors
for ASCVD
EMPA-REG Patients with T2D and
OUTCOME high CV risk
SCORED Patients with T2DM and
CKD; eGFR of 25-
60 ml/min/1.73 m2
CREDENCE Patients with T2D and
CKD; eGFR of 30 to
90 ml/min/1.73 m2
and UACR of 300 to
5000 mg/g
CKD
DAPA-CKD Patients with CKD; eGFR
of 25 to 75 ml/
min/1.73 m2 and UACR
of 200 to 5,000 mg/g
EMPA-Kidney Patients with CKD; eGFR
of 20 to 45 ml/
min/1.73 m2 or 45 to
90 ml/min/1.73 m2
and UACR
of $200 mg/g
Canagliflozin Placebo Composite of death from CV
causes, nonfatal
myocardial infarction, or
nonfatal stroke
Dapagliflozin Placebo Composite of CV death or
hospitalization for HF;
major adverse CV events
(CV death, myocardial
infarction, or ischemic
stroke)
Empagliflozin Standard care Composite of CV death,
nonfatal myocardial
infarction, or nonfatal
stroke
Sotagliflozin Placebo Composite of death from CV
causes, hospitalizations,
and urgent visits for HF
Canagliflozin Placebo Composite of ESKD, a
doubling of the serum
creatinine level, or death
from kidney or CV causes
Dapagliflozin Placebo Composite of sustained In the dapagliflozin group, the primary composite
decline in the eGFR of at
least 50%, ESKD, or death
from kidney or CV causes
Empagliflozin Placebo Composite of kidney disease
progression or death from
CV causes
Canagliflozin reduced the risk of CV events in
patients with T2D and high CV risk; however,
it increased the risk of amputation. The
primary outcome was a composite of death
from CV causes, nonfatal myocardial
infarction, or nonfatal stroke.
Dapagliflozin resulted in lower rates of CV death
or hospitalization for HF than placebo among
patients with T2D and ASCVD or multiple risk
factors for ASCVD (HR: 0.83; 95% CI: 0.73-
0.95; P ¼ 0.005); however, it did not result in
a lower rate of major adverse CV event
defined as CV death, myocardial infarction, or
ischemic stroke.
Empagliflozin, when added to standard care,
reduced the risk of CV death, nonfatal
myocardial infarction, or nonfatal stroke
among patients with T2D and high CV risk.
Sotagliflozin led to a lower rate of death from CV
causes and hospitalizations and urgent visits
for HF compared to placebo in patients with
T2D and CKD with an eGFR of 25-60 ml/
min/1.73 m2.
Canagliflozin significantly reduced the primary
outcome (composite of ESKD, a doubling of
the serum creatinine level, or death from
kidney or CV causes) compared to placebo in
patients with T2D and CKD with an eGFR of 30
to 90 ml/min/1.73 m2 and a UACR of 300 to
5,000 mg/g.
outcome (sustained decline in the eGFR of at
least 50%, ESKD, or death from kidney or CV
causes) was significantly reduced compared to
the placebo group in patients with CKD and a
UACR of 200 to 5,000 mg/g.
The primary outcome (composite of kidney
disease progression or death from CV causes)
was significantly lower in the empagliflozin
group than the placebo group, with consistent
results in those with or without diabetes and
across the range of eGFR studied, in patients
with CKD and an eGFR of 20 mL/min/1.73 m2

CKD ¼ chronic kidney disease; CV ¼ cardiovascular; eGFR ¼ estimated glomerular filtration rate; HF ¼ heart failure; HFrEF ¼ HF with reduced ejection fraction; T2D ¼ type 2 diabetes.

