of general population and is likely to affect about 50% of patients of type 2 diabetes (T2D) and also heart failure [1]. In diabetic patients, hypertension has been one of the significant risk factors for microangiopathy and various cardiovascular (CV) complications. Clinical effects of mineralocorticoid receptor (MR) antagonists for decreasing the aggravation of diabetic nephropathy and also the decreased value of active renin concentration are shown in diabetic retinopathy [2]. It may imply the involvement of MR overactivation for diabetic complications. A variety of mechanisms would exist for MR overactivation in diabetic patients. Especially, it can focus on post translation of MR modifications and O-linked N-acetylglucosamine (O-GlcNAc) modification. They are implicated in MR protein overactivation and stabilization under hyperglycemia situation. When the role of MR overactivation would be considered during hyperglycemia, it can become one of the promising targets for decreasing diabetic complications.

Two well-known significant trials have been well-known, which are the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial [3] and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial [4]. These two trials of FIDELIO-DKD and FIGARO-DKD are wholly called as FIDELITY trials. The purpose of FIDELITY analysis was to conduct the analysis of safety and efficacy across various CKD spectrum for providing more robust evaluation of finerenone compared with the placebo [5]. Both trials demonstrated several benefits of finerenone for decreasing risk for renal and cardiovascular outcomes in T2D and CKD patients. In both trials, patients with different levels of renal function were enrolled [6].

Evidence and benefits of MR antagonists have been accumulating until now. How can these be utilized in clinical practice? Among them, the standard information, adequate management and beneficial treatment would be described in the following. Diabetic kidney disease (DKD) has been a progressive disease for long years. As clinical stage progresses, the morbidity and mortality of renal and cardiovascular diseases increases. Therefore, regular monitoring of albuminuria and eGFR is required, and earlier therapeutic intervention would be important. For the therapeutic goal of DKD, intensive treatment of blood glucose, blood pressure by RAS inhibitors, and weight will be desirable from the stage of normal to micro albuminuria. For DKD cases with eGFR >15-20 mL/min/1.73m², combination treatment with RAS inhibitors and SGLT2-i can be considered. This method has been shown to improve heart failure hospitalization and renal outcomes independent of glycemic control. Furthermore, treatment to reduce residual risk should be considered. The following three factors become crucial for the progression of DKD, which are hemodynamics, metabolic abnormalities, and inflammation/ fibrosis. Excessive activation of MR is clinically important for inflammation/fibrosis as residual risks from MR-related hypertension and organ damage. Then, RAS inhibitors and finerenone treatment significantly improved renal and cardiovascular outcomes. For DKD, administration of SGLT2-i and MR antagonists in addition to RAS inhibitors can reduce the residual risk. When administering, start each drug in turn after confirming the stability of blood pressure, blood glucose, body fluid volume, and eGFR. Continue treatment while monitoring eGFR with initial dip and serum potassium while observing the responsiveness (Figure 1).

Figure 1: Benefits of combined SGLT2-i and MR antagonist for CKD associated with T2D.

The relationship among 24-hour blood pressure (BP), diabetic retinopathy (DR) and serum active renin concentration (ARC) were investigated [7]. DR was classified for no DR, simple DR and severe DR including preproliferative and proliferative. Cases with severe DR revealed significantly higher BP associated with systolic/diastolic BP, HbA1c, and diabetic duration. Ambulatory BP showed significant inverse association with ARC. In sever DR cases, ARC was significantly lower than other DR cases as 3.2 vs 9.8 pg/mL (p<0.05). Thus, cases with severe DR showed higher BP and lower ARC. Consequently, MR overactivation may play certain role for elevated BP and exacerbated DR.

From the latest research, GLP-1Ra seems to emerge for additional or alternative treatment for cardiorenal protection [8]. Meta-analysis was performed for clinical efficacy of finerenone vs SGLT2-i and GLP-1Ra [9]. Furthermore, MR antagonist can show renoprotection in DKD patient. It is because preservation by the glomerular endothelial glycocalyx would be established as a key function mechanism [10]. For the patients with diabetic nephropathy and resistant hypertension, beneficial efficacy of MR antagonists was studied by post-translational modification of the MR using O-linked-N-acetylglucosamine (O-GlcNAc) [11]. From coimmunoprecipitation assays for HEK293T cells, MR was shown as a target of the O-GlcNAcylation. The expression levels as well as transcriptional activities of the receptor have been elevated in parallel with the degree of O-GlcNAcylation during hyperglycemic status. In addition to MR protein analysis and in vivo research, recent study suggested that MR O-GlcNAcylation would increase protein degree and transcriptional mechanism in hyperglycemic status in vivo and in vitro [11].

Regarding another latest investigation, clinical efficacy of finerenone was analyzed concerning cardiorenal outcomes in T2D patients [12]. The applicants included urinary albumin/creatinine as 30-5000 mg/g, and eGFR as >25 mL/min/1.73m². The protocol included 13,026 T2D cases with 3-years follow-up in median. Finerenone showed significant reduction for renal composite outcome as 23% vs. placebo, where Hazard ratio (HR) was 0.77. Finerenone also showed significant decrease of end-stage kidney disease (ESKD) by 20% vs. placebo (HR=0.80). Regarding adverse events, hyperkalemia associated leading to discontinuation showed significant increase for finerenone vs. placebo as 2.4% vs. 0.8%. Consequently, finerenone showed improvement of renal outcomes, decreased hazard of ESKD, associated with well-tolerated clinical progress.

In the United States, meaningful large study was conducted by applying the National Health and Nutrition Examination Survey (NHANES) data sets [13]. They included 2009-2018 data, and many applicants were included for representing US population. They were about 1 million cases with stage 3-4 CKD for FIDELIO?DKD, and about 2 million cases with broader stages for FIGARO-DKD. Totally, 2.23 million cases in US met the criteria for starting finerenone.

In summary, latest reports and perspectives for MR antagonist, finerenone have been described in this article. MR antagonist will contribute various patients with hypertension, heart disease, diabetes, CKD and DKD in the future.

Conflict of Interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

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