"This is an exciting discovery because we have had many other failed discoveries in this high-risk population of diabetes and chronic kidney disease," Dr. Rajiv Agarwal of Indiana University, in Indianapolis, said in a press briefing.
He presented the study results during KidneyWeek, hosted by the American Society of Nephrology (ASN). The results were simultaneously published in The New England Journal of Medicine.
Overactivation of the mineralocorticoid receptor is thought to play a role in cardiorenal diseases, including CKD and diabetes, through inflammation and fibrosis that lead to progressive kidney and cardiovascular dysfunction, the authors explain in their paper.
Finerenone is a nonsteroidal antimineralocorticoid with stronger antiinflammatory and antifibrotic effects than the steroidal antimineralocorticoid spironolactone.
The FIDELIO-DKD trial included 5,734 patients with type-2 diabetes and CKD, who were randomized to finerenone or placebo. About half of the patients had an estimated glomerular filtration rate (eGFR) of less than 45 ml/min/1.73 m2. The median urinary albumin-to-creatinine ratio is about 800 and nearly 90% of them have "very high albumin," Dr. Agarwal noted in his presentation.
The primary composite endpoint was time to kidney failure, defined as either a 40% decline in eGFR from baseline or death from kidney failure. The key secondary composite endpoint was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
"Both the primary and the key secondary endpoints were met," Dr. Agarwal reported.
During a median follow-up period of 2.6 years, significantly fewer patients on finerenone than placebo suffered a primary outcome event (17.8% vs. 21.1%; hazard ratio, 0.82; P=0.001). Likewise, significantly fewer patients on finerenone experienced a secondary outcome event (13.0% vs. 14.8%; HR, 0.86; P=0.03).
The frequency of serious adverse events and adverse events were balanced between the two groups.
"Hyperkalemia was really the major side effect that we saw in the trial," Dr. Agarwal noted, with an 18.3% incidence of investigator-reported hyperkalemia compared to 9.0% in the placebo group. The incidence of hyperkalemia-related discontinuation was also higher in the finerenone group (2.3% vs. 0.9%).
As a nonsteroidal mineralocorticoid-receptor antagonist, finerenone "would be expected to produce hyperkalemia and we did see more hyperkalemia in patients who are treated with finerenone compared to placebo," Dr. Agarwal noted. "An ideal drug would cause no hyperkalemia. But if you look at the absolute risk, it's a fraction of what we see when we use spironolactone in this vulnerable population."
In a linked editorial, Dr. Julie Ingelfinger of Tufts University in Boston and Dr. Clifford Rosen of Maine Medical Center Research Institute in Scarborough say this study shows a benefit of finerenone with respect to CKD progression among patients with relatively advanced CKD and type-2 diabetes "and thus for persons at high risk for kidney-related (and heart-related) events."
"A cardiovascular benefit was evident early (as soon as a month) and continued; the kidney-related benefit was seen after 1 year," they point out.
However, the apparent benefit with respect to CKD progression was less than that reported with canagliflozin in the CREDENCE trial. One explanation for the different findings in the two trials, as noted by the authors, is the fact that SGLT2 inhibitors were permitted in the current trial, whereas patients treated with mineralocorticoid receptor antagonists were excluded from the CREDENCE trial.
"Phase 3 trials of the other dihydropyridine mineralocorticoid receptor antagonists are awaited. In addition, trials that are longer term than the FIDELIO-DKD trial will be important. That being said, a way to decrease the relative hyperaldosteronism in patients with CKD seems a promising strategy," the editorialists conclude.
The study was funded by Bayer, which is developing finerenone. The company employed two of the authors and has financial ties to others, too, including Dr. Agarwal. Bayer also paid for preparation of the article.
By Megan Brooks
SOURCE: https://bit.ly/37w2i4p and https://bit.ly/2Ht0mPl New England Journal of Medicine, online October 23, 2020.
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