compared to placebo. These effects were seen early
and consistently. Statistical significance for separa-
tion between the empagliflozin and the placebo arms
occurred by day 18 for time to CV death or HF hos-
pitalization (HR at 18 days 0.41, 95% CI: 0.17-0.99),
after which this benefit was sustained with the
boundary of the upper CI below unity for the rest of
the trial period. Finally, The DELIVER trial showed
that dapagliflozin reduced CV death or worsening HF
events in patients with HF with mildly reduced or
preserved ejection fraction. The time to first nominal
statistical significance for the primary end point was
13 days (HR: 0.45; 95% CI: 0.20-0.99; P ¼ 0.046), and
significance was sustained from day 15 onwards. First
and sustained statistical significance was reached for
worsening HF events (HR: 0.45; 95% CI: 0.21-0.96;
P ¼ 0.04) by day 16 after randomization. Significant
benefits for the primary end point and worsening HF
events were sustained at 30 days, 90 days, 6 months,
1 year, 2 years, and final follow-up (primary end
point: HR: 0.82; 95% CI: 0.73-0.92; worsening HF
events: HR: 0.79; 95% CI: 0.69-0.91).
USING HOSPITALIZATION AS AN OPPORTUNITY FOR
MEDICATION OPTIMIZATION. Clinical inertia is one
of the most important barriers for initiation of GDMT
in HF with many potential contributing physician,
patient, and system factors. The fear of medication
adverse events is one of the major reasons for
physician and patient clinical inertia. 24 Hospitaliza-
tions are additional touch points in the care of some
patients with HF and they offer a unique opportunity
JACC: ADVANCES, VOL. 3, NO. 7, 2024
JULY 2024:101024
C ENTR AL I LL U STRA T I O N Challenges and Opportunities for Inpatient SGLT2i Initiation
Unlu O, et al. JACC Adv. 2024;3(7):101024.
to overcome inertia by allowing close monitoring of
adverse events after initiation or up-titration of
medications. In addition, it also gives the clinical
team a chance to educate the patient about their
disease and potential treatments, as well as address
potential issues around cost before discharge.
During hospitalization, there is a unique opportu-
nity to educate patients about HF, its management,
and the importance of adhering to the medication
regimen. Studies have shown that effective commu-
nication about reasons for medication prescriptions
and potential adverse drug events is critical and can
Unlu et al 5
Inpatient SGLT2i Initiation
improve adherence to therapies. Therefore, hospi-
talizations can provide the time for various members
of the clinical team to educate the patients and rein-
force the importance of HF therapies. 25 In addition,
hospitalizations provide an opportunity for a moni-
tored setting to observe tolerability of prescribed HF
therapies where any adverse events can be promptly
addressed. It might also prevent reactionary and
incorrect discontinuation of therapies based on find-
ings such as an expected transient change in renal
function, described as eGFR dip. The initial decline in
eGFR after initiation of dapagliflozin in patients with
6 Unlu et al
Inpatient SGLT2i Initiation
HFrEF was found to be relatively small and was
associated with better clinical outcomes compared to
a similar decline on placebo. 26
POTENTIAL BARRIERS AND SOLUTIONS FOR
INITIATION OF SGLT2i IN HOSPITALIZED PATIENTS
Clinical inertia or deferral to outpatient care can pose
significant barriers to the initiation of SGLT2i in hos-
pitalized patients. This is often due to perceived
lower clinical risk or reluctance to initiate a new
therapy, especially among patients who appear clin-
ically stable with relatively mild symptoms. 24 How-
ever, as discussed above, data from DAPA-HF,
EMPEROR-Reduced, EMPEROR-Preserved, and
DELIVER trials underscored the rapid clinical benefits
observed with the SGLT2i, highlighting key opportu-
nities for the early identification and prompt man-
agement of this patient population. Furthermore, in
multiple observational studies, deferral of initiation
of other GDMT has been shown to be associated with
never initiation of GDMT.27-29 When the GDMT is
started before hospital discharge, the compliance
with GDMT posthospitalization and the chance of
target-dose achievement in the short- and longer-
term follow-up increases significantly.29 In the
IMPACT-HF trial, at 60 days follow-up, patients
started on carvedilol predischarge had higher use of
beta-blockers than those who did not (91.2% vs
73.4%, P < 0.0001). Multiple strategies have been
investigated to increase the initiation of GDMT during
hospitalization. One potential strategy is to create
teams to rapidly identify hospitalized patients with
HF who are not on optimal medical therapy and
