What is the place in therapy for empagliflozin for heart failure?

Introduction

In February 2022, the Food and Drug Administration (FDA) granted approval to empagliflozin to reduce the risk of death and hospitalization for heart failure in patients with heart failure.1 Empagliflozin was previously approved in patients with heart failure with reduced ejection fraction (HFrEF), so the updated indication is an expansion to include patients with heart failure with preserved ejection fraction (HFpEF). Empagliflozin is the first sodium glucose cotransporter-2 (SGLT-2) inhibitor to receive approval for use in patients with HFpEF (without diabetes), which has prompted new consideration for its place in therapy for heart failure.

Literature with empagliflozin in heart failure

Beneficial outcomes with empagliflozin in patients with heart failure were first seen in the EMPA-REG OUTCOME cardiovascular outcomes trial.2 EMPA-REG OUTCOME included 7020 patients with type 2 diabetes who received empagliflozin 10 or 25 mg or placebo daily. A secondary outcome of hospitalization for heart failure occurred significantly less frequently in the empagliflozin group (2.7%) compared to the placebo group (4.1%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.50 to 0.85). This finding prompted further study of empagliflozin in patients with both chronic and acute failure, including in patients without diabetes (Table).

Table. Studies of empagliflozin in patients with heart failure.3-11
Study design and durationSubjects
InterventionsResultsaConclusions
Chronic heart failure
Anker 20213 
EMPEROR-Preserved
 
DB, PC, event-driven, RCT
 
Median follow-up 26.2 months		N=5988
 
Patients with HFpEF with or without T2DM
 
Mean age: 71 y
Mean LVEF: 54%
T2DM: 49%		Empagliflozin 10 mg once daily
 
Placebo		Composite of death from CV causes or hospitalization for HF: 13.8% empagliflozin vs. 17.1% placebo (HR, 0.79; 95% CI, 0.69 to 0.90; p<0.001)
 
CV death:
7.3% empagliflozin vs. 8.2% placebo (HR, 0.91; 95% CI, 0.76 to 1.09)
 
Hospitalization for HF:
8.6% empagliflozin vs. 11.8% placebo (HR, 0.71; 95% CI, 0.60 to 0.83)		Empagliflozin reduced the combined risk of CV death or hospitalization for HF in patients with HFpEF, mainly due to a reduction in HF hospitalization
Packer 20204
 
EMPEROR-Reduced
 
DB, PC, event-driven, RCT
 
Median follow-up 16 months		N=3726
 
Patients with HFrEF with or without T2DM
 
Mean age: 67 y
Mean LVEF: 27%
T2DM: 50%		Empagliflozin 10 mg once daily
 
Placebo		Composite of death from CV causes or hospitalization for HF: 19.4% empagliflozin vs. 24.7% placebo (HR, 0.75; 95% CI, 0.65 to 0.86; p<0.001)
 
CV death:
10.0% empagliflozin vs. 10.8% placebo (HR, 0.92; 95% CI, 0.75 to 1.12)
 
Hospitalization for HF:
13.2% empagliflozin vs. 18.3% placebo (HR, 0.69; 95% CI, 0.59 to 0.81)		Empagliflozin in patients with HFrEF reduced the combined risk of CV death or hospitalization for HF, mainly due to a reduction in HF hospitalization
Abraham 20215
 
EMPERIAL-Reduced and EMPERIAL-Preserved
 
DB, PC, RCT
 
Duration 12 weeks		Patients with symptomatic HFrEF or HFpEF with or without a history of T2DM

EMPERIAL-Reduced:
N=312
Mean age: 69 y
Mean LVEF: 30%
T2DM: 60%
6MWTD: 307.5 m

EMPERIAL-Preserved:
N=315
Mean age: 74 y
Mean LVEF: 53%
T2DM: 51%
6MWTD: 299 m		Empagliflozin 10 mg once daily
 
Placebo		EMPERIAL-Reduced:

Empagliflozin and placebo improved 6MWTD by a median of 13.5 m and 18 m, respectively (difference, -4; 95% CI, -16 to 6; p=0.42)
 
