Chapter 7 1 Finerenone: Third Generation Mineralocorticoid Receptor Antagonist 2 for the Treatment of Heart Failure and Diabetic Kidney Disease 3

University of Groningen

Novel therapies in heart failure Liu, Licette Cécile Yang

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2016

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Liu, L. C. Y. (2016). Novel therapies in heart failure. Rijksuniversiteit Groningen.

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 24-09-2021 PART III Drug Evaluations of Novel Drugs for the Treatment of Heart Failure with Reduced Ejection Fraction

Finerenone in Heart Failure and Diabetic Kidney Disease ○ 179 Chapter 7 1 Finerenone: Third Generation Mineralocorticoid Receptor Antagonist 2 for the Treatment of Heart Failure and Diabetic Kidney Disease 3

Licette C.Y Liu, Elise Schutte, Ron T. Gansevoort, Peter van der Meer, 8 and Adriaan A. Voors

Expert Opinion on Investigational Drugs 2015;24(8):1123-35 Abstract

Introduction The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel non-steroidal MRA, with higher selectivity towards the mineralocorticoid receptor compared to spironolactone and stronger mineralocorticoid receptor binding affinity than eplerenone.

Areas This paper will discuss the chemistry, pharmacokinetics, clinical efficacy covered and safety of finerenone.

Expert The selectivity and greater binding affinity of finerenone to the opinion mineralocorticoid receptor may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with heart failure and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease, and diabetic kidney disease showed promising results. Phase III trials will have to show whether finerenone might become the third generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease.

Key words Aldosterone, non-steroidal mineralocorticoid receptor antagonist, heart failure, chronic kidney disease, diabetic kidney disease, diabetic nephropathy, finerenone, BAY 94-8862 Finerenone in Heart Failure and Diabetic Kidney Disease ○ 181

Introduction

To date, only two steroidal compounds of mineralocortocoid receptor antagonists (MRAs) have been developed for therapeutic use. Spironolactone represents the first-generation MRA and was introduced in 1960.1 Spironolactone is highly potent, but is structurally similar to progesterone, thereby allowing sex-steroid receptor cross-reactivity. Its administration is therefore often accompanied with associated adverse effects such as gynecomastia, impotence and menstrual irregularities.2,3 The second-generation MRA, eplerenone, has improved selectivity, but showed a relatively low affinity.4,5 Despite the evidence for their benefit in two common diseases in developed countries which are closely interrelated - heart failure (HF) and chronic kidney disease (CKD),6-13 MRAs are under-used (Table 1).14-18 One would expect that these low numbers are owed to their characteristic side effects.3,19,20 However, the aftermath of the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) study demonstrated that eplerenone was at least as beneficial in high risk patients – including patients older than 75 years, patients with a history of diabetes mellitus, patients with renal dysfunction and hypotensive patients – as in the other patients, without an increase in risk of serious hyperkalemia or worsening renal function.21 In fact, the absolute reduction in mortality by eplerenone was even higher in high risk patients, compared to patients at low risk (4.1 vs 1.0 death per 100 patient-years).22 These results make it difficult to understand why MRAs remain under-utilized, as the concern of developing of hyperkalemia and worsening renal function seems unjust. These limitations have stimulated further research to a more cardioselective MRA with less renal side effects, resulting in the development of finerenone (BAY 94-8862).23 In this review, we discuss properties of finerenone and its possible use in HF and diabetic kidney disease. 7 Aldosterone and the mineralocortical receptor

One of the well-known actions of aldosterone is Na + reabsorption and K+ excretion in the distal nephron, in order to maintain electrolyte balance and volume homeostatis.24 Besides sodium retention, aldosterone also induces a variety of pathologic processes leading to inflammation, remodeling and fibrosis.25,26 Activation of the mineralocorticoid receptor (MR) by aldosterone may also have a direct vasoconstrictor effect of the vascular wall.27-29 Also, aldosterone has been shown to elicit direct renal tissue damage, resulting in increased proteinuria/albuminuria.30-33 Excessive levels of aldoste- 182 ○ Chapter 7

Drug summary Box Drug name Finerenone (BAY 94-8862) Stage of development Phase II Indication heart failure with mild/moderate chronic kidney dysfunction and diabetic kidney disease Mechanism of action Non-steroidal mineralocorticoid receptor antagonist Route of administration Oral Chemical structure

Pivotal trials Phase II randomized controlled trial in heart failure patients with mild/moderate chronic kidney dysfunction, consisting of two parts Part A: safety, tolerability and renal eff ects of oral fi nerenone (2.5, 5, 10 mg once daily) compared with placebo Part B: change in serum potassium after treatment with oral fi nerenone compared with placebo, and spironolactone (25 mg, 50 mg). In total 457 patients received study medication (part A: 65, part B: 392). 5 and 10 mg/ day fi nerenone decreased levels of BNP, NT-proBNP and albuminuria to at least in the same degree as spironolactone 25 or 50 mg/day, while the incidence of hyperkalemia and worsening renal function was lower compared with the spironolactone treated group.50

Phase IIb randomized controlled trial in patients with type 2 diabetes mellitus and a clinical diagnosis of DN who were receiving a RAS inhibitor In total 823 were randomized to oral fi nerenone 1.25 – 20 mg or placebo once daily. Treatment with fi nerenone resulted in a dose-dependent reduction of UACR at day 90, with signifi cant reductions in patients treated with fi nerenone 7.5 – 20 mg.87

rone, result in conditions as HF, hypertension and CKD,34-38 and inhibiting the activity of the renin-angiotensin-aldosterone system (RAAS) results in improved outcomes. However, treatment with angiotensin converting enzyme inhibitors (ACEi) or aldosterone receptor blockers (ARB) may not block the RAAS suffi ciently, as several studies demonstrated that patients treated with these agents still have high aldosterone levels.39-43 This ‘aldosterone breakthrough’ may contribute to the progression of renal and cardiovascular dysfunction.43-46 Patients experiencing aldosterone breakthrough during treatment with RAAS inhibiting agents may therefore benefi t from treatment with MRAs. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 183

