RCT on effects of combination treatment with dapagliflozin and spironolactone in HFmrEF/HFpEF

ESC Heart Failure 2025 – In the cross-over trial SOGALDI-PEF, dapagliflozin/spironolactone combination therapy resulted in a greater NT-proBNP reduction in HF patients with LVEF >40% but also a greater eGFR decline and a larger serum potassium increase than dapagliflozin only.

This summary is based on the presentation of João Pedro Ferreira, MD, PhD (Porto, Portugal) at the ESC Heart Failure Congress 2025 - SOGALDI-PEF: SOdium-Glucose cotransporter 2 inhibitor with and without an ALDosterone AntagonIst for heart failure with preserved ejection fraction.

Introduction and methods

Both SGLT2 inhibitors and MRAs improve outcomes in patients with HFmrEF or HFpEF. However, RCT data on the effects of simultaneous treatment with these 2 drug classes compared with an SGLT2 inhibitor only are scarce.

The SOGALDI-PEF (SOdium-Glucose cotransporter 2 inhibitor with and without an ALDosterone AntagonIst for heart failure with preserved ejection fraction) trial was an investigator-initiated, prospective, randomized, open-label, blinded-endpoint (PROBE) cross-over trial conducted at 2 centers in Portugal. In this RCT, 108 patients with HFmrEF/HFpEF (LVEF >40%), NYHA class II–IV HF symptoms, and elevated NT-proBNP levels were randomized to either combination therapy with dapagliflozin and spironolactone or dapagliflozin only for 12 weeks, after which participants were crossed over to receive the other treatment for another 12 weeks. There was a third study arm, consisting of spironolactone only, but this was dropped as a mid-term protocol amendment after publication of the results of the EMPEROR-Preserved and DELIVER trials.

The primary efficacy endpoint was the NT-proBNP level (log-transformed). Key secondary endpoints included the proportion of patients with NT-proBNP reduction ≥20% and changes from baseline in systolic blood pressure (SBP), eGFR, urinary albumin-to-creatinine ratio (UACR; log-transformed), levels of creatinine and serum potassium, and body weight. Safety assessment included the incidence of adverse events, such as hyperkalemia (serum potassium >5.5 mmol/L), eGFR decline ≥40%, hypotension (SBP <100 mmHg), and urinary tract infections.

Main results

• The difference in log NT-proBNP levels (primary efficacy endpoint) between patients treated with dapagliflozin/spironolactone combination therapy and those receiving dapagliflozin only was –0.11 (95%CI: –0.22 to –0.01; P=0.035).
• More patients in the combination therapy group reached NT-proBNP reduction ≥20% than those in the dapagliflozin-only group (ratio: 2.27; 95%CI: 1.16–4.44; P=0.016).
• The change in SBP from baseline was greater in the combination therapy group than the dapagliflozin-only group (difference: –5.2 mmHg; 95%CI: –8.4 to –2.0; P=0.002), as were the changes in eGFR (difference: –6.4 mL/min/1.73 m²; 95%CI: –8.3 to –4.4; P<0.001) and serum potassium level (difference: 0.32 mmol/L; 95%CI: 0.23–0.41; P<0.001).
• Patients in the combination therapy group also experienced a creatinine increase and reductions in log UACR and body weight compared with those in the dapagliflozin-only group (all P≤0.003).
• Compared with patients receiving dapagliflozin only, participants on combination therapy showed higher frequencies of hyperkalemia (0.9% vs. 4.8%), eGFR decline ≥40% (2.9% vs. 7.6%), and hypotension (3.8% vs. 8.6%).

Conclusion

In the SOGALDI-PEF trial, dapagliflozin/spironolactone combination therapy resulted in a greater NT-proBNP reduction in HFmrEF/HFpEF patients but also a greater eGFR decline and a larger serum potassium increase than dapagliflozin only.

- Our reporting is based on the information provided at the ESC Heart Failure Congress 2025 and publication of the study design at ClinicalTrials.gov -

The findings of this study will be published in J Am Coll Cardiol.