Relationship of Dapagli ﬂ ozin With Serum Sodium Findings From the DAPA-HF Trial

OBJECTIVES This study aimed to assess the prognostic importance of hyponatremia and the effects of dapagli ﬂ ozin on serum sodium in the DAPA-HF (Dapagli ﬂ ozin And Prevention of Adverse outcomes in Heart Failure) trial. BACKGROUND Hyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain. METHODS We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category ( # 135 and > 135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modi ﬁ ed the treatment effect of dapagli ﬂ ozin; and 2) the effect of dapagli ﬂ ozin on serum sodium. RESULTS Of 4,740 participants with a baseline measurement, 398 (8.4%) had sodium # 135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular ﬁ ltration rate. Hyponatremia was associated with worse outcomes

H yponatremia is common in patients hospitalized with decompensated heart failure (HF), occurring in 20% to 30% of such individuals. [1][2][3][4] In these patients, hyponatremia is an established predictor of adverse outcomes, associated with both inpatient and longer-term mortality. [1][2][3][4] The causes of hyponatremia in HF are complex, but they can be simplified into those causing impaired water excretion and those increasing sodium loss (both reduced water excretion and increased sodium loss can contribute to hyponatremia). [4][5][6][7] Reninangiotensin-aldosterone system and sympathetic nervous system activation lead to a nonosmotically mediated release of arginine vasopressin which inhibits free-water excretion and stimulates thirst, leading to increased water intake. [4][5][6][7] Reduced glomerular filtration (and as a result, renal tubular flow) leads to an impaired ability of the kidney to excrete free water. [4][5][6][7] Large doses of diuretic agents may lead to excessive sodium loss, especially if coupled with restriction of sodium intake; thiazide diuretic agents may also inhibit urinary dilution. [4][5][6][7] Whether hyponatremia is causally related to mortality or is simply a marker of the severity of HF remains unknown, although low serum sodium concentration remains an independent predictor of mortality in adjusted models incorporating other prognostic variables. [4][5][6]8 Much less is known about the prevalence or the prognostic significance of hyponatremia in ambulatory patients with heart failure and reduced ejection fraction (HFrEF), especially in such individuals receiving contemporary treatments. [9][10][11] Sodium glucose cotransporter 2 (SGLT2) inhibitors have been recently introduced as a treatment for HFrEF. [12][13][14] SGLT2 inhibitors inhibit proximal renal tubular reabsorption of glucose, coupled with sodium, leading to an initial osmotic diuresis and natriuresis. The effects of these agents (added to conventional diuretic agents and mineralocorticoid receptor antagonists) on serum sodium concentration in HFrEF are unknown and probably complex. Therefore, we inves- Chronic Heart Failure") trial. 12 We also examined whether sodium concentration at baseline modified the effects of dapagliflozin on clinical outcomes in the DAPA-HF trial.

HYPOTHESIS
This study was designed to investigate the prognostic significance of hyponatremia in ambulatory patients with HFrEF, the efficacy of dapagliflozin according to baseline serum sodium concentration, and the effect of dapagliflozin on serum sodium in the DAPA-HF trial.

METHODS
DAPA-HF was a prospective, randomized, doubleblind, controlled trial in patients with HFrEF, which evaluated the efficacy and safety of dapagliflozin 10 mg once daily, compared with matching placebo, added to standard care. 12  receiving optimal pharmacological and device therapy. 12   All analyses were conducted using Stata version 16.0 (StataCorp) and SAS version 9.4 (SAS Institute).
A value of P < 0.05 was considered statistically significant.

RESULTS
A baseline serum sodium measurement was available in 4,740 patients and showed a normal distribution (Supplemental Figure 1); 398 (8.4%) participants had a value #135 mmol/L (  Values are mean AE SD, n (%), or median (IQR). a Anemia: Hemoglobin <130 g/L in males and hemoglobin <120 g/L in females.
The net result of these changes was that more patients in the dapagliflozin group had hyponatremia (n ¼ 260, 11.3%) than in the placebo group (n ¼ 218,  SAFETY AND ADVERSE EVENTS. Each of the adverse events of interest was uncommon. There was a higher rate of adverse events related to volume depletion and renal dysfunction in the low-sodium group compared with the normal-sodium group ( Table 5).
The other adverse events of interest were very infrequent in each sodium subgroup. Baseline serum sodium did not notably modify the rate of adverse events in patients assigned to either placebo or dapagliflozin ( Table 5).

DISCUSSION
In a contemporary, well-treated ambulatory cohort of patients with HFrEF, most of whom had mild symptoms, the prevalence of hyponatremia was low Initially, compared with placebo, dapagliflozin led to a small, although statistically significant, decrease in sodium. However, after 2 weeks, the opposite pattern was observed.
Although hyponatremia is recognized as the most common electrolyte disorder among hospitalized patients with HF, there are few reports of   Tables 1 and 2.

FIGURE 2 Dapagliflozin Treatment Effect
Effect of dapagliflozin on key outcomes in patients with and without hyponatremia at baseline. CV ¼ cardiovascular; other abbreviation as in Figure 1. prior study where such extensive adjustment was made, including for natriuretic peptide level, in ambulatory patients. [9][10][11] Moreover, most studies to date have only reported the association between hyponatremia and all-cause mortality, whereas we have also shown that low sodium was independently predictive of worsening HF events (principally HF hospitalization) and symptoms. 16,17 The prognostic importance of a single sodium measurement was remarkable given the rapid and inhibitors is believed to lead to a reduction in intravascular volume and blood pressure, and the increased delivery of sodium to the distal nephron results in a decline in eGFR by inducing tubuloglomerular feedback. [22][23][24][25] However, it has been hypothesized that SGLT2 inhibitors reduce blood volume less than conventional diuretics. 26 Although the initial decrease in sodium mirrors the early decline in eGFR after starting dapagliflozin, subsequently, serum sodium concentration increased more in the dapagliflozin group than the placebo group, to the extent that the mean concentration was eventually  Values are n/N (%). The analysis was truncated at 16 months because there were fewer than 100 people in one or both treatment groups among those who had hyponatremia at baseline.