Finrenone and sodium-glucose cotransporter 2 inhibitor polypill: how “CONFIDENT” are we?
Article information
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide, and albuminuria reflects the structural and hemodynamic alterations inflicted on the nephron in the pathogenesis of DN [1]. The aim of DN management is to inhibit glomerular hyperfiltration, reduce albuminuria, prevent glomerular and tubulointerstitial inflammation, and halt progression to chronic kidney disease [1]. The recently concluded CONFIDENCE trial [2] demonstrated a 29% reduction in urine albumin-to-creatinine ratio (uACR) in the combination group of finrenone and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin compared with finrenone alone, as well as a 32% reduction in uACR compared with empagliflozin alone. uACR was used as a practical surrogate clinical endpoint in this trial because only 807 patients were required to fulfil the statistical requirements. Finrenone, a nonsteroidal mineralocorticoid antagonist, binds to mineralocorticoid receptors and inhibits the transcription of pro-inflammatory and pro-fibrotic pathways in kidney cells such as podocytes, endothelial cells, fibroblasts, mesangial cells, and macrophages, thereby preventing histological changes of interstitial fibrosis, glomerular sclerosis, and tubular atrophy [3]. SGLT2 inhibitors exert nephroprotective effects by controlling hyperglycaemia, reducing glomerular hyperfiltration, reducing tubular transport work, increasing cortical oxygen availability, and enhancing erythropoietin synthesis by stimulating hypoxia-inducible factor [4]. Hence, it is rational to consider the enhanced kidney protection provided by this combination therapy owing to the additive effects of both drugs.
However, there are some important factors to consider when interpreting the results of the CONFIDENCE trial [2]. The trial did not evaluate the hard-core composite kidney endpoints such as kidney failure, estimated glomerular filtration rate (eGFR) decline ≥40%, or kidney-related death due to feasibility constraints of enrolling 41,000 participants, considering the active comparators (i.e., no double placebo arm) with each participant requiring a 3-year follow-up. The trial groups were not designed for a long follow-up period to evaluate differences in cardiovascular outcomes or kidney disease progression. There was a greater decrease in eGFR in the combination group (6.3%), albeit reversible, compared to 1.1% in the empagliflozin group and 3.8% in the finrenone group, with unclear long-term kidney outcomes in this subset of patients. Only 25% of female patients were enrolled in the trial, which represents under-recruitment in such a major cardiometabolic renal study. However, there are major advantages of this landmark study, which include a higher percentage of Asian patients (higher propensity to develop diabetes-related complications), less hyperkalemia in the combination group, very low symptomatic hypotension (1%), comparable genital mycotic infection rate, and absence of new-onset heart failure during the 6-month follow-up period.
At present, we can consider the possibility of incorporating this combination therapy cautiously in our clinical practice in eligible patients, considering the paramount benefits and additive effects of this magical polypill awaiting long-term follow-up data from future research.
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Conflicts of interest
The author has no conflicts of interest to declare.
Data sharing statement
The data for substantiating the findings of this study are available with the corresponding author and can be made available on request.