intervene to recommend GDMT optimization.
IMPLEMENT- HF investigated if this strategy can be
implemented by using a virtual multidisciplinary
team of physicians and pharmacists and showed that
the virtual care team–based strategy improved the net
intensification of GDMTduring a hospitalization (44%
vs 24% for net intensification, P ¼ 0.002). 30 Similarly,
in a pilot-randomized trial that investigated the effi-
cacy of a virtual HF intervention on GDMT optimiza-
tion on patients with HFrEF admitted with any cause
showed a mean improvement of 0.75 in optimal
medical therapy score at discharge in the intervention
group compared.
An emerging concern among clinicians is the
discharge of patients on SGLT2i, without ensuring
adequate follow-up. This apprehension stems from
potential challenges patients may face in adhering to
their treatment plan, recognizing and managing side
effects, and accessing necessary healthcare services
postdischarge. Effective communication and
JACC: ADVANCES, VOL. 3, NO. 7, 2024
JULY 2024:101024
establishing a clear, accessible follow-up plan are
paramount to address these concerns. Therefore, the
most recent AHA/ACC/HFSA guidelines for the man-
agement of HF highlight the importance of compre-
hensive care management, including the use of
multidisciplinary teams. These teams can facilitate
GDMT and support for managing symptoms, thus
potentially reducing rehospitalization rates and
improving survival outcomes for patients with HF.8
In a meta-analysis that pooled the randomized clin-
ical trials investigating the effectiveness of
pharmacist-involved multidisciplinary teams for the
management of HF, it found a notable decrease in the
rates of hospitalizations due to HF (OR: 0.72, 95%CI
0.55-0.93, P ¼ 0.01, I2 ¼ 39%) and in hospitalizations
for any cause (OR: 0.76, 95% CI: 0.60-0.96, P ¼ 0.02,
I2 ¼ 52%), which can be attributed, in part, to
improved adherence to medication regimens. Addi-
tionally, they observed significant enhancements in
the understanding of HF among participants. 31
Provider knowledge and comfort with the medi-
cation class are crucial for the successful initiation of
SGLT2i in hospitalized patients. Therefore, recurring
and iterative education of providers regarding bene-
fits and potential adverse effects of SGLT2i is impor-
tant. In PROMPT-HF trial, providers were given
access to a customized order set that displayed all
available medications within the classes not currently
prescribed, listed alphabetically along with their
indication.32 This was supplemented with a hyperlink
to the study webpage that contained informational
documents expanding on evidence-based medical
therapy recommended by current guidelines for pa-
tients with HFrEF. This approach was found to be
effective in increasing provider knowledge and com-
fort level with HFrEF guidelines. In addition to the
potential expected effects, providers should also be
educated about adjustments in diabetic and diuretic
regimens when initiating SGLT2is. Notably, in the
pivotal trials, hypoglycemic events were rare and
occurred at similar rates in those without diabetes. 4,5
Nonetheless, combining SGLT2is with insulin or
agents that stimulate insulin production (like glinides
and sulfonylureas) could elevate hypoglycemia risk;
therefore, it has been recommended to lower the
dosage of sulfonylureas or glinides by half or reduce
basal insulin by 20% upon initiating SGLT2i treat-
ment, particularly if the patient’s HbA1C is within the
normal range or if they have a history of hypoglyce-
mia.33,34 Similarly, studies investigated diuretic ef-
fects of SGLT2i, and its interplay with loop diuretics
showed that it was effective across all spectrums of
loop diuretic doses, and the diuretic dose did not
change in most patients during follow-up and the
JACC: ADVANCES, VOL. 3, NO. 7, 2024
JULY 2024:101024
change were similar to the placebo group.35 There-
fore, provider education on the generally minimal to
no adjustments required for diuretics could help
reduce concerns related to monitoring and following
up with patients.
A particular focus should be given to education
about the expected effects of SGTL2i on eGFR. Con-
cerns for a decline in eGFR are common when initi-
ating SGLT2i therapy and can be a barrier for
initiation or inappropriate discontinuation of SGLT2i.
Importantly, a secondary analysis of the DAPA-HF
trial showed that the mean reduction in eGFR after
dapagliflozin was 4.2 ml/min/1.73 m 2 compared to
1.1 ml/min/1.73 m2 in the placebo group. However,
this initial decline was not associated with higher
rates of long-term worsening kidney function or other
adverse events. In fact, those with more than 10%