Table 1 ○ Use of mineralocorticoid receptor antagonist in heart failure

Author, Acronym Period n Study Medication use at Medication use at Ref. Publication population admission (AHF)/ discharge Date baseline(CHF) Europe Nieminen et EHFS II 2004- 3580 Patients Beta-blockers: 43% Beta-blockers:61% 13 al., 2006 2005 hospitalized ACEi: 55% ACEi: 71% for AHF MRA: 28% MRA: 48% Maggioni et ESC-HF 2009- 5118 Patients AHF: AHF: 14 al., 2010 Pilot 2010 admitted for Beta-blockers: 62% Beta-blockers: 80% AHF, and ACEi/ARBs: 60% ACEi/ARBs:78 % patients with MRA: 33% MRA: 55% CHF CHF: Beta-blockers: 86.7% ACEi/ARBs: 88.5 % MRA: 43.7% United States Fonarow et. IMPROVE- 2005- 15381 Patients with CHF: 15 al., 2008 HF 2007 CHF Beta-blockers: 86% ACEi/ARBs: 80 % MRA: 36% Albert et al., GWTG-HF 2005- 43625 Patients with unknown Beta-blockers: 89.7% 16 2009 2007 AHF ACEi/ARBs: 89.0 % MRA: 32.5% Krantz et GWTG-HF 2009- 9474 Patients with Beta-blockers: 72.6% Beta-blockers: 94.6% 17 al.,2011 2010 AHF ACEi/ARBs: 65.3 % ACEi/ARBs: 92.9 % MRA: 15.6% MRA: 32.2% Abbreviations: ACEi: Angiotensin converting enzyme inhibitor; AHF: Acute heart failure; ARB: Angiotensin receptor blocker; CHF: Chronic heart failure; HF: Heart failure; MRA: Mineralocorticoid receptor antagonist.

Chemistry of finerenone

Ultra-high-throughput-screening revealed that 1.4-dihydropyridines possess MR antagonistic activity in vitro23 – an interesting observation as dihydropyridines (DHP) were known for their activity to antagonize L-type calcium channel (nifedipine, 7 nimodipine, amlodipine).23 DHP 1 was identified as a primary candidate, since the compound demonstrated promising selectivity over the glucocorticoid receptor (>20 fold), but also over the androgen and progesterone receptor. However, DHP 1 was associated with a low metabolic stability and a significant interaction with the L-type calcium channel, and was therefore further explored. The first step in success of the development of finerenone was achieved by replacement of the chromenone head group with a 4-cyano-2-methoxyphenyl moiety in the naphthyridene series, which can be considered as conformationally frozen bioisosteres of 1.4-DHP esters, resulting in the dihydronaphthyridine series.23 Chiral high performance liquid chromatography 184 ○ Chapter 7

resolution led to a more active enantiomer. Then a methyl group was introduced at C8, followed by replacement of the C3 cyano group by a primary amide. This final step led to a compound with greater potency and selectivity: finerenone. Finerenone is a

potent non-steroidal MRA with an half maximal inhibitory concentration (IC50) of 18 nM (spironolactone: 24 nM, eplerenone: 990 nM) with exceptional selectivity versus the glucocorticoid receptor, androgen receptor and progesterone receptor (> 500-fold).23 2+ 23 Finerenone demonstrated no L-type Ca channel activity (IC50 > 10 µM). The specific- ity was demonstrated as it showed no significant effects on 65 different enzymes and ion channels. In rats, finerenone has a low blood clearance and long half-life (0.014 L h-1kg-1 and 8.5 h).23 Compared with eplerenone, finerenone showed more natriuretic effects as it exhibits a three-to tenfold greater potency and higher efficacy.23

Pharmacodynamics

Similar to spironolactone and eplerenone, finerenone competitively antagonizes the MR. In rodents, finerenone showed both cardiac and renal protection (Table 2). Com- pared to eplerenone, finerenone resulted in more pronounced end organ protective activity reflected by higher dosages of eplerenone being needed to achieve similar effects.47,48 In healthy males, finerenone reversed the diminishing effect of fludocortisone on urinary sodium/potassium ratio and resulted in dose-dependent natriuresis compared to eplerenone 50 mg.49 In HF patients with mild-to-moderate CKD, finerenone dose-dependently increased serum aldosterone levels, but decreased Brain Natriuretic Peptide (BNP) and N- terminal prohormone of BNP (NT-proBNP) levels, and urinary albumin creatinine ratio. 50 Although treatment with finerenone resulted in a rise in potassium and a decrease in estimated glomerular filtration rate (eGFR), these changes were significantly smaller than in the spironolactone group (Figure 1).50

Pharmacokinetics

Finerenone is administrated as oral, immediate-release tablet. In healthy humans, the plasma half-life of finerenone is approximately 2 hours, which is lower than the half-lives of the active metabolites of spironolactone, and eplerenone (respectively >12 hours and 3-5 hours).4,49-55 Quantitative whole-body autoradiography of rodents Finerenone in Heart Failure and Diabetic Kidney Disease ○ 185

Figure 1 ○ Results from the ARTS-study A) Mean change from baseline in serum potassium concentration in patients receiving fi nerenone, placebo, or spironolactoneB ) Mean change from baseline in the estimated glomerular fi ltration rate in patients receiving fi nerenone, placebo, or spironolactone. Reprinted with permission from Oxford University Press. ARTS: Mineralocorticoid Receptor Antagonist Tolerability Study; b.i.d.: Twice daily; eGFR: Esti- mated glomerular fi ltration rate; q.d.: Once daily; SD: Standard deviation. 186 ○ Chapter 7

