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Eplerenone for Diabetic Proteinuria/Albuminuria & Finerenone too
  Download the PDF here
Download the PDF here
Download the PDF here
Download the PDF here
Selective Aldosterone Blockade with Eplerenone Reduces
Albuminuria in Patients with Type 2 Diabetes

Murray Epstein,* Gordon H. Williams, Myron Weinberger, Andrew Lewin, Scott Krause, Robin Mukherjee, Rajiv Patni, and Bruce Beckerman
*University of Miami School of Medicine, Miami, Florida; Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts; Indiana University School of Medicine, Indianapolis, Indiana; National Research Institute, Los Angeles, California; and Pfizer Inc., New York, New York
Previous studies have shown that the selective aldosterone blocker eplerenone, in doses of up to 200 mg/d, reducesalbuminuria in patients with type 2 diabetes. This study was conducted to ascertain whether lower doses of eplerenone (50or 100 mg/d) co-administered with the angiotensin-converting enzyme (ACE) inhibitor enalapril would produce a similarantialbuminuric effect while obviating the hyperkalemia observed previously. After open-label run-in with enalapril 20 mg/d,patients with diabetes and a urinary albumin:creatinine ratio (UACR) >50 mg/g were randomly assigned to receive enalaprilplus one of three double-blind daily treatments for 12 wk: placebo, eplerenone 50 mg (EPL50), or eplerenone 100 mg (EPL100).
After week 4, amlodipine 2.5 to 10 mg/d was allowed for BP control (systolic/diastolic BP < 130/80 mmHg). The primary studyend points were the percentage change from baseline at week 12 in UACR and the incidence of hyperkalemia. Secondary endpoints included percentage changes from baseline in UACR at weeks 4 and 8 and changes from baseline in systolic anddiastolic BP. Treatment with EPL50 or EPL100 but not placebo significantly reduced albuminuria from baseline. By week 12,UACR was reduced by 7.4% in the placebo group, by 41.0% in the EPL50 group, and by 48.4% in the EPL100 group (botheplerenone groups, P < 0.001 versus placebo). The incidences of sustained and severe hyperkalemia were not significantlydifferent in any of the three treatment arms and did not differ on the basis of quartile of estimated GFR (all NS). For thesecondary end points, both eplerenone treatment groups significantly reduced albuminuria from baseline as early as week 4(P < 0.001), whereas placebo treatment (including enalapril) did not result in any significant decreases in UACR. Systolic BPdecreased significantly in all treatment groups at all time points, but, generally, all treatment groups experienced similardecreases in BP. Co-administration of EPL50 or EPL100 with an ACE inhibitor as compared with an ACE inhibitor alonesignificantly reduces albuminuria in patients with diabetes without producing significant increases in hyperkalemia.
Clin J Am Soc Nephrol 1: 940–951, 2006
Effect of Finerenone on Albuminuria in Patients
With Diabetic Nephropathy
A Randomized Clinical Trial
George L. Bakris, MD; Rajiv Agarwal, MD; Juliana C. Chan, MD; Mark E. Cooper,MD, PhD; Ron T. Gansevoort, MD, PhD; Hermann Haller,MD, PhD; Giuseppe Remuzzi, MD; Peter Rossing, MD; Roland E. Schmieder, MD; Christina Nowack, MD; Peter Kolkhof, PhD; Amer Joseph, MBBS; Alexander Pieper, DiplStat; Nina Kimmeskamp-Kirschbaum, PhD; Luis M. Ruilope,MD, PhD; for the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group
IMPORTANCE Steroidal mineralocorticoid receptor antagonists, when added to arenin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidneydisease but may be underused because of a high risk of adverse events.
OBJECTIVE To evaluate the safety and efficacy of different oral doses of the non steroidalmineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetesand high or very high albuminuria who are receiving an angiotensin-converting enzymeinhibitor or an angiotensin receptor blocker.
DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled,parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June2013 to February 2014 and the study was completed in August 2014. Of 1501 screenedpatients, 823 were randomized and 821 received study drug.
INTERVENTIONS Participants were randomly assigned to receive oral, once-daily finerenone(1.25mg/d, n = 96; 2.5mg/d, n = 92; 5mg/d, n = 100; 7.5mg/d, n = 97; 10mg/d, n = 98;15mg/d, n = 125; and 25mg/d, n = 119) or matching placebo (n = 94) for 90 days.
MAIN OUTCOMES AND MEASURES The primary outcomewas the ratio of the urinaryalbumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changesfrom baseline in serum potassium and estimated glomerular filtration rate.
RESULTS The mean age of the participants was 64.2 years; 78%were male. At baseline,36.7%of patients treated had very high albuminuria (UACR300mg/g) and 40.0%had anestimated glomerular filtration rate of 60 mL/min/1.73m2 or lower. Finerenone demonstrateda dose-dependent reduction in UACR. The primary outcome, the placebo-corrected meanratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-,and 20-mg/d groups (for 7.5mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10mg/d, 0.76[90% CI, 0.65-0.88; P = .001]; for 15mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemialeading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups;incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%,respectively. There were no differences in the incidence of the pre specified secondaryoutcome of an estimated glomerular filtration rate decrease of 30% or more or in incidencesof adverse events and serious adverse events between the placebo and finerenone groups.
CONCLUSIONS AND RELEVANCE Among patients with diabetic nephropathy, most receiving anangiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition offinerenone compared with placebo resulted in improvement in the urinary albumin-creatinineratio. Further trials are needed to compare finerenone with other active medications.
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