The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Peter Kolkhof - One of the best experts on this subject based on the ideXlab platform.
-
the novel non steroidal mr antagonist Finerenone improves metabolic parameters in high fat diet fed mice and activates brown adipose tissue via ampk atgl pathway
The FASEB Journal, 2020Co-Authors: Vincenzo Marzolla, Peter Kolkhof, Alessandra Feraco, Stefania Gorini, Caterina Mammi, Carmen Marrese, Valentina Mularoni, Carla Boitani, Marc Lombes, Maria Rosa CirioloAbstract:Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA Finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN-mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN-treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT-specific effect of FIN. Mechanistically, FIN increased activation of AMP-activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein-1 in brown adipocytes.
-
SAT-LB106 Metabolic and Brown Adipose Tissue-Specific Effects of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in a Mouse Model of Diet-Induced Obesity
Journal of the Endocrine Society, 2020Co-Authors: Vincenzo Marzolla, Peter Kolkhof, Alessandra Feraco, Stefania Gorini, Caterina Mammi, Carmen Marrese, Carla Boitani, Marc Lombes, Maria Rosa Ciriolo, Andrea ArmaniAbstract:Abstract In this work we studied the metabolic effects of the novel non-steroidal MR antagonist Finerenone (FIN) in mice fed a high-fat diet (HFD, 60% kcal as fat). We also investigated the signaling pathways underlying the beneficial metabolic effects of MR antagonism. After 3 months of HFD, mice treated with FIN showed an improvement of glucose tolerance compared to control mice as shown by intraperitoneal glucose tolerance tests. Despite this metabolic improvement, FIN-treated mice did not show a reduction in body weight compared to control mice. In order to elucidate the favourable effect of FIN on glucose tolerance we performed histological and molecular analyses at level of different adipose depots. We did not observe significant differences in classical white adipose depots (subcutaneous and visceral) between control and FIN-treated mice. Interestingly, interscapular brown adipose tissue (iBAT) of FIN-treated mice showed an increased multilocularity and a reduced size of lipid droplets, suggesting an iBAT-specific effect of FIN. We than analyzed mRNA and protein expression of uncoupling protein 1 (UCP-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PCG1-alpha), showing a significant increase of both markers at iBAT level in FIN-treated mice. Furthermore, leptin and adenylate cyclase 5 (Adyc5) (specific white adipose tissue markers) mRNA expression was reduced at level of iBAT in FIN-treated mice. Finally, we demonstrated that FIN-induced MR antagonism determined an increased activation of AMP-activated protein kinase (AMPK) which, in turn, stimulated adipose triglyceride lipase (ATGL) activity, with subsequent up-regulation of genes involved in fatty acids oxidation, tricarboxylic acid cycle and thermogenesis, in iBAT. In summary, our study shows that FIN protects from iBAT dysfunction and improves glucose tolerance in HFD-fed mice. Importantly, FIN effects on iBAT are mediated by a MR-AMPK-ATGL-UCP-1 signaling cascade. Therefore, MR antagonism by FIN in clinical settings might offer metabolic advantages, on top of its anti-fibrotic action, in multi-morbid cardiorenal patients.
-
population pharmacokinetic and exposure response analysis of Finerenone insights based on phase iib data and simulations to support dose selection for pivotal trials in type 2 diabetes with chronic kidney disease
Clinical Pharmacokinectics, 2020Co-Authors: Nelleke Snelder, Roland Heinig, Peter Kolkhof, Amer Joseph, Henk-jan Drenth, Jörg Lippert, Dirk Garmann, Bart Ploeger, Thomas EissingAbstract:Background Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease. Methods We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). Results The pharmacokinetics of Finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation. Conclusion Our dose-exposure-response modeling and simulation indicates effects were largely saturated at Finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.
-
Population Pharmacokinetic and Exposure–Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease
Clinical Pharmacokinetics, 2020Co-Authors: Nelleke Snelder, Roland Heinig, Peter Kolkhof, Amer Joseph, Henk-jan Drenth, Jörg Lippert, Dirk Garmann, Bart Ploeger, Thomas EissingAbstract:Background Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease. Methods We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668). Results The pharmacokinetics of Finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration–time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure–response. The concentration–effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic–pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2–3 h and steady state was achieved after 2 days, indicating timescale separation. Conclusion Our dose–exposure–response modeling and simulation indicates effects were largely saturated at Finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.
