TOPLINE:
In patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), adding the mineralocorticoid receptor antagonist (MRA) spironolactone to the SGLT2 inhibitor, dapagliflozin significantly lowered the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with dapagliflozin alone, but led to hyperkalemia and a greater decline in the estimated glomerular filtration rate (eGFR).
METHODOLOGY:
- Researchers conducted a prospective crossover trial to evaluate the efficacy and safety of combination therapy with dapagliflozin and spironolactone vs dapagliflozin alone in patients with HFmrEF/HFpEF.
- They included 108 adults (median age, 76 years; 57% women) with symptomatic heart failure (New York Heart Association class II-IV), a left ventricular ejection fraction > 40%, and elevated levels of NT-proBNP (median, 746 pg/mL); all had an eGFR of 30 mL/min/1.73 m2 or more and a serum potassium level of 5.5 mmol/L or lower.
- Patients were randomly assigned to 12-week treatment sequences of either 10 mg/d dapagliflozin alone or a combination of dapagliflozin and spironolactone, with spironolactone dosed from 25 mg every other day up to 25 mg daily.
- The primary outcome was the difference in circulating levels of log-transformed NT-proBNP between treatment with the dapagliflozin-spironolactone combination and dapagliflozin alone.
- Secondary outcomes included the difference in the proportion of patients achieving a reduction of 20% or more in levels of NT-proBNP and effects on parameters such as eGFR, serum potassium levels, and blood pressure.
TAKEAWAY:
- The combination of dapagliflozin and spironolactone reduced log NT-proBNP by 0.11 units compared with dapagliflozin alone (P = .035), corresponding to an 11% relative reduction.
- The odds of achieving a reduction in levels of NT-proBNP of 20% or more were 2.27-fold greater with the combination therapy than with dapagliflozin alone (P = .016).
- While the combination therapy reduced systolic blood pressure by 5.2 mm Hg (P = .002) compared with dapagliflozin alone, eGFR reduced by 6.4 mL/min/1.73 m2(P < .001) and serum potassium increased by 0.32 mmol/L (P < .001).
- Hyperkalemia and declines in kidney function were both more frequent and more pronounced with the combination therapy than with dapagliflozin alone.
IN PRACTICE:
“SOGALDI-PEF is the first dedicated randomized trial to evaluate the impact of dapagliflozin/spironolactone combination on clinically important biomarkers and key safety parameters,” the researchers reported. “In patients with HFmrEF/HFpEF, dapagliflozin/spironolactone combination led to a greater NT-proBNP reduction than dapagliflozin or spironolactone alone. A greater eGFR decline and serum potassium increase with dapagliflozin/spironolactone combination was observed,” they added.
Acute declines in kidney function after the initiation of treatment with an SGLT2 inhibitor or MRA remains “a major reason for premature drug discontinuation,” experts wrote in an editorial accompanying the journal article.
“A well-intentioned strategy of simultaneous initiation of SGLT2i and MRAs may paradoxically increase the likelihood of premature discontinuation, undermining the benefits of combination therapy,” they added.
SOURCE:
This study was led by João Pedro Ferreira, MD, PhD, of the Universidade do Porto in Portugal. It was published online on July 28, 2025, in the Journal of the American College of Cardiology.
LIMITATIONS:
As a relatively small trial, this study was not adequately powered to evaluate hard clinical outcomes, including hospitalizations or mortality. The administration of treatments in an open-label fashion may have influenced the decisions of physicians and patients. Different operators performed and analyzed the echocardiograms.
DISCLOSURES:
This study received support from AstraZeneca-Produtos Farmacéuticos, Lda, and national funds through FCT — Portuguese Foundation for Science and Technology. Several authors reported receiving research support and consulting or speaker fees from multiple pharmaceutical and healthcare companies, including AstraZeneca.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.