Renin, Aldosterone, and Treatment Response to Dapagliflozin, Spironolactone, and Their Combination: An Analysis From...

Hypertension and heart failure with preserved ejection fraction (HFpEF) often coexist, and sodium retention is a common feature of both conditions. Renin levels are suppressed in the setting of sodium overload and may modulate the blood pressure (BP) response to mineralocorticoid receptor antagonists (MRAs). The role of renin and aldosterone, and their influence on the response to dapagliflozin, spironolactone, and their combination, has not been tested in HFpEF.

The aim of this study was to assess the role of renin and aldosterone in patients with HFpEF enrolled in the SOGALDI-PEF (Dapagliflozin With or Without Spironolactone for HFpEF) trial.

Plasma renin and aldosterone levels were measured at baseline and at each study visit within a crossover design. Two main sequences were evaluated: dapagliflozin alone and spironolactone/dapagliflozin combination, each administered for 12 weeks.

A total of 106 patients were included. The median (percentile 25-75) renin level at baseline was 29.7 mU/L (17.6-61.6 mU/L); tertile 1 comprised patients with renin levels ≤21 mU/L. Compared with patients with higher renin (tertile 2/tertile 3), those with lower levels had higher BP (systolic blood pressure/diastolic blood pressure), serum sodium, lateral E/e', pulse wave velocity, and peripheral edema. Renin levels, but not aldosterone levels, modified the effect on BP: compared with dapagliflozin alone, the spironolactone/dapagliflozin combination reduced systolic blood pressure by -10.9 mm Hg (95% CI: -16.4 to -5.4 mm Hg) among patients with low renin (tertile 1) but had no significant effect at higher renin levels: tertile 2, -5.6 mm Hg (95% CI: -11.3 to 0.02 mm Hg); and tertile 3, 1.5 mm Hg (95% CI: -4.1 to 7.0 mm Hg) (interaction P trend = 0.007). Echocardiographic parameters and pulse wave velocity followed a similar pattern. The correlation between plasma renin and aldosterone was poor (rho = 0.15; P = 0.12).

Low plasma renin levels (≤21 mU/L) identify a high BP, sodium overload state and predict a more pronounced BP reduction with the spironolactone/dapagliflozin combination compared with dapagliflozin alone. Additional findings support a favorable impact of spironolactone/dapagliflozin in cardiovascular structure and function in patients with low renin levels. Aldosterone levels did not predict treatment response. (Dapagliflozin With or Without Spironolactone for HFpEF [SOGALDI-PEF]; NCT05676684).