EMPERIAL-Preserved:
 
Empagliflozin and placebo improved 6MWTD by a median of 10 m and 5 m, respectively (difference, 4; 95% CI, -5 to 13; p=0.37)		Empagliflozin did not improve exercise ability (as measured by 6MWTD) in either HFrEF or HFpEF patients with or without T2DM
Santos-Gallego 20216
 
EMPA-TROPISM (ATRU-4)
 
DB, PC, RCT
 
Duration 6 months		N=84
 
Patients with HFrEF without a history of T2DM
 
Mean age: 62 y
Mean LVEF: 36%
 
Empagliflozin 10 mg once daily
 
Placebo		LV end-diastolic volume:
-25.1 ± 26 mL empagliflozin vs. -1.5 ± 25.4 mL placebo (p<0.001)
 
LV end-systolic volume:
-26.6 ± 20.5 mL empagliflozin vs. -0.5 ± 21.9 mL placebo (p<0.001)		Empagliflozin improved LV volume in patients with HFrEF with no history of T2DM
Acute heart failure/heart failure hospitalization
Voors 20227
 
EMPULSE
 
DB, PC, RCT
 
Duration 90 days		N=530
 
Patients hospitalized with acute de novo or decompensated HF with reduced or preserved LVEF, with or without diabetes
 
Median age: 71 y
Median LVEF: 31% to 32%
Diabetes: 44% to 47%		Empagliflozin 10 mg once daily
 
Placebo		Composite clinical benefit outcome (time to all-cause death, HF event frequency, time to first HF event, or change in KCCQ-TSS) at 90 days: hierarchical testing stratified win ratio for empagliflozin vs. placebo 1.36 (95% CI, 1.09 to 1.68; p=0.0054)Empagliflozin demonstrated significant clinical benefit in patients hospitalized for acute HF, whether with or without a previous history of HF
Perez-Belmonte 20228
 
Real-world observational cohort with propensity score matching		N=158

Older patients (≥80 y) with T2DM hospitalized for ADHF who had been taking empagliflozin for at least 3 months
 
Mean age: 85 y
Mean LVEF: 47%		Continuation of pre-admission empagliflozin 10 or 25 mg once daily + once-daily basal insulin
 
Conventional glucose lowering hospital regimen (mealtime bolus insulin + once-daily basal insulin)		VAS dyspnea score at discharge:
similar with empagliflozin vs. conventional treatment (p=0.101)
 
NT-proBNP level at discharge:
significantly lower with empagliflozin vs. conventional treatment (p=0.021)
 
Diuretic response:
greater in patients receiving empagliflozin (p=0.044)
 
Urine output:
greater in patients receiving empagliflozin (p=0.042)
 
No difference in worsening HF, length of hospital stay, or in-hospital death between groups		Empagliflozin improved NT-proBNP levels, diuretic response, and urine output in older patients with T2DM hospitalized for ADHF
Perez-Belmonte 20219
 
Real-world observational cohort with propensity score matching		N=182
 
Patients with T2DM hospitalized for ADHF who had been taking empagliflozin for at least 3 months
 
Mean age: 72 y
Mean LVEF: 47%		Continuation of pre-admission empagliflozin 10 or 25 mg once daily + once-daily basal insulin
 
Conventional glucose lowering hospital regimen (mealtime bolus insulin + once-daily basal insulin)		VAS dyspnea score at discharge:
similar with empagliflozin vs. conventional treatment (p=0.148)
 
NT-proBNP level at discharge:
significantly lower with empagliflozin vs. conventional treatment (p=0.032)
 
Diuretic response:
similar in both groups (p=0.094)
 
Urine output:
greater in patients receiving empagliflozin (p=0.037)
 
No difference in worsening HF, length of hospital stay, or in-hospital death between groups		Empagliflozin reduced NT-proBNP levels and increased urine output in patients with T2DM hospitalized for ADHF
Tamaki 202110
 
OL, RCT
N=59b
 
Patients with T2DM hospitalized for ADHF
 
Mean age: 81 y
Mean LVEF: 39% to 44%
 


 
 