eGFR decline in the dapagliflozin group had a lower
rate of primary outcome which was a composite of
worsening HF or CV death,26 suggesting this is likely
to be a pharmcodynamic effect of the therapy rather
than true acute kidney injury.
The safety data from existing clinical trials for
SGLT2i showed that the number of safety events were
low and consistent across trials. In the SOLOIST-WHF
trial, sotagliflozin was administered to patients with
diabetes who had recently been hospitalized for
worsening HF. Diarrhea was more common with
sotagliflozin than with placebo (6.1% vs 3.4%), as was
severe hypoglycemia (1.5% vs 0.3%). 6 However, the
percentage of patients with hypotension was similar
in the sotagliflozin group and the placebo group
(6.0% and 4.6%, respectively), as was the percentage
with acute kidney injury (4.1% and 4.4%, respec-
tively). In the EMPULSE trial, empagliflozin was
initiated in patients hospitalized for acute HF,
regardless of LVEF. There were no significant differ-
ences of safety events between the empagliflozin
group and the placebo group for volume depletion
(12.7% vs 10.2%, respectively), hypoglycemia (1.9%,
1.5%, respectively), acute renal failure (7.7% vs 12.1%,
respectively), and urinary tract infection (4.2% vs
6.4%, respectively).23 Overall, serious adverse events
were reported in 32.3% of the empagliflozin-treated
patients and 43.6% of the placebo-treated patients.
These findings suggest that SGLT2i can be safely
initiated in hospitalized patients, providing signifi-
cant clinical benefits in the months following treat-
ment initiation.
The cost and lack of cost transparency of SGLT2i is
another significant consideration in their use. While
the specific cost of these medications can vary based
on factors such as location, insurance coverage, and
specific medication, they are generally more
Unlu et al 7
Inpatient SGLT2i Initiation
expensive than some other classes of GDMT given
that they have been added to the armamentarium of
HF therapies. However, they can provide significant
health benefits in patients with multiple comorbid-
ities including T2D, CAD, CKD, and HF. Therefore, the
trade-offs between health benefits of SGLT2i and
increased costs should be carefully examined to
justify their clinical use. The cost-effectiveness of
treatments for HF, including SGLT2is, is a complex
issue with multiple perspectives. The value of treat-
ment is often framed within a willingness-to-pay
model, which can vary significantly among stake-
holders such as patients, healthcare providers, and
insurance companies. Cost per quality-adjusted life
year (QALY) is a common measure of value,
with <$50,000 per QALY is considered high value
and $$150,000 per QALY is considered low value. 36
However, perspectives on what constitutes a cost-
effective intervention can differ. For example, the
American College of Cardiology and American Heart
Association consider a health intervention that ex-
ceeds three times the GDP per capita per QALY as not
cost-effective.37 From the patient’s perspective, the
concept of value also includes out-of-pocket costs
and insurance premiums. The cost differences be-
tween HF treatments can significantly impact a pa-
tient’s willingness to pay for a treatment and affect
patients’ adherence to treatment regimens.38 There-
fore, the cost of SGLT2is is a crucial factor in their
adoption and use, and it represents a significant
barrier that needs to be addressed to improve patient
outcomes. Importantly, in a cost-effectiveness anal-
ysis based on a hypothetical cohort with patients
similar to DAPA-HF trial cohort showed that dapa-
gliflozin had an incremental cost-effectiveness ratio
of $68 300 per QALY gained (95% UI, $54 600-$117
600 per QALY gained) which makes it cost-effective at
current US prices.39 However, recent analyses from
Medicare data underscore the significant financial
burden these medications can impose on patients. In
2020, Medicare plans often required tier 3 cost-
sharing for SGLT2i, with median annual out-of-
pocket (OOP) costs for quadruple therapy, including
SGLT2i, reaching $2,217.40 This is in stark contrast to a
fully generic regimen, excluding SGLT2i/ARNIs,
which had a median annual OOP cost of merely $3. 40
Such high OOP costs likely render SGLT2i therapies
unaffordable for many Medicare beneficiaries,
despite their proven efficacy and the guidelines rec-
ommending their use in HFrEF. Moreover, the re-
striction of coverage through high-tier cost-sharing
and the complexities around insurance policies
further complicate patient access to these life-saving
medications, highlighting a critical need for policy
8 Unlu et al JACC: ADVANCES, VOL. 3, NO. 7, 2024

