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 (1.25-20mg) 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 (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/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.
Subject(s)
Albuminuria/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/drug therapy , Kidney/drug effects , Mineralocorticoid Receptor Antagonists/therapeutic use , Naphthyridines/therapeutic use , Renal Insufficiency/drug therapy , Aged , Albuminuria/etiology , Biomarkers/blood , Biomarkers/urine , Diabetic Nephropathies/blood , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/urine , Disease Progression , Dose-Response Relationship, Drug , Double-Blind Method , Drug Therapy, Combination/adverse effects , Female , Follow-Up Studies , Glomerular Filtration Rate/drug effects , Humans , Japan , Kidney/physiopathology , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/adverse effects , Naphthyridines/administration & dosage , Naphthyridines/adverse effects , Renal Insufficiency/complications , Renal Insufficiency/metabolism , Renal Insufficiency/physiopathology , Renin-Angiotensin System/drug effects , Reproducibility of ResultsABSTRACT
Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 +/- 1.6%, low dose (100 IU/kg): 22.1 +/- 2.4%, control: 40.0 +/- 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.