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      Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone

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          Abstract

          Despite the standard of care, patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) progress to dialysis, are hospitalized for heart failure and die prematurely. Overactivation of the mineralocorticoid receptor (MR) causes inflammation and fibrosis that damages the kidney and heart. Finerenone, a nonsteroidal, selective MR antagonist, confers kidney and heart protection in both animal models and Phase II clinical studies; the effects on serum potassium and kidney function are minimal. Comprising the largest CKD outcomes program to date, FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) and FIGARO-DKD (FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease) are Phase III trials investigating the efficacy and safety of finerenone on kidney failure and cardiovascular outcomes from early to advanced CKD in T2D. By including echocardiograms and biomarkers, they extend our understanding of pathophysiology; by including quality of life measurements, they provide patient-centered outcomes; and by including understudied yet high-risk cardiorenal subpopulations, they have the potential to widen the scope of therapy in T2D with CKD.

          Trial registration number: FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049)

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          Most cited references42

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          Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

          Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
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            Diabetic Kidney Disease: Challenges, Progress, and Possibilities.

            Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.
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              The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.

              Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.
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                Author and article information

                Journal
                Nephrol Dial Transplant
                Nephrol Dial Transplant
                ndt
                Nephrology Dialysis Transplantation
                Oxford University Press
                0931-0509
                1460-2385
                June 2022
                06 December 2020
                06 December 2020
                : 37
                : 6
                : 1014-1023
                Affiliations
                [1 ] Richard L. Roudebush VA Medical Center and Indiana University , Indianapolis, IN, USA
                [2 ] Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin , Berlin, Germany
                [3 ] Department of Medicine, University of Chicago Medicine , Chicago, IL, USA
                [4 ] National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital , Athens, Greece
                [5 ] Department of Medicine, University of Michigan School of Medicine , Ann Arbor, MI, USA
                [6 ] Steno Diabetes Center Copenhagen , Gentofte, Denmark
                [7 ] Department of Clinical Medicine, University of Copenhagen , Copenhagen, Denmark
                [8 ] Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12 , Madrid, Spain
                [9 ] IBER-CV, Hospital Universitario , 12 de Octubre, Madrid, Spain
                [10 ] Faculty of Sport Sciences, European University of Madrid , Madrid, Spain
                [11 ] Research and Development, Statistics and Data Insights , Bayer AG, Berlin, Germany
                [12 ] Research and Development, Preclinical Research Cardiovascular , Bayer AG, Wuppertal, Germany
                [13 ] Research and Development, Clinical Development Operations , Bayer AG, Wuppertal, Germany
                [14 ] Cardiology and Nephrology Clinical Development , Bayer AG, Berlin, Germany
                Author notes
                Correspondence to: Rajiv Agarwal; E-mail: ragarwal@ 123456iu.edu
                Author information
                https://orcid.org/0000-0001-8355-7100
                Article
                gfaa294
                10.1093/ndt/gfaa294
                9130026
                33280027
                4a40820c-5344-4529-a4d6-52b8d7909acd
                © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 July 2020
                : 21 September 2020
                Page count
                Pages: 10
                Funding
                Funded by: Bayer AG, DOI 10.13039/100004326;
                Categories
                Review
                AcademicSubjects/MED00340

                Nephrology
                albuminuria,ckd,clinical trial,diabetic kidney disease,mineralocorticoid receptor antagonist

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