Table 2 ○ Pre-clinical finerenone studies

Author, Animal model Treatment arms n Results Ref. Publication Date Kolkhof Spontaneously Finerenone 12 per Finerenone resulted in reduction in mortality, 97 et al., hypertensive, stroke -10 mg/kg/day group compared to placebo. 2012 prone male rats on Eplerenone Finerenone reduced urinary/protein ratio, high salt diet -30 mg/kg/day compared to vehicle group (0.4 ± 0.03 vs. 1.99 Spironolactone ± 0.40), urinary osteopontin protein and mRNA -30mg/kg/day in kidneys, reduction of vascular, glomerular and Vehicle tubule-interstitial damage. No mortality benefit , nor reduction in osteopontin concentration and vascular, glomerular and tubule-interstitial damage were observed in eplerenone or spironolactone group. Kolkhof et Sprague-Dawley rat Finerenone 7-12 Finerenone reduced systolic blood pressure and 46, 47 al., 2014 hypertensive-driven - 0.1mg/kg/day per heart weight-to-body weight ratio, proBNP levels heart failure model -1 mg/kg/day group and resulted in a dose-dependent protection from Delbeck et (deoxycorticosterone -10 mg/kg/day structural heart injury. al., 201 acetate/salt model) Eplerenone Also, finerenone resulted in functional as well as (abstract) -30 mg/kg/day structural protection from kidney injury. Relative -100 mg/kg/day kidney weights were decreased and proteinuria Vehicle was dose-dependently reduced by treatment with finerenone. In addition, treatment with finerenone dose-dependently protected from glomerular, tubular and vascular damage, and reduced expression of remodeling marker genes PAI-1, MCP-1, OPN, MMP-2. More pronounced end organ protective activity was observed in finerenone treated rats compared to eplerenone treated rats. Kolkhof et Male Wistar rats with Finerenone 10-14 Finerenone improved left ventricular systolic 47, 98 al., 2014 heart failure induced -0.1 mg/kg/day per dysfunction in heart failure – terms of contractility by left anterior -0.3mg/kg/day group (dp/dtmax) and relaxation (dp/dtmin). Albrecht- descending coronary -1 mg/kg/day Finerenone reduced plasma pro-BNP levels. Kuepper artery ligation Eplerenone Osteopontin levels dose-dependently decreased et al., 2012 -100 mg/kg/day by finerenone. (abstract) Vehicle Abbreviations: MCP-1: Monocyte chemoattractant protein; MMP-2: Matrix metalloproteinase; OPN: Osteopon- tin; PAI-1: Plasminogen activator inhibitor-1; proBNP: Pro-brain natriuretic peptide.

revealed that finerenone is distributed equally into cardiac (4409 ug-eq/L) and renal tissue (3782 ug-eq/L). This is in contrast to spironolactone and eplerenone, which have respectively, a six-fold and three-fold higher renal drug concentration in comparison to cardiac concentrations.48,52,54 This unequal distribution may explain the pronounced pharmacologic effects of all steroidal MRAs in the kidneys in relation to the effects in the heart. Indeed, the doses of a steroidal MRA needed to induce natriuresis or renal electrolyte handling in rats, are actually lower than the doses needed to achieve cardiac protective effects – in terms of relative heart weight reduction and BNP reduction.56-59 Finerenone in Heart Failure and Diabetic Kidney Disease ○ 187

Clinical efficacy

Heart failure

In current HF guidelines, MRAs are recommended in all patients with HFrEF who are still symptomatic (New York Heart Association (NYHA) II-IV) despite treatment with diuretics, ACEi and beta-blockers.60 The Randomized Aldactone Evaluation Study (RALES) evaluated the effect of spironolactone versus placebo in severe symptomatic (NYHA III-IV) patients with chronic HF with reduced ejection fraction. RALES was the first trial to demonstrate mortality benefit of a MRA in HF patients.8 The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that treatment with eplerenone also resulted in improved outcomes in patients with acute myocardial infarction complicated by HF due to left ventricular dysfunction.13 This study was followed by EMPHASIS-HF.6 During EMPHASIS-HF, patients with NYHA II heart failure were randomly assigned to eplerenone (up to 50 mg daily) or placebo. The trial was terminated early due to distinct benefit of treatment with eplerenone after a median follow-up of 21 months. Despite recommendations of current guidelines, widespread prescription of these steroidal MRAs is limited. Several observational studies illustrate the under-use of MRA among HF patients (Table 1).14-18 In the largest observational study, only 32.5% of eligible patients received a MRA at hospital discharge, while 89.7% and 89.0% patients received beta-blockers and ACEi and ARB respectively. One would expect that the concern of hyperkalemia and renal dysfunction was the main reason of the modestly use of MRAs. However, inappropri- ate use was rare: 3.1% had at least a documented contraindication, serum creatinine level ≥ 3.0 mg/dL or greater, or a serum potassium level ≥ 6.0 mEq/L. The safety and tolerability of finerenone was recently investigated during the minerAlo- corticoid-Receptor Antagonist Tolerability Study (ARTS) in patients with chronic HF and mild/moderate CKD.50,61 A total of 457 patients were randomized to finerenone, placebo or spironolactone and received study drug for 4 weeks. Treatment with 5 and 10 mg 7 finerenone per day was associated with less increase of serum potassium and slower renal function decline, compared to spironolactone 25 or 50 mg per day, while the reduction in BNP, NT-proBNP levels and albuminuria were at least similar50 (Figure 2). Fol- lowing these positive outcomes, the MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was initiated (NCT01807221), investigating the effects of finerenone in patients with worsening chronic systolic HF and type 2 diabetes and/ or chronic kidney disease. In this phase IIb trial, the treatment effect of finerenone on NT-proBNP levels will be compared to eplerenone in patients with worsening chronic HF and either type II diabetes with or without CKD or chronic kidney disease alone. 188 ○ Chapter 7

Figure 2 ○ Change from baseline in serum BNP (A: median change), NT-proBNP (B: median change), UACR (C: geometric mean change), and serum aldosterone in the ARTS-study. BNP, Brain natriuretic peptide; IQR, inter-quartile range; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; UACR, urinary albumin:creatinine ratio. Reprinted with permission from Oxford University Press.b.i.d.: Twice daily; BNP: Brain natriuretic peptide; IQR: Interquartile range; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; q.d.: Once daily; UACR: Urinary albumin:creatinine ratio. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 189

