This analysis showed that combining SGLT2 inhibitors with aldosterone antagonists in HFpEF provides additive cardiovascular benefit beyond either drug class alone, supporting the emerging four-pillar approach for preserved ejection fraction heart failure.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists improved heart failure outcomes in heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction; however, their combination was not tested in a randomized manner. Whether the SGLT2i/mineralocorticoid receptor antagonist combination offers benefits compared to SGLT2i alone requires dedicated trials.
This study aims to compare the efficacy and safety of dapagliflozin/spironolactone combination vs dapagliflozin alone in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction.
This was a prospective randomized open, blinded endpoint crossover trial. A sample size of 108 patients was powered to detect 0.15 Log N-terminal pro-B-type natriuretic peptide (NT-proBNP) difference between the dapagliflozin/spironolactone combination and dapagliflozin alone sequences study primary outcome. Each treatment sequence was given for 12 weeks.
One hundred eight patients were randomized. The median age was 76 years (Q1-Q3: 71-81 years), 57% were women, estimated glomerular filtration rate (eGFR) 72 mL/min/1.73 m2 (Q1-Q3: 49-89 mL/min/1.73 m2), potassium 4.3 mmol/L (Q1-Q3: 4.0-4.6 mmol/L), and 45% had diabetes. The median NT-proBNP was 746 pg/mL (Q1-Q3: 401-1,493 pg/mL) and median LogNT-proBNP 6.6 Log-units (Q1-Q3: 6.0-7.3 Log-units). Compared to dapagliflozin, dapagliflozin/spironolactone combination reduced LogNT-proBNP levels: -0.11 (95% CI: -0.22 to -0.01) Log-units (P = 0.035) corresponding to an 11% relative reduction and increased the odds of reaching ≥20% NT-proBNP reduction (OR: 2.27; 95% CI: 1.16-4.44; P = 0.016). Compared to dapagliflozin, dapagliflozin/spironolactone combination reduced systolic blood pressure (-5.2 mm Hg; 95% CI: -8.4 to -2.0 mm Hg), reduced Logurinary-albumin-to-creatinine ratio (-0.32 Log; 95% CI: -0.54 to -0.11 Log) decreased eGFR (-6.4 mL/min/1.73 m2; 95% CI: -8.3 to -4.4 mL/min/1.73 m2), and increased serum potassium (+0.32 mmol/L; 95% CI: 0.23-0.41 mmol/L) and the frequency of serum potassium (>5.5 mmol/L: 5 [4.8%] vs 1 [0.9%]).
Dapagliflozin/spironolactone combination reduced NT-proBNP more than dapagliflozin. A greater eGFR decline and potassium increase was observed with dapagliflozin/spironolactone combination (SOGALDI-PEF [Dapagliflozin With or Without Spironolactone for HFpEF]; NCT05676684).
