SGLT2 inhibitor with and without ALDosterone AntagonIst for heart failure with preserved ejection fraction: Design paper

Abstract

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRA) reduce heart failure (HF) events in patients with heart failure and mildly reduced or preserved ejection fraction (HFmr/pEF). The randomized comparison of SGLT2i/MRA combination versus SGLT2i or MRA alone requires further testing in HFmr/pEF. Aims: To compare the efficacy (NT-proBNP change as primary outcome) and safety (potassium, creatinine, and blood pressure changes) of dapagliflozin/spironolactone combination versus dapagliflozin alone (primary comparison) and spironolactone alone (exploratory comparison). Methods: SOGALDI-PEF (SOdium-Glucose cotransporter 2 inhibitor, ALDosterone AntagonIst, or both for heart failure with preserved ejection fraction; NCT05676684), a proof-of-concept investigator-initiated two-centre randomized cross-over trial comparing three arms (dapagliflozin, spironolactone, or both) for three periods of 12 weeks each intercalated by a wash-out period of 4 weeks. After two independent trials demonstrating efficacy of SGLT2i in HFmr/pEF, a mid-trial protocol amendment dropped the spironolactone alone sequence and reduced the wash-out period to 1 week. A sample size of 108 patients was estimated to provide 80% power, at a 0.05 alfa level, to detect a 0.15 LogNT-proBNP difference between the spironolactone/dapagliflozin combination and dapagliflozin alone sequence. Results: SOGALDI-PEF included 108 patients with a median age of 76 years, 57% women, 42% with atrial fibrillation, 46% with type 2 diabetes, 33% having an eGFR below 60 mL/min/1.73m2, and 93% having an ejection fraction ≥ 50%. The median serum potassium was 4.3 mmol/L, and the median NT-proBNP was 764 pg/mL. Most patients were treated with renin–angiotensin blockers (68%), beta-blockers (70%) and loop diuretics (69%). Compared to other HFmr/pEF trials, SOGALDI-PEF patients were older, were more frequently women, had a high prevalence of atrial fibrillation, and had more often a preserved ejection fraction. Conclusions: SOGALDI-PEF will be the first trial in HFmr/pEF to test the combination of dapagliflozin/spironolactone vs dapagliflozin alone in a randomized manner. SOGALDI-PEF will provide information on the potential efficacy and safety of concomitant administration of spironolactone with dapagliflozin vs dapagliflozin alone in an elderly population with HFmr/pEF.