 
 
Add-on empagliflozin 10 mg once daily
 
Conventional glucose-lowering therapy
NT-proBNP levels at day 7:
lower with empagliflozin vs. conventional therapy (p=0.040)

Urine output within the first 24 h:
higher with empagliflozin vs. conventional therapy (p=0.005)

Change in body weight at day 7:
No difference between groups (p=0.205)
Empagliflozin as an add-on therapy during hospitalization for ADHF significantly reduced congestion (as measured by NT-proBNP levels) in patients with T2DM
Damman 202011
 
EMPA-RESPONSE-AHF
 
DB, PC, RCT
 
Follow-up 30 days		N=79
 
Patients hospitalized for ADHF with or without T2DM
 
Mean age: 76 y
Mean LVEF: 36%
T2DM: 28% to 38%		Empagliflozin 10 mg once daily
 
Placebo		Change in dyspnea VAS over 4 days:
No difference with empagliflozin vs. placebo (p=0.18)

Diuretic response through day 4:
No difference with empagliflozin vs. placebo (p=0.37)
 
Change in NT-proBNP through day 4:
No difference with empagliflozin vs. placebo (p=0.63)
 
Length of hospital stay:
No difference with empagliflozin vs. placebo (p=0.58)		Use of empagliflozin did not improve dyspnea, NT-proBNP levels, diuretic response, or length of hospital stay compared to placebo in patients hospitalized for ADHF
a Results mainly reflect primary outcomes or the strongest clinical outcomes.
b Trial was stopped early due to the COVID-19 pandemic.
Abbreviations: 6MWTD=6-minute walk test distance; ADHF=acute decompensated heart failure; DB=double-blind; CI=confidence interval; CV=cardiovascular; HF=heart failure; HFpEF= heart failure with preserved ejection fraction; HFrEF= heart failure with reduced ejection fraction; HR=hazard ratio; KCCQ-TSS=Kansas City Cardiomyopathy Questionnaire-Total Symptom Score; LV=left ventricular; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro-B-type natriuretic peptide; OL=open-label; PC=placebo-controlled; RCT=randomized controlled trial; T2DM=type 2 diabetes mellitus; VAS=visual analogue scale.

Chronic heart failure

In patients with chronic heart failure, studies have shown that empagliflozin reduces hospitalization for heart failure in patients with both HFrEF and HFpEF (49% to 60% of whom had diabetes at baseline).3,4 A meta-analysis of 7 studies (n=5150) found that empagliflozin significantly reduced hospitalization for heart failure, patient-reported symptoms, and body weight from baseline.12 Empagliflozin has not shown a reduction in cardiovascular death in this population, but no studies have been powered to detect a difference in this outcome alone (only as part of a composite outcome).3,4

A post-hoc analysis of the EMPEROR-Reduced trial (n=3730) found that the effect of empagliflozin on the primary outcome was consistent among patients who were and were not receiving optimized background therapy doses (eg, angiotensin converting enzyme inhibitors, beta-blockers), and among patients receiving various combinations of background therapies.13 A pooled analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials reported that risk of hospitalization for heart failure was reduced in patients with all degrees of ejection fraction between <25% and 65% who received empagliflozin, but patients with the highest ejection fractions (≥65%) did not receive benefit compared to placebo.14 Another pooled analysis of both trials suggests that renal benefit of empagliflozin may be limited to patients with HFrEF since the EMPEROR-Preserved trial found no difference in serious renal outcomes between groups.15

Acute heart failure

The strongest data with empagliflozin in patients with acute heart failure is the randomized EMPULSE trial (n=530), which found that empagliflozin resulted in more statistical “wins” compared to placebo in a composite clinical outcome of all-cause death, heart failure events, and heart failure symptoms.7 Limitations of this study include lack of statistical comparison of the components of the composite primary outcome, patients were hospitalized for a median of 3 days before randomization, and outcomes such as length of hospital stay or rates of rehospitalization for heart failure were not assessed. Further study is needed to establish the role of empagliflozin in the setting of acute heart failure.

