Real-world use of finerenone in patients with chronic kidney disease and type 2 diabetes based on large-scale clinical studies: FIDELIO-DKD and FIGARO-DKD.

Abstract

Finerenone is a new mineralocorticoid receptor antagonist that does not have a steroid skeleton, and in two large-scale clinical studies targeting patients with chronic kidney disease (CKD) complicated with type 2 diabetes (FIDELIO-DKD and FIGARO-DKD), it significantly reduced the composite endpoints due to the progression of renal disease, and the composite endpoints of cardiovascular disease. Recently, we published two databases summarizing how finerenone is used in clinical practice in Japan (FINEROD). In this paper, we examines how best to use finerenone to get the most out of its effects. The most important side effect of finerenone is hyperkalemia, and the risk of hyperkalemia increases as renal function declines. By starting treatment early when eGFR is maintained, it is expected that side effects will be reduced. Furthermore, the FIDELITY analysis (a pooled analysis of FIDELIO-DKD and FIGARO-DKD) has shown that the clinical effect is stronger when finerenone treatment is started at an early stage of CKD. The simultaneous use of RAS inhibitors (ACE inhibitor or ARB), finerenone, and SGLT2 inhibitors appears to be a promising treatment. Further, it is important to continue the medications of RAS inhibitors and MR antagonists as long as possible. To prevent hyperkalemia, the most reliable and safest method is to use a new oral potassium adsorbent. It is important to think of a new oral potassium adsorbent not as something that will lower serum potassium levels, but as something that will allow you to avoid discontinuing or increase the dose of RAS inhibitors or MR antagonists. Differences between steroidal and non-steroidal mineralocorticoid receptor (MR) antagonists. Mineralocorticoid receptors (MR) are present in epithelial tissues such as renal tubules and intestinal epithelium, as well as in non-epithelial tissues such as the brain, heart, and blood vessel walls. Although the MR itself is exactly the same in both tissues, its physiological actions are completely different. In epithelial tissues, cortisol is inactivated by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11 β-HSD2), and aldosterone selectively binds to the MR. On the other hand, in non-epithelial tissues, 11 β-HSD2 is almost nonexistent or is only weakly active, so that cortisol, which outnumbers it, binds to almost all the MR, and aldosterone binds to the very few remaining MR. Spironolactone, a representative MR antagonist with a steroid skeleton, has a high affinity for renal tubules, and concentrates there, where it is highly effective. Therefore, it is classified as a potassium-sparing diuretic. However, if it does not have a steroid skeleton, its affinity for epithelial and non-epithelial tissues is equal. In other words, its effect on epithelial tissues is relatively weak, and its effect on non-epithelial tissues is relatively strong. Finerenone does not cross the blood-brain barrier (BBB), and does not reach the central nervous system. The central MR, especially the periventricular MR, is strongly involved in hypertension, and esaxerenone, another nonsteroidal MR antagonist, which can cross the BBB although only to a small extent and reach the central nervous system, has a strong antihypertensive effect.