Diabetic kidney disease

With the growing worldwide prevalence of diabetes mellitus, diabetic kidney disease is one of the common causes of CKD.62-64 RAAS activation, hypertension, hypergly- cemia, dyslipidemia and proteinuria are established risk factors for progression of diabetic kidney disease. There is accumulating evidence that aldosterone/MR signaling is involved in the development of renal injury, leading to glomerular and tubular sclerosis independent of angiotensin II.30,31 The precise mechanism is yet unknown. Aldosterone/MR signaling may have harmful effects on non-aldosterone-sensitive kidney cells, such as mesangial cells and renal fibroblast31-33, and may induce apopto- sis or alteration of adhesive capacity of podocytes, enhancing protein leakage.65-68 In addition, animal studies revealed that aldosterone is involved in renal inflammation, oxidative stress, fibrosis, and mesangial cell proliferation.69-72 ACEi, ARBs, and more recently renin inhibitors, are frequently used in these patients. However, full doses of these drugs slow down but do not stop renal function decline. MRAs have been recognized as a novel approach to slow down residual CKD progression.73-78 Several studies have investigated the additional renal protective effects of MRA on top of ACEi and/or ARB treatment in patients with diabetic kidney disease (Table 3). In both type 1 and 2 diabetes patients with diabetic kidney disease receiving either ACEi or an ARB, additive treatment with MRAs lowered urinary albumin/protein excretion by 30 to 60%.11,79-87 (e)GFR declined significantly in most studies shortly after start MRA treatment.11,82,83,85,86 Two of the longer term studies reported that eGFR stabilized after the first months of treatment,11,83 which may indicate that the initial fall in eGFR found in short term studies may be an acute and reversible hemodynamic effect on the kidney, similar to the effects known from ACEi and ARBs.88,89 It should be noted that there was substantial heterogeneity among the studies, not only in the type and dose of the MRA that was used, but also with respect to the choice for control treatment (placebo or ACEi or ACEi and ARB combination therapy). Furthermore, the results of these studies cannot easily be extrapolated to the treatment of the general diabetic population, as most studies were small, included high doses of MRAs and included 7 patients had in general preserved renal function (mean eGFR in all studies was >60 ml/min/1.73). Recently, preliminary results of the MinerAlocorticoid Receptor Antagonist Tolerability Study - Diabetic Nephropathy (ARTS-DN) study were presented, a large phase IIb trial including 823 type 2 diabetes patients with diabetic kidney disease defined as albuminuria of at least 30 mg/g and treated with a RAS blocker prior to the screening visit, which investigated the safety and efficacy of different oral doses of finerenone.87 Patients were randomized to receive either 90 day treatment with placebo, or 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg finerenone, on top of standard care 190 ○ Chapter 7

Table 3 ○ Clinical trials with mineralocorticoid receptor antagonists in diabetic kidney disease

Author, n Study Treatment arms Results Study Ref. Publication population duration Date Schjoedt et 20 Type 1 DM Crossover trial 30% reduction in albuminuria, no 2 x 2 months 79 al. 2005 with ACEi or ARB + significant difference in GFR, potassium spironolactone 25 mg and 24-hour ambulatory blood pressure vs placebo Rossing et al. 20 Type 2 DM Crossover trial 33% reduction in albuminuria, 6 mmHg 2 x 2 months 80 2005 with ACEi or ARB + reduction in systolic blood pressure, spironolactone 25 mg potassium increase of 0.3 mmol/L, no vs placebo significant difference in GFR. Schjoedt et 20 Type 1 and Crossover trial 32% reduction in albuminuria, 6 mmHg 2 x 2 months 81 al. 2006 type 2 DM with ACEi or ARB + reduction in systolic blood pressure, spironolactone 25 mg no significant difference in GFR and vs placebo potassium Epstein et al. 268 Type 2 DM Enalapril + placebo 42% and 50% reduction in albuminuria 3 months 82 2006 vs for eplerenone 50 and 100 mg enalapril + respectively, vs 9% reduction in the eplerenone 50 mg placebo group. No additional BP lowering vs effect of eplerenone. eGFR reduction enalapril + in eplerenone groups (-2 to -4 ml/ eplerenone 100 mg min/1.73m2) No difference in incidence of hyperkalemia between the three study groups. Van den 59 Type 2 DM ACEi or ARB + 41% reduction in albuminuria, 7 mmHg 1 year 11 Meiracker et Spironolactone 50 reduction in SBP, more eGFR decline al. 2006 mg vs placebo in the spironolactone group compared to placebo during the first 3 months of treatment, 0.5 mmol/L increase in serum potassium. Saklayen et 30 Type 2 DM Crossover trial, 57% reduction in proteinuria, 12 mmHg 7 months 83 al. 2008 ACEi or ARB + reduction in SBP, eGFR decreased 7 ml/ spironolactone 50 mg min/1.73m2 during the first 30 days of (first month 25 mg) treatment and was stable during the vs placebo remainder of the trial. Serum potassium increased 0.4 mEq/L Mehdi et al. 80 Type 1 and ACEi + losartan 100 34% reduction in albuminuria 1 year 84 2009 type 2 DM mg vs spironolactone (spironolactone compared to placebo), 25 mg vs vs placebo no difference in SBP and eGFR between the treatment arms. Serum potassium higher and more hyperkalemia in the active treatment arms compared to placebo Nielsen et al. 21 Type 1 DM Crossover trial, 60% reduction in albuminuria, GFR 4 months 85 2012 ACEi or ARB + decreased 6 ml/min/1.73m2 during spironolactone 25 mg the first 2 months of treatment with vs placebo spironolactone, no significant difference in SBP or increase in serum potassium, yet 6 patients experienced hyperkalemia on spironolactone Finerenone in Heart Failure and Diabetic Kidney Disease ○ 191

Table 3 ○ Clinical trials with mineralocorticoid receptor antagonists in diabetic kidney disease (continued)

