1-MINUTE CONSULT

Osamah Z. Badwan, MD Lorenzo Braghieri, MD Warren Skoza, MD

Department of Internal Medicine, Department of Internal Medicine, Department of Internal Medicine,
Cleveland Clinic, Cleveland, OH Cleveland Clinic, Cleveland, OH Cleveland Clinic, Cleveland, OH

Ankit Agrawal, MD Venu Menon, MD W. H. Wilson Tang, MD

Department of Cardiovascular Medicine, Department of Cardiovascular Medicine, Department of Cardiovascular Medicine,
Cleveland Clinic, Cleveland, OH Cleveland Clinic, Cleveland, OH; Cleveland Clinic, Cleveland, OH;
Professor, Cleveland Clinic Lerner College Professor, Cleveland Clinic Lerner College BRIEF
of Medicine of Case Western Reserve of Medicine of Case Western Reserve ANSWERS
University, Cleveland, OH University, Cleveland, OH
TO SPECIFIC
CLINICAL
QUESTIONS

Q: When should we consider SGLT-2

inhibitors in patients with acute
decompensated heart failure?
A: Sodium-glucose cotransporter 2 (SGLT-2)
inhibitors should be started as early as possi-
ble in patients hospitalized with acute decompensated
The EMPA-RESPONSE-AHF trial (Effects
of Empagliflozin on Clinical Outcomes in Patients
With Acute Decompensated Heart Failure),7 with
heart failure who do not have clear contraindications to 79 patients, found patients who were randomized to
them, and continued after discharge (Figure 1). These empagliflozin within 24 hours of admission had a signif-
medications are well tolerated, can aid in decongestion icant reduction in the composite outcome of worsening
without worsening renal function, and have multiple heart failure, rehospitalization for heart failure, or death
cardiovascular benefits. at 60 days compared with placebo.
Introduced in 2012, SGLT-2 inhibitors were devel- The EMPULSE trial (Empagliflozin in Patients
oped to treat type 2 diabetes by reducing reabsorption Hospitalized With Acute Heart Failure Who Have
of glucose from the renal filtrate, but they have since Been Stabilized)3 found that patients who were ran-
been found to have multiple cardiovascular benefits domized to receive empagliflozin 10 mg daily within
beyond glucose-lowering,1 which may be attributed to 5 days of admission had a significant reduction in
their natriuretic and osmotic diuretic effects and other the combined primary end point, ie, a hierarchical
metabolic effects.2–4 Of note, they lower N-terminal composite of death from any cause, number of heart
pro-B-type natriuretic peptide levels, which may be a failure events, and time to first heart failure event, or a
key determinant of improved clinical outcomes regard- 5-point or greater difference in change from baseline in
less of left ventricular ejection fraction.3–5 the Kansas City Cardiomyopathy Questionnaire Total
Symptom Score at 90 days compared with placebo.
■ BENEFITS OF STARTING EARLY The DELIVER trial (Dapagliflozin Evaluation to
Improve the Lives of Patients With Preserved Ejection
Acute decompensated heart failure is one of the lead-
Fraction Heart Failure),12 in a prespecified analysis of
ing reasons for hospital admissions worldwide and is
654 (10.4%) of the trial patients who were randomized
associated with considerable morbidity and mortality.6
to receive dapagliflozin or placebo while hospitalized
As outlined below and in Table 1,3,4,7–11 studies have
for heart failure or within 30 days of hospital discharge,
suggested that patients hospitalized for acute decom-
pensated heart failure could tolerate SGLT-2 inhibi- demonstrated a reduced risk of worsening heart failure
tors and derive cardiac benefit from them, especially or cardiovascular death. The investigators calculated
when these drugs were started early. While most of that the number needed to treat with dapagliflozin to
the patients in these trials had reduced left ventricular prevent 1 primary outcome event was 28 patient-years
ejection fraction, the benefits were consistent across all in recently hospitalized patients and 65 patient-years
left-ventricular-ejection-fraction groups. in patients not recently hospitalized.
The SOLOIST-WHF trial (Effect of Sotagliflozin on
doi:10.3949/ccjm.91a.23034 Cardiovascular Events in Patients With Type 2 Diabetes
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SGLT-2 INHIBITORS IN ACUTE HEART FAILURE

Patient hospitalized with

acute decompensated heart failure

Assess volume status, blood pressure,

and renal function

Hypotension (SBP < 90 mm Hg)

Acute kidney injury or
eGFR < 20–25a mL/min/1.73 m2
NT-proBNP < 300 pg/mL
Dehydrating illness or clear
contraindications
Yes No

Do not initiate SGLT-2 inhibitor On an SGLT-2 inhibitor before admission?

Yes No
Start an SGLT-2 inhibitor at heart failure
study doseb:
Continue SGLT-2 inhibitor
Empagliflozin 10–25 mg twice daily
Dapagliflozin 10 mg once daily
Sotagliflozin 200–400 mg once daily

Follow up in clinic in 2–4 weeks with repeat

renal function panel

At baseline eGFR or < 30% reduction?

