Most subjects had elevated UACRs
The study run by Dr. Agarwal and his associates used data from 12,512 of the more than 13,000 people enrolled in either FIDELITY-DKD or FIGARO-DKD who had UACR measurements recorded at baseline, at 4 months into either study, or both. Their median UACR at the time they began on finerenone or placebo was 514 mg/g, with 67% having a UACR of at least 300 mg/g (macroalbuminuria) and 31% having a UACR of 30-299 mg/g (microalbuminuria). By design, virtually all patients in these two trials were on a renin-angiotensin system inhibitor (either an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker), but given the time period when the two trials enrolled participants (during 2015-2018) only 7% of those enrolled were on a sodium-glucose cotransporter 2 inhibitor and only 7% were on a glucagonlike peptide–1 receptor agonist.
Four months after treatment began, 53% of those randomized to finerenone treatment and 27% of those in the placebo arm had their UACR reduced by at least 30% from baseline, the cutpoint chosen by Dr. Agarwal based on the American Diabetes Association guideline.
Kaplan-Meier analyses showed that the incidence of the primary kidney outcome – kidney failure, a sustained ≥ 57% decrease in eGFR from baseline, or kidney death – showed close correlation with at least a 30% reduction in UACR regardless of whether the patients in this subgroup received finerenone or placebo.
A different correlation was found in those with a less than 30% reduction in their UACR from baseline to 4 months, regardless of whether this happened on finerenone or placebo. People in the two finerenone trials who had a lesser reduction from baseline in their UACR also had a significantly higher rate of adverse kidney outcomes whether they received finerenone or placebo.
84% of finerenone’s kidney benefit linked to lowering of UACR
The causal-mediation analysis run by Dr. Agarwal quantified this observation, showing that 84% of finerenone’s effect on the kidney outcome was mediated by the reduction in UACR.
“It seems like the kidney benefit [from finerenone] travels through the level of albuminuria. This has broad implications for treatment of people with type 2 diabetes and CKD,” he said.
The link with reduction in albuminuria was weaker for the primary cardiovascular disease outcome: CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The strongest effect on this outcome was only seen in Kaplan-Meier analysis in those on finerenone who had at least a 30% reduction in their UACR. Those on placebo and with a similarly robust 4-month reduction in UACR showed a much more modest cardiovascular benefit that resembled those on either finerenone or placebo who had a smaller, less than 30% UACR reduction. The mediation analysis of these data showed that UACR reduction accounted for about 37% of the observed cardiovascular benefit seen during the trials.
“The effect of UACR is much stronger for the kidney outcomes,” summed up Dr. Agarwal. The results suggest that for cardiovascular outcomes finerenone works through factors other than lowering of UACR, but he admitted that no one currently knows what those other factors might be.