Importance of NT-proBNP and Effect of Empagliflozin in HFrEF

Quick Takes

  • Higher baseline NT-proBNP levels are associated with higher risk for poor CV and renal outcomes.
  • Empagliflozin is associated with a reduction in adverse outcomes despite baseline NT-proBNP level.
  • NT-proBNP level after starting treatment may provide better prognostic value compared to baseline values.

Study Questions:

What is the relationship between N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and the effects of empagliflozin in heart failure with reduced ejection fraction (HFrEF)?


Data from the EMPEROR-Reduced trial were used for this analysis. The primary endpoint was time to first event for a composite of cardiovascular (CV) death or heart failure (HF) hospitalization. The two secondary endpoints were total HF hospitalization and slope of the change in estimated glomerular filtration rate (eGFR). Empagliflozin reduced the risk of these outcomes compared to placebo in participants with HFrEF in the original study.

For this analysis, study participants had NT-proBNP levels collected at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Participants were divided into quartiles according to baseline NT-proBNP levels for comparison of outcomes. Study participants were further categorized as having a low (lowest quartile) or high (highest three quartiles) NT-proBNP level at baseline and 12 weeks. Four groups were identified based on NT-proBNP category at baseline/12 weeks: low/low, high/low, low/high, high/high. Subsequent outcomes were compared for these groups.


Baseline NT-proBNP data for 3,728 participants were available. The following NT-proBNP quartiles were identified: <1,115 pg/mL; 1,115-1,909 pg/mL; 1,910-3,479 pg/mL; ≥3,480 pg/mL. The following were key findings from this study:

  • Rates of the composite outcome of CV death or HF hospitalization increased with increasing NT-proBNP quartile.
  • Rates of total HF hospitalizations and a prespecified composite renal outcome increased with increasing NT-proBNP quartile.
  • Rates of decline in eGFR were highest in the highest NT-proBNP quartile.
  • Rates of the primary endpoint, total HF hospitalizations, and the renal composite endpoint were reduced with empagliflozin compared to placebo across NT-proBNP quartiles.
  • Empagliflozin reduced NT-proBNP levels at all testing time points compared to placebo, with the largest decrease of 13% at 52 weeks.
  • At 12 weeks, having an NT-proBNP level in the lowest quartile despite the baseline value (low/low and high/low groups) was associated a reduced risk of subsequent events.
  • Empagliflozin treatment led to a 27% higher adjusted odds of having an NT-proBNP in the lowest quartile compared to placebo.


In the EMPEROR-Reduced trial, having a higher baseline NT-proBNP level was associated with increased risk for poor cardiovascular and renal outcomes. Use of empagliflozin compared to placebo reduced this risk across NT-proBNP quartiles. Follow-up NT-proBNP at 12 weeks of treatment appeared to have better prognostic value than baseline (pretreatment) values.


It has been previously demonstrated that natriuretic peptides in HF are associated with both symptoms and prognosis. This was the first study to look at the prognostic value of NT-proBNP measurements with empagliflozin use in HFrEF. Not surprisingly, this study demonstrates that worse CV and renal outcomes are associated with higher NT-proBNP levels. It is reassuring, though, that empagliflozin use led to a reduction in the risk for poor outcomes despite baseline NT-proBNP levels. It is also helpful to note that empagliflozin use also leads to a sustained reduction in NT-proBNP level compared to placebo, and that participants with NT-proBNP levels in the lowest quartile after treatment initiation had better overall outcomes. While this study does not elucidate the mechanism or exact relationship between SGLT2 inhibitor use and NT-proBNP reductions, it provides a potential prognostic biomarker for empagliflozin use.

Clinical Topics: Anticoagulation Management, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Benzhydryl Compounds, Biomarkers, Geriatrics, Glomerular Filtration Rate, Glucosides, Heart Failure, Metabolic Syndrome, Natriuretic Peptide, Brain, Natriuretic Peptides, Peptide Fragments, Renal Insufficiency, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume

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