Inpatient SGLT2i Initiation JULY 2024:101024

T A B L E 2 Ongoing SGLT2i Randomized Clinical Trials

EMPACT-MI DICTATE-AHF DAPA-ACT HF TIMI-68 Ertugliflozin in AHF

Investigational Empagliflozin 10 mg/placebo Dapagliflozin 10 mg plus diuretic Dapagliflozin 10 mg/placebo Ertugliflozin/metolazone/

treatment/control
Patient population
Primary endpoint
Key secondary
endpoints
Patients hospitalized for acute
myocardial infarction with high
risk of HF defined as signs or
symptoms of congestion or
newly developed LVEF <45%
Time to first hospitalization for HF
or all-cause death
Total HHF or all-cause death
Total nonelective CV
hospitalizations or all-cause
death
Total nonelective all-cause
hospitalizations or all-cause
death
Total hospitalizations for MI or
all-cause death
Time to CV death
therapy/diuretic therapy
Patients with or without T2D
hospitalized with acute
decompensated HF
Diuretic response measured by
cumulative change in weight
Incidence of worsening HF
Hospital readmission within 30 d
placebo
Patients who have been stabilized Acute and postacute
during hospitalization for acute HF hospitalized heart failure
patients with or without
diabetes
Time to CV death or worsening heart Change in urine sodium and
failure total body water at days 1, 7,
and 42
Time to CV death or rehospitalization
for HF or urgent HF visit
Time to CV death or rehospitalization
for HF
Time to rehospitalization for HF or
urgent HF visit
Hospital readmission within 30 d
Time to CV death
Time to all-cause death

CV ¼ cardiovascular; HF ¼ heart failure; HHF ¼ hospitalization for heart failure; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; T2D ¼ type 2 diabetes.

