Advertisement

Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus

Open AccessPublished:October 14, 2022DOI:https://doi.org/10.1016/j.mayocpiqo.2022.09.002

      Abstract

      Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin–angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide–1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.

      Abbreviations and Acronyms:

      ACEi (angiotensin-converting enzyme inhibitor), ADA (American Diabetes Association), AR (androgen receptor), ARB (angiotensin II receptor blocker), ARTS (minerAlocorticoid Receptor Antagonist Tolerability Study), BP (blood pressure), CKD (chronic kidney disease), CV (cardiovascular), CVD (cardiovascular disease), DM (diabetes mellitus), DN (diabetic nephropathy), eGFR (estimated glomerular filtration rate), ESKD (end-stage kidney disease), FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease), FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease), GLP-1 RA (glucagon-like peptide 1 receptor agonists), GR (glucocorticoid receptor), HF (heart failure), HFrEF (heart failure with reduced ejection fraction), KDIGO (Kidney Disease Improving Global Outcomes), MR (mineralocorticoid receptor), MRA (mineralocorticoid receptor antagonist), PR (progesterone receptor), RAAS (renin–angiotensin–aldosterone system), RAS (renin–angiotensin system), SGLT-2i (sodium-glucose cotransporter 2 inhibitor), T2DM (type 2 diabetes mellitus), UACR (urinary albumin-creatine ratio)
      Article Highlights
      • Chronic kidney disease (CKD) is frequently associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease.
      • Aberrant and chronic activation of the mineralocorticoid receptor by aldosterone in patients with T2DM triggers detrimental effects.
      • Over the past few decades, T2DM-associated CKD has been treated with renin–angiotensin–androgen system blockers, including mineralocorticoid receptor antagonists (MRAs), but with undesirable adverse effects.
      • Recent US Food and Drug Administration approval of a nonsteroidal MRA, finerenone, and a revised label for a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, are expected to influence the treatment of patients with CKD.
      • We hereby review the history of MRA development and discuss the possibility of combination treatment with other agents.

      Diabetes, Heart Failure, and Chronic Kidney Disease

      Diabetes mellitus (DM) is a major global health concern. It is estimated that 463 million people worldwide had DM in 2019, with that number projected to reach 700 million by 2045.
      International Diabetes Federation
      IDF Diabetes Atlas.
      Chronic hyperglycemia stimulates inflammatory cytokines, growth factors, and the renin–angiotensin system (RAS).

      Amorim RG, Guedes GDS, Vasconcelos SML, Santos JCF. Kidney disease in diabetes mellitus: cross-linking between hyperglycemia, redox imbalance and inflammation. Arq Bras Cardiol. 2019;112(5):577-587. Published correction appears in 2019;113(1):182.

      ,
      • Elmarakby A.A.
      • Abdelsayed R.
      • Yao Liu J.
      • Mozaffari M.S.
      Inflammatory cytokines as predictive markers for early detection and progression of diabetic nephropathy.
      Resultant oxidative stress is linked to the formation of advanced glycation end products as well as activation of protein kinase C and polyol and hexosamine metabolic pathways.

      Amorim RG, Guedes GDS, Vasconcelos SML, Santos JCF. Kidney disease in diabetes mellitus: cross-linking between hyperglycemia, redox imbalance and inflammation. Arq Bras Cardiol. 2019;112(5):577-587. Published correction appears in 2019;113(1):182.

      ,
      • Elmarakby A.A.
      • Abdelsayed R.
      • Yao Liu J.
      • Mozaffari M.S.
      Inflammatory cytokines as predictive markers for early detection and progression of diabetic nephropathy.
      Up-regulation of profibrotic growth factors, such as transforming growth factor beta, results in mature collagen deposition, which is one of the characteristic features of diabetic nephropathy (DN).
      • Yokoyama H.
      • Deckert T.
      Central role of TGF-beta in the pathogenesis of diabetic nephropathy and macrovascular complications: a hypothesis.
      Diabetic nephropathy is the leading cause of chronic kidney disease (CKD), defined as persistently (>3 months) elevated urine albumin excretion level (≥30 mg/g creatinine) and/or reduced estimated glomerular filtration rate (eGFR; <60 mL/min per 1.73 m2).
      National Kidney Foundation
      KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update.
      ,
      • Thomas R.L.
      • Halim S.
      • Gurudas S.
      • Sivaprasad S.
      • Owens D.R.
      IDF Diabetes Atlas: a review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018.
      Although considerable progress has been made in treatments aimed at modifying the course of disease in DN, progression to kidney failure and end-stage kidney disease (ESKD) remains a major concern.
      International Diabetes Federation
      IDF Diabetes Atlas.
      Globally, >80% of ESKD is caused by DM and/or hypertension, and the prevalence of ESKD is up to 10 times higher in patients with DM than those without DM.
      International Diabetes Federation
      IDF Diabetes Atlas.
      According to the Centers for Disease Control and Prevention, 1 of every 3 adults with DM in the United States may have kidney disease.
      Centers for Disease Control and Prevention
      Chronic Kidney Disease in the United States. Updated.
      Diseases of the kidney are the ninth leading cause of death in the United States.
      Centers for Disease Control and Prevention
      Chronic Kidney Disease in the United States. Updated.
      ,
      US Department of Health and Human Services
      Advancing American Kidney Health. Updated.
      In 2019, the Advancing American Kidney Health initiative was launched with the following 3 major goals: (1) reduce the risk of kidney failure; (2) improve access to and quality of person-centered treatment options; and (3) increase access to kidney transplants.
      US Department of Health and Human Services
      Advancing American Kidney Health. Updated.
      Type 2 DM (T2DM) and heart failure (HF) often coexist, with DM occurring in up to 24% of patients with chronic HF and in up to 40% of those hospitalized with acute HF.
      • Dei Cas A.
      • Khan S.S.
      • Butler J.
      • et al.
      Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure.
      ,
      • Fonarow G.C.
      • Abraham W.T.
      • Albert N.M.
      • et al.
      Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF.
      Up to 50% of patients with HF also present with CKD, which significantly increases the mortality risk.
      • Damman K.
      • Valente M.A.
      • Voors A.A.
      • O'Connor C.M.
      • van Veldhuisen D.J.
      • Hillege H.L.
      Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis.
      ,
      • Löfman I.
      • Szummer K.
      • Hagerman I.
      • Dahlström U.
      • Lund L.H.
      • Jernberg T.
      Prevalence and prognostic impact of kidney disease on heart failure patients.
      The United States Renal Data System 2020 Annual Data Report suggests that the 24-month survival probability after the first diagnosis of HF in patients with stage 3 and stage 4-5 CKD declines by 7% and 23%, respectively, compared with those without CKD.
      United States Renal Data System
      USRDS Annual Data Report: Epidemiology of kidney disease in the United States. 2020.
      Kidney Disease Improving Global Outcomes (KDIGO) 2020 Clinical Practice Guideline for Diabetes Management in CKD suggests that patients with T2DM and CKD should be treated with a comprehensive approach by modifying a range of factors associated with the progression of CKD and cardiovascular disease (CVD), including glycemic and blood pressure (BP) control, lipid management, weight loss, exercise, and smoking cessation.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      Using the KDIGO 2020 drug treatment guidelines as an example, recommendations include using the following: (1) a combination of a sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and metformin for patients with eGFR ≥30 mL/min per 1.73 m2; (2) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients who are unable to achieve glycemic targets despite use of metformin and SGLT-2i; (3) RAS blockers, including angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), for patients with albuminuria and hypertension; and (4) antiplatelet therapies for patients with acute coronary syndrome or percutaneous coronary intervention.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      The KDIGO 2020 guidelines also emphasize the need for more randomized clinical studies to evaluate the following: (1) the effect of ACEis and ARBs on the outcome of albuminuria reduction and progression of DM and CKD; (2) the effect of mineralocorticoid receptor (MR) antagonists (MRAs) on the progression of CKD and CVD; (3) clinical benefits of preventing hyperkalemia (ie, with potassium binders) during RAS blockade; and (4) decision aids for hyperkalemia risk and testing during RAS blockade.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      In this review, we present an overview of the role of aldosterone in the pathophysiology and progression of CKD and CVD in patients with DM as well as current and future therapeutic options with a particular emphasis on the evolution of MRAs, including traditional steroidal agents and new nonsteroidal ones.

      Literature Search

      The searches for this narrative review were performed nonsystematically and “as needed” (when new relevant publications were available). A MEDLINE-based literature review was undertaken (limited to English language journals) using the following search terms: diabetes, chronic kidney disease, diabetic kidney disease, mineralocorticoid receptor, and aldosterone, and currently available treatments and investigational treatments for CKD and diabetes.

