Dapagliflozin, Baseline Hyponatremia, and Clinical Outcomes for Patients With HFrEF

Baseline serum sodium concentration among patients with heart failure with reduced ejection fraction (HFrEF) was not a significant modifier for the benefits of dapagliflozin on morbidity and mortality. These findings were published in JACC: Heart Failure.

Data for this analysis were sourced from the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF; ClinicalTrials.gov identifier: NCT03036124), which was a prospective, randomized, double-blind, controlled trial. Patients (N=4740) with HFrEF were recruited at 410 centers in 20 countries. For this prespecified analysis, the effect of dapagliflozin on the primary composite outcome of worsening heart failure (HF) or cardiovascular death was evaluated on the basis of low (£135 mmol/L) or normal (>135 mmol/L) serum sodium concentration.

The hyponatremia (n=398) and normal sodium (n=4342) cohorts were aged mean 66.1±10.6 and 66.4±10.9 years; 20.6% and 23.7% were women; 66.8% and 70.5% were White; BMI was 27.1±5.4 and 28.3±6.0 (P <.001); and left ventricular ejection fraction was 29.8%±7.2% and 31.2%±6.7% (P <.001), respectively.

The primary endpoint occurred among 28.9% of the low and 17.8% of the normal sodium cohorts. The patients with hyponatremia at baseline were associated with increased risk for the primary composite endpoint (adjusted hazard ratio [aHR], 1.50; 95% CI, 1.23-1.84; P <.001).

Stratified by individual events, low sodium was also associated with increased risk for all-cause mortality (aHR, 1.59; 95% CI, 1.26-2.01; P <.001), cardiovascular death (aHR, 1.52; 95% CI, 1.18-1.97; P =.001), and hospitalization for HF (aHR, 1.36; 95% CI, 1.05-1.77; P =.022).

Among all participants, dapagliflozin was favored for the composite outcome, all-cause mortality, cardiovascular death, and HF hospitalization. Stratified by baseline sodium level, dapagliflozin was favored for all outcomes among the normal sodium group and tended to be favored for those with low sodium. Compared between subgroups, no significant interactions were observed.

During the first 14 days, more dapagliflozin recipients developed hyponatremia than placebo (7.6% vs 5.7%; P =.013) but the pattern switched between 14 days and 12 months (2.6% vs 4.8%; P <.001).

During the first 14 days, nearly half of the patients with baseline hyponatremia had resolution of symptoms regardless of active and placebo treatment assignment (49.5% vs 48.4%), increasing to 73.7% among the dapagliflozin recipients and 69.4% for the placebo group at 12 months.

The safety profile of dapagliflozin was similar among the hyponatremia and normal sodium cohorts. Any discontinuation occurred among 10.0%-15.1% and discontinuation due to adverse events among 4.6%-5.7%. The most common adverse events were renal and volume depletion complications.

This study may have been limited by the low rate of hyponatremia overall and may suggest that this trial enrolled a population with relatively low risk for hyponatremia.

“Compared with placebo, dapagliflozin improved mortality and worsening HF events and symptoms, regardless of serum sodium concentration,” the study authors wrote. “Dapagliflozin led to a small early and transient increase in the risk of hyponatremia but a long-term sustained decrease in this risk.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Yeoh SE, Docherty KF, Jhund PS, et al. Relationship of dapagliflozin with serum sodium: Findings from the DAPA-HF trial. J American College of Cardiol HF. Published online April 6, 2022. doi:10.1016/j.jchf.2022.01.019