No Yes
Hold SGLT-2 inhibitor, assess alternative
causes of worsening nephropathy, Continue or resume SGLT-2 inhibitor
and treat if present

Figure 1. Proposed algorithm for initiating sodium-glucose cotransporter 2 inhibitors in acute decompen-
sated heart failure.
a
Dapagliflozin: No dosage adjustment for eGFR ≥ 25 mL/min/1.73 m2. Manufacturer labeling does not recommend initiation of therapy at eGFR < 25 mL/min/1.73 m2.
Sotagliflozin is not indicated for patients with eGFR < 25 mL/min/1.73 m2. For heart failure, empagliflozin is not indicated for eGFR < 20 mL/min/1.73 m2. For type 2
diabetes mellitus, empagliflozin is not indicated for eGFR < 30 mL/min/1.73 m2.
b
Direct evidence on the effects of canagliflozin and ertugliflozin on heart failure outcomes is available only in patients with type 2 diabetes mellitus. It remains to be
determined if they have similar effects in patients without type 2 diabetes.
eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro-B-type natriuretic peptide; SBP = systolic blood pressure;
SGLT-2 = sodium-glucose cotransporter 2

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 BADWAN AND COLLEAGUES

TABLE 1
Randomized controlled trials of sodium-glucose cotransporter 2 inhibitors in acute
decompensated heart failure
Trial Patients Treatment Results
3
EMPULSE N = 530, Empagliflozin 10 mg/day or Early benefit, defined by a hierarchical
67% with left ventricular placebo for 90 days, started a composite that incorporated all-cause mortality,
ejection fraction (LVEF) median of 3 days after hospital time to heart failure events, and quality of life
< 40% admission (measured by Kansas City Cardiomyopathy
Questionnaire Total Symptom Score) with
empagliflozin use

EMPAG-HF4 N = 59, Empagliflozin 25 mg/day or A 25% increase in cumulative urine output

mean LVEF 45 ± 16% placebo for 5 days, started within over 5 days without affecting markers of renal
12 hours of admission function with empagliflozin use

SOLOIST-WHF8,9 N = 1,222, Sotagliflozin 200–400 mg/day or A 33% reduction of a composite of

79% with LVEF < 50% placebo for a median of 9 months, cardiovascular death and hospitalizations or
initiated before or shortly after urgent visits for heart failure and apparent
hospital discharge improvement in quality of life as measured by
the Kansas City Cardiomyopathy Questionnaire
12 score at 4 months in sotagliflozin group

EMPA-RESPONSE-AHF7 N = 79, Empagliflozin 10 mg/day or Significantly reduced composite outcome

100% with LVEF < 50% placebo for 30 days, initiated of worsening heart failure, rehospitalization
within 24 hours of presentation for heart failure, or death at 60 days in
while on intravenous diuretics empagliflozin group

DAPA-RESIST10 N = 61, Dapagliflozin 10 mg or metolazone Significant weight reductions at up to 96 hours

44% with LVEF ≤ 40% 5–10 mg for up to 3 consecutive of dapagliflozin use compared with metolazone
days, initiated within 24 hours of group
trial screening

DICTATE-AHF11 N = 240, Dapagliflozin 10 mg/day + Strong signal of improved diuretic efficiency

52% with LVEF < 40% protocolized diuretic titration or (defined as weight change divided by loop
protocolized diuretic titration diuretic dose) until day 5 of hospitalization or
alone, initiated within 24 hours of discharge if sooner
presentation

DAPA-RESIST = Dapagliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic Resistance, DICTATE-AHF = Efficacy and Safety of Dapagliflozin
in Acute Heart Failure, EMPAG-HF = Empagliflozin in Acute Decompensated Heart Failure, EMPA-RESPONSE-AHF = Effects of Empagliflozin on Clinical Outcomes
in Patients With Acute Decompensated Heart Failure, EMPULSE = Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized,
SOLOIST-WHF = Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure

Post Worsening Heart Failure),8 in a prespecified anal- failure events through 30 and 90 days after discharge.9
ysis based on timing of the first dose of the SGLT-1/2 However, no trials to date have directly compared
inhibitor sotagliflozin, found the degree of benefit in SGLT-2 inhibitors with combined SGLT-1/2 inhibitors.
the primary end point (the total number of deaths from Another advantage of starting these medications
cardiovascular causes and hospitalizations and urgent while the patient is in the hospital is the opportunity
visits for heart failure) was similar regardless of whether to address medication reconciliation and potential bar-
the drug was started during the admission (48.8% of the riers to adherence, which we usually do on discharge.
overall group) or within 3 days after discharge. Similarly,
a post hoc analysis of this trial demonstrated that starting ■ SGLT-2 INHIBITORS HELP REMOVE FLUID
sotagliflozin before discharge in patients with type 2 dia- Congestion is thought to be the primary reason patients
betes hospitalized for acute decompensated heart failure are hospitalized with acute decompensated heart fail-
significantly decreased cardiovascular deaths and heart ure.13 Excreting more sodium early during decongestive
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SGLT-2 INHIBITORS IN ACUTE HEART FAILURE

