Impact of Empagliflozin on Serum Calcium and Phosphate in Heart Failure

BACKGROUND Alterations in serum calcium (Ca2+) and phosphate (Pi) balance have been associated with poor outcomes in heart failure (HF). However, these data are mostly derived from small observational studies. Moreover, the impact of SGLT2 inhibitors on Ca2+and Pi levels have not been explored in large, randomized HF trials. AIMS Using EMPEROR-Pooled data we aim to study the prognostic associations of serum Ca2+ and Pi in patients with HF and study the impact of empagliflozin on Ca2+ and Pi levels. METHODS EMPEROR-Pooled (N=9718) was used to create serum Ca2+ and Pi categories (quintiles, Q). Cox and mixed-effects models were used. RESULTS Mean Ca2+ levels were 2.35±0.12 mmol/L and Pi 1.14±0.18 mmol/L. Compared to patients with higher Ca2+ levels (Q5, mean 2.5±0.1 mmol/L), those with lower Ca2+ (Q1, mean 2.2±0.1 mmol/L) presented more peripheral edema and higher NT-proBNP levels (P<0.05). Low Ca2+ was modestly associated with a higher risk of cardiovascular death or HF hospitalization. The effect of empagliflozin (vs placebo) on cardiovascular death or HF hospitalization was not influenced by serum Ca2+ levels (interaction-P>0.1), while the mortality reduction appeared more marked among patients with higher serum Ca2+ (interaction-P=0.08). Serum phosphate levels were not associated with outcomes and did not influence the effect of empagliflozin (interaction-P>0.1). Empagliflozin induced a minor increase in serum Ca2+ and Pi levels over time: +0.004 (0.001-0.006) mmol/L (P=0.002), and +0.030 (0.026-0.034) mmol/L (P<0.001), respectively. CONCLUSION Low serum Ca2+ may be associated with poor outcomes but did not influence the effect of empagliflozin in a statistically significant manner.