      Aldosterone and the MR

      Aldosterone is a mineralocorticoid steroid hormone, synthesized and secreted in response to an increase in potassium levels, angiotensin II, and corticotropin and/or sodium depletion in the adrenal cortex.
      • Kolkhof P.
      • Joseph A.
      • Kintscher U.
      Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - new perspectives for combination therapy.
      Although mineralocorticoids are traditionally believed to be produced only in the adrenal cortex,
      • Rossier B.C.
      • Baker M.E.
      • Studer R.A.
      Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited.
      a gradient of elevating aldosterone levels from the coronary sinus to the aortic root was reported in patients with acute myocardial infarction.
      • Hayashi M.
      • Tsutamoto T.
      • Wada A.
      • et al.
      Relationship between transcardiac extraction of aldosterone and left ventricular remodeling in patients with first acute myocardial infarction: extracting aldosterone through the heart promotes ventricular remodeling after acute myocardial infarction.
      Similarly, in patients with HF and hypertension, plasma aldosterone levels were found to be greater in the cardiac vein than in the aorta, whereas no such difference was observed in healthy persons.
      • Mizuno Y.
      • Yoshimura M.
      • Yasue H.
      • et al.
      Aldosterone production is activated in failing ventricle in humans.
      ,
      • Yamamoto N.
      • Yasue H.
      • Mizuno Y.
      • et al.
      Aldosterone is produced from ventricles in patients with essential hypertension.
      These results suggest de novo synthesis of aldosterone in the heart under pathologic conditions, although the exact mechanism behind the local increase of aldosterone in the heart is not fully understood.
      • He B.J.
      • Anderson M.E.
      Aldosterone and cardiovascular disease: the heart of the matter.
      ,
      • Taves M.D.
      • Gomez-Sanchez C.E.
      • Soma K.K.
      Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function.
      Aldosterone functions by activating the MR, which is expressed in many tissues, such as the kidney, colon, heart, central nervous system, adipose tissue, and sweat glands.
      • Jaisser F.
      • Farman N.
      Emerging roles of the mineralocorticoid receptor in pathology: Toward new paradigms in clinical pharmacology.
      The enzyme 11β-hydroxysteroid dehydrogenase II confers specificity on the renal MR by inactivating the glucocorticoid, cortisol, which it does by metabolizing cortisol to cortisone (cortisone which has no affinity for the MR), and thus keeps the MR free for aldosterone binding.
      • Palmer B.F.
      Regulation of potassium homeostasis.
      The aldosterone-MR system plays a major role in the following: (1) control of BP and extracellular volume homeostasis by stimulating renal sodium reabsorption; and (2) the control of serum potassium by regulating potassium excretion. The mechanism of action of aldosterone in relation to its role in regulating potassium excretion is to first, increase the intracellular potassium levels by stimulating the activity of sodium-potassium adenosine triphosphate [ATP] ases in the basolateral membrane. Second, it stimulates sodium reabsorption across the luminal membrane, thereby increasing electronegativity of the lumen, which increases the electrical gradient-favoring potassium excretion. Third, it has a direct effect on the luminal membrane, thereby increasing potassium permeability.
      • Palmer B.F.
      • Clegg D.J.
      Extrarenal effects of aldosterone on potassium homeostasis.
      Hyperkalemia can occur in states of aldosterone deficiency or RAS blockade.
      • Bandak G.
      • Sang Y.
      • Gasparini A.
      • et al.
      Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
      ,
      • DeFronzo R.A.
      Hyperkalemia and hyporeninemic hypoaldosteronism.
      Aldosterone binds to and activates the MR, resulting in the transcriptional activation of genes involved in electrolyte homeostasis in health. When abnormally elevated over a long-term, the aldosterone-MR complex also activates proinflammatory and profibrotic genes through hormone response elements in their promoters.
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      In epithelial tissues, including the kidney, MR activates the expression of ionic transporters in the cellular membrane that controls salt and water homeostasis. In nonepithelial tissues, including the heart, the aldosterone-MR complex up-regulates genes involved in cell proliferation, fibrosis, vascular injury, and tissue inflammation.
      • Viengchareun S.
      • Le Menuet D.
      • Martinerie L.
      • Munier M.
      • Pascual-Le Tallec L.
      • Lombès M.
      The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.
      In addition to these genomic MR effects, its expression in immune cells appears to contribute to the inflammation process through DNA binding–independent signaling in macrophages as well as T-cell activation, as summarized in a recent review by Barrera-Chimal et al.
      • Barrera-Chimal J.
      • Lima-Posada I.
      • Bakris G.L.
      • Jaisser F.
      Mineralocorticoid receptor antagonists in diabetic kidney disease—mechanistic and therapeutic effects.
      Early clinical results revealed that the magnitude of plasma aldosterone increase correlated with the degree of renal insufficiency,
      • Berl T.
      • Katz F.H.
      • Henrich W.L.
      • de Torrente A.
      • Schrier R.W.
      Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure.
      ,
      • Hené R.J.
      • Boer P.
      • Koomans H.A.
      • Mees E.J.
      Plasma aldosterone concentrations in chronic renal disease.
      and preclinical results suggested that administration of aldosterone resulted in renal and cardiac injury.
      • Rocha R.
      • Chander P.N.
      • Zuckerman A.
      • Stier Jr., C.T.
      Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.
      ,
      • Rocha R.
      • Stier Jr., C.T.
      • Kifor I.
      • et al.
      Aldosterone: a mediator of myocardial necrosis and renal arteriopathy.
      Administration of an MRA in rat models of CVD and kidney disease reduced proteinuria and tissue inflammation, fibrosis, and end-organ lesions.
      • Rocha R.
      • Stier Jr., C.T.
      • Kifor I.
      • et al.
      Aldosterone: a mediator of myocardial necrosis and renal arteriopathy.
      ,
      • Bauersachs J.
      • Jaisser F.
      • Toto R.
      Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases.
      These findings suggest that the suppression of aldosterone at an early stage in patients with DM may prevent organ damage, including CKD.

      Aldosterone Breakthrough During Treatment With RAS Blockers

      Over the past 2 decades, hypertension and albuminuria have been managed in patients with T2DM and CKD with RAS blockers, which lower plasma aldosterone levels.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      Although clinical studies found that the use of ACEis/ARBs in patients with diabetes and CKD slows the progression of CKD, neither an ACEi nor ARB alone completely prevents CKD progression.

      Zheng CM, Wang JY, Chen TT, et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blocker monotherapy retard deterioration of renal function in Taiwanese chronic kidney disease population. Sci Rep. 2019;9(1):2694. Published correction appears in Sci Rep. 2020;10(1):6631.Pubmed Partial Author articletitle

      This is, in part, due to persistently elevated aldosterone levels during long-term RAS blockade with either ACEi or ARB, also known as aldosterone breakthrough.
      • Bomback A.S.
      • Klemmer P.J.
      The incidence and implications of aldosterone breakthrough.
      ,
      • Schrier R.W.
      Aldosterone 'escape' vs 'breakthrough.
      Aldosterone breakthrough has been shown to occur in approximately 50% of patients treated with RAS blockers.
      • Bomback A.S.
      • Klemmer P.J.
      The incidence and implications of aldosterone breakthrough.
      ,
      • Sato A.
      • Fukuda S.
      Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist.
      The clinical implication of aldosterone breakthrough in kidney disease progression was examined in patients treated with an ARB, demonstrating that higher levels of aldosterone were associated with a higher rate of eGFR decline than lower aldosterone levels.
      • Schjoedt K.J.
      The renin-angiotensin-aldosterone system and its blockade in diabetic nephropathy: main focus on the role of aldosterone.
      Although dual RAS blockade with ACEis/ARBs was examined in clinical studies, results demonstrated not only the lack of additional efficacy with respect to the progression of CKD but also an increased incidence of acute kidney injury, hypotension, and hyperkalemia.

      Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. Published correction appears in N Engl J Med. 2014;158:A7255.

      • Imai E.
      • Chan J.C.
      • Ito S.
      • et al.
      Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study.
      • Yusuf S.
      • Teo K.K.
      • Pogue J.
      • et al.
      ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events.
      Dual RAS blockade with an ACEi or ARB and aliskiren (a direct renin inhibitor [DRI]) did not benefit patients with DM and CVD either. Although aliskiren lowers BP, both as monotherapy and combination therapy,

      Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007;370(9583):221-229. Published correction appears in Lancet. 2007;370(9598):1542.

      ,
      • Villamil A.
      • Chrysant S.G.
      • Calhoun D.
      • et al.
      Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide.
      and may not allow aldosterone breakthrough,
      • Schrier R.W.
      Aldosterone 'escape' vs 'breakthrough.
      patients treated with aliskiren and ARB or ACEi have shown a greater risk of developing hyperkalemia and renal impairment.
      • Parving H.H.
      • Brenner B.M.
      • McMurray J.J.
      • et al.
      Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
      ,
      • Zheng S.L.
      • Roddick A.J.
      • Ayis S.
      Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: a systematic review and meta-analysis of 13,395 patients.
      Clinical guidelines from the American Diabetes Association

      American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: Standards of medical care in diabetes-2022. Diabetes Care. 2022;45(suppl 1):S144-S174. Published correction appears in Diabetes Care. 2022;45(5):1296.

      and KDIGO 2020
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      recommend the use of either an ACEi or an ARB alone, but not dual RAS blockade or the combination of ACEi or ARB with a DRI, for the treatment of hypertension. Strategies aimed at blocking the deleterious effects of aldosterone breakthrough, other than the use of combinations of ACEi/ARB and DRI, may be advantageous.

      Steroidal MRAs: Spironolactone and Eplerenone

      Spironolactone was the first steroidal MRA, initially launched as a diuretic and natriuretic drug for the control of hypertension and primary aldosteronism and later for the treatment of HF.
      • Kolkhof P.
      • Joseph A.
      • Kintscher U.
      Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - new perspectives for combination therapy.
      ,
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      Spironolactone can be regarded as a prodrug with a short half-life (<2 hours) that generates 3 active metabolites with longer half-lives (>12-24 hours) (Table 1).
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      ALDACTONE (spironolactone). Prescribing Information. Pfizer.
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      • Mann N.M.
      Gynecomastia during therapy with spironolactone.
      • Hughes B.R.
      • Cunliffe W.J.
      Tolerance of spironolactone.
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      • Cook C.S.
      • Berry L.M.
      • Bible R.H.
      • Hribar J.D.
      • Hajdu E.
      • Liu N.W.
      Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.
      • Bärfacker L.
      • Kuhl A.
      • Hillisch A.
      • et al.
      Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
      • Gerisch M.
      • Heinig R.
      • Engelen A.
      • et al.
      Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
      • Heinig R.
      • Kimmeskamp-Kirschbaum N.
      • Halabi A.
      • Lentini S.
      Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment.
      • Amazit L.
      • Le Billan F.
      • Kolkhof P.
      • et al.
      Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
      • Le Billan F.
      • Perrot J.
      • Carceller E.
      • et al.
      Antagonistic effects of finerenone and spironolactone on the aldosterone-regulated transcriptome of human kidney cells.
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      • Grune J.
      • Beyhoff N.
      • Smeir E.
      • et al.
      Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      • Craft J.
      Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure.
      • Weinberger M.H.
      • Roniker B.
      • Krause S.L.
      • Weiss R.J.
      Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.
      Spironolactone may cause gynecomastia and impotence in males through its binding with the androgen receptor (AR) as an antagonist and menstrual irregularities and breast tenderness in women through its binding with the progesterone receptor (PR) as an agonist.
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      ,
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      • Mann N.M.
      Gynecomastia during therapy with spironolactone.
      • Hughes B.R.
      • Cunliffe W.J.
      Tolerance of spironolactone.
      ,
      • Corvol P.
      • Michaud A.
      • Menard J.
      • Freifeld M.
      • Mahoudeau J.
      Antiandrogenic effect of spirolactones: mechanism of action.
      Research programs aimed at identifying more receptor-specific steroidal MRAs to decrease these side effects, led to the discovery of eplerenone. Differences in molecular structure and MRA activity underpin the distinct effects of spironolactone and eplerenone observed in preclinical and clinical studies (Table 1).
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      ALDACTONE (spironolactone). Prescribing Information. Pfizer.
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      • Mann N.M.
      Gynecomastia during therapy with spironolactone.
      • Hughes B.R.
      • Cunliffe W.J.
      Tolerance of spironolactone.
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      • Cook C.S.
      • Berry L.M.
      • Bible R.H.
      • Hribar J.D.
      • Hajdu E.
      • Liu N.W.
      Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.
      • Bärfacker L.
      • Kuhl A.
      • Hillisch A.
      • et al.
      Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
      • Gerisch M.
      • Heinig R.
      • Engelen A.
      • et al.
      Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
      • Heinig R.
      • Kimmeskamp-Kirschbaum N.
      • Halabi A.
      • Lentini S.
      Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment.
      • Amazit L.
      • Le Billan F.
      • Kolkhof P.
      • et al.
      Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
      • Le Billan F.
      • Perrot J.
      • Carceller E.
      • et al.
      Antagonistic effects of finerenone and spironolactone on the aldosterone-regulated transcriptome of human kidney cells.
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      • Grune J.
      • Beyhoff N.
      • Smeir E.
      • et al.
      Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      • Craft J.
      Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure.
      • Weinberger M.H.
      • Roniker B.
      • Krause S.L.
      • Weiss R.J.
      Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.
      Table 1Differences Among Spironolactone, Eplerenone, and Finerenone
      SpironolactoneEplerenoneFinerenone
      Structural aspectsFlat (steroidal)
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      Bulky, passive antagonist (nonsteroidal)
      • Amazit L.
      • Le Billan F.
      • Kolkhof P.
      • et al.
      Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
      ,
      • Kintscher U.
      • Bakris G.L.
      • Kolkhof P.
      Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
      MRA structureSteroidalSteroidalNonsteroidal
      MetabolitesMultiple, active metabolites
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      No active metabolites
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      No active metabolites
      • Gerisch M.
      • Heinig R.
      • Engelen A.
      • et al.
      Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
      Half-lifeSpironolactone: <2 hours

      Active metabolites: >12-24 hours
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      ,
      ALDACTONE (spironolactone). Prescribing Information. Pfizer.
      4 hours
      • Cook C.S.
      • Berry L.M.
      • Bible R.H.
      • Hribar J.D.
      • Hajdu E.
      • Liu N.W.
      Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.
      2-3 hours
      • Gerisch M.
      • Heinig R.
      • Engelen A.
      • et al.
      Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
      ,
      • Heinig R.
      • Kimmeskamp-Kirschbaum N.
      • Halabi A.
      • Lentini S.
      Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment.
      Tissue distributionHeart < kidney
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      Heart < kidney
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      Heart ≈ kidney
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      Affinity to MRFinerenone > spironolactone >> eplerenone
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      ,
      • Bärfacker L.
      • Kuhl A.
      • Hillisch A.
      • et al.
      Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
      Affinity to AR, GR, and PRSpironolactone >> eplerenone ≈ finerenone
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      Inhibitory effect on aldosterone-dependent gene activationFinerenone > spironolactone
      • Le Billan F.
      • Perrot J.
      • Carceller E.
      • et al.
      Antagonistic effects of finerenone and spironolactone on the aldosterone-regulated transcriptome of human kidney cells.
      Sexual side effectsObserved
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      • Mann N.M.
      Gynecomastia during therapy with spironolactone.
      • Hughes B.R.
      • Cunliffe W.J.
      Tolerance of spironolactone.
      Low frequency
      • Craft J.
      Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure.
      Not observed or rare
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      Effect on SBPSpironolactone > finerenone
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.