Author, n Study Treatment arms Results Study Ref. Publication population duration Date Esteghamati 136 Type 2 DM Enalapril (30-40 mg) After 1 year: 53% reduction in albuminuria 1.5 years 86 et al. 2013 and losartan (50-100 vs 20% reduction in ACEi+ARB group, mg) vs losartan 7 mmHg decrease in SBP, eGFR decline (50-100 mg) and of 7 ml/min/1.73m2, serum potassium spironolactone 25 mg increase of 0.2 mEq/L, and 3 patients on spironolactone experiencing hyperkalemia. No hyperkalemia in the ACEi+ARB group Ruilope et al. 823 Type 2 DM ACEi or ARB + Dose-dependent reduction in albuminuria 3 months 87 2015 finerenone (7 doses of 21 to 38% in the dose range of ranging from 1.25 to finerenone 7.5 to 20 mg. 1.8% of patients 20 mg) vs placebo in the 7.5 to 20mg groups developed hyperkalemia. Abbreviations: ACEi: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; BP: Blood pressure; DM: Diabetes mellitus; eGFR: Estimated GFR; GFR: Glomerular filtration rate; SBP: Systolic blood pressure. which included a RAS blocker. Finerenone showed a dose-dependent reduction in the primary endpoint of UACR at day 90, with significant reductions in the finerenone 7.5 – 20 mg groups. The top of the dose response curve was reached at the dose of 20 mg, with a UACR decrease of 38%. Safety variables in this study were change in serum potassium, and incidence of hyperkalemia. Serum potassium increased by 0.11 mmol/L to 0.46 mmol/L in the 7.5 - 20 mg groups and hyperkalemia occurred in 1.8% in the patients treated with finerenone 7.5 – 20 mg. In conclusion, the ARTS-DN trial showed promising results, yet it must be noted that this was a study with short duration and the long-term effects of finerenone are to be investigated in a phase III study.

Safety and tolerability 7

Homeostasis of potassium is regulated by potassium excretion according to dietary intake and potassium distribution between intracellular and extracellular fluid com- partments.90 Under normal conditions, excessive intake of potassium does not lead to hyperkalemia, as the kidney, the primary organ of potassium excretion, is able to excrete a large amount of potassium.91 However, chronic kidney dysfunction can lead to impaired renal potassium secretion and patients suffering from CKD thus have a predisposition to a positive potassium balance, and are susceptible to develop hyperkalemia.92,93 Aldosterone stimulates the activity of both Na,K-ATPase and H,K- 192 ○ Chapter 7

ATPase, thereby promoting Na+ absorption and K+ secretion in the distal nephron.92,93 Hyperkalemia is therefore considered as one of the most important adverse effects of MRA therapy.94 Although the risk of serious hyperkalemia can be minimized by routine monitoring of potassium and renal function, with timely dose adjustment, physicians are not eager to prescribe these drugs in patients with renal dysfunction. Diabetic patients are considered to be even at higher risk for the development hyperkalemia due to insulin deficiency, hypertonity, and hyporeninemic hypoaldosteron- ism.95,96 In a proof-of-concept study and phase I study, finerenone was safe and well tolerated.49,61 In the ARTS study, HF patients with mild/moderate CKD treated with finerenone treated patients experienced a lower incidence of hyperkalemia (serum +K ≥ 5.8 mmol/L measured by central laboratory or serum K+ ≥ 5.2 mmol/L measured by local laboratory) compared with spironolactone (5.3% vs. 12.7%, P = 0.048) after day 29 ± 2 days of treatment.50 Figure 1 summarizes the increases in serum potassium between finerenone and spironolactone during the ARTS trial. To date, there are no direct comparisons on the incidence of hyperkalemia between finerenone and eplerenone in HF patients. Nevertheless, the numbers of incidence of increased potassium levels reported in previous studies may be used for observational comparison. In the RALES trial, serious hyperkalemia (serum K+ ≥ 6.0 mmol/L) occurred in 3.9% patients and hyperkalemia (serum K+ ≥ 5.5 mmol/L) occurred in 19% patients treated with spironolactone during a mean follow-up period of 24 month (versus 1.2% and 5.6% respectively in the placebo group).97 In the EPHESUS trial, serious hyperkalemia (serum K+ ≥ 6.0 mmol/L) occurred in 5.5% of patients after one year of treatment with eplerenone group (versus 3.9% in the placebo group).13 In the EMPHASIS trial, serious hyperkalemia (serum K+ > 6.0 mmol/L) occurred in 2.5% of patients and a serum potassium level > 5.5 mmol/L occurred in 11.8% patients treated with eplerenone after a median follow-up period of 21 months (versus 1.9% and 7.2% respectively in the placebo group).6 Thus, based on the numbers of the ARTS, EPHESUS and EMPHASIS trials, the incidence numbers of hyperkalemia were 5.3% for finerenone, 12.7% for spironolactone and 11.8% for eplerenone. These numbers may indicate that the incidence of hyperkalemia are lower with finerenone. It should be noted however, that the treatment duration was different between these studies. Furthermore, the incidence of hyperkalemia (serum potassium ≥5.6 mmol/L) in the ARTS-DN study was only 1.5%, and only one case of serum potassium ≥6.0 mmol/L was observed.87 These observations underscore the safety profile of finerenone. Previous studies describe that treatment with a MRA may induce worsening of renal function.6,98,98 In the ARTS trial, the incidence of renal failure was higher in the finerenone group compared with placebo (1.5% vs. 0%), while the incidence of renal impairment was lower (3.8% vs. 9.2%). Compared to spironolactone, the incidences of renal failure and renal impairment were lower in the finerenone group (1.5% vs. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 193

7.9%, and 3.8% vs. 28.6% respectively). Mean change in eGFR in finerenone and placebo treated patients in the ARTS-HF study are presented in Figure 1. Again, there are no direct comparisons between finerenone and eplerenone with respect to the risk of worsening renal function published. In the EPHESUS trial, eGFR declined gradually by 4.6 ± 0.9 mL/min/1.73m2 and 2.7 ± 0.9 mL/min/1.73m2 in the eplerenone and placebo groups.98 In the EMPHASIS trial, eGFR was reduced annually by 0.288 (95% CI -0.395 to -0.182) mL/min per 1.73 m2 in the eplerenone group and was reduced by 0.066 (95% CI -0.174 to -0.042) mL/min per 1.73 m2 in the placebo group.99 A >20% reduction of eGFR occurred in 30.1% of patients treated with eplerenone and in 24.4% of patients treated with placebo.99 A >30% reduction of eGFR occurred in 14.0% of patients treated with eplerenone and 16.1% of patients treated with placebo.99 At least in comparison with spironolactone, the incidence of worsening renal function is lower in patients treated with finerenone.

