• Rajiv Agarwal, Wanzhu Tu, Alfredo E Farjat, FaragYoussef M KYMK0000-0003-1692-1851Bayer U.S. LLC, Cambridge, Massachusetts (Y.M.K.F.)., Robert Toto, Sanjay Kaul, Robert Lawatscheck, Katja Rohwedder, Luis M Ruilope, Peter Rossing, Bertram Pitt, Gerasimos Filippatos, Stefan D Anker, George L Bakris, and FIDELIO-DKD and FIGARO-DKD Investigators.
• Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, Indiana (R.A.).
• Ann. Intern. Med. 2023 Dec 1; 176 (12): 160616161606-1616.

BackgroundIn patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular and kidney failure outcomes. Finerenone also lowers the urine albumin-to-creatinine ratio (UACR). Whether finerenone-induced change in UACR mediates cardiovascular and kidney failure outcomes is unknown.ObjectiveTo quantify the proportion of kidney and cardiovascular risk reductions seen over a 4-year period mediated by a change in kidney injury, as measured by the change in log UACR between baseline and month 4.DesignPost hoc mediation analysis using pooled data from 2 phase 3, double-blind trials of finerenone. (ClinicalTrials.gov: NCT02540993 and NCT02545049).SettingSeveral clinical sites in 48 countries.Patients12 512 patients with CKD and T2D.InterventionFinerenone and placebo (1:1).MeasurementsSeparate mediation analyses were done for the composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline [approximately a doubling of serum creatinine], or kidney disease death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) outcomes.ResultsAt baseline, median UACR was 514 mg/g. A 30% or greater reduction in UACR was seen in 3338 (53.2%) patients in the finerenone group and 1684 (27.0%) patients in the placebo group. Reduction in UACR (analyzed as a continuous variable) mediated 84% and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively. When change in UACR was analyzed as a binary variable (that is, whether the guideline-recommended 30% reduction threshold was met), the proportions mediated for each outcome were 64% and 26%, respectively.LimitationThe current findings are not readily extendable to other drugs.ConclusionIn patients with CKD and T2D, early albuminuria reduction accounted for a large proportion of the treatment effect against CKD progression and a modest proportion of the effect against cardiovascular outcomes.Primary Funding SourceBayer AG.

26 keywords...

hide…