By Michael H. Crawford, MD, Editor
Synopsis: A prospective, open-label, blinded outcome crossover trial of dapagliflozin plus spironolactone vs. dapagliflozin alone in patients with heart failure with preserved or mildly reduced left ventricular ejection fraction resulted in a greater reduction in natriuretic peptides, which was accompanied by a greater decline in kidney function and a rise in serum potassium.
Source: Ferreira JP, Vasques-Novoa F, Saraiva F, et al. Sodium-glucose cotransporter 2 inhibitor with and without an aldosterone antagonist for heart failure with preserved ejection fraction: The SOGALDI-PEF trial. J Am Coll Cardiol. 2025;86(5):320-333.
Both sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been recommended for the treatment of heart failure with preserved ejection fraction (HFpEF). However, there is little evidence on the combined use of these two classes of drugs. Thus, these investigators from two academic medical centers in Portugal conducted a proof of concept, prospective, randomized, open-label, blinded outcome crossover trial comparing dapagliflozin plus spironolactone to dapagliflozin alone in outpatients with heart failure (HF) symptoms and left ventricular ejection fractions (LVEF) > 40%.
Other inclusion criteria included the presence of structural heart disease (left atrial enlargement, left ventricular [LV] hypertrophy, or LV diastolic dysfunction), age ≥ 50 years, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥ 220 pg/mL, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2, serum potassium (K+) < 5.5 mmol/L, and no hospitalization for HF or use of the study drugs in the last 30 days. Because of the known increase in natriuretic peptides with the onset of atrial fibrillation (AF), the entry NT-proBNP required for enrollment was tripled (660 pg/mL) in those with AF. The dose of dapagliflozin was 10 mg/day and the dose of spironolactone was either 25 mg/day or every other day, depending on the K+ and eGFR throughout the trial.
The primary endpoint was the difference in LogNT-proBNP between the combination vs. dapagliflozin alone. Secondary endpoints included systolic blood pressure (SBP), K+, eGFR, and urinary albumin to creatinine ratio (UACR). The patients were sequenced through 12-week study periods of combination therapy or dapagliflozin alone. Since several trials now have demonstrated that SGLT2s improve outcomes in HFpEF, spironolactone alone was not studied, and it likely will not be a recommended therapy alone.
From 2022 to 2024, 108 patients were enrolled, and 105 patients completed the study (two withdrew and there was one death). Their median age was 76 years, 57% were women, and 41% had AF. Hypertensive cardiomyopathy was the most frequent underlying condition. Compared to dapagliflozin alone, combination therapy reduced LogNT-proBNP levels by -0.11 (95% confidence interval [CI], 0.22 to 0.01 Log units; P = 0.035), which increased the odds of reaching a ≥ 20% reduction in NT-proBNP (odds ratio [OR], 2.27; 95% CI, 1.16 to 4.44; P = 0.016). Also, combination therapy showed greater changes in SBP (-5.2 mmHg; 95% CI, -8.4 to -2.0), eGFR (-6.4 mL/min/1.73 m2; 95% CI, -8.3 to -4.4), K+ (+0.32 mmol/L; 95% CI, 0.23 to 0.41), and the frequency of K+ > 5.5 mmol/L (5% vs. 1%). The authors concluded that the combination of dapagliflozin and spironolactone therapy in patients with HFpEF resulted in a greater decrease in NT-proBNP and eGFR and an increase in K+ compared to dapagliflozin alone.
Commentary
This study focuses on the initiation of additional guideline-directed medical therapy (GDMT) to HFpEF patients (EF > 40%) who already are taking two or more GDMT drugs (usually renin-angiotensin inhibitors and beta-blockers). It highlights the implementation challenges we all face in this situation.
The value of combination therapy with an SGLT2 and an MRA compared to an SGLT2 alone in reducing LogNT-proBNP was modest (11%) and accompanied by significant decreases in SBP and eGFR and increases in K+. Needless to say, these are barriers to initiating this combination therapy. Also, there now are at least three trials that show a clear outcome benefit of SGLT2 agents alone. So, unless a trial demonstrating longer-term outcome benefits with combination therapy is undertaken, I doubt many physicians will embrace this combination therapy.
There also are limitations to SOGALDI-PEF to consider. It is a small crossover study that used NT-proBNP as a surrogate for hard outcomes. This is not entirely unreasonable, since other studies have shown that reductions in natriuretic peptides correlate with improvements in hard outcomes, but given the adverse effects of this combination therapy, it would need to be demonstrated that hard outcome gains outweighed the downsides. Also, this was an older population (median age 76 years), so it is conceivable that this combination would be better tolerated by younger patients. In addition, there was a high incidence of AF (41%), and we know that AF affects natriuretic peptide levels. So, the management of AF during the study could have affected the NT-proBNP levels.
Finally, there is a new nonsteroidal MRA drug — finerenone — that has shown benefits in hard outcomes in HFpEF patients, which now has a class IIa recommendation in the guidelines, whereas spironolactone is class IIb because of the ambiguous results of the TOPCAT study. However, we do not yet have much combination therapy information on finerenone.
The clinical message of this trial is that the combination of an SGLT2 and spironolactone may be more efficacious than an SGLT2 alone, but careful patient selection and close monitoring of renal function and K+ are required. Given the lack of clear hard outcome benefits from this combination and the potential for serious adverse effects, many of us may wait for more data. There are several trials in the works.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
