bay-94-8862 and Diabetes-Mellitus

Finerenone is a novel, non-steroidal mineralocorticoid receptor antagonist (MRAs) that has been investigated for the management of cardiorenal conditions. This article provides an overview of recent evidence of benefits on cardiovascular (CV) outcomes.. The recently published phase III FIDELIO-DKD and FIGARO-DKD, alone and pooled, in patients with CKD and diabetes demonstrate that finerenone reduces the composite of CV death, non-fatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure (HF) with hospitalization for HF being the primary driver of this composite. Finerenone is indicated to reduce renal and CV outcomes in patients with CKD and diabetes. Future investigations of this agent include patients with non-diabetic CKD, HF with preserved ejection fraction, and with the use of sodium-glucose transporter type 2 inhibitors.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

The purpose of this review is to provide an overview of recent preclinical and clinical studies, which demonstrate new insights for the treatment of diabetic kidney disease (DKD) and to outline future directions with respect to novel therapies.. Positive findings with respect to new glucose-lowering agents such as sodium-dependent glucose transporter 2 inhibitors may lead to a change in the way we treat diabetic individuals with or at risk of DKD. Additional positive phase 2 clinical studies with drugs that have hemodynamic actions such as endothelin antagonists and mineralocorticoid receptor antagonists have led to larger phase 3 trials with atrasentan and finerenone, respectively, in order to address if these drugs indeed delay the development of end-stage renal disease. A number of other pathways are currently under active preclinical investigation and hopefully over the next decade will lead to promising drug candidates for subsequent clinical trials.. DKD remains an area of active preclinical and clinical investigation. Positive results with some of the more promising agents should lead to strategies to reverse, attenuate or prevent DKD.

Topics: Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Atrasentan; Diabetes Mellitus; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Endothelin Receptor Antagonists; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Naphthyridines; Pyrrolidines; Renal Artery; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sympathectomy

Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.. Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Topics: Adult; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Hyperkalemia; Japan; Naphthyridines; Natriuretic Peptide, Brain; Patient Safety; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.

Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Humans; Mice; Mineralocorticoid Receptor Antagonists; Mitochondria; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Albuminuria; Diabetes Mellitus; Diabetic Nephropathies; Humans; Naphthyridines; Renin-Angiotensin System

Topics: Atrial Fibrillation; Diabetes Mellitus; Humans; Naphthyridines; Renal Insufficiency, Chronic