      Spironolactone > eplerenone
      • Weinberger M.H.
      • Roniker B.
      • Krause S.L.
      • Weiss R.J.
      Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.


      Eplerenone ≈ finerenone
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      Effect on inflammation and fibrosis in animalsEplerenone < finerenone
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      ,
      • Grune J.
      • Beyhoff N.
      • Smeir E.
      • et al.
      Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity.
      Risk of hyperkalemiaEplerenone ≈ finerenone
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.


      Spironolactone > finerenone
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      AR, androgen receptor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; PR, progesterone receptor; SBP, systolic blood pressure.
      Eplerenone is a second-generation MRA for the treatment of hypertension and HF.
      • Jaisser F.
      • Farman N.
      Emerging roles of the mineralocorticoid receptor in pathology: Toward new paradigms in clinical pharmacology.
      In a steroid hormone receptor binding assay, eplerenone was found to be considerably more selective for the MR, but less potent than spironolactone (Table 2).
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      ,

      Bramlage P, Swift SL, Thoenes M, Minguet J, Ferrero C, Schmieder RE. Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail. 2016;18(1):28-37. Published correction appears in Eur J Heart Fail. 2017;19(6):811.

      ,
      • Fagart J.
      • Hillisch A.
      • Huyet J.
      • et al.
      A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
      Eplerenone has no active metabolites, and its half-life of 4 hours is longer than that of spironolactone but much shorter than spironolactone’s active metabolites.
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      ,
      • Cook C.S.
      • Berry L.M.
      • Bible R.H.
      • Hribar J.D.
      • Hajdu E.
      • Liu N.W.
      Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.
      The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),

      Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. Published correction appears in N Engl J Med. 2003;348(22):2271.

      a multicenter, international, randomized, double-blind, placebo-controlled phase 3 study in patients with acute myocardial infarction complicated by left ventricular dysfunction and HF, demonstrated a significant reduction in morbidity and mortality among patients treated with eplerenone as compared with placebo, but with a significant increase in severe hyperkalemia (serum potassium concentration ≥6.0 mmol/L). Although still recommended, in particular for patients who have intolerable sex hormone–mediated side effects associated with the use of spironolactone, hyperkalemia and cost have limited the broad utilization of eplerenone in patients with HF.
      • Pitt B.
      • Pedro Ferreira J.
      • Zannad F.
      Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives.
      Table 2In Vitro Selectivity of MRAs in Functional Cell-Based Steroid Hormone Receptor Assays
      SpironolactoneEplerenoneFinerenone
      MR IC50, nM24.299017.8
      AR IC50, nM77.1≥21,240≥10,000
      GR IC50, nM2410≥21,980≥10,000
      PR EC50, nM740≥31,210≥10,000
      AR, androgen receptor; EC50, concentration of ligand required to achieve 50% activation of the receptor; GR, glucocorticoid receptor; IC50, concentration of antagonist required to inhibit 50% activation of receptor; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; PR, progesterone receptor.
      Adapted from Eur J Heart Fail and J Biol Chem.
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      ,
      • Fagart J.
      • Hillisch A.
      • Huyet J.
      • et al.
      A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
      Higher and lower IC50 values are correlated with lower and higher affinities, respectively, between MRAs and steroid hormone receptors.

      Treatment With Steroidal MRAs in Combination With ACEi/ARB

      Several systematic reviews have suggested that the addition of a steroidal MRA to a regimen including an ACEi or ARB can improve organ protection for patients with CKD or DN but increase the risk of hyperkalemia. A Cochrane systematic review published in 2020 (44 studies with a duration of 1-36 months involving 5745 patients with CKD treated with MRAs)
      • Chung E.Y.
      • Ruospo M.
      • Natale P.
      • et al.
      Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
      confirmed conclusions made in 2009
      • Navaneethan S.D.
      • Nigwekar S.U.
      • Sehgal A.R.
      • Strippoli G.F.M.
      Aldosterone antagonists for preventing the progression of chronic kidney disease.
      and 2014.
      • Bolignano D.
      • Palmer S.C.
      • Navaneethan S.D.
      • Strippoli G.F.M.
      Aldosterone antagonists for preventing the progression of chronic kidney disease.
      Mineralocorticoid receptor antagonists may reduce proteinuria and systolic BP in adults who have mild-to-moderate CKD but probably increase the risk of hyperkalemia, acute kidney injury, and gynecomastia when combined with ACEi/ARB treatment.
      • Chung E.Y.
      • Ruospo M.
      • Natale P.
      • et al.
      Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
      Evidence for the effect of MRAs on the progression of CKD, cardiovascular (CV) events, and death is inconclusive, and data for treatment effects of nonsteroidal MRAs were not sufficient for precise estimates and meta-analysis. An increased incidence of hyperkalemia in patients receiving treatment with steroidal MRAs in addition to ACEi/ARB as compared with ACEi/ARB alone was also reported in an analyses of 8 studies involving patients with DN.
      • Mavrakanas T.A.
      • Gariani K.
      • Martin P.Y.
      Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review.
      Similar findings were reported in a meta-analysis of 19 studies involving 1646 patients with stage 1-5 CKD, treated with MRAs (14 spironolactone and 5 eplerenone) and ACEi/ARB, in which MRAs were shown to reduce BP and albuminuria, but with a threefold higher risk of patients withdrawing from the study because of hyperkalemia than those receiving ACEi/ARB alone.
      • Currie G.
      • Taylor A.H.
      • Fujita T.
      • et al.
      Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.
      In another systematic review of 18 randomized, controlled studies (duration: 5 weeks-18 months), involving 1786 patients with DN treated with MRAs (15 spironolactone, 2 eplerenone, and 1 finerenone), significant reductions in urinary albumin excretion and BP and improvement in the urinary albumin-creatine ratio (UACR) were observed, without a decrease in eGFR in patients treated with MRAs in combination with ACEi/ARB as compared with those receiving ACEi/ARB alone; however, the incidence of hyperkalemia was significantly higher in the former group.
      • Sun L.J.
      • Sun Y.N.
      • Shan J.P.
      • Jiang G.R.
      Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy.
      These analyses also noted several common limitations. First, for most of the studies, treatment duration was too short to evaluate surrogate end points (eg, proteinuria), and patient-centered outcomes (eg, death and kidney or cardiac failure) were absent or sparse. Second, patients with severe CKD were rarely included. Third, quality of reporting study methods and outcomes was inconsistent, and study design and duration were variable. Finally, data were extracted almost exclusively from studies with steroidal MRAs.

      Nonsteroidal MRAs: Apararenone, Esaxerenone, and Finerenone

      Evidence suggesting that MR blockade with steroidal MRAs combined with ACEi/ARB is associated with an increased risk of hyperkalemia prompted the development of nonsteroidal MRAs with novel physicochemical properties that may reduce electrolyte and hormonal complications.
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      Several pharmaceutical companies have identified numerous novel nonsteroidal MRA compounds, including Eli Lilly’s LY2623091, Mitsubishi Tanabe Pharma Corporation’s MT-3995 (apararenone), AstraZeneca’s AZD 9977, Pfizer’s PF-03882845, Daiichi Sankyo’s CS-3150 (esaxerenone), KBP Biosciences’s KBP5074, Dainippon Sumitomo Pharma’s SM-368229 and DSR-71167, and Bayer’s BR-4628 and BAY 94-8862 (finerenone).
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      ,
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      ,
      • Sueta D.
      • Yamamoto E.
      • Tsujita K.
      Mineralocorticoid receptor blockers: novel selective nonsteroidal mineralocorticoid receptor antagonists.
      ,
      • Bakris G.
      • Pergola P.E.
      • Delgado B.
      • et al.
      Effect of KBP-5074 on blood pressure in advanced chronic kidney disease: results of the BLOCK-CKD study.
      Finerenone is currently the most studied first-generation nonsteroidal MRA. Finerenone showed higher selectivity towards MR than spironolactone and a higher affinity for MR than eplerenone. Its affinity for AR, glucocorticoid receptor (GR), and PR is lower than that of spironolactone and is comparable to that of eplerenone (Table 2).
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      ,
      • Bärfacker L.
      • Kuhl A.
      • Hillisch A.
      • et al.
      Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
      ,

      Bramlage P, Swift SL, Thoenes M, Minguet J, Ferrero C, Schmieder RE. Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail. 2016;18(1):28-37. Published correction appears in Eur J Heart Fail. 2017;19(6):811.