Conclusions

Finerenone, a non-steroidal MRA, could become the third generation MRA for the treatment of HF and diabetic kidney disease. The first results with finerenone are encouraging. MRAs improve prognosis in HF patients and attenuate progression of renal impairment in patients with CKD, but the risk of hyperkalemia and worsening renal function may limit prescriptions. Finerenone seems to exert the same beneficial effects, with lower risks of renal dysfunction and hyperkalemia, compared with spironolactone and eplerenone. The first large phase IIb study of finerenone in patients with diabetic kidney disease showed promising results with significant reduction of albuminuria and a low rate of hyperkalemia, and the results of a large phase IIb study in patients with HF are pending. 7

Expert opinion

The time-span of development of first to third generation MRA is remarkable. Since the introduction of first MRA in 1960, it took half a century to develop a MRA with improved potency and higher selectivity for the MR receptor. Compared to spironolactone and eplerenone, finerenone has a lower IC50 for the MR, indicating that finerenone is a stronger MR antagonist. Further, the magnitude of selectivity of finerenone versus other members of the oxo-steroid receptor family is higher compared to spironolac- 194 ○ Chapter 7

tone, suggesting that the risk of developing progestogenic and antiandrogenic related side effects during finerenone administration would be minimal. In addition, lower doses of finerenone were needed to achieve similar cardiorenal protective effects compared to both spironolactone and eplerenone. Although these observations illustrate improved potency, greater affinity and selectivity to the mineralocorticoid receptor of finerenone, it needs to be established whether these differences will translate into meaningful improvements in clinical outcome. Only a few animal studies have investigated the effects of finerenone. Interestingly, these pre-clinical studies demonstrated that finerenone is equally distributed in cardiac and renal tissues in animals, in contrast to spironolactone and eplerenone, which have higher renal concentrations than in the cardiac tissue.48 The lower concentration of finerenone in the kidney may be an explanation for the lower incidence of hyperkalemia in patients. To date, there are three clinical studies that have investigated the effects of finerenone in patients. The first two studies included patients with chronic HF and mild or moderate CKD (with/ without diabetes). One of these two studies, was published in 2013, and included 457 HF patients. The other study, including approximately 1060 HF patients, was recently completed, and results are now pending. The first results with finerenone are promising. However, it should be noted that both studies were phase II studies, and the primary endpoints were ‘soft’ endpoints (serum potassium, eGFR, albuminuria and NT-proBNP levels). The third study was the ARTS-DN trial including 823 type 2 diabetes patients with diabetic kidney disease. The primary endpoint was also a ‘soft’ endpoint (UACR). Although MRAs have been proven to be lifesaving, these drugs are under prescribed due to their adverse effects. The novel selective non-steroidal MRA finerenone may be an answer to the known disadvantages of current MRAs. The results in preclinical studies and phase I/II studies are positive, but need to be confirmed by further studies (phase III) investigating whether the beneficial effects of finerenone translate into improved clinical outcomes (e.g. death, hospitalizations, incidence of end-stage renal disease) in these patients. Hyperkalemia appears to be a feared adverse effect of MRA therapy. In addition to the relatively low incidence of hyperkalemia during treatment with finerenone compared to other MRAs, other therapies to avoid and/or treat hyperkalemia in patient with HF are currently being developed. Until recently, treatment of hyperkalemia with MRAs was limited to stopping or decreasing the dose of the MRA, or co-prescription of potassium loosing diuretics or potassium binding polymer resins. These resins in general have poor tolerability. Two novel potassium-binding medications (Patiromer and ZS-9) are currently being investigated and the first results are promising, with respect to potassium lowering as well as tolerability.100,101 It is therefore reassuring that in the near future the benefits of RAAS-blockage may become available to patients with a high risk of hyperkalemia, with on the one hand the availability of novel MRAs Finerenone in Heart Failure and Diabetic Kidney Disease ○ 195 with a lower risk of hyperkalemia and on the other hand better treatment options for incident hyperkalemia.

7 196 ○ Chapter 7

References

1. J.A. Cella RCT. Steroidal aldosterone blockers. II. J Org Chem. 1959;24: 1109‑19. 2. Greenblatt DJ, Koch-Weser J. Gynecomastia and impotence: Complications of spironolactone therapy. JAMA. 1973 Jan 1;223(1):82. 3. Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J. Antiandrogenic effect of spirolactones: Mechanism of action. Endocrinology. 1975 Jul;97(1): 52‑8. 4. Garthwaite SM, McMahon EG. The evolution of aldosterone antagonists. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):27‑31. 5. Hu X, Li S, McMahon EG, Lala DS, Rudolph AE. Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone. Mini Rev Med Chem. 2005 Aug;5(8): 709‑18. 6. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1): 11‑21. 7. Pitt B, White H, Nicolau J, Martinez F, Gheorghiade M, Aschermann M, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005 Aug 2;46(3): 425‑31. 8. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. randomized aldactone evaluation study investigators. N Engl J Med. 1999 Sep 2;341(10): 709‑17. 9. Ma TK, Szeto CC. Mineralocorticoid receptor antagonist for renal protection. Ren Fail. 2012;34(6): 810‑7. 10. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003 Jan;41(1):64‑8. 11. van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spirono- lactone in type 2 diabetic nephropathy: Effects on proteinuria, blood pressure and renal function. J Hypertens. 2006 Nov;24(11):2285‑92. 12. Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: An emerging paradigm in chronic kidney disease. Kidney Int. 2011 May;79(10): 1051‑60. 13. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309‑21. 14. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart failure survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population. Eur Heart J. 2006 Nov;27(22):2725‑36. 15. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, et al. EURObservational research programme: The heart failure pilot survey (ESC-HF pilot). Eur J Heart Fail. 2010 Oct;12(10): 1076‑84. 16. Fonarow GC, Yancy CW, Albert NM, Curtis AB, Stough WG, Gheorghiade M, et al. Heart failure care in the outpatient cardiology practice setting: Findings from IMPROVE HF. Circ Heart Fail. 2008 Jul; 1(2):98‑106. 17. Albert NM, Yancy CW, Liang L, Zhao X, Hernandez AF, Peterson ED, et al. Use of aldosterone antagonists in heart failure. JAMA. 2009 Oct 21;302(15):1658‑65. 18. Krantz MJ, Ambardekar AV, Kaltenbach L, Hernandez AF, Heidenreich PA, Fonarow GC, et al. Pat- terns and predictors of evidence-based medication continuation among hospitalized heart failure patients (from get with the guidelines-heart failure). Am J Cardiol. 2011 Jun 15;107(12):1818‑23. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 197

