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Early albuminuria reduction with finerenone (Kerendia) drove protection against chronic kidney disease (CKD) progression in people with type 2 diabetes, according to a post-hoc mediation analysis.

In the pooled analysis using data on 12,512 patients from the FIDELIO-DKD and FIGARO-DKD trials, reduction in urine albumin-to-creatinine ratio (UACR) by month 4 mediated 84% of the treatment effect on kidney outcomes and 37% of the effect on cardiovascular outcomes over 4 years, Rajiv Agarwal, MD, MS, of Indiana University School of Medicine and Richard L. Roudebush VA Medical Center in Indianapolis, and colleagues reported in .

At baseline, median UACR was 514 mg/g. By month 4 of treatment, median UACR was reduced by 33.6% and 2.6% in the finerenone and placebo groups, respectively.

A total of 53.2% of finerenone-treated patients had a 30% or greater reduction in UACR versus 27% of those on placebo. When UACR was analyzed as a binary variable -- comparing patients who achieved the 30% threshold of UACR reduction versus those who didn't -- albuminuria reduction mediated kidney outcomes by 64% and cardiovascular outcomes by 26%.

"Most of [the] kidney protection and a modest amount of cardiovascular protection is mediated by a short-term reduction in albuminuria reduction," Agarwal explained to 麻豆传媒.

"In people with diabetes, suggest lowering UACR by 30% with therapy. These data support these guidelines by demonstrating that lowering albuminuria is the causal pathway of both kidney and cardiovascular protection," Agarwal noted. "Clinicians caring for people with diabetes should not only screen for kidney disease with annual UACR testing, but also may consider monitoring the level of UACR to gauge treatment benefits."

When it came to the composite kidney outcome (time to first onset of kidney failure, sustained 57% or greater decrease in estimated glomerular filtration rate [eGFR] from baseline over 4 or more weeks, or kidney disease death), finerenone increased mean survival time by 15%, while it led to a 12% increase in mean survival time in regards to the composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure).

Albuminuria reduction appeared to have a dose-dependent relationship with kidney outcomes. Patients who fell into the moderately increased albuminuria group -- under 300 mg/g -- had few kidney outcomes, but those who fell into the severely increased albuminuria group -- 300 mg/g or more -- had the most kidney events.

Approved by the FDA in July 2021, finerenone was the first non-steroidal, selective mineralocorticoid receptor antagonist to slow CKD progression in type 2 diabetes. It's indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adults.

Underpinning finerenone's approval was data from the phase III FIDELIO-DKD trial, which reported an 18% reduced risk of a primary outcome event -- kidney failure, a sustained decrease of at least 40% in eGFR from baseline, or death from renal causes -- with finerenone versus placebo. The trial also reported a 14% risk reduction for death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.

This isn't the first treatment to show that treatment-induced albuminuria reduction led to renal and cardiovascular risk reduction. The angiotensin II antagonist losartan, plus SGLT2 inhibitors canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga) have also shown this effect.

But other drugs like the renin inhibitor , angiotensin II receptor blocker , and investigational endothelin-A antagonist have all reported similar reductions in albuminuria without showing net clinical benefits, but also weren't tested in a mediation analysis like this.

"We hope that other therapies will similarly test mediation in large randomized trials to assess whether these benefits are limited to finerenone or are broadly applicable to other treatments," said Agarwal.

The researchers added that "the upstream mechanisms that underlie the reduction in albuminuria -- in this case, mineralocorticoid receptor overactivation -- may be critically important and distinct from other mechanisms."

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