Finerenone in Persons with Chronic Kidney Disease without Diabetes

Welcome to AudioScholar. Today we're covering Finerenone in Persons with Chronic Kidney Disease without Diabetes, by Heerspink H and colleagues, published in New England Journal of Medicine.

For years, managing chronic kidney disease has felt like a tale of two populations. For patients with type two diabetes, therapeutic options have expanded rapidly. We have seen the rise of sodium-glucose cotransporter two inhibitors and nonsteroidal mineralocorticoid receptor antagonists like finerenone, which have fundamentally changed the cardiorenal prognosis. But for patients with non-diabetic chronic kidney disease, the therapeutic landscape has remained far more restricted. Aside from renin-angiotensin system inhibitors and, more recently, SGLT2 inhibitors, these patients have had fewer targeted options. Mineralocorticoid receptor overactivation is not unique to diabetes; it is a key driver of inflammation and fibrosis that leads to progressive nephron loss regardless of the underlying cause. While steroidal mineralocorticoid receptor antagonists like spironolactone reduce proteinuria, their clinical utility is severely limited by hyperkalemia, endocrine side effects, and a lack of robust clinical trial data showing hard kidney outcomes. This is where the FIND-CKD trial steps in, asking a crucial question: can the kidney-protective benefits of the highly selective, nonsteroidal mineralocorticoid receptor antagonist finerenone be extended to patients with chronic kidney disease who do not have diabetes?

To answer this, investigators conducted a multicenter, randomized, double-blind, placebo-controlled, phase three trial across twenty-four countries. They enrolled adults with a clinical diagnosis of chronic kidney disease without diabetes who were at high risk of disease progression. To be eligible, participants had to be on a stable, maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker, with a serum potassium level of four point eight millimoles per liter or less at screening. The investigators defined high risk using estimated glomerular filtration rate and albuminuria. Most participants had an eGFR between twenty-five and ninety milliliters per minute per one point seven three square meters, combined with a urinary albumin-to-creatinine ratio between five hundred and thirty-five hundred milligrams per gram. A smaller cohort, capped at ten percent of the total population, could have an eGFR up to sixty with lower-level proteinuria between two hundred and five hundred milligrams per gram. Patients with type one or type two diabetes, or a glycated hemoglobin of six point five percent or higher, were strictly excluded, as were those with uncontrolled hypertension, symptomatic heart failure with reduced ejection fraction, polycystic kidney disease, or active glomerulonephritis requiring recent immunosuppressive therapy.

Ultimately, fifteen hundred and eighty-four participants were randomized in a one-to-one ratio to receive either oral finerenone or a matching placebo. Finerenone was started at ten or twenty milligrams once daily based on baseline kidney function, with protocol-directed up-titration to twenty milligrams after one month if potassium and eGFR remained stable. The primary efficacy outcome was the total eGFR slope, representing the mean annual rate of change in eGFR from baseline to month thirty-two. This was analyzed using a two-slope model to separate the expected early hemodynamic decline, from baseline to month three, from the chronic decline phase from month three onward.

Over a median treatment duration of thirty-six point six months, the trial yielded compelling results. Looking at the primary outcome, kidney function declined significantly slower in the finerenone group compared to the placebo group. The total eGFR slope was minus three point three milliliters per minute per one point seven three square meters per year with finerenone, compared to minus four point zero with placebo. This represents a treatment difference of zero point seven milliliters per minute per one point seven three square meters per year in favor of finerenone, which was statistically significant.

When we break down the eGFR trajectory, we see a classic biphasic pattern that is highly familiar to clinicians who prescribe these classes of medications. During the first three months, patients initiating finerenone experienced an acute hemodynamic dip in eGFR that was one point two milliliters per minute greater than that seen with placebo. However, after this initial phase, the chronic rate of decline was substantially slower with finerenone. From month three to the end of treatment, the chronic eGFR slope was minus two point nine in the finerenone group versus minus four point one in the placebo group, yielding a chronic treatment difference of one point two milliliters per minute per year. Reassuringly, after treatment was discontinued at the end of the study, eGFR rebounded in the finerenone group, confirming that the initial dip was indeed hemodynamic and fully reversible.