19. Samuel JL, Delcayre C. Heart failure: Aldosterone antagonists are underused by clinicians. Nat Rev Cardiol. 2010 Mar;7(3):125‑7. 20. Funder JW. Mineralocorticoid-receptor blockade, hypertension and heart failure. Nat Clin Pract Endocrinol Metab. 2005 Nov;1(1):4‑5. 21. Eschalier R, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: Analyses of the EMPHASIS-HF study subgroups (eplerenone in mild patients hospitalization and SurvIval study in heart failure). J Am Coll Cardiol. 2013 Oct 22;62(17): 1585‑93. 22. Collier TJ, Pocock SJ, McMurray JJ, Zannad F, Krum H, van Veldhuisen DJ, et al. The impact of eplerenone at different levels of risk in patients with systolic heart failure and mild symptoms: Insight from a novel risk score for prognosis derived from the EMPHASIS-HF trial. Eur Heart J. 2013 Sep;34(36):2823‑9. 23. Barfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Perez S, Heckroth H, et al. Discovery of BAY 94- 8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem. 2012 Aug;7(8):1385‑403. 24. Williams JS, Williams GH. 50th anniversary of aldosterone. J Clin Endocrinol Metab. 2003 Jun;88(6): 2364‑72. 25. Gilbert KC, Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):199‑204. 26. Nguyen Dinh Cat A, Jaisser F. Extrarenal effects of aldosterone. Curr Opin Nephrol Hypertens. 2012 Mar;21(2):147‑56. 27. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006 Mar;47(3): 312‑8. 28. Gunaruwan P, Schmitt M, Taylor J, Lee L, Struthers A, Frenneaux M. Lack of rapid aldosterone effects on forearm resistance vasculature in health. J Renin Angiotensin Aldosterone Syst. 2002 Jun; 3(2):123‑5. 29. Gunaruwan P, Schmitt M, Sharman J, Lee L, Struthers A, Frenneaux M. Effects of aldosterone on forearm vasculature in treated chronic heart failure. Am J Cardiol. 2005 Feb 1;95(3): 412‑4. 30. Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008 Aug;12(4): 233‑42. 31. Nishiyama A, Yao L, Fan Y, Kyaw M, Kataoka N, Hashimoto K, et al. Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability. Hypertension. 2005 Apr;45(4):710‑6. 32. Nagai Y, Miyata K, Sun GP, Rahman M, Kimura S, Miyatake A, et al. Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in rat renal fibroblasts. Hypertension. 2005 Oct;46(4):1039‑45. 7 33. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: Roles of oxidative stress and Sgk1. Hypertension. 2007 Feb;49(2): 355‑64. 34. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004 Jul 1;351(1): 33‑41. 35. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006 Dec 5; 48(11):2293‑300. 36. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002 Dec;40(6): 892‑6. 37. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001 Dec 6;345(23): 1689‑97. 198 ○ Chapter 7

38. Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, et al. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006 Jun 14;295(22): 2638‑45. 39. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy. Cardiovasc Drugs Ther. 1995 Feb;9(1):145‑9. 40. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981 Dec;91(3): 457‑65. 41. Sato A, Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens. 2003 Sep;16(9 Pt 1):781‑8. 42. Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Cabrini G, et al. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol. 2001 Jun 1;37(7): 1808‑12. 43. Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia. 2004 Nov;47(11): 1936‑9. 44. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003 Jan;41(1):64‑8. 45. Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res. 2001 Jan-Feb;29(1): 13‑21. 46. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007 Sep;3(9):486‑92. 47. Delbeck M, Kretschmer A, Kast R, Baerfacker L, Hartmann E, Schaefer S, et al. Cardiorenal protection by BAY 94-8862, a novel mineralocorticoid receptor antagonist in a preclinical model of hypertension and diastolic heart Failure (abstract). 48. Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Barfacker L, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014 Jul;64(1): 69‑78. 49. Lentini S, Kimmeskamp-Kirschbaum N, Wensing G, Heining R. BAY 94-8862 exerts a potent natriuretic effect in healthy male subjects pre-treated with fludrocortisone: Findings from a proof- of-concept study (abstract). 50. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, 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 Aug;34(31):2453‑63. 51. Overdiek HW, Hermens WA, Merkus FW. New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther. 1985 Oct;38(4):469‑74. 52. Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: Prospects for novel therapeutics. Mol Cell Endocrinol. 2012 Mar 24;350(2): 310‑7. 53. Cook CS, Berry LM, Bible RH, Hribar JD, Hajdu E, Liu NW. Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans. Drug Metab Dispos. 2003 Nov;31(11):1448‑55. 54. Review and evaluation of pharmacology and toxicology data INSPRA [Internet]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-437S002_Inspra_Pharmr.pdf. 55. Label information ALDACTONE [Internet]. Available from: http://www.accessdata.fda.gov/drug- satfda_docs/label/2014/012151s072lbl.pdf. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 199