-
Finerenone reduces intrinsic arterial stiffness in munich wistar fromter rats a genetic model of chronic kidney disease
American Journal of Nephrology, 2020Co-Authors: Marta Gilortega, Peter Kolkhof, L M Ruilope, Raquel Gonzalezblazquez, Elena Vegamartin, Angela Schulz, Miriam Martinramos, Helena Pulidoolmo, Gema Ruizhurtado, Beatriz SomozaAbstract:Background: Development of albuminuria and arterial stiffness in Munich Wistar Fromter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity. Methods: Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks. Results: Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered β-index, a measure of intrinsic stiffness independent of geometry, in MWF (βMWF-FIN = 7.7 ± 0.4 vs. βMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in β-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C. Conclusion: FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria.
Faiez Zannad - One of the best experts on this subject based on the ideXlab platform.
-
a randomized controlled study of Finerenone vs eplerenone in patients with worsening chronic heart failure and diabetes mellitus and or chronic kidney disease
European Heart Journal, 2016Co-Authors: Gerasimos Filippatos, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist Finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily Finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg Finerenone groups, respectively ( P = 0.42–0.88). Except for the 2.5→5 mg Finerenone group, the composite clinical endpoint occurred numerically less frequently in Finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the Finerenone 10→20 mg group should be further explored in a large outcomes trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01807221&atom=%2Fehj%2F37%2F27%2F2105.atom
-
A randomized controlled study of Finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease
European Heart Journal, 2016Co-Authors: Gerasimos Filippatos, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist Finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily Finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg Finerenone groups, respectively ( P = 0.42–0.88). Except for the 2.5→5 mg Finerenone group, the composite clinical endpoint occurred numerically less frequently in Finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the Finerenone 10→20 mg group should be further explored in a large outcomes trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01807221&atom=%2Fehj%2F37%2F27%2F2105.atom
-
Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF)
European Journal of Heart Failure, 2015Co-Authors: Bertram Pitt, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Michael Boehm, Faiez ZannadAbstract:AimsTo investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist Finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. Methods and resultsThe MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7days of emergency presentation to hospital for worsening chronic HF to receive Finerenone (one of five doses in the range 2.5-20.0mg once daily) or eplerenone (25mg every second day to 50mg once daily for 90days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 902) of different oral doses of Finerenone compared with eplerenone. Other objectives are to assess the effects of Finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. Conclusions ARTS-HF is the first phase 2b clinical trial to investigate the effects of Finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.
-
rationale and design of mineralocorticoid receptor antagonist tolerability study heart failure arts hf a randomized study of Finerenone vs eplerenone in patients who have worsening chronic heart failure with diabetes and or chronic kidney disease
European Journal of Heart Failure, 2015Co-Authors: Bertram Pitt, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:AimsTo investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist Finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. Methods and resultsThe MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7days of emergency presentation to hospital for worsening chronic HF to receive Finerenone (one of five doses in the range 2.5-20.0mg once daily) or eplerenone (25mg every second day to 50mg once daily for 90days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 902) of different oral doses of Finerenone compared with eplerenone. Other objectives are to assess the effects of Finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. Conclusions ARTS-HF is the first phase 2b clinical trial to investigate the effects of Finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.
Frederic Jaisser - One of the best experts on this subject based on the ideXlab platform.
-
abstract p2022 the jak3 pathway is involved in the benefit of the mineralocorticoid receptor antagonist Finerenone in acute and chronic kidney injury following ischemia reperfusion
Hypertension, 2019Co-Authors: Frederic Jaisser, Peter Kolkhof, Gabriel R Estela, Jonatan BarrerachimalAbstract:Introduction: Mineralocorticoid receptor antagonists (MRA) prevent ischemic acute kidney injury (AKI) and its transition to chronic kidney disease (CKD). The specific contribution of interleukin-4 ...