      ,
      • Fagart J.
      • Hillisch A.
      • Huyet J.
      • et al.
      A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
      The plasma half-life is ∼2 hours in healthy subjects
      • Gerisch M.
      • Heinig R.
      • Engelen A.
      • et al.
      Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
      and 2-3 hours in patients with kidney failure.
      • Heinig R.
      • Kimmeskamp-Kirschbaum N.
      • Halabi A.
      • Lentini S.
      Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment.
      In healthy rats, spironolactone and eplerenone accumulate more in the kidneys than in the heart, whereas, finerenone is distributed evenly between the 2 organs.
      • Kolkhof P.
      • Borden S.A.
      Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
      Finerenone acts as an MR antagonist, whereas spironolactone possesses at least partial aldosterone-like activity.
      • Amazit L.
      • Le Billan F.
      • Kolkhof P.
      • et al.
      Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
      ,
      Finerenone (Kerenida)
      Prescribing Information.
      Furthermore, RNA sequencing analyses showed that approximately 20% of transcripts induced by aldosterone were antagonized by finerenone, whereas, only 5% were antagonized by spironolactone.
      • Le Billan F.
      • Perrot J.
      • Carceller E.
      • et al.
      Antagonistic effects of finerenone and spironolactone on the aldosterone-regulated transcriptome of human kidney cells.
      Chromatin immunoprecipitation assays in the SCNN1A promoters suggest that although finerenone prevents the basal recruitment of the MR and steroid receptor coactivator 1 (SRC-1), spironolactone mildly promotes basal recruitment of these 2 regulators (aldosterone-dependent recruitment of the MR, SRC-1, and RNA polymerase II was also prevented by finerenone).
      • Amazit L.
      • Le Billan F.
      • Kolkhof P.
      • et al.
      Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
      These results suggest that finerenone confers a more profound antagonistic effect on mineralocorticoid target genes than spironolactone.
      Both preclinical and clinical studies have suggested that finerenone offers end-organ protection and lower or similar incidence of hyperkalemia as compared with steroidal MRAs (Tables 1 and 3).
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      ,
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      ,
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes.
      • Ruilope L.M.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
      • Sato N.
      • Ajioka M.
      • Yamada T.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease.
      • Katayama S.
      • Yamada D.
      • Nakayama M.
      • et al.
      A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.
      • Filippatos G.
      • Bakris G.L.
      • Pitt B.
      • et al.
      Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes.
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial.
      In preclinical studies, finerenone provided greater reduction in proteinuria and end-organ damage than eplerenone when they were compared in equinatriuretic doses (finerenone 1 mg/kg vs eplerenone 30 mg/kg; finerenone 10 mg/kg vs 100 mg/kg), determined in rats based on the equivalent natriuretic responses achieved by both MRAs.
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      In the multicenter, randomized, double-blind, placebo-controlled, phase 2 minerAlocorticoid Receptor Antagonist Tolerability Study (ARTS, NCT01345656),
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      in HF patients with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40%) and mild CKD, finerenone reduced the levels of cardiac biomarkers of hemodynamic stress (B-type natriuretic peptide and N-terminal pro-hormone B-type natriuretic peptide) and albuminuria as effectively as spironolactone. Finerenone was associated with a lower incidence of hyperkalemia, a smaller increase in serum potassium concentration, and a lower incidence of worsening kidney function (defined as increase in serum creatinine by ≥0.3 mg/dL from baseline and/or decrease in eGFR by ≥25% from baseline) as compared with spironolactone. Hormone side effects, such as gynecomastia, were not examined because of the short duration of the study and a small number of patients.
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      Results from ARTS-HF (NCT01807221), a phase 2b study involving 1066 patients with HFrEF (LVEF ≤40%) and concomitant T2DM and/or CKD, showed that finerenone improved outcomes, including CV hospitalizations and death, as compared with eplerenone. Although incidence of hyperkalemia was similar between the finerenone and eplerenone groups, mean changes from baseline to day 90 in serum potassium concentration were lower in the finerenone dose groups as compared with the eplerenone group.
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      ARTS-Diabetic Nephropathy (ARTS-DN, NCT01874431),
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      a multicenter, randomized, double-blind, parallel-group, phase 2b study, compared the efficacy and safety of different once-daily oral doses of finerenone and placebo in patients with T2DM and persistent albuminuria (UACR ≥30 mg/g) who were receiving ACEi/ARB. The addition of finerenone to an ACEi or ARB resulted in a decrease in UACR in a dose-dependent manner in patients with DN.
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      Hyperkalemia developed in 8 (1.1%) of 727 patients treated with a finerenone dose used during the study (1.25-20 mg/d) and 0 of 94 treated with placebo (relative risk, 2.22; 95% CI, 0.13-38.13),
      • Chung E.Y.
      • Ruospo M.
      • Natale P.
      • et al.
      Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
      whereas no hyperkalemia leading to discontinuation was observed in the finerenone 10 mg/d group.
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      Unlike with steroidal MRAs,
      • Bolignano D.
      • Palmer S.C.
      • Navaneethan S.D.
      • Strippoli G.F.M.
      Aldosterone antagonists for preventing the progression of chronic kidney disease.
      only a modest reduction in BP was observed even with the highest dose of finerenone in ARTS and ARTS-DN.
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      ,
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      The differential effect of steroidal MRAs and finerenone on BP is attributed to the fact that steroidal MRAs, unlike finerenone,
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      can cross the blood-brain barrier
      • Pitt B.
      • Pedro Ferreira J.
      • Zannad F.
      Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives.
      ,
      • Schmiedek P.
      • Sadée W.
      • Baethmann A.
      Cerebral uptake of a 3 H-labelled spirolactone compound in the dog.
      and may act centrally on MRs.
      • Gomez-Sanchez E.P.
      • Gomez-Sanchez C.E.
      Central regulation of blood pressure by the mineralocorticoid receptor.
      Preclinical studies (rodents) have suggested that aldosterone is synthesized in the rodent brain, and that is critical for the regulation of BP and the development of sodium-induced hypertension even in the presence of adrenal aldosterone.
      • Taves M.D.
      • Gomez-Sanchez C.E.
      • Soma K.K.
      Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function.
      The mechanism of renal and CV protection with finerenone appears to be attributable to anti-inflammatory and antifibrotic effects, as suggested in preclinical studies,
      • Kolkhof P.
      • Delbeck M.
      • Kretschmer A.
      • et al.
      Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
      ,
      • Grune J.
      • Beyhoff N.
      • Smeir E.
      • et al.
      Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity.
      ,
      • Lattenist L.
      • Lechner S.M.
      • Messaoudi S.
      • et al.
      Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injury-mediated chronic kidney disease: role of oxidative stress.
      ,
      • Barrera-Chimal J.
      • Estrela G.R.
      • Lechner S.M.
      • et al.
      The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling.
      rather than hemodynamic ones. Given its high potency and selectivity to MR, safety profiles with lower serum potassium concentration and/or hyperkalemia incidence than steroidal MRAs, and pharmacologic features distinctive from steroidal MRAs, finerenone emerged as a candidate for larger studies among patients with CKD and CVD associated with T2DM.
      Table 3Clinical Studies for Finerenone
      StudyPhaseNPatientsStudy drugControlDuration, wkKey findings
      ARTS (NCT01345656)
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      2457HFrEF with LVEF and mild
      eGFR: 60 <90 mL/min per 1.73 m2.
      -to-moderate
      eGFR: 30 <60 mL/min per 1.73 m2.
      CKD
      FinerenonePlacebo/spironolactone>4Finerenone was as effective as spironolactone in reducing hemodynamic stress and was associated with lower incidences of hyperkalemia with a smaller increase in serum potassium concentration and less worsening renal function than spironolactone. Hormone side effects were not examined because of its short duration and small number of patients.
      ARTS-HF (NCT01807221)
      • Filippatos G.
      • Anker S.D.
      • Böhm M.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
      2b1066Worsening HFrEF with T2DM and/or CKD
      eGFR: >30 mL/min per 1.73 m2 in patients with T2DM; 30-60 mL/min per 1.73 m2 in patients without T2DM.
      FinerenoneEplerenone12.9The safety profile of finerenone was comparable to that of eplerenone. Death from any cause, CV hospitalization, or emergency presentation of worsening HF was lower in most of the finerenone dose groups than the eplerenone group. Whereas incidences of hyperkalemia were similar between the finerenone and eplerenone groups, mean changes from baseline in serum potassium concentration were lower in the finerenone dose groups than the eplerenone group.
      ARTS-HF Japan (NCT01955694)
      • Sato N.
      • Ajioka M.
      • Yamada T.
      • et al.
      A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease.
      2b72Worsening HFrEF with T2DM and/or CKD
      eGFR: >30 mL/min per 1.73 m2 in patients with T2DM; 30-60 mL/min per 1.73 m2 in patients without T2DM.
      FinerenoneEplerenone12.9Because of the small number of individuals per treatment group, no robust conclusions were drawn.
      ARTS-DN (NCT01874431)
      • Bakris G.L.
      • Agarwal R.
      • Chan J.C.
      • et al.
      Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
      2b823DN (T2DM)
      UACR: ≥30 mg/g and eGFR >30 mL/min per 1.73 m2.
      Finerenone + ACEi/ARBPlacebo + ACEi/ARB12.9Finerenone in combination with an ACEi/ARB showed a dose-dependent reduction in UACR compared with the placebo. No hyperkalemia leading to discontinuation was observed in the finerenone 10 mg/d group.
      ARTS-DN Japan (NCT01968668)
      • Katayama S.
      • Yamada D.
      • Nakayama M.
      • et al.
      A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.
      2b96DN (T2DM)
      UACR: ≥30 mg/g and eGFR >30 mL/min per 1.73 m2.
      Finerenone + ACEi/ARBPlacebo + ACEi/ARB12.9Finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.
      FIDELIO-DKD (NCT02540993)
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes.
      ,
      • Filippatos G.
      • Bakris G.L.
      • Pitt B.
      • et al.
      Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes.