56. Delyani JA, Robinson EL, Rudolph AE. Effect of a selective aldosterone receptor antagonist in myocardial infarction. Am J Physiol Heart Circ Physiol. 2001 Aug;281(2): H647‑54. 57. Fraccarollo D, Galuppo P, Hildemann S, Christ M, Ertl G, Bauersachs J. Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003 Nov 5; 42(9):1666‑73. 58. Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H1802‑10. 59. Brandish PE, Forest TW, Chen H, Gatto NT, Molon-Noblot S, Zwierzynski I, et al. Eplerenone de- creases inflammatory foci in spontaneously hypertensive rat hearts with minimal effects on blood pressure. J Cardiovasc Pharmacol. 2009 Jan;53(1): 44‑51. 60. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology. developed in collaboration with the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2012 Aug;14(8): 803‑69. 61. Pitt B, Filippatos G, Gheorghiade M, Kober L, Krum H, Ponikowski P, 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 Jun;14(6): 668‑75. 62. Park CW. Diabetic kidney disease: From epidemiology to clinical perspectives. Diabetes Metab J. 2014 Aug;38(4): 252‑60. 63. Fioretto P, Barzon I, Mauer M. Is diabetic nephropathy reversible? Diabetes Res Clin Pract. 2014 Jun;104(3):323‑8. 64. Adler S. Diabetic nephropathy: Linking histology, cell biology, and genetics. Kidney Int. 2004 Nov; 66(5):2095‑106. 65. Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T, Fujita T. Podocyte injury underlies the glo- merulopathy of dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension. 2006 Jun;47(6):1084‑93. 66. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: Roles of oxidative stress and Sgk1. Hypertension. 2007 Feb;49(2):355‑64. 67. Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: Implication in proteinuric kidney disease. Nat Med. 2008 Dec;14(12):1370‑6. 68. Mundel P, Reiser J. Proteinuria: An enzymatic disease of the podocyte? Kidney Int. 2010 Apr;77(7): 7 571‑80. 69. Briet M, Schiffrin EL. Aldosterone: Effects on the kidney and cardiovascular system. NatRev Nephrol. 2010 May;6(5):261‑73. 70. Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996 Aug 15;98(4):1063‑8. 71. Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, et al. Possible contributions of reac- tive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension. 2004 Apr;43(4):841‑8. 72. Ma J, Weisberg A, Griffin JP, Vaughan DE, Fogo AB, Brown NJ. Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 69(6):2006 Mar; 1064‑72. 200 ○ Chapter 7

73. Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006 May;17(5): 1362‑72. 74. Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, et al. Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats. Eur J Pharmacol. 2008 Jul 28;589(1-3):264‑71. 75. Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int. 2004 Oct;66(4): 1493‑502. 76. Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, et al. Mineralocor- ticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology. 2006 Nov;147(11):5363‑73. 77. Kang YS, Ko GJ, Lee MH, Song HK, Han SY, Han KH, et al. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dial Transplant. 2009 Jan;24(1):73‑84. 78. Mavrakanas TA, Cheva A, Kallaras K, Karkavelas G, Mironidou-Tzouveleki M. Effect of ramipril alone compared to ramipril with eplerenone on diabetic nephropathy in streptozocin-induced diabetic rats. Pharmacology. 2010;86(2): 85‑91. 79. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005 Dec;68(6): 2829‑36. 80. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: A randomized, double-masked, cross-over study. Diabetes Care. 2005 Sep;28(9):2106‑12. 81. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int. 2006 Aug;70(3): 536‑42. 82. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006 Sep;1(5): 940‑51. 83. Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: Results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med. 2008 Apr;56(4): 714‑9. 84. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009 Dec;20(12):2641‑50. 85. Nielsen SE, Persson F, Frandsen E, Sugaya T, Hess G, Zdunek D, et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: A randomized placebo-controlled crossover study. Diabet Med. 2012 Aug;29(8):e184‑90. 86. Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M. Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: A randomized clinical trial. Nephrol Dial Transplant. 2013 Nov;28(11): 2823‑33. 87. Ruilope LM, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of finerenone in patients with diabetic Nephropathy (abstract). World Congress of Nephrology 2015, March 13–17, 2015, Cape Town, South Africa. 2015;WCN15-0366. 88. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: Is this a cause for concern? Arch Intern Med. 2000 Mar 13;160(5): 685‑93. Finerenone in Heart Failure and Diabetic Kidney Disease ○ 201

89. Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011 Aug;80(3):282‑7. 90. Youn JH, McDonough AA. Recent advances in understanding integrative control of potassium homeostasis. Annu Rev Physiol. 2009;71:381‑401. 91. Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol. 2014 Nov; 10(11):653‑62. 92. Salem MM, Rosa RM, Batlle DC. Extrarenal potassium tolerance in chronic renal failure: Implica- tions for the treatment of acute hyperkalemia. Am J Kidney Dis. 1991 Oct;18(4): 421‑40. 93. van Ypersele de Strihou C. Potassium homeostasis in renal failure. Kidney Int. 1977 Jun;11(6): 491‑504. 94. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004 Aug 5;351(6): 543‑51. 95. Piotrowski DW. Mineralocorticoid receptor antagonists for the treatment of hypertension and diabetic nephropathy. J Med Chem. 2012 Sep 27;55(18):7957‑66. 96. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Diabetes mellitus and electrolyte disorders. World J Clin Cases. 2014 Oct 16;2(10):488‑96. 97. Vardeny O, Claggett B, Anand I, Rossignol P, Desai AS, Zannad F, et al. Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail. 2014 Jul;7(4):573‑9. 98. Rossignol P, Cleland JG, Bhandari S, Tala S, Gustafsson F, Fay R, et al. Determinants and conse- quences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: Insights from the eplerenone post-acute myocardial infarction heart failure efficacy and survival study. Circulation. 2012 Jan 17;125(2): 271‑9. 99. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: Results from the eplerenone in mild patients hospitalization and survival study in heart failure (EMPHASIS-HF). Circ Heart Fail. 2014 Jan;7(1):51‑8. 100. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015 Jan 15;372(3):211‑21. 101. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, et al. Sodium zirco- nium cyclosilicate in hyperkalemia. N Engl J Med. 2015 Jan 15;372(3): 222‑31. 7