ESTIMATED GLOMERULAR FILTRATION RATE, SYSTOLIC BLOOD PRESSURE, AND URINARY ALBUMIN-TO-CREATININE RATIO — UNRAVELLING THE INTERPLAY IN COMBINATION: FINDINGS FROM THE RANDOMIZED CONFIDENCE TRIAL

An estimated glomerular filtration rate (eGFR) drop is common with nonsteroidal mineralocorticoid receptor antagonist (nMRA) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) therapy, often leading to treatment interruption and potentially curtailing cardiovascular and kidney benefits. Treatment benefits of combination therapy with the nMRA finerenone and the SGLT2i empagliflozin in reducing urinary albumin-to-creatinine ratio (UACR) have been reported in the CONFIDENCE trial (NCT05254002), where combination therapy use and its components were associated with changes in eGFR and systolic blood pressure (SBP). This analysis examined the interplay among UACR, eGFR, and SBP in CONFIDENCE.

The CONFIDENCE trial enrolled adults with chronic kidney disease (eGFR 30–90 mL/min/1.73 m²) and albuminuria (UACR 100–5000 mg/g) receiving stable doses of renin–angiotensin system inhibitors. Participants were randomized 1:1:1 to once-daily finerenone (10 or 20 mg) + empagliflozin (10 mg), finerenone (10 or 20 mg) + placebo, or empagliflozin (10 mg) + placebo. The assigned treatment was stopped 180 days after randomization. Creatinine-based eGFR, seated SBP, and UACR were measured at baseline; at Days 14, 30, 90, and 180; and at Day 210, 30 days post-treatment discontinuation. The primary outcome was change in UACR from baseline to Day 180. This analysis assessed mean changes from baseline in eGFR, the determinants of a discrete change from baseline in eGFR of ≥30%, and the change from baseline in eGFR at Day 14 causally mediating any changes in UACR at Day 180.

In total, 790 randomized participants were included in this analysis (mean age 66.5 years, 75% male). At baseline, mean (standard deviation) eGFR was 54 (17) mL/min/1.73 m2, mean SBP was 135.2 (13.3) mmHg and median UACR (interquartile range) was 583 (292–1096) mg/g. An eGFR drop of ≥30% occurred in 133/779 participants (17.1%): 59/265 (22.3%) with combination therapy, 45/255 (17.1%) with finerenone, and 29/259 (11.1%) with empagliflozin. Combination treatment was associated with a greater decline in eGFR. For all participants, at Day 14, those with an eGFR decline ≥30% had higher baseline eGFR and greater diuretic use. Over 180 days, determinants of eGFR decline ≥30% were increasingly higher eGFR, increasingly higher UACR, and any diuretic use at baseline. Participants with a higher baseline level of SBP had a marginally greater acute reduction in eGFR at Day 14 but SBP was not associated with the eGFR trajectory. Hyperkalemia was seen in 113/790 (14.3%) participants; 23.3% of those with an eGFR drop ≥30% compared to 12.5% of those without. While 28.1% of the UACR reduction at Day 180 was mediated by eGFR change induced by empagliflozin, only 5.2% of the UACR reduction was mediated by eGFR change induced by finerenone at Day 14. Changes in eGFR reversed following treatment cessation.

Short-term decline in eGFR occurred more often in participants receiving combination therapy, those with higher baseline eGFR, and those taking a diuretic. In addition, baseline UACR and eGFR modified the trajectory of eGFR over 6 months. The low mediation percentage for finerenone’s additive benefit to empagliflozin highlights a nonhemodynamic pathway of protection that, combined with eGFR-driven SGLT2i effects, provides a mechanistic rationale for combination therapy.