Key result
Empagliflozin maintains HF benefits regardless of baseline sodium or chloride levels.
Why the study?
Prior studies in HF suggested that SGLT2 inhibitors slightly increase serum sodium over time, but little was known about their impact on serum chloride and the sodium-chloride interplay.
Does baseline serum sodium and chloride interplay modify prognostic outcomes or the treatment effect of empagliflozin in patients with ambulatory heart failure?
Does baseline serum sodium and chloride interplay modify prognostic outcomes or the treatment effect of empagliflozin in patients with ambulatory heart failure?
In ambulatory heart failure, low serum chloride drives poor prognosis independently of sodium, while the clinical benefits of empagliflozin remain consistent regardless of baseline sodium or chloride levels.
Answers are grounded in this paper and cite their sources.
Empagliflozin benefits remain consistent across electrolyte strata; leaves open whether chloride informs risk stratification or therapy selection in HF.
SGLT2 inhibitors promote changes in the kidney that influence water and electrolyte handling. Prior studies in heart failure (HF) suggested that SGLT2 inhibitors produce a slight increase in serum sodium over time, but little is known about their impact on serum chloride and the sodium-chloride interplay. To study the serum sodium-chloride interdependence, their prognostic associations, and the impact of empagliflozin on their levels over time. EMPEROR-Pooled data ( N = 9718) was used to create four mutually exclusive sodium-chloride categories based on quintiles (Q) of variable values distribution at baseline: (1) Q1Na + /Q1Cl − ; (2) Q1Na + / ≥ Q2Cl − ; 3) ≥ Q2Na + /Q1Cl − ; and (4) ≥ Q2Na + / ≥ Q2Cl − . Cox models were used to study the association of these categories with outcomes. Mixed models for repeated measures were used to study the impact of empagliflozin vs placebo on sodium and chloride levels over time. Mean serum sodium levels were 140.9 ± 3.0 mmol/L and chloride 100.9 ± 3.6 mmol/L. Patients with both Na + < 140 mmol/L and Cl − < 99 mmol/L (Q1Na + /Q1Cl − ) were more frequently treated with loop diuretics and experienced 1.3 to 1.7-fold higher rates of HF events and mortality compared to patients with ≥ Q2Na + / ≥ Q2Cl − . Patients with Q1Cl − exhibited higher mortality rates, irrespective of Na + levels. The beneficial effects of empagliflozin were not influenced by Na + /Cl − levels; interaction P > 0.1. Compared to placebo, empagliflozin slightly increased Na + and Cl − by + 0.1 mmol/L on average, particularly from week 32 onwards ( P < 0.05), while reducing serum bicarbonate levels by −0.2 mmol/L on average ( P < 0.05). In ambulatory HF, lower serum chloride levels were associated with poor outcomes independently of sodium, whereas lower sodium levels were associated with poor outcomes only in the presence of relatively low chloride. The beneficial effects of empagliflozin were not impacted by sodium or chloride. Summary of the study main findings. Legend: HR, hazard ratio; CI, confidence interval; Q, quintile; Q1Na+ =baseline serum sodium <140 mmol/L; Q1Cl- =baseline serum chloride <99 mmol/L; Q2, higher values than Q1; Primary outcome, composite of first heart failure hospitalization or cardiovascular death.
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Ferreira et al. (2026) studied Ambulatory heart failure (n=9,718). Empagliflozin was evaluated on Prognostic outcomes and serum sodium/chloride levels over time. Empagliflozin benefits in HF were unaffected by baseline sodium (140.9±3.0 mmol/L) or chloride (100.9±3.6 mmol/L), while low chloride independently predicted poor outcomes.
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