therapy is strongly associated with better postdischarge ■ PATIENTS WITH RENAL DYSFUNCTION
outcomes, and sodium excretion is a better prognos-
tic indicator than urine output, net fluid balance, or While SGLT-2 inhibitors have been shown to slow
weight change.14 the progression of chronic kidney disease, they gen-
A concern about starting SGLT-2 inhibitors as an erally are not indicated for patients whose eGFR is
add-on therapy (in addition to loop diuretics) is the less than 20 or 25 mL/min/1.73 m2 (depending on the
potential for excessively rapid intravascular volume particular SGLT-2 inhibitor). A reason for caution
removal and renal injury. Nevertheless, empagliflozin in this situation is that SGLT-2 inhibitors cause a
was shown to achieve decongestion without worsening temporary drop in eGFR and persistent reductions
renal function in patients with type 2 diabetes hospital- in plasma volume. However, this initial nadir in
ized for acute decompensated heart failure.15 This might eGFR early after starting SGLT-2 inhibitors partially
be explained by the natriuresis and osmotic diuresis reverses over the subsequent 6 to 8 weeks. Further,
caused by SGLT-2 inhibition, leading to reduced continuation is associated with improved renal and
plasma volume and, subsequently, reduced preload.2 cardiovascular outcomes, and new studies suggest that
Furthermore, SGLT-2 inhibitors may act synergistically SGLT-2 inhibitors should not be discontinued unless
with loop diuretics for decongestion and have other the eGFR decreases by more than 30%.17
beneficial metabolic effects.16
■ DIABETIC KETOACIDOSIS AND INFECTIONS
The 2023 DAPA-RESIST trial (Dapagliflozin Ver-
sus Thiazide Diuretic in Patients With Heart Failure SGLT-2 inhibitors are not approved for patients with
and Diuretic Resistance)10 showed that dapagliflozin type 1 diabetes, since their use may promote hypoglycemia
10 mg daily was as effective as metolazone 5 to 10 in patients without sufficient insulin secretagogue activity,
mg daily in alleviating congestion in patients with a situation also posing a risk for euglycemic diabetic keto-
acute decompensated heart failure with resistance to acidosis.18 Also, prescribers have been cautioned about
loop diuretics. Although patients in the dapagliflozin genital mycotic infections and the rare severe compli-
group received a higher total amount of furosemide, cation of Fournier gangrene in patients at high risk (eg,
they encountered fewer biochemical disturbances than older men and those with diabetes, alcohol use disorder,
those in the metolazone group. obesity, or immunocompromising conditions).
Fortunately, none of the previously mentioned trials
■ PATIENTS ALREADY ON SGLT-2 INHIBITORS found a higher risk of these complications in patients
started on SGLT-2 inhibitors during admissions for
Although SGLT-2 inhibitors lowered blood pressure
acute decompensated heart failure.
only slightly by themselves in large heart failure clinical
trials, it is important to consider volume status, espe-
■ THE BOTTOM LINE
cially in those receiving other heart failure agents such
as angiotensin receptor-neprilysin inhibitors and loop In patients with acute decompensated heart failure
diuretics, which can increase the risk of orthostasis and without clear contraindications to these agents, an
falling after the patient goes home. Nevertheless, unless SGLT-2 inhibitor should be started as early as pos-
patients have a clear contraindication such as severe sible or continued if the patient is already receiving
hypotension (systolic blood pressure < 90 mm Hg), one. As an adjuvant therapy for decongestion, they
shock, acute kidney injury, estimated glomerular filtra- have been shown to be well tolerated and can aid in
tion rate (eGFR) less than 20 or 25 mL/min/1.73 m2 decongestion without worsening renal function. Their
(depending on the specific agent), or diabetic keto- use early during hospitalization and their continuation
acidosis (including euglycemic ketoacidosis), those after discharge may translate into long-term clinical
who are already receiving SGLT-2 inhibitors and are benefits. ■
admitted with acute decompensated heart failure would
benefit from continuing this therapy.3,7–9,12 ■ DISCLOSURES
Of note, evidence of the beneficial effects of cana- Dr. Tang has disclosed consulting for Boston Scientific, CardiaTec Bio-
gliflozin and ertugliflozin on heart failure outcomes is sciences, Cardiol Therapeutics, Genomics, Intellia Therapeutics, Kiniksa
Pharmaceuticals, preCARDIA, Relypsa, Renovacor, Sequana Medical,
available only in patients with type 2 diabetes, and WhiteSwell, and Zehna Therapeutics; board examination writing/
there is even less evidence currently for outcomes with approval committee for American Board of Internal Medicine; and
editorship/authorship for SpringerNature. The other authors report no
bexagliflozin. It remains to be determined if these drugs relevant financial relationships which, in the context of their contribu-
have similar effects in patients without type 2 diabetes. tions, could be perceived as a potential conflict of interest.

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 BADWAN AND COLLEAGUES

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10. Yeoh SE, Osmanska J, Petrie MC, et al. Dapagliflozin vs metola- Address: W. H. Wilson Tang, MD, Department of Cardiovascular Medi-
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44(31):2966–2977. doi:10.1093/eurheartj/ehad341 [email protected]

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