reforms aimed at reducing medication costs and
improving transparency in drug pricing.41 Only
through concerted efforts to address these cost bar-
riers can we ensure broader patient access to SGLT2i,
thereby leveraging their full potential in improving
outcomes for patients with HF and other comorbid
conditions.
Finally, patients with indications to use SGLT2i
often have multiple comorbidities requiring several
medications, which can lead to complex medication
regimens. This complexity can lead to medication
nonadherence, adverse drug reactions, and decreased
quality of life which in turn can play a role in patients’
decisions to use SGLT2i. As an example, one obser-
vational study found that 84% of patients with HF
used five or more medications at hospital admission
and 42% used 10 or more medications.42 In addition,
patients who have non-GDMT polypharmacy were
less likely to achieve optimization of GDMT on follow-
up. 43 Therefore, careful review of patients’ medica-
tions should be performed for each patient and non-
GDMT medications that pose harm or minimal
benefit should be deprescribed. Hospitalizations pro-
vide a great opportunity to achieve this and monitor
for potential adverse events following multiple
medication changes. Furthermore, SGLT2i has been
shown to reduce the risk of hyperkalemia, potentially
enabling the use of renin aldosterone angiotensin in-
hibitors and mineralocorticoid receptor antagonists. 44
We are on the verge of digital transformation in
healthcare and innovative health delivery strategies
that takes advantage of rapidly emerging technolo-
gies, which has the potential to address economic
challenges in the treatment of HF. Remote patient
encounters, telehealth, and mobile health are some of
the platforms paving the way for an expansion of
virtual care. These platforms are being used to gather
health data, share it with healthcare providers, and
empower patients for self-management of chronic
diseases which can increase quality, reduce costs, and
improve the coordination of care.38
ONGOING TRIALS AND FUTURE DIRECTIONS
Several trials are currently underway to further
investigate the benefits of SGLT2i in various patient
populations and settings including EMPACT-MI,
DICTATE-AHF, DAPA-ACT HF TIMI 68, and the ertu-
gliflozin in AHF trial (Table 2). Furthermore, several
implementation studies are being conducted to
investigate a variety of interventions to improve
SGLT2i prescriptions or broader GDMT initiation
(Table 3).
In addition to possibly expanding the role of
SGLT2i with the results of these trials, implementa-
tion research will be fundamental in accelerating the
uptake and utilization of proven therapies and
establishing innovative care delivery models such as
PROMPT-HF and IMPLEMENT-HF. It is highly
important to examine not only the efficacy of new
care delivery models but also their impacts on costs
and burden on patients and providers. Another
approach to rapid initiation of SGLT2i has been to
initiate and titrate the medications either right before
or shortly after the hospitalization. STRONG-HF
investigated such a strategy with initiation of 4 class
JACC: ADVANCES, VOL. 3, NO. 7, 2024 Unlu et al 9
JULY 2024:101024 Inpatient SGLT2i Initiation

T A B L E 3 Ongoing Randomized Clinical Trials Investigating Care Delivery Methods to Initiate SGLT2i

Estimated
Completion
Trial Name ClinicalTrials.gov ID Setting Start Date Date Intervention/Treatment Population Objective

COPILOT-HF: NCT05734690 Mass General May 2023 June 2025 Pharmacist and Patients with Heart Test two remote care
Cooperative Brigham navigator driven failure strategies for
Program for remote care team optimizing GDMT
Implementation prescription across
of Optimal the spectrum of LVEF:
Therapy in Education and remote
Heart Failure management
simulatenously vs
education first
followed by remote
care
PROMPTHF-Inova: NCT05433220 Inova Health August 2022 August 2024 Best Practice Advisory Patients with heart failure Test effectiveness of EHR
PRagmatic Trial Care Services using Electronic and reduced ejection best practice advisory
Of Messaging to Health Record fraction to improve GDMT
Providers About prescriptions for HF
Treatment of
Heart Failure at
Inova
Addressing Diffusion NCT05463705 Brigham and May 2023 May 2024 Behavioral intervention Primary care physicians Test impact of addressing
of Responsibility Women’s to address diffusion caring for patients diffusion of
and Prescribing Hospital of responsibility and with type 2 diabetes responsibility on
Burden to simplification of and HbA1c >7.5% SGLT-2i and GLP-1RAs
Improve Use of prescribing with a compelling prescribing
Diabetes indication for SGLT-2i
Medications or GLP-1RA
INITIATE-HFrEF NCT05989503 Universidade do August 2023 February Drug: Sacubitril- Patients with Compare simultaneous vs
Porto 2025 valsartan, Heart Failure with sequential initiation of
Drug: SGLT2 Reduced Ejection ARNi and SGLT2i for
inhibitor Fraction (HFrEF) safety and efficacy
GREAT-HF Care NCT05990296 Geisinger Clinic August 2023 January Behavioral: Multiprong Heart Failure with Evaluate a multifaceted
2025 CDS with referral to Reduced Ejection interdisciplinary
pharmacist co- Fraction intervention to
management, improve GDMT use,
Behavioral: reduce mortality, and
Multiprong CDS future heart failure
with GDMT order events in patients
set, Behavioral: with HFrEF
Focused education

GDMT ¼ guideline-directed medical therapy; HF ¼ heart failure; HFrEF ¼ HF with reduced ejection fraction; LVEF ¼ left ventricular ejection fraction; SGLT2i ¼ sodium–glucose cotransporter 2 inhibitor.

