Adding the mineralocorticoid receptor antagonist finerenone to standard renin-angiotensin system (RAS) blockade decreased albuminuria and improved the urinary albumin/creatinine ratio in an industry-sponsored phase IIB clinical trial of diabetic nephropathy, according to a report published online Sept. 1 in JAMA.
Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist (MRA), had greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro. It also reduced proteinuria and end-organ damage to a greater degree in animal studies, and was less likely to induce hyperkalemia than either of those related drugs in preliminary human studies. “Thus, finerenone may be able to address the unmet medical need of safely managing albuminuria without adversely affecting serum potassium in patients with type 2 diabetes mellitus who have a clinical diagnosis of diabetic kidney disease,” said Dr. George L. Bakris of the ASH Comprehensive Hypertension Center, University of Chicago, and his associates.
Dr. George L. Bakris
To investigate this possibility, they performed the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN), an international randomized, double-blind trial comparing seven oral doses of finerenone against matching placebo in 823 patients who had type 2 diabetes and persistent albuminuria and who were already taking an RAS blocker (an ACE inhibitor or ARB). These study participants (mean age 64 years) were treated for 90 days at 148 medical centers in 23 countries.
The primary outcome measure was the change in urinary albumin/creatinine ratio at the conclusion of treatment. Compared with placebo, the four highest doses of finerenone reduced this ratio in a dose-dependent manner: the ratio was 0.79 with the 7.5-mg dose, 0.76 with the 10-mg dose, 0.67 with the 15-mg dose, and 0.62 with the 20-mg dose. This represents reductions in urinary albumin/creatinine ratio ranging from 21% to 38%, compared with placebo. In addition, only 13.6% of the placebo group achieved a decrease of at least half in urinary albumin/creatinine ratio, compared with 17.2%, 17.2%, 33.6%, and 40.2%, respectively, of these four highest-dose groups, Dr. Bakris and his associates said (JAMA. 2015 Sept 1. doi: 10.1001/jama.2015.10081). The incidences of adverse events and of serious adverse events were similar across all the study groups. A total of 1.5% of patients had serious adverse events thought to be related to treatment, including 12 patients who discontinued finerenone because of increases in serum potassium.
Longer-term studies are needed to assess clinical rather than just laboratory endpoints, the longer-term effects of finerenone on kidney disease progression, and potential beneficial antifibrotic or anti-inflammatory effects, the investigators added.
The ARTS-DN study was funded by Bayer HealthCare AG. Dr. Bakris reported receiving research support from and serving as an advisor/consultant to Takeda, Bayer HealthCare AG, Medtronic, Relypsa, AbbVie, Bristol-Myers Squibb, CVRx, Elcelyx, Eli Lilly/Boehringer Ingelheim, Janssen, Novartis, GlaxoSmithKline, Tengion, and ZS Pharma. His associates reported ties to numerous industry sources.