Literature with other SGLT-2 inhibitors

The only other SGLT-2 inhibitor that is approved in the setting of heart failure (without diabetes) is dapagliflozin.16 Dapagliflozin is approved to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with HFrEF (NYHA class II to IV). Efficacy supporting this indication is based on the DAPA-HF trial, which reported a lower occurrence of the primary outcome (a composite of cardiovascular death or worsening heart failure, defined as hospitalization or need for intravenous therapy) with dapagliflozin 10 mg (16.3%) compared to placebo (21.2%; HR, 0.74; 95% CI, 0.65 to 0.85) in patients with a baseline ejection fraction of ~31%.17 At baseline, 41.8% of patients had diabetes. When analyzed separately, both components of the primary outcome were reduced with dapagliflozin compared to placebo. Dapagliflozin has also demonstrated improved heart failure symptoms and exercise capacity in a placebo-controlled randomized trial in patients with HFpEF, but mortality outcomes with dapagliflozin in this population will not be available until completion of the ongoing DELIVER trial.18,19

Meta-analyses of SLGT-2 inhibitors in patients with heart failure have reported reductions in cardiovascular mortality and heart failure hospitalizations, but these findings were based mainly on trials in patients with HFrEF and some analyses included an SGLT-2 inhibitor that is not available in the United States (ie, sotagliflozin).20-22 Network meta-analyses in patients with chronic heart failure have not identified significant differences in outcomes between individual SGLT-2 inhibitors.23 Comparative data with SGLT-2 inhibitors in patients with acute heart failure are too limited to make any meaningful conclusions.24

Clinical guideline recommendations

The American College of Cardiology/American Heart Association/Heart Failure Society of America guideline on management of heart failure does not address the role of SGLT-2 inhibitors in patients with heart failure.25 A 2021 expert consensus decision pathway focused on HFrEF recommended using an SGLT-2 inhibitor in patients with ejection fraction ≤40% with or without diabetes, with New York Heart Association class II to IV, and in combination with background guideline-directed heart failure therapy.26 Background therapy does not need to be dose-optimized before starting an SLGT-2 inhibitor. Due to limitations of clinical trial inclusion criteria, empagliflozin and dapagliflozin should not be used in patients with heart failure and estimated glomerular filtration (eGFR) rate <20 mL/min/1.73 m2 or <30 mL/min/1.73 m2, respectively. Renal function and volume status should be monitored carefully after patients start an SGLT-2 inhibitor.

The 2022 American Diabetes Association (ADA) standards of medical care in diabetes support using SGLT-2 inhibitors or glucagon-like peptide-1 inhibitors in patients with established (or high risk for) heart failure atherosclerotic cardiovascular disease.27 Recommendations do not specifically distinguish between patients with HFrEF and HFpEF, but the citations and narrative text focus almost exclusively on HFrEF due to a lack of published data in patients with HFpEF. An expert consensus decision pathway authored by the American College of Cardiology supports the ADA recommendations.28

Conclusion

Several clinical trials have reported cardiovascular outcome benefits with empagliflozin compared to placebo in patients with chronic heart failure. The ongoing comparative effectiveness EMPRISE trial has also reported less hospitalization for heart failure among patients with diabetes compared to another first-line antidiabetic agent (sitagliptin).29 Further studies are needed on comparative efficacy and safety among the SGLT-2 inhibitors and with longer term follow-up. Empagliflozin can be considered as a therapeutic option in patients with chronic heart failure with or without diabetes who are already receiving guideline-recommended therapy, with close monitoring of renal function and volume status. Guidelines support empagliflozin use in patients with HFrEF but no guidelines yet provide direct recommendations for its use in patients with HFpEF. Until guideline updates are available to further define its place in therapy, clinicians can consider empagliflozin as a treatment option in both populations. Compelling data are lacking with empagliflozin in patients with acute heart failure; additional study is needed in this setting.

References

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Prepared by:
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist

Rosa Macrito, PharmD Candidate
University of Illinois at Chicago College of Pharmacy

April 2022

The information presented is current as of February 25, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.