Discussion
T2D, HFpEF, CKD, chronic kidney disease, cardiometabolic diseases, cardio ankle, vascular stiffness, MR, heart failure, diabetes
EVENTS, SECONDARY, SEPARATION, HEART FAILURE, TYPE 2 DIABETES, DIABETES
The ongoing FIVE-STAR trial aims to investigate the effects of finerenone, relative to placebo, on vascular stiffness and relevant cardiorenal surrogate biomarkers in patients with T2D and CKD (Fig. Graphical abstract of the FIVE-STAR trial. CAVI, cardio ankle vascular index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HFrEF: heart failure with reduced ejection fraction; LVEF: left ventricular ejection fraction; MR: mineralocorticoid receptor; MRA: mineralocorticoid receptor antagonist; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratioDespite the use of evidence-based pharmacological therapies (conventional RAS blockers and emerging SGLT2 inhibitors), the mortality and morbidity rates of T2D and CKD remain high, thereby indicating residual pathological targets that are not covered by existing medications. Finerenone, a novel nonsteroidal selective MRA, has been recently approved for treating patients with T2D and CKD based on its clinical benefits and safety according to the landmark cardiorenal outcome trials, FIDELIO-DKD [In the previously mentioned clinical trials, the cardiorenal benefits of finerenone were theoretically driven by the suppression of MR overactivation, followed by anti-inflammatory and anti-fibrotic response in the kidney, heart, and vasculatures. Since finerenone can be widely use in clinical settings, its possible underlying mechanisms that mediate the aforementioned clinical benefits, should be explored in detail to help clinicians and researchers to better understand its clinical roles and cardiorenal actions. Considering the essential pharmacological action of finerenone, the early separation of the Kaplan–Meier curves for cardiovascular outcomes, and the delayed separation for renal outcomes in the aforementioned outcome trials [CAVI will be measured to assess the effect of finerenone on vascular stiffness, which is the primary endpoint of the FIVE-STAR trial. It is associated with cardiorenal function and the risk of adverse cardiorenal events in several cardiometabolic diseases, including diabetes and CKD [In addition, serum and urinary biomarkers will be evaluated as secondary efficacy endpoints, thereby possibly providing practical evidence to monitor the cardiorenal efficacy of finerenone in clinical settings. Cardiac parameters, including left ventricular systolic and diastolic function, will also be measured on echocardiography. Although the trial will exclude symptomatic patients with HFrEF, patients with HF who have preserved ejection fraction (HFpEF) can participate in this trial. In our trial, evaluating the impact of finerenone therapy on cardiac function may be partly mutually related to the interpretation of an ongoing study to evaluate the efficacy and safety of finerenone in patients with HFpEF (FINEARTS-HF: NCT04435626) in the future. Furthermore, proteomics analysis using the OlinkSGLT2 inhibitor is recommended to reduce the risk of adverse cardiovascular and renal events in patients with CKD, irrespective of diabetes status [This trial may have several methodological limitations at the current stage. First, the study sample size is relatively small. Second, the study duration may be relatively short for evaluating changes in vascular stiffness and remodeling. Third, the number of evaluation visits for most efficacy endpoints of interest is limited and does not allow for serial evaluation of the therapeutic impact, especially immediately after treatment initiation. In addition, no association between the therapeutic impacts of finerenone on the study endpoints and subsequent long-term cardiorenal outcomes will be assessed in our study. Finally, although there are no eligible criteria regarding race and nationality, the current study will mainly include Japanese patients.In conclusion, the FIVE-STAR trial is the first mechanistic clinical study that will examine the therapeutic effects of finerenone on vascular stiffness as assessed using CAVI and cardiorenal biomarkers in patients with T2D and CKD. This study will possibly provide a better understanding on the detailed mechanisms associated with the clinical benefits observed in previous cardiorenal outcome trials of finerenone.