      35734T2DM with CKD
      UACR: 30 to <300 mg/g and eGFR 25 to <60 mL/min per 1.73 m2 or UACR ≥300 mg/g and eGFR ≥25 to <75 mL/min per 1.73 m2.
      Finerenone
      All patients were treated with either ACEi or ARB at maximum tolerated labeled dose that did not have unacceptable side effects.
      Placebo135.6Finerenone demonstrated lower risks of CKD progression and CV events than placebo. Discontinuation because of hyperkalemia was infrequent in patients who received finerenone (2.3%) and placebo (0.9%). Gynecomastia was rare and was comparable to placebo (0.2% vs 0.2%).
      FIGARO-DKD (NCT02545049)
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      ,
      • Ruilope L.M.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
      ,
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial.
      37352T2DM with CKD
      UACR: 30 to <300 mg/g and eGFR 25 to ≤90 mL/min per 1.73 m2 or UACR ≥300 mg/g and eGFR ≥60 mL/min per 1.73 m2.
      Finerenone
      All patients were treated with either ACEi or ARB at maximum tolerated labeled dose that did not have unacceptable side effects.
      Placebo176.8Finerenone improved CV outcomes compared with placebo with lower incidence of hospitalization for HR. Finerenone reduced new-onset HF and improved other HF outcomes. The incidence of hyperkalemia-related discontinuation was higher with finerenone (1.2%) than placebo (0.4%). Gynecomastia was rare and was comparable to placebo (0.1% vs 0.1%).
      ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARTS, minerAlocorticoid Receptor Antagonist Tolerability Study; CKD, chronic kidney disease; CV, cardiovascular; DN, diabetic nephropathy; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIGARO-DKD, Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; T2DM, type 2 diabetes mellitus; UACR, urinary albumin-creatine ratio; wk, weeks.
      a eGFR: 60 <90 mL/min per 1.73 m2.
      b eGFR: 30 <60 mL/min per 1.73 m2.
      c eGFR: >30 mL/min per 1.73 m2 in patients with T2DM; 30-60 mL/min per 1.73 m2 in patients without T2DM.
      d UACR: ≥30 mg/g and eGFR >30 mL/min per 1.73 m2.
      e UACR: 30 to <300 mg/g and eGFR 25 to <60 mL/min per 1.73 m2 or UACR ≥300 mg/g and eGFR ≥25 to <75 mL/min per 1.73 m2.
      f All patients were treated with either ACEi or ARB at maximum tolerated labeled dose that did not have unacceptable side effects.
      g UACR: 30 to <300 mg/g and eGFR 25 to ≤90 mL/min per 1.73 m2 or UACR ≥300 mg/g and eGFR ≥60 mL/min per 1.73 m2.
      Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD, NCT02540993) is a phase 3 study investigating the efficacy of finerenone on kidney outcomes in patients with CKD and T2DM, who were treated with an ACEi/ARB at optimized doses.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes.
      ,
      • Filippatos G.
      • Bakris G.L.
      • Pitt B.
      • et al.
      Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes.
      ,
      • Agarwal R.
      • Anker S.D.
      • Bakris G.
      • et al.
      Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone.
      Treatment with finerenone resulted in a 31% reduction in UACR from baseline to month 4 as compared with placebo, and the effect was maintained thereafter. Patients treated with finerenone showed a significant reduction in the risk of primary composite outcome, ie, kidney failure, sustained decrease of ≥40% in eGFR from baseline, and death from renal causes, as compared with those who received placebo. Patients treated with finerenone also demonstrated a significantly lower risk of achieving key secondary composite outcome, which included death from CV causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for HF, as compared with those who received placebo. Finerenone was found to be associated with a higher overall risk of hyperkalemia than placebo (15.8% vs 7.8%). However, discontinuation of finerenone because of hyperkalemia occurred in 2.3% of participants,
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      which was lower than that previously reported with dual RAS blockade with ACEi/ARB.
      • Imai E.
      • Chan J.C.
      • Ito S.
      • et al.
      Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study.
      ,
      • Parving H.H.
      • Brenner B.M.
      • McMurray J.J.
      • et al.
      Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
      Gynecomastia was found to be rare and comparable with placebo (0.2% vs 0.2%).
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      For a subpopulation at high risk of kidney and CV events, the benefits of receiving finerenone were observed after 12 months for kidney outcomes and 1 month for CV outcomes, and thereafter the effect persisted throughout the study.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      FIDELIO-DKD is the first study demonstrating that dual-renin–angiotensin–aldosterone system (RAAS) blockade with an MRA and an ACEi/ARB is beneficial for renal and CV composite outcomes.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Sridhar V.S.
      • Liu H.
      • Cherney D.Z.I.
      Finerenone-A new frontier in renin-angiotensin-aldosterone system inhibition in diabetic kidney disease.
      In another phase 3 study, Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD, ClinicalTrials.gov identifier: NCT02545049),
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      ,
      • Ruilope L.M.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
      ,
      • Filippatos G.
      • Anker S.D.
      • Agarwal R.
      • et al.
      Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial.
      ,
      • Agarwal R.
      • Anker S.D.
      • Bakris G.
      • et al.
      Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone.
      finerenone reduced the composite risk of time to the first occurrence of CV death and nonfatal CV events in patients with T2DM and CKD who were treated with ACEi/ARB. Hyperkalemia leading to permanent discontinuation occurred in 1.2% and 0.4% of participants in the finerenone and placebo groups, respectively. Gynecomastia was rare and was comparable to placebo (0.1% vs 0.1%). On July 9, 2021, the US Food and Drug Administration approved finerenone for the treatment of patients with T2DM-associated CKD.
      Finerenone (Kerenida)
      Prescribing Information.
      A prespecified efficacy and safety analysis in the FIDELITY study (pooled analysis of FIDELIO-DKD and FIGARO-DKD studies) found that as compared with placebo, finerenone reduced the risk of clinically important kidney and CV outcomes in patients with T2DM and a broad spectrum of CKD stages.

      Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. Published correction appears in Eur Heart J. 2022;43(20):1989.

      Esaxerenone is a highly potent and selective nonsteroidal MRA that has shown inhibition of aldosterone-dependent activation of human MR in a cell-based assay and higher potency compared with steroidal MRAs.
      • Arai K.
      • Homma T.
      • Morikawa Y.
      • et al.
      Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
      ,
      • Arai K.
      • Tsuruoka H.
      • Homma T.
      CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats.
      In a steroid hormone receptor binding assay, esaxerenone bound to MR, whereas no detectable interaction with GR, PR, and AR was observed.
      • Sueta D.
      • Yamamoto E.
      • Tsujita K.
      Mineralocorticoid receptor blockers: novel selective nonsteroidal mineralocorticoid receptor antagonists.
      ,
      • Arai K.
      • Homma T.
      • Morikawa Y.
      • et al.
      Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
      Other preclinical studies using rat models demonstrated that esaxerenone reduced BP, proteinuria, and renal hypertrophy with better outcomes in cardiorenal injury than steroidal MRAs.
      • Arai K.
      • Homma T.
      • Morikawa Y.
      • et al.
      Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
      ,
      • Arai K.
      • Tsuruoka H.
      • Homma T.
      CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats.
      A randomized, double-blind, placebo-controlled, phase 2 study involving 365 Japanese patients with T2DM and microalbuminuria reported that the addition of esaxerenone to an ACEi/ARB, for 12 weeks, reduced UACR by approximately 50%, with increasing rates of UACR remission rate (defined UACR <30 mg/g creatinine at the end of treatment and ≥30% decrease from baseline), in a dose-dependent manner (JapicCTI-152774, ClinicalTrials.gov identifier: NCT02345057).
      • Ito S.
      • Shikata K.
      • Nangaku M.
      • Okuda Y.
      • Sawanobori T.
      Efficacy and safety of esaxerenone (CS-3150) for the treatment of type 2 diabetes with microalbuminuria: a randomized, double-blind, placebo-controlled, phase II trial.
      Incidences of hyperkalemia observed with up to 2.5 mg/d of esaxerenone were similar to placebo (up to 3% vs 1%). Although these results are promising, larger studies of longer duration evaluating the efficacy and safety of esaxerenone are needed.
      Apararenone is highly selective nonsteroidal MRA; results from an in vitro study reported that apararenone has a strong affinity with human MR while having almost no binding affinity for the GR, PR, AR, and estrogen receptor.

      Kikkawa K, Shirata N, Takakuwa M, et al. MT-3995, a novel non-steroidal mineralocorticoid receptor antagonist, has pharmacological profiles differentiated from eplerenone and spironolactone. Presented at: ASN Kidney Week; October 31-Nov 5, 2017; New Orleans, LA.

      A randomized, double-blind, placebo-controlled, phase 2 study involving 293 Japanese patients with T2DM and stage 2 DN demonstrated that treatment with apararenone for 24 weeks reduced UACR in a dose-dependent manner, regardless of concomitant ACEi/ARB use.
      • Wada T.
      • Inagaki M.
      • Yoshinari T.
      • et al.
      Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
      No cases of discontinuation because of hyperkalemia were reported over 52 weeks of treatment.
      KBP-5074 is another selective nonsteroidal MRA that has shown strong MR binding affinity. A study using a steroid hormone receptor binding assay found that KBP-5074 binds to human MR, GR, and PR with half-maximal inhibitory concentration values of 2.7 nM, 2410 nM, and 122 nM, respectively, and no binding activities were observed between KBP-5074 and AR (see Table 2
      • Pitt B.
      • Filippatos G.
      • Gheorghiade M.
      • et al.
      Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
      ,
      • Fagart J.
      • Hillisch A.
      • Huyet J.
      • et al.
      A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
      and Chow et al
      • Chow C.P.
      • Liu J.R.
      • Tan X.J.
      • Huang Z.H.
      Pharmacological profile of KBP-5074, a novel nonsteroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases.
      for value ranges for other MRAs). Preclinical results suggested that KBP-5074 can not only reduce BP but may also offer renoprotection.
      • Chow C.P.
      • Liu J.R.
      • Tan X.J.
      • Huang Z.H.
      Pharmacological profile of KBP-5074, a novel nonsteroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases.
      BLOCK-CKD, a randomized, double-blind, placebo-controlled, phase 2b study involving 162 patients with advanced CKD, demonstrated that KBP-5074 lowered BP with a comparable incidence of hyperkalemia, thereby leading to discontinuation from the study (3.7% vs 3.5% for placebo).
      • Bakris G.
      • Pergola P.E.
      • Delgado B.
      • et al.
      Effect of KBP-5074 on blood pressure in advanced chronic kidney disease: results of the BLOCK-CKD study.
      The rate of hyperkalemia associated discontinuation (3.7%) in patients treated with KBP-5074 was comparable to those treated with finerenone (2.3%) in the FIDELIO-DKD trial
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      and was much lower than that in an HF subgroup treated with spironolactone (23%) in the AMBER trial.
      • Rossignol P.
      • Williams B.
      • Mayo M.R.
      • et al.
      Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): results in the pre-specified subgroup with heart failure.
      A larger study of longer duration is ongoing (CLARION-CKD, ClinicalTrials.gov identifier: NCT04968184).

      Management of Hyperkalemia

      Hyperkalemia is a common complication of treatment with steroidal or nonsteroidal MRAs. In the FIDELIO-DKD and FIGARO-DKD trials, 2- to 3-fold more patients treated with finerenone demonstrated hyperkalemia-related events than those treated with placebo.
      • Bakris G.L.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
      ,
      • Pitt B.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
      Moura-Neto and Ronco
      • Moura-Neto J.A.
      • Ronco C.
      The RALES legacy and finerenone use on CKD patients.
      have suggested that the decision to prescribe finerenone may need to be made cautiously, referring to a substantial rise in the number of hospital admissions and deaths from iatrogenic hyperkalemia associated with the significant increase in the use of spironolactone after publication of the Randomized Aldactone Evaluation Study (RALES) in patients with HF.
      • Moura-Neto J.A.
      • Ronco C.
      The RALES legacy and finerenone use on CKD patients.
      When it develops, hyperkalemia can be managed by measures, such as avoiding potassium-containing salt substitutes or food products, medications that may impair kidney excretion of potassium, initiating treatment with diuretics, and considering concomitant treatment with potassium binders (compounds that bind potassium in the gastrointestinal tract to prevent its absorption).
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      ,
      • Palmer B.F.
      Potassium binders for hyperkalemia in chronic kidney disease-diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis.
      In patients requiring the use of RAS blockers and MRA who are considered at higher risk for developing hyperkalemia, these measures can be instituted prophylactically. Recently, 2 potassium binders, sodium zirconium cyclosilicate and patiromer, were approved for the treatment of hyperkalemia; a review published by Palmer et al
      • Palmer B.F.
      Potassium binders for hyperkalemia in chronic kidney disease-diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis.
      gives an overview of the key clinical trials involving these 2 drugs and their efficacy in terms of reducing hyperkalemia when used with RAAS inhibitors. A double-blind, randomized, phase 2 study involving patients with CKD and resistant hypertension (AMBER) demonstrated that patiromer enabled more patients to continue treatment with spironolactone, thereby pointing towards the lower incidence of hyperkalemia.
      • Agarwal R.
      • Rossignol P.
      • Romero A.
      • et al.
      Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
      Notably, after the previous spironolactone dose, 75% and 36% of patients who were treated with and then discontinued spironolactone had detectable metabolites at 2 and 3 weeks, respectively.
      • Agarwal R.
      • Rossignol P.
      • Romero A.
      • et al.
      Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
      Hyperkalemia may be managed more easily during treatment with finerenone than steroidal MRAs via transient treatment interruption, because of finerenone’s shorter half-life and lack of active metabolites (Table 1).
      • Agarwal R.
      • Kolkhof P.
      • Bakris G.
      • et al.
      Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
      ,
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      ,
      • Pitt B.
      • Kober L.
      • Ponikowski P.
      • et al.
      Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
      Although studies with patiromer suggest that it might allow long-term optimization of RAAS inhibition therapy in patients at risk of hyperkalemia (eg, CKD and/or HF),
      • Palmer B.F.
      • Carrero J.J.
      • Clegg D.J.
      • et al.
      Clinical management of hyperkalemia.
      large, event-driven studies with it or sodium zirconium cyclosilicate are being conducted (STABILIZE-CKD, ClinicalTrials.gov identifier: NCT05056727; OPRA-HF, ClinicalTrials.gov identifier: NCT04789239).

