Effect of finerenone and an SGLT2 inhibitor on the urine proteome: A CONFIDENCE analysis

The CONFIDENCE trial demonstrated that simultaneous initiation of the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (versus monotherapy) further reduced albuminuria in patients with diabetic CKD. We studied drug-induced changes in the urine proteome to delineate the mechanisms which may underpin finerenone’s and empagliflozin’s clinical benefits. 

This study included 719 participants from CONFIDENCE with urine proteome measurements. Patients were randomized to finerenone, empagliflozin or the combination. First morning void urine samples were collected at baseline, month 1 and 6 for analysis on Olink ExploreHT. Drug-induced changes in protein levels were assessed using mixed models for repeated measurements. Gene set enrichment was done for each treatment arm separately. 

Participants had a mean age of 66.6 years, 24.9% were female, all had CKD and type 2 diabetes (T2D). At baseline, the mean estimated glomerular filtration rate was 54.5 mL/min/1.73 m2 (standard deviation, SD, 17.2) and the median urinary albumin-to-creatinine ratio was 572 mg/g (interquartile range, 284-1065). At month 6, 236 of 239 significantly (FDRq<0.05) modulated proteins were decreased versus baseline by finerenone monotherapy, while 3 were increased. Highly downregulated markers are involved in extracellular matrix remodeling (PGLYRP2, lumican, transforming growth factor β-induced, ECM1), transport processes (TTR, SHBG), and complement/coagulation pathways (C2-C5, C7-C9, Factor B/D/H, plasminogen, FII/FIX, kallikreins, SERPINs). Several small proteins (apoliproteins, selenoprotein P, FABP1) were reduced by finerenone suggestive of improved tubular reabsorption. Transferrin was the most-upregulated marker. With empagliflozin monotherapy, 177/264 treatment-responsive proteins were decreased versus 87 proteins which were increased (FDRq<0.05). Empagliflozin modulated members of central metabolic pathways (carbohydrate and amino acid metabolism, e.g. GOT1, KYAT1), acid-base handling (carbonic anhydrase 14), markers of the lysosome (NAGA, CTSC) and tubular epithelial transmembrane proteins (aquaporin-1, PROM1). Combination therapy, finerenone plus empagliflozin, largely reflected the effects observed with either monotherapy suggesting complementary effects. Here, 697 proteins decreased, 57 increased (FDRq<0.05). Notably, the effect on coagulation and complement-related markers was amplified in the combination arm, possibly due to restoration of glomerular integrity and dampening of pathway activity. The net contribution of finerenone to urinary proteome changes (i.e. the difference between combination and empagliflozin alone) is largely driven by complement and coagulation proteins. In pathway analyses these were suppressed with finerenone, whereas empagliflozin monotherapy was associated with an increase in metabolic enzymes. 

This study sheds insights into the dynamics of the urine proteome in patients with T2D and CKD treated with finerenone in combination with SGLT2 inhibition. It provides hypotheses on how both drugs confer renoprotection warranting further mechanistic investigation. Finerenone and empagliflozin appear to act synergistically on distinct pathways: finerenone may alter remodeling and complement-driven inflammatory cues while empagliflozin may optimize metabolic workload, thereby slowing CKD progression.