Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial.
OBJECTIVE
Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease 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 nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.


METHODS
Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug.


METHODS
Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days.


METHODS
The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from 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 (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading 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 prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.


CONCLUSIONS
Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications.


BACKGROUND
clinicaltrials.gov Identifier: NCT1874431.
University of Chicago Medicine, Chicago, Illinois.
George L
GL
Bakris
Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis.
Rajiv
R
Agarwal
Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China.
Juliana C
JC
Chan
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Mark E
ME
Cooper
Department of Nephrology, University Medical Center Groeningen, Groeningen, the Netherlands.
Ron T
RT
Gansevoort
Departments of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
Hermann
H
Haller
Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica (Bergamo), Italy8Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
Giuseppe
G
Remuzzi
Steno Diabetes Center, Gentofte, Denmark10University of Copenhagen, Copenhagen, Denmark11Aarhus University, Aarhus, Denmark.
Peter
P
Rossing
Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen, Germany.
Roland E
RE
Schmieder
Global Clinical Development, Bayer HealthCare AG, Wuppertal, Germany.
Christina
C
Nowack
Heart Diseases Research, Global Drug Discovery, Bayer HealthCare AG, Wuppertal, Germany.
Peter
P
Kolkhof
Global Clinical Development, Bayer PLC, Newbury, England.
Amer
A
Joseph
MARCO GmbH & Co KG, Düsseldorf, Germany.
Alexander
A
Pieper
Global Research and Development Statistics, Bayer HealthCare AG, Leverkusen, Germany.
Nina
N
Kimmeskamp-Kirschbaum
Institute of Investigation and Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain.
Luis M
LM
Ruilope
D000284:Administration, Oral; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy*; D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000208:ethnology / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000208:ethnology / Q000503:physiopathology / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced / Q000453:epidemiology; D015994:Incidence; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D009287:Naphthyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011188:Potassium / Q000097:blood
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; C576501:finerenone; D003404:Creatinine; D011188:Potassium