      Future Perspective: Combination Therapies to Reduce the Risk of CKD and/or CVD

      When associated with cardiorenal complications, treatment of DM requires a comprehensive strategy.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      Although an ACEi/ARB has been generally recommended as standard therapy for the treatment of DM plus hypertension and/or albuminuria,
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      ,

      Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248. Published correction appears in J Am Coll Cardiol. 2018;71(19):2275-2279.

      there is lesser consensus for the optimal second- or third-line agents for preventing CKD progression.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      ,
      • Ku E.
      • Lee B.J.
      • Wei J.
      • Weir M.R.
      Hypertension in CKD: core curriculum 2019.
      • Bashier A.
      • Bin Hussain A.
      • Abdelgadir E.
      • Alawadi F.
      • Sabbour H.
      • Chilton R.
      Consensus recommendations for management of patients with type 2 diabetes mellitus and cardiovascular diseases.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022.
      SGLT-2is, glucose-lowering agents, have emerged as first-line treatment for patients with T2DM and CKD, with not only blood glucose-lowering benefits, but also reno-protective and cardio-protective effects without elevating hyperkalemia risk.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      ,
      • Ni L.
      • Yuan C.
      • Chen G.
      • Zhang C.
      • Wu X.
      SGLT2i: beyond the glucose-lowering effect.
      • Pirklbauer M.
      Anti-inflammatory potential of empagliflozin.
      • Yavin Y.
      • Mansfield T.A.
      • Ptaszynska A.
      • Johnsson K.
      • Parikh S.
      • Johnsson E.
      Effect of the SGLT2 inhibitor dapagliflozin on potassium levels in patients with type 2 diabetes mellitus: a pooled analysis.

      Butler J, Usman MS, Khan MS, et al. Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta-analysis. ESC Heart Fail. 2020;7(6):3298-3309. Published correction appears in ESC Heart Fail. 2021;8(3):2362.

      The American Diabetes Association guidelines recommend SGLT-2is for patients with T2DM and CKD to reduce CKD progression and CV risk. Finerenone is recommended for patients who are at increased risk of CV events or CKD progression or are unable to use an SGLT-2i.
      • Draznin B.
      • Aroda V.R.
      • Bakris G.
      • et al.
      American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022.
      GLP-1 RAs, glucose-lowering agents, are recommended in the KDIGO 2020 guidelines for patients with CKD and T2DM who fail to achieve glycemic targets despite the use of metformin and SGLT-2is or who are unable to use either drug type.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      GLP-1 RAs offer both CV and renal benefits, including reducing BP and albuminuria as well as slowing the rate of eGFR decline. Therefore, they are also recommended as a first-line therapy with SGLT-2is in patients with T2D and CVD
      • Grant P.J.
      • Cosentino F.
      The 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: new features and the ‘Ten Commandments’ of the 2019 Guidelines are discussed by Professor Peter J. Grant and Professor Francesco Cosentino, the Task Force chairmen.
      and as a second-line therapy in patients with T2D and CKD.
      Kidney Disease: Improving Global Outcomes Diabetes Work Group
      KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
      Because targets of SGLT-2is and GLP-1 RAs are different from those of RAAS blockade, a combination treatment strategy using a nonsteroidal MRA and an SGLT-2i may bring an additive or synergistic effect to renal and CV outcomes. For SGLT-2is, recent data from an open-label, crossover trial in patients with CKD suggested that the combination of dapagliflozin and eplerenone robustly lowered albuminuria with a lower frequency of hyperkalemia events than eplerenone alone.
      • Provenzano M.
      • Puchades M.J.
      • Garofalo C.
      • et al.
      Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized crossover clinical trial.
      A subgroup analysis of FIDELIO-DKD suggested that there may be a clinically relevant improvement in albuminuria by combining finerenone with an SGLT-2i (Table 4).

      Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. Published correction appears in Eur Heart J. 2022;43(20):1989.

      ,
      • Rossing P.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy.
      Table 4 also shows the results of a prespecified subgroup analysis of CV outcomes in patients receiving SGLT-2i versus no SGLT-2i at baseline plus finerenone or placebo in the FIDELITY study (pooled analysis of FIDELIO-DKD and FIGARO-DKD).

      Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. Published correction appears in Eur Heart J. 2022;43(20):1989.

      In the Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure study (DAPA-HF, ClinicalTrials.gov identifier: NCT03036124), patients with HFrEF treated with an MRA and dapagliflozin had significantly reduced risk of moderate-to-severe hyperkalemia compared with an MRA alone, suggesting that SGLT-2is help with limiting hyperkalemia linked to MRA use.
      • Kristensen S.L.
      • Docherty K.F.
      • Jhund P.S.
      • et al.
      Dapagliflozin reduces the risk of hyperkalaemia in patients with heart failure and reduced ejection fraction: a secondary analysis DAPA-HF.
      Indeed, results from a subgroup analysis based on patients who received finerenone with an SGLT-2i at baseline, accounting for about 5% of patients in the FIDELIO-DKD study, showed a 55% lower risk of hyperkalemia vs the overall group (HR, 0.45; 95% CI, 0.27-0.75), suggesting the potential benefit of a synergistic effect and fixed-dose combination.

      Agarwal R, Wilson D, Joseph A, et al. Incidence and predictors of hyperkalemia in patients with CKD and T2D in the FIDELIO-DKD trial. Presented at: ISN World Congress of Nephrology; April 15-19, 2021: Virtual.

      It should be noted, however, that when analyses were conducted for patients who received an SGLT-2i at any time during the trial, no significant difference in the risk of hyperkalemia was observed.
      • Rossing P.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy.
      For GLP-1 RA, although no randomized trials have been performed in combination with nonsteroidal MRAs, results from a recent preclinical study suggest that combination treatment with potassium canrenoate, a steroidal MRA, does not demonstrate any beneficial effects in animals with HF.
      • Demkes E.J.
      • Wenker S.
      • Silvis M.J.M.
      • et al.
      Neutral effects of combined treatment with GLP-1R agonist exenatide and MR antagonist potassium canrenoate on cardiac function in porcine and murine chronic heart failure models.
      A further subgroup analysis from FIDELIO-DKD demonstrated no additional benefit of GLP-1 RA use for the primary renal or secondary CV outcome in patients treated with finerenone.
      • Rossing P.
      • Agarwal R.
      • Anker S.D.
      • et al.
      Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: a subgroup analysis from the FIDELIO-DKD trial.
      Table 4Subanalyses of Phase 3 Studies Investigating CV and Renal Outcomes in Patients With T2DM and CKD Treated With Finerenone or Placebo With or Without an SGLT-2i at Baseline.
      StudyNRenal outcomes, finerenone versus placebo HR (95% CI)CV outcomes, finerenone versus placebo HR (95% CI)
      FIDELIO-DKD
      • Rossing P.
      • Filippatos G.
      • Agarwal R.
      • et al.
      Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy.
      5674

      SGLT-2i: 259

      No SGLT-2i: 5415
      Primary composite outcome:
      Kidney failure, a sustained decrease of ≥40% in eGFR from baseline (for ≥4 wks), or renal death.


      SGLT-2i: 1.38 (0.61-3.10)

      No SGLT-2i: 0.82 (0.72-0.92)

      P=.21

      Secondary composite outcome:
      Kidney failure, a sustained decrease of ≥57% in eGFR from baseline (for ≥4 wks), or renal death.


      SGLT-2i: 0.50 (0.12-1.99)

      No SGLT-2i: 0.77 (0.65-0.91)

      P=.54
      Composite outcome:
      Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.


      SGLT-2i: 1.12 (0.55-2.30)

      No SGLT-2i: 0.85 (0.74-0.98)

      P=.46
      FIDELITY

      Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. Published correction appears in Eur Heart J. 2022;43(20):1989.

      13,026

      SGLT-2i: 877

      No SGLT-2i: 12,149
      NRComposite outcome:
      Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.


      SGLT-2i: 0.63 (0.40-<1.00)

      No SGLT-2i: 0.87 (0.79-0.96)

      P=.41
      P-values for SGLT-2i use at baseline-by-treatment interaction are shown.
      CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; FIDELIO-DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; NR, not reported; SGLT-2i, sodium-glucose cotransporter 2 inhibitor; T2DM, type 2 diabetes mellitus.
      a Kidney failure, a sustained decrease of ≥40% in eGFR from baseline (for ≥4 wks), or renal death.
      b Kidney failure, a sustained decrease of ≥57% in eGFR from baseline (for ≥4 wks), or renal death.
      c Cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
      To further elucidate the additional benefits of SGLT-2is with nonsteroidal MRAs on CKD associated with T2DM, the ongoing phase 2 CONFIDENCE study (ClinicalTrials.gov identifier: NCT05254002) will investigate the efficacy and safety of finerenone plus the SGLT-2i empagliflozin, versus finerenone, or empagliflozin alone in patients with T2DM and CKD. Finerenone effect in nondiabetic CKD is also being investigated in FIND-CKD (ClinicalTrials.gov identifier: NCT05047263), an ongoing phase 3 study of finerenone efficacy and safety (vs placebo) in nondiabetic patients with CKD.
      The ongoing phase 2 MIRACLE study (ClinicalTrials.gov identifier: NCT04595370) will assess the efficacy, safety, and tolerability of the selective MR modulator AZD9977 plus the SGLT-2i dapagliflozin in patients with HF (with LVEF <60%) and CKD. In addition, 2 studies are evaluating the effects of a novel nonsteroidal MRA (KBP-5074) and a novel aldosterone antagonist (CIN-107) to treat uncontrolled hypertension in patients with CKD—Clarion-CKD (ClinicalTrials.gov identifier: NCT04968184), a phase 3 study of KBP-5074 in patients with severe/moderate CKD (vs placebo) and a phase 2 study of CIN-107 (vs placebo) (ClinicalTrials.gov identifier: NCT05432167).

      Conclusion

      In 2017, Kolkhof and Bärfacker
      • Kolkhof P.
      • Bärfacker L.
      30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
      summarized 60 years of MRA research with 3 major waves: (1) identification, shortly after the isolation of aldosterone, of spironolactone as the first MRA in the 1950s; (2) identification of receptor-specific steroidal MRAs like eplerenone in the late 1980s; and (3) identification of novel nonsteroidal MRAs with safety and efficacy for a broader spectrum of diseases than steroidal MRAs since 2010. Over the past 10 years, remarkable progress has been made in the preclinical and clinical characterization of nonsteroidal MRAs, including finerenone, which demonstrated clinical benefits for patients with T2DM, CKD, and CV risk in FIDELIO-DKD and FIGARO-DKD. Although more studies are necessary, other nonsteroidal MRAs, including KBP5074, apararenone, and esaxerenone, may also be beneficial for patients with CKD. Further clinical studies will help determine the efficacy of nonsteroidal MRAs in combination with SGLT-2is, GLP-1 RAs, and/or potassium binders in patients with T2DM and CKD. The application of nonsteroidal MRAs to other diseases, including nondiabetic CKD and HF, also awaits evidence.

