Effect of Empagliflozin on Clinical Stability in Patients with Heart Failure and Reduced LV Ejection Fraction

Introduction

Empagliflozin belongs to a class of gliflozins that prevent the reabsorption of glucose and sodium in the kidneys by inhibiting the sodium-glucose cotransporter 2 (SGLT2). The mechanism of action of the drug involves therapeutic glycosuria associated with a decrease in blood glucose levels, but also body weight, as the excreted glucose cannot be used as an energy substrate in the body. Previous extensive clinical studies have shown that empagliflozin also has cardioprotective effects, including reducing the risk of hospitalization for heart failure in patients with type 2 diabetes, HFrEF, and chronic kidney disease (CKD).

However, hospitalizations for heart failure represent only a small fraction of all events in these patients. If the goal of treatment is to maintain the clinical stability of the patient, therapy should also have a favorable impact on other manifestations of worsening chronic heart failure, including reduced functional capacity, or worsening symptoms requiring adjustment of chronic therapy (especially diuretics) and acute or urgent treatment.

Analyzed Data and Assessed Population

The EMPEROR-Reduced study included patients with NYHA class II–IV heart failure with reduced left ventricular ejection fraction (LVEF) ≤ 40%, who had adequate therapy (diuretics, renin-angiotensin-aldosterone system inhibitors and neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and, if indicated, pacemakers). The study preferably included patients with LVEF ≤ 30%; for patients with LVEF > 30%, a positive history of hospitalization for heart failure in the last 12 months or elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) was required.

Patients were randomized in a 1:1 ratio to receive empagliflozin 10 mg once daily or a placebo. Heart failure treatment could be adjusted at the investigator's discretion.

Study Results

A total of 3730 patients participated in the study, with 1863 receiving empagliflozin and 1867 receiving placebo. The median treatment duration was 16 months.

Empagliflozin administration, compared with placebo, was associated with a reduction in the risk of the composite endpoint including death, hospitalization for heart failure, or acute/urgent treatment requiring intravenous therapy (415 vs. 519 patients; hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.67–0.87; p < 0.0001). The beneficial effect of empagliflozin reached statistical significance just 12 days after randomization.

Empagliflozin also reduced the total number of hospitalizations for heart failure requiring intensive care (HR 0.67; 95% CI 0.50–0.90; p = 0.008) and vasopressor or positive inotropic pharmacotherapy or mechanical or surgical intervention (HR 0.64; 95% CI 0.47–0.87; p = 0.005). Compared to placebo, fewer patients on empagliflozin required intensification of diuretic therapy (297 vs. 414; HR 0.67; 95% CI 0.56–0.78; p < 0.0001). Additionally, patients treated with empagliflozin were 20–40% more likely to improve their NYHA functional class and 20–40% less likely to worsen compared to placebo. This effect reached statistical significance 28 days after randomization and was maintained throughout the follow-up period.

The risk of heart failure worsening events requiring outpatient treatment or hospitalization was high in the placebo group (48.1/100 patients/year during the follow-up period), and empagliflozin administration significantly reduced it (HR 0.70; 95% CI 0.63–0.78; p < 0.0001).

Conclusion

Empagliflozin use in adequately treated HFrEF patients reduced the risk of heart failure worsening events requiring outpatient treatment or hospitalization compared to placebo. This benefit was observed in both diabetic and non-diabetic patients. The treatment benefit was noted shortly after initiation and was maintained throughout the follow-up period.

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Source: Packer M., Anker S. D., Butler J. et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Circulation 2021; 143 (4): 326–336, doi: 10.1161/CIRCULATIONAHA.120.051783.