Lower Serum Chloride Predicts Poor Heart Failure Outcomes Independently of Sodium

In ambulatory heart failure, lower serum chloride levels are associated with poor clinical outcomes independently of sodium, whereas lower sodium levels are associated with poor outcomes only in the presence of relatively low chloride. These findings were established through a pooled analysis of the EMPEROR trials involving 9,718 patients, designed to evaluate the interdependence of serum sodium and chloride, their prognostic associations, and the longitudinal impact of the sodium-glucose cotransporter 2 inhibitor empagliflozin compared with placebo.

Using EMPEROR-Pooled baseline data, investigators established four mutually exclusive categories based on quintile distributions: the lowest quintile of sodium with the lowest quintile of chloride (Q1Na+/Q1Cl−), the lowest quintile of sodium with chloride in the second quintile or higher (Q1Na+/ ≥ Q2Cl−), sodium in the second quintile or higher with the lowest quintile of chloride (≥ Q2Na+/Q1Cl−), and both electrolytes in the second quintile or higher (≥ Q2Na+/ ≥ Q2Cl−). Across the overall cohort, mean baseline serum sodium was 140.9 ± 3.0 mmol/L and mean chloride was 100.9 ± 3.6 mmol/L, with lowest quintile thresholds defined as sodium below 140 mmol/L and chloride below 99 mmol/L.

Cox models evaluating clinical outcomes—specifically the composite primary outcome of first heart failure hospitalization or cardiovascular death—demonstrated that patients presenting with both sodium below 140 mmol/L and chloride below 99 mmol/L were more frequently treated with loop diuretics and experienced 1.3- to 1.7-fold higher rates of heart failure events and mortality compared to patients with both electrolytes at or above the second quintile. Furthermore, patients with baseline chloride below 99 mmol/L exhibited elevated mortality rates irrespective of their serum sodium concentrations.

Mixed models for repeated measures showed that empagliflozin slightly increased serum sodium and chloride by an average of +0.1 mmol/L compared with placebo, particularly from week 32 onwards (P < 0.05), while reducing serum bicarbonate levels by an average of −0.2 mmol/L (P < 0.05). SGLT2 inhibitors promote renal changes influencing water and electrolyte handling, but the beneficial clinical effects of empagliflozin were not influenced by baseline sodium or chloride levels, demonstrating an interaction P value greater than 0.1.

Subject of Research: Serum sodium and chloride interplay and empagliflozin effects in heart failure

Article Title: Serum sodium and chloride interplay and the effect of empagliflozin in heart failure: an EMPEROR-Pooled analysis

Article References: Ferreira, J. P., Zannad, F., Filippatos, G., Marques, P., Vasques-Nóvoa, F., Butler, J., Anker, S. D., & Packer, M. (2026). Serum sodium and chloride interplay and the effect of empagliflozin in heart failure: an EMPEROR-Pooled analysis. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03047-6

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03047-6

Keywords: Heart Failure, Empagliflozin, Serum Sodium, Serum Chloride, SGLT2 Inhibitors, EMPEROR-Pooled, Loop Diuretics, Cardiovascular Mortality, Serum, sodium, chloride, interplay