      Potential Competing Interests

      Dr Wish has served on advisory boards for AstraZeneca, Akebia, CSL Behring, Rockwell Medical, Otsuka, and Vifor Pharma; has been a consultant for FibroGen; has been on the speakers bureau for AstraZeneca and Akebia; and has received registration fee for 2021 European Renal Association Meeting supported by AstraZeneca. Dr Pergola has received research support and consulting fees from Akebia, Ardelyx, AstraZeneca, Bayer, Corvidia Therapeutics, FibroGen, Gilead Sciences, Otsuka, Reata Pharmaceuticals, Tricida, and Unicycive Therapeutics; reports ownership interest with Unicycive Therapeutics and has received research funding as principal investigator or sub-investigator on multiple clinical trials with his practice; has acted as scientific advisor or has membership with Ardelyx and Unicycive Therapeutics; and is on the speakers bureau for AstraZeneca.

      Acknowledgments

      Drs Wish and Pergola contributed equally to this article. Medical writing support was provided by Tomo Sawado, PhD, and John Bilbruck, PharmD, of the Alligent–Envision Pharma Group, and this was funded by Bayer Corporation . Envision Pharma Group’s services complied with international guidelines for Good Publication Practice (GPP3).

      Supplemental Online Material

      References

        • International Diabetes Federation
        IDF Diabetes Atlas.
        9th ed. International Diabetes Federation, 2019
      1. Amorim RG, Guedes GDS, Vasconcelos SML, Santos JCF. Kidney disease in diabetes mellitus: cross-linking between hyperglycemia, redox imbalance and inflammation. Arq Bras Cardiol. 2019;112(5):577-587. Published correction appears in 2019;113(1):182.

        • Elmarakby A.A.
        • Abdelsayed R.
        • Yao Liu J.
        • Mozaffari M.S.
        Inflammatory cytokines as predictive markers for early detection and progression of diabetic nephropathy.
        EPMA J. 2010; 1: 117-129
        • Yokoyama H.
        • Deckert T.
        Central role of TGF-beta in the pathogenesis of diabetic nephropathy and macrovascular complications: a hypothesis.
        Diabet Med. 1996; 13: 313-320
        • National Kidney Foundation
        KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update.
        Am J Kidney Dis. 2012; 60: 850-886
        • Thomas R.L.
        • Halim S.
        • Gurudas S.
        • Sivaprasad S.
        • Owens D.R.
        IDF Diabetes Atlas: a review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018.
        Diabetes Res Clin Pract. 2019; 157107840
        • Centers for Disease Control and Prevention
        Chronic Kidney Disease in the United States. Updated.
        • US Department of Health and Human Services
        Advancing American Kidney Health. Updated.
        • Dei Cas A.
        • Khan S.S.
        • Butler J.
        • et al.
        Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure.
        JACC Heart Fail. 2015; 3: 136-145
        • Fonarow G.C.
        • Abraham W.T.
        • Albert N.M.
        • et al.
        Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF.
        Arch Intern Med. 2008; 168: 847-854
        • Damman K.
        • Valente M.A.
        • Voors A.A.
        • O'Connor C.M.
        • van Veldhuisen D.J.
        • Hillege H.L.
        Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis.
        Eur Heart J. 2014; 35: 455-469
        • Löfman I.
        • Szummer K.
        • Hagerman I.
        • Dahlström U.
        • Lund L.H.
        • Jernberg T.
        Prevalence and prognostic impact of kidney disease on heart failure patients.
        Open Heart. 2016; 3e000324
        • United States Renal Data System
        USRDS Annual Data Report: Epidemiology of kidney disease in the United States. 2020.
        National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2020
        https://adr.usrds.org/2020/
        Date accessed: October 6, 2022
        • Kidney Disease: Improving Global Outcomes Diabetes Work Group
        KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease.
        Kidney Int. 2020; 98 (S1-S115)
        • Kolkhof P.
        • Joseph A.
        • Kintscher U.
        Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - new perspectives for combination therapy.
        Pharmacol Res. 2021; 172105859
        • Rossier B.C.
        • Baker M.E.
        • Studer R.A.
        Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited.
        Physiol Rev. 2015; 95: 297-340
        • Hayashi M.
        • Tsutamoto T.
        • Wada A.
        • et al.
        Relationship between transcardiac extraction of aldosterone and left ventricular remodeling in patients with first acute myocardial infarction: extracting aldosterone through the heart promotes ventricular remodeling after acute myocardial infarction.
        J Am Coll Cardiol. 2001; 38: 1375-1382
        • Mizuno Y.
        • Yoshimura M.
        • Yasue H.
        • et al.
        Aldosterone production is activated in failing ventricle in humans.
        Circulation. 2001; 103: 72-77
        • Yamamoto N.
        • Yasue H.
        • Mizuno Y.
        • et al.
        Aldosterone is produced from ventricles in patients with essential hypertension.
        Hypertension. 2002; 39: 958-962
        • He B.J.
        • Anderson M.E.
        Aldosterone and cardiovascular disease: the heart of the matter.
        Trends Endocrinol Metab. 2013; 24: 21-30
        • Taves M.D.
        • Gomez-Sanchez C.E.
        • Soma K.K.
        Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function.
        Am J Physiol Endocrinol Metab. 2011; 301: E11-E24
        • Jaisser F.
        • Farman N.
        Emerging roles of the mineralocorticoid receptor in pathology: Toward new paradigms in clinical pharmacology.
        Pharmacol Rev. 2016; 68: 49-75
        • Palmer B.F.
        Regulation of potassium homeostasis.
        Clin J Am Soc Nephrol. 2015; 10: 1050-1060
        • Palmer B.F.
        • Clegg D.J.
        Extrarenal effects of aldosterone on potassium homeostasis.
        Kidney360. 2022; 3: 561-568
        • Bandak G.
        • Sang Y.
        • Gasparini A.
        • et al.
        Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
        J Am Heart Assoc. 2017; 6e005428
        • DeFronzo R.A.
        Hyperkalemia and hyporeninemic hypoaldosteronism.
        Kidney Int. 1980; 17: 118-134
        • Agarwal R.
        • Kolkhof P.
        • Bakris G.
        • et al.
        Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.
        Eur Heart J. 2021; 42: 152-161
        • Viengchareun S.
        • Le Menuet D.
        • Martinerie L.
        • Munier M.
        • Pascual-Le Tallec L.
        • Lombès M.
        The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.
        Nucl Recept Signal. 2007; 5e012
        • Barrera-Chimal J.
        • Lima-Posada I.
        • Bakris G.L.
        • Jaisser F.
        Mineralocorticoid receptor antagonists in diabetic kidney disease—mechanistic and therapeutic effects.
        Nat Rev Nephrol. 2022; 18: 56-70
        • Berl T.
        • Katz F.H.
        • Henrich W.L.
        • de Torrente A.
        • Schrier R.W.
        Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure.
        Kidney Int. 1978; 14: 228-235
        • Hené R.J.
        • Boer P.
        • Koomans H.A.
        • Mees E.J.
        Plasma aldosterone concentrations in chronic renal disease.
        Kidney Int. 1982; 21: 98-101
        • Rocha R.
        • Chander P.N.
        • Zuckerman A.
        • Stier Jr., C.T.
        Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.
        Hypertension. 1999; 33: 232-237
        • Rocha R.
        • Stier Jr., C.T.
        • Kifor I.
        • et al.
        Aldosterone: a mediator of myocardial necrosis and renal arteriopathy.
        Endocrinology. 2000; 141: 3871-3878
        • Bauersachs J.
        • Jaisser F.
        • Toto R.
        Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases.
        Hypertension. 2015; 65: 257-263
      2. Zheng CM, Wang JY, Chen TT, et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blocker monotherapy retard deterioration of renal function in Taiwanese chronic kidney disease population. Sci Rep. 2019;9(1):2694. Published correction appears in Sci Rep. 2020;10(1):6631.Pubmed Partial Author articletitle

        • Bomback A.S.
        • Klemmer P.J.
        The incidence and implications of aldosterone breakthrough.
        Nat Clin Pract Nephrol. 2007; 3: 486-492
        • Schrier R.W.
        Aldosterone 'escape' vs 'breakthrough.
        Nat Rev Nephrol. 2010; 6: 61
        • Sato A.
        • Fukuda S.
        Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist.
        Hypertens Res. 2013; 36: 879-884
        • Schjoedt K.J.
        The renin-angiotensin-aldosterone system and its blockade in diabetic nephropathy: main focus on the role of aldosterone.
        Dan Med Bull. 2011; 58: B4265
      3. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. Published correction appears in N Engl J Med. 2014;158:A7255.

        • Imai E.
        • Chan J.C.
        • Ito S.
        • et al.
        Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study.
        Diabetologia. 2011; 54: 2978-2986
        • Yusuf S.
        • Teo K.K.
        • Pogue J.
        • et al.
        ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events.
        N Engl J Med. 2008; 358: 1547-1559
      4. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007;370(9583):221-229. Published correction appears in Lancet. 2007;370(9598):1542.

        • Villamil A.
        • Chrysant S.G.
        • Calhoun D.
        • et al.
        Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide.
        J Hypertens. 2007; 25: 217-226
        • Parving H.H.
        • Brenner B.M.
        • McMurray J.J.
        • et al.
        Cardiorenal end points in a trial of aliskiren for type 2 diabetes.
        N Engl J Med. 2012; 367: 2204-2213
        • Zheng S.L.
        • Roddick A.J.
        • Ayis S.
        Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: a systematic review and meta-analysis of 13,395 patients.
        Diab Vasc Dis Res. 2017; 14: 400-406
      5. American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: Standards of medical care in diabetes-2022. Diabetes Care. 2022;45(suppl 1):S144-S174. Published correction appears in Diabetes Care. 2022;45(5):1296.