-
short and long term administration of the non steroidal mineralocorticoid receptor antagonist Finerenone opposes metabolic syndrome related cardio renal dysfunction
Diabetes Obesity and Metabolism, 2018Co-Authors: Marianne Lachaux, Peter Kolkhof, Jonatan Barrerachimal, Lionel Nicol, Isabelle Remyjouet, Sylvanie Renet, Anais Dumesnil, Didier Wecker, Vincent Richard, Frederic JaisserAbstract:Aim: To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage. Materials and methods: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist Finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). Results: Long-term (90 days) Finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously , long-term Finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) Finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term Finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased. Conclusions: In rats with metabolic syndrome, the non-steroidal MR antagonist Finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/ increased NO bioavailability, as well as long-term effects, such as modifications in the myocar-dial structure. K E Y W O R D S animal pharmacology, cardiovascular disease, diabetes complications, drug development, experimental pharmacology, type 2 diabetes
-
Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.
Journal of Molecular and Cellular Cardiology, 2018Co-Authors: Benjamin Bonnard, Peter Kolkhof, Frederic Jaisser, Marie Pieronne-deperrois, Zoubir Djerada, Soumaya El-moghrabi, Antoine Ouvrard-pascaud, Paul Mulder, Smail MessaoudiAbstract:Abstract Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and Finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of Finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.
-
Short‐ and long‐term administration of the non‐steroidal mineralocorticoid receptor antagonist Finerenone opposes metabolic syndrome‐related cardio‐renal dysfunction
Diabetes Obesity and Metabolism, 2018Co-Authors: Marianne Lachaux, Peter Kolkhof, Jonatan Barrera-chimal, Lionel Nicol, Sylvanie Renet, Anais Dumesnil, Didier Wecker, Vincent Richard, Isabelle Remy-jouet, Frederic JaisserAbstract:Aim: To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage. Materials and methods: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist Finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). Results: Long-term (90 days) Finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously , long-term Finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) Finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term Finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased. Conclusions: In rats with metabolic syndrome, the non-steroidal MR antagonist Finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/ increased NO bioavailability, as well as long-term effects, such as modifications in the myocar-dial structure. K E Y W O R D S animal pharmacology, cardiovascular disease, diabetes complications, drug development, experimental pharmacology, type 2 diabetes
-
The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling
Kidney International, 2018Co-Authors: Jonatan Barrera-chimal, Peter Kolkhof, Sebastian M Lechner, Soumaya El Moghrabi, Gabriel R. Estrela, Sébastien Giraud, Shiem Kaaki, Thierry Hauet, Frederic JaisserAbstract:Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist Finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from Finerenone-treated or myeloid mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b + , F4/80 + , Ly6C high macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.
Adriaan A Voors - One of the best experts on this subject based on the ideXlab platform.
-
a randomized controlled study of Finerenone vs eplerenone in patients with worsening chronic heart failure and diabetes mellitus and or chronic kidney disease
European Heart Journal, 2016Co-Authors: Gerasimos Filippatos, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist Finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily Finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg Finerenone groups, respectively ( P = 0.42–0.88). Except for the 2.5→5 mg Finerenone group, the composite clinical endpoint occurred numerically less frequently in Finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the Finerenone 10→20 mg group should be further explored in a large outcomes trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01807221&atom=%2Fehj%2F37%2F27%2F2105.atom
-
A randomized controlled study of Finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease
European Heart Journal, 2016Co-Authors: Gerasimos Filippatos, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist Finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily Finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7–10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg Finerenone groups, respectively ( P = 0.42–0.88). Except for the 2.5→5 mg Finerenone group, the composite clinical endpoint occurred numerically less frequently in Finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. Conclusion Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the Finerenone 10→20 mg group should be further explored in a large outcomes trial. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01807221&atom=%2Fehj%2F37%2F27%2F2105.atom
-
Finerenone third generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease
Expert Opinion on Investigational Drugs, 2015Co-Authors: Elise Schutte, Ron T Gansevoort, Peter Van Der Meer, Adriaan A VoorsAbstract:Introduction: The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) 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 nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone.Areas covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of Finerenone.Expert opinion: The selectivity and greater binding affinity of Finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and...
