Dapagliflozin/spironolactone-induced eGFR decline in HFmrEF/HFpEF not linked to kidney injury

In SOGALDI-PEF among patients with HFmrEF/HFpEF, dapagliflozin/spironolactone combination therapy induced an eGFR dip that was associated with hemodynamic changes and not with kidney injury.

This summary is based on the publication of Ferreira JP, Mascarenhas J, Marques P, et al. - Impact of dapagliflozin, spironolactone and their combination on markers of kidney function and injury: an analysis from SOGALDI-PEF. Eur J Heart Fail. 2026 Apr 8:xuag117. [Online ahead of print]. doi: 10.1093/ejhf/xuag117.

Introduction and methods

Background

SGLT2 inhibitors and MRAs are disease-modifying therapies for HFmrEF/HFpEF. Both drug classes can induce an early decline in eGFR, commonly referred to as the “eGFR dip” [1-2]. Whether this decline reflects true kidney injury or only transient hemodynamic changes remains clinically relevant.

Aim of the study

The aim of this study was to evaluate the effects of dapagliflozin, spironolactone, and their combination on kidney function markers, kidney injury biomarkers, and albuminuria in patients with HFmrEF/HFpEF enrolled in the SOGALDI-PEF trial.

Methods

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 in patients with HFmrEF/HFpEF. Participants received dapagliflozin alone, spironolactone alone, or the combination for 12-week treatment periods. Analyses assessed changes in serum creatinine, cystatin C, creatinine- and cystatin C-based eGFR equations, urinary albumin-to-creatinine ratio (UACR), and biomarkers of kidney injury including kidney injury molecule-1 (KIM-1) and fibroblast growth factor-23 (FGF-23).

Main results

• The dapagliflozin/spironolactone combination produced the largest decline in kidney function parameters, with creatinine-based eGFR decreasing by 9.7 mL/min/1.73m² (95%CI: -11.9 to -7.5; P<0.001).
• Dapagliflozin alone reduced creatinine-based eGFR by 3.3 mL/min/1.73m² (95%CI: -5.5 to -1.1; P=0.004), while spironolactone alone reduced it by 5.8 mL/min/1.73m² (95%CI: -9.0 to -2.7; P<0.001).
• Dapagliflozin/spironolactone combination produced elevations in both serum creatinine and serum cystatin C. There was no difference in these levels with either treatment alone.
• Despite the eGFR decline, neither KIM-1 nor FGF-23 increased significantly with any treatment sequence, suggesting absence of kidney injury.
• UACR decreased with all treatments and most prominently with combination therapy (-0.98 Log2 mg/g; 95%CI: -1.32 to -0.64; P<0.001).
• Reductions in blood pressure were independently associated with eGFR decline (P<0.001).

Conclusion

In patients with HFmrEF/HFpEF, dapagliflozin/spironolactone combination therapy induced a greater early decline in eGFR than either treatment alone, but this was not accompanied by increases in biomarkers of kidney injury. According to the authors, “[o]verall, these results support that the eGFR “dip” observed with SGLT2i and MRAs in HFpEF is predominantly driven by hemodynamic changes and not associated with “true” kidney injury.”

Find this article online at Eur J Heart Fail.

References

1. Rastogi T, Ferreira JP, Butler J, Kraus BJ, Mattheus M, Brueckmann M, Filippatos G, Wanner C, Pocock SJ, Packer M, et al. Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved. Eur J Heart Fail. 2024;26:885-896. doi: 10.1002/ejhf.3136
2. Matsumoto S, Jhund PS, Henderson AD, Bauersachs J, Claggett BL, Desai AS, Brinker M, Schloemer P, Viswanathan P, Mares JW, et al. Initial Decline in Glomerular Filtration Rate With Finerenone in HFmrEF/HFpEF: A Prespecified Analysis of FINEARTS-HF. J Am Coll Cardiol. 2025;85:173-185. doi: 10.1016/j.jacc.2024.11.020