GDMT at hospital discharge for patients with HFrEF
followed by rapid up-titration posthospitalization. 45
The study showed that the intensive
reduced the composite of HF readmission or all-cause
death up to day 180 and did not increase serious
adverse events. However, real-world implementation
and scaling of such a program requires substantial
resources and is difficult to sustain when the costs
associated with HF management are already exces-
sive. As a potential mitigation strategy, remote care
strategies can be effective. A remote team-based
strategy in a nonrandomized study using algorithms
was shown to be a successful strategy for rapid GDMT
initiation in patient with HFrEF. 46 To further inves-
tigate this strategy in a larger patient population with
all HF, the COPILOT-HF trial (NCT05734690) was
designed. COPILOT-HF is a pragmatic randomized
trial to determine if a remote clinic that implements a
standardized, stepped-approach to
optimization in patients with HF will achieve a higher
rate of GDMT than a strategy of patient and provider
strategy education followed by remote HF clinic management.
CONCLUSIONS
SGLT2i have shown significant promise in the treat-
ment and prevention of chronic diseases such as HF,
T2D, CAD, and CKD. The results of various clinical
trials have demonstrated the efficacy and safety of
SGLT2i in these patient populations. Despite the ev-
idence, utilization of SGLT2i remains low and hospi-
talizations provide a potential opportunity to
improve prescription rates. To overcome the poten-
tial barriers to initiation of SGLT2i in hospitalized
patients, such as clinical inertia, provider knowledge,
cost, and patient preference, innovative strategies
need to be developed. Ongoing trials to expand the
medication indications of SGLT2i as well as novel care delivery
10 Unlu et al JACC: ADVANCES, VOL. 3, NO. 7, 2024

Inpatient SGLT2i Initiation JULY 2024:101024

models are expected to provide further insights into
the optimal use of SGLT2i in various clinical settings
and appropriate integration into practice.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
This work was supported by Boehringer Ingelheim Pharmaceuticals,
Inc. (BIPI) and Lilly USA, LLC. The authors meet criteria for author-
ship as recommended by the International Committee of Medical
Journal Editors (ICMJE). The authors received no payment related to
the development of the manuscript. Graphical support was provided
by Envision Pharma Group, contracted and funded by Boehringer
Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. BIPI and
Lilly were given the opportunity to review the manuscript for medical
and scientific accuracy as well as intellectual property considerations.
Dr Unlu has received funding from the National Heart Lung and Blood
Institute under award number T32HL007604. Dr Bhatt has received
grant support to his institution from National Institutes of Health/
National Heart, Lung, and Blood Institute, National Institutes of
Health/National Institute on Aging, American College of Cardiology
Foundation, and the Centers for Disease Control and Prevention and
has received consulting fees from Sanofi Pasteur, Novo Nordisk, and
the Kinetix Group. Dr Blood has received grant support from Novo
Nordisk, Boehringer Ingelheim, GE Healthcare, Eli Lilly; consulting
fees from Walgreens Health, Color Health, Flare Capital, Arsenal
Capital Partners, Novo Nordisk, Milestone Pharmaceuticals; and has
equity holdings in Knownwell; and has received grant support from
National Institutes of Health/ National Heart, Lung, and Blood Insti-
tute and under Equity “Signum Technologies and Porter Health”.
ADDRESS FOR CORRESPONDENCE: Dr Alexander J.
Blood, Brigham and Women’s Hospital, 75 Francis
Street, Boston, Massachusetts 02115, USA. E-mail:
ABlood@BWH.Harvard.Edu. @AJBloodMD.

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KEY WORDS guideline-directed medical
therapy, in-hospital initiation, Sodium–
glucose cotransporter 2 inhibitors