-
Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF)
European Journal of Heart Failure, 2015Co-Authors: Bertram Pitt, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Michael Boehm, Faiez ZannadAbstract:AimsTo investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist Finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. Methods and resultsThe MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7days of emergency presentation to hospital for worsening chronic HF to receive Finerenone (one of five doses in the range 2.5-20.0mg once daily) or eplerenone (25mg every second day to 50mg once daily for 90days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 902) of different oral doses of Finerenone compared with eplerenone. Other objectives are to assess the effects of Finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. Conclusions ARTS-HF is the first phase 2b clinical trial to investigate the effects of Finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.
-
rationale and design of mineralocorticoid receptor antagonist tolerability study heart failure arts hf a randomized study of Finerenone vs eplerenone in patients who have worsening chronic heart failure with diabetes and or chronic kidney disease
European Journal of Heart Failure, 2015Co-Authors: Bertram Pitt, Michael Bohm, Stefan D. Anker, Mihai Gheorghiade, Lars Kober, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez ZannadAbstract:AimsTo investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist Finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. Methods and resultsThe MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7days of emergency presentation to hospital for worsening chronic HF to receive Finerenone (one of five doses in the range 2.5-20.0mg once daily) or eplerenone (25mg every second day to 50mg once daily for 90days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 902) of different oral doses of Finerenone compared with eplerenone. Other objectives are to assess the effects of Finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. Conclusions ARTS-HF is the first phase 2b clinical trial to investigate the effects of Finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.
Christina Nowack - One of the best experts on this subject based on the ideXlab platform.
-
design and baseline characteristics of the Finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial
American Journal of Nephrology, 2019Co-Authors: Peter Kolkhof, Christina Nowack, George L. Bakris, Rajiv Agarwal, Stefan D. Anker, Gerasimos Filippatos, Amer Joseph, L M Ruilope, Nicole MentenichAbstract:Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of Finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of Finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of Finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
-
Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
American Journal of Nephrology, 2019Co-Authors: Luis M. Ruilope, Peter Kolkhof, Christina Nowack, George L. Bakris, Rajiv Agarwal, Stefan D. Anker, Gerasimos Filippatos, Amer Joseph, Nicole Mentenich, Bertram PittAbstract:Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of Finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of Finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to
-
Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial.
American Journal of Nephrology, 2019Co-Authors: George L. Bakris, Peter Kolkhof, Christina Nowack, Rajiv Agarwal, Stefan D. Anker, Bertram Pitt, Luis M. Ruilope, Anna C. Ferreira, Patrick Schloemer, Gerasimos FilippatosAbstract:Background: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of Finerenone on renal and CV outcomes has not been investigated in long-term trials yet. Methods: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial aims to assess the efficacy and safety of Finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25–
-
design and baseline characteristics of the Finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial
American Journal of Nephrology, 2019Co-Authors: George L. Bakris, Peter Kolkhof, Christina Nowack, Rajiv Agarwal, Stefan D. Anker, Bertram Pitt, Luis M. Ruilope, Anna C. Ferreira, Patrick Schloemer, Gerasimos FilippatosAbstract:Background: Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of Finerenone on renal and CV outcomes has not been investigated in long-term trials yet. Methods: The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial aims to assess the efficacy and safety of Finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25–<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30–≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. Conclusion: FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of Finerenone to their treatment regimen.
-
a randomized controlled study of Finerenone versus placebo in japanese patients with type 2 diabetes mellitus and diabetic nephropathy
Journal of Diabetes and Its Complications, 2017Co-Authors: Shigehiro Katayama, Peter Kolkhof, Daishiro Yamada, Mikihiro Nakayama, Takashi Yamada, Masafumi Myoishi, Masaharu Kato, Christina Nowack, Yoshimitsu YamasakiAbstract:Abstract Aims Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of Finerenone (1.25–20 mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. Methods ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. Results Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of Finerenone. The UACR at day 90 relative to baseline for each Finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the Finerenone treatment groups (0.025–0.167 mmol/L) compared with the placebo group (− 0.075 mmol/L); no patients developed hyperkalemia. Conclusion When given in addition to a RAS inhibitor, Finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.