        • Kolkhof P.
        • Bärfacker L.
        30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.
        J Endocrinol. 2017; 234: T125-T140
        • Pitt B.
        • Kober L.
        • Ponikowski P.
        • et al.
        Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
        Eur Heart J. 2013; 34: 2453-2463
      6. ALDACTONE (spironolactone). Prescribing Information. Pfizer.
        • Kolkhof P.
        • Borden S.A.
        Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.
        Mol Cell Endocrinol. 2012; 350: 310-317
        • Mann N.M.
        Gynecomastia during therapy with spironolactone.
        JAMA. 1963; 184: 778-780
        • Hughes B.R.
        • Cunliffe W.J.
        Tolerance of spironolactone.
        Br J Dermatol. 1988; 118: 687-691
        • Pitt B.
        • Filippatos G.
        • Gheorghiade M.
        • et al.
        Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.
        Eur J Heart Fail. 2012; 14: 668-675
        • Cook C.S.
        • Berry L.M.
        • Bible R.H.
        • Hribar J.D.
        • Hajdu E.
        • Liu N.W.
        Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans.
        Drug Metab Dispos. 2003; 31: 1448-1455
        • Bärfacker L.
        • Kuhl A.
        • Hillisch A.
        • et al.
        Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.
        ChemMedChem. 2012; 7: 1385-1403
        • Gerisch M.
        • Heinig R.
        • Engelen A.
        • et al.
        Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro.
        Drug Metab Dispos. 2018; 46: 1546-1555
        • Heinig R.
        • Kimmeskamp-Kirschbaum N.
        • Halabi A.
        • Lentini S.
        Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment.
        Clin Pharmacol Drug Dev. 2016; 5: 488-501
        • Amazit L.
        • Le Billan F.
        • Kolkhof P.
        • et al.
        Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1.
        J Biol Chem. 2015; 290: 21876-21889
        • Le Billan F.
        • Perrot J.
        • Carceller E.
        • et al.
        Antagonistic effects of finerenone and spironolactone on the aldosterone-regulated transcriptome of human kidney cells.
        FASEB J. 2021; 35e21314
        • Kolkhof P.
        • Delbeck M.
        • Kretschmer A.
        • et al.
        Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
        J Cardiovasc Pharmacol. 2014; 64: 69-78
        • Filippatos G.
        • Anker S.D.
        • Böhm M.
        • et al.
        A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
        Eur Heart J. 2016; 37: 2105-2114
        • Grune J.
        • Beyhoff N.
        • Smeir E.
        • et al.
        Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone's antifibrotic activity.
        Hypertension. 2018; 71: 599-608
        • Bakris G.L.
        • Agarwal R.
        • Anker S.D.
        • et al.
        Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.
        N Engl J Med. 2020; 383: 2219-2229
        • Pitt B.
        • Filippatos G.
        • Agarwal R.
        • et al.
        Cardiovascular events with finerenone in kidney disease and type 2 diabetes.
        N Engl J Med. 2021; 385: 2252-2263
        • Kintscher U.
        • Bakris G.L.
        • Kolkhof P.
        Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.
        Br J Pharmacol. 2022; 179: 3220-3234
        • Craft J.
        Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure.
        Proc (Bayl Univ Med Cent). 2004; 17: 217-220
        • Weinberger M.H.
        • Roniker B.
        • Krause S.L.
        • Weiss R.J.
        Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.
        Am J Hypertens. 2002; 15: 709-716
        • Corvol P.
        • Michaud A.
        • Menard J.
        • Freifeld M.
        • Mahoudeau J.
        Antiandrogenic effect of spirolactones: mechanism of action.
        Endocrinology. 1975; 97: 52-58
      7. Bramlage P, Swift SL, Thoenes M, Minguet J, Ferrero C, Schmieder RE. Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail. 2016;18(1):28-37. Published correction appears in Eur J Heart Fail. 2017;19(6):811.

        • Fagart J.
        • Hillisch A.
        • Huyet J.
        • et al.
        A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
        J Biol Chem. 2010; 285: 29932-29940
      8. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. Published correction appears in N Engl J Med. 2003;348(22):2271.

        • Pitt B.
        • Pedro Ferreira J.
        • Zannad F.
        Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives.
        Eur Heart J Cardiovasc Pharmacother. 2017; 3: 48-57
        • Chung E.Y.
        • Ruospo M.
        • Natale P.
        • et al.
        Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
        Cochrane Database Syst Rev. 2020; 10: CD007004
        • Navaneethan S.D.
        • Nigwekar S.U.
        • Sehgal A.R.
        • Strippoli G.F.M.
        Aldosterone antagonists for preventing the progression of chronic kidney disease.
        Cochrane Database Syst Rev. 2009; 3: CD007004
        • Bolignano D.
        • Palmer S.C.
        • Navaneethan S.D.
        • Strippoli G.F.M.
        Aldosterone antagonists for preventing the progression of chronic kidney disease.
        Cochrane Database Syst Rev. 2014; 4: CD007004
        • Mavrakanas T.A.
        • Gariani K.
        • Martin P.Y.
        Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review.
        Eur J Intern Med. 2014; 25: 173-176
        • Currie G.
        • Taylor A.H.
        • Fujita T.
        • et al.
        Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.
        BMC Nephrol. 2016; 17: 127
        • Sun L.J.
        • Sun Y.N.
        • Shan J.P.
        • Jiang G.R.
        Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy.
        J Diabetes Investig. 2017; 8: 609-618
        • Sueta D.
        • Yamamoto E.
        • Tsujita K.
        Mineralocorticoid receptor blockers: novel selective nonsteroidal mineralocorticoid receptor antagonists.
        Curr Hypertens Rep. 2020; 22: 21
        • Bakris G.
        • Pergola P.E.
        • Delgado B.
        • et al.
        Effect of KBP-5074 on blood pressure in advanced chronic kidney disease: results of the BLOCK-CKD study.
        Hypertension. 2021; 78: 74-81
        • Finerenone (Kerenida)
        Prescribing Information.
        Bayer HealthCare Pharmaceuticals Inc, 2021
        • Bakris G.L.
        • Agarwal R.
        • Chan J.C.
        • et al.
        Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.
        JAMA. 2015; 314: 884-894
        • Filippatos G.
        • Anker S.D.
        • Agarwal R.
        • et al.
        Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes.
        Circulation. 2021; 143: 540-552
        • Ruilope L.M.
        • Agarwal R.
        • Anker S.D.
        • et al.
        Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial.
        Am J Nephrol. 2019; 50: 345-356
        • Sato N.
        • Ajioka M.
        • Yamada T.
        • et al.
        A randomized controlled study of finerenone vs. eplerenone in Japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease.
        Circ J. 2016; 80: 1113-1122
        • Katayama S.
        • Yamada D.
        • Nakayama M.
        • et al.
        A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.
        J Diabetes Complications. 2017; 31: 758-765
        • Filippatos G.
        • Bakris G.L.
        • Pitt B.
        • et al.
        Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes.
        J Am Coll Cardiol. 2021; 78: 142-152
        • Filippatos G.
        • Anker S.D.
        • Agarwal R.
        • et al.
        Finerenone reduces risk of incident heart failure in patients with chronic kidney disease and type 2 diabetes: analyses from the FIGARO-DKD trial.
        Circulation. 2022; 145: 437-447
        • Schmiedek P.
        • Sadée W.
        • Baethmann A.
        Cerebral uptake of a 3 H-labelled spirolactone compound in the dog.
        Eur J Pharmacol. 1973; 21: 238-241
        • Gomez-Sanchez E.P.
        • Gomez-Sanchez C.E.
        Central regulation of blood pressure by the mineralocorticoid receptor.
        Mol Cell Endocrinol. 2012; 350: 289-298
        • Lattenist L.
        • Lechner S.M.
        • Messaoudi S.
        • et al.
        Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injury-mediated chronic kidney disease: role of oxidative stress.
        Hypertension. 2017; 69: 870-878
        • Barrera-Chimal J.
        • Estrela G.R.
        • Lechner S.M.
        • et al.
        The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling.
        Kidney Int. 2018; 93: 1344-1355
        • Agarwal R.
        • Anker S.D.
        • Bakris G.
        • et al.
        Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone.
        Nephrol Dial Transplant. 2022; 37: 1014-1023
        • Sridhar V.S.
        • Liu H.
        • Cherney D.Z.I.
        Finerenone-A new frontier in renin-angiotensin-aldosterone system inhibition in diabetic kidney disease.
        Am J Kidney Dis. 2021; 78: 309-311
      9. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. Published correction appears in Eur Heart J. 2022;43(20):1989.

        • Arai K.
        • Homma T.
        • Morikawa Y.
        • et al.
        Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.
        Eur J Pharmacol. 2015; 761: 226-234
        • Arai K.
        • Tsuruoka H.
        • Homma T.
        CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats.
        Eur J Pharmacol. 2015; 769: 266-273
        • Ito S.
        • Shikata K.
        • Nangaku M.
        • Okuda Y.
        • Sawanobori T.
        Efficacy and safety of esaxerenone (CS-3150) for the treatment of type 2 diabetes with microalbuminuria: a randomized, double-blind, placebo-controlled, phase II trial.
        Clin J Am Soc Nephrol. 2019; 14: 1161-1172
      10. Kikkawa K, Shirata N, Takakuwa M, et al. MT-3995, a novel non-steroidal mineralocorticoid receptor antagonist, has pharmacological profiles differentiated from eplerenone and spironolactone. Presented at: ASN Kidney Week; October 31-Nov 5, 2017; New Orleans, LA.

        • Wada T.
        • Inagaki M.
        • Yoshinari T.
        • et al.
        Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
        Clin Exp Nephrol. 2021; 25: 120-130
        • Chow C.P.
        • Liu J.R.
        • Tan X.J.
        • Huang Z.H.
        Pharmacological profile of KBP-5074, a novel nonsteroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases.
        J Drug Res Dev. 2017; 3: 1-9
        • Rossignol P.
        • Williams B.
        • Mayo M.R.
        • et al.
        Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): results in the pre-specified subgroup with heart failure.
        Eur J Heart Fail. 2020; 22: 1462-1471
        • Moura-Neto J.A.
        • Ronco C.
        The RALES legacy and finerenone use on CKD patients.
        Clin J Am Soc Nephrol. 2021; 16: 1432-1434
        • Palmer B.F.
        Potassium binders for hyperkalemia in chronic kidney disease-diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis.
        Mayo Clin Proc. 2020; 95: 339-354
        • Agarwal R.
        • Rossignol P.
        • Romero A.
        • et al.
        Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
        Lancet. 2019; 394: 1540-1550
        • Palmer B.F.
        • Carrero J.J.
        • Clegg D.J.
        • et al.
        Clinical management of hyperkalemia.
        Mayo Clin Proc. 2021; 96: 744-762
      11. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248. Published correction appears in J Am Coll Cardiol. 2018;71(19):2275-2279.

        • Ku E.
        • Lee B.J.
        • Wei J.
        • Weir M.R.
        Hypertension in CKD: core curriculum 2019.
        Am J Kidney Dis. 2019; 74: 120-131
        • Bashier A.
        • Bin Hussain A.
        • Abdelgadir E.
        • Alawadi F.
        • Sabbour H.
        • Chilton R.
        Consensus recommendations for management of patients with type 2 diabetes mellitus and cardiovascular diseases.
        Diabetol Metab Syndr. 2019; 11: 80
        • Draznin B.
        • Aroda V.R.
        • Bakris G.
        • et al.
        American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022.
        Diabetes Care. 2022; 45: S175-S184
        • Ni L.
        • Yuan C.
        • Chen G.
        • Zhang C.
        • Wu X.
        SGLT2i: beyond the glucose-lowering effect.
        Cardiovasc Diabetol. 2020; 19: 98
        • Pirklbauer M.
        Anti-inflammatory potential of empagliflozin.
        Inflammopharmacology. 2021; 29: 573-576
        • Yavin Y.
        • Mansfield T.A.
        • Ptaszynska A.
        • Johnsson K.
        • Parikh S.
        • Johnsson E.
        Effect of the SGLT2 inhibitor dapagliflozin on potassium levels in patients with type 2 diabetes mellitus: a pooled analysis.
        Diabetes Ther. 2016; 7: 125-137
      12. Butler J, Usman MS, Khan MS, et al. Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta-analysis. ESC Heart Fail. 2020;7(6):3298-3309. Published correction appears in ESC Heart Fail. 2021;8(3):2362.

        • Grant P.J.
        • Cosentino F.
        The 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: new features and the ‘Ten Commandments’ of the 2019 Guidelines are discussed by Professor Peter J. Grant and Professor Francesco Cosentino, the Task Force chairmen.
        Eur Heart J. 2019; 40: 3215-3217
        • Provenzano M.
        • Puchades M.J.
        • Garofalo C.
        • et al.
        Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized crossover clinical trial.
        J Am Soc Nephrol. 2022; 33: 1569-1580
        • Rossing P.
        • Filippatos G.
        • Agarwal R.
        • et al.
        Finerenone in predominantly advanced CKD and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy.
        Kidney Int Rep.