Turning to the secondary outcomes, the investigators evaluated a key composite kidney-cardiovascular endpoint. This composite included a sustained decline in eGFR of fifty-seven percent or more, kidney failure, hospitalization for heart failure, or cardiovascular death. This composite event occurred in thirteen point nine percent of the finerenone group compared to sixteen point nine percent of the placebo group. This translates to a twenty-three percent reduction in risk, with a hazard ratio of zero point seven seven that was statistically significant. When looking closely at the individual components of this composite, the benefit was clearly driven by kidney-specific outcomes. Cardiovascular events were overall very infrequent in this non-diabetic population, and there was no significant difference between the groups for the cardiovascular composite alone.

In terms of exploratory outcomes, finerenone led to a rapid and sustained reduction in albuminuria. By month six, there was a thirty-five point four percent greater reduction in the urinary albumin-to-creatinine ratio in the finerenone group compared to placebo. More than half of the patients taking finerenone achieved at least a thirty percent reduction in albuminuria, compared to only about a quarter of those on placebo.

Of course, with any mineralocorticoid receptor antagonist, safety and potassium monitoring are paramount. Overall adverse events and serious adverse events were similar between the two groups. As anticipated, hyperkalemia was more common with finerenone, occurring in seventeen percent of patients compared to thirteen point three percent in the placebo group. However, serious hyperkalemia events were rare, occurring in only one percent of the finerenone group and zero point six percent of the placebo group. There were no fatal hyperkalemia events, and permanent discontinuation of the study drug due to high potassium was low, at just one point five percent with finerenone versus point one percent with placebo.

Now, let's look at the strengths and limitations of this study. A major strength of the FIND-CKD trial is its robust, double-blind, randomized design and its successful execution over nearly three years, providing the first large-scale, high-quality evidence for a nonsteroidal mineralocorticoid receptor antagonist in a non-diabetic chronic kidney disease population.

However, there are several key limitations we must consider when translating these findings to clinical practice. First, while the trial featured broad geographic recruitment, the cohort was not fully representative of the global chronic kidney disease population. For instance, fewer than five percent of the participants identified as Black, which limits our ability to generalize these results to this highly affected demographic. Second, because the protocol excluded patients with polycystic kidney disease and those with active, recently treated lupus nephritis or Anca-associated vasculitis, we cannot assume these benefits apply to those specific etiologies.

Perhaps the most significant clinical question left unanswered is how finerenone interacts with SGLT2 inhibitors. When the trial was designed, SGLT2 inhibitors were just emerging as foundational therapy, and as a result, only seventeen percent of participants were taking an SGLT2 inhibitor at baseline. While the protocol allowed patients to start these medications during the trial, we lack detailed data on how many actually did. This makes it difficult to determine the precise incremental benefit of adding finerenone to a patient who is already established on an SGLT2 inhibitor. However, recent data from other trials, such as the CONFIDENCE study in diabetic kidney disease, suggest that combining these therapies can yield additive reductions in albuminuria without compounding safety concerns.

So, what is the clinical bottom line for practicing physicians? The FIND-CKD trial successfully demonstrates that the kidney-protective benefits of finerenone extend beyond diabetic kidney disease. For your adult patients with non-diabetic chronic kidney disease, an eGFR between twenty-five and ninety, and significant albuminuria who are already optimized on an Ace inhibitor or ARB, adding finerenone can significantly slow the long-term decline of kidney function and lower albuminuria.

When implementing this in practice, expect an initial, reversible dip in eGFR of about one to two milliliters per minute during the first three months. You should monitor serum potassium closely, especially in the first month and after dose titration, aiming to keep potassium at or below five millimoles per liter. While we still need more data on the routine upfront combination of finerenone and SGLT2 inhibitors in non-diabetic chronic kidney disease, this trial provides a powerful new tool to help prevent progression to end-stage kidney disease in a population that has long had limited options.

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