Nonsteroidal MRA Drug Cuts Risks in Earlier Diabetic Kidney Disease

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Finerenone (Kerendia) prevents cardiovascular (CV) and some renal events in type 2 diabetes patients with earlier stages of kidney disease, the FIGARO-DKD trial showed.

In the trial’s stage 1 to 4 kidney disease patients with moderate-to-severe albuminuria, the nonsteroidal mineralocorticoid receptor antagonist (MRA) reduced the composite of CV death, nonfatal myocardial infarction or stroke, or heart failure hospitalization by a relative 13% compared with placebo (12.4% vs 14.2%, P=0.03). The number needed to treat was 47 at 3.5 years.

The effect was driven by heart failure hospitalization (3.2% vs 4.4%, HR 0.71, 95% CI 0.56-0.90), reported Bertram Pitt, MD, of the University of Michigan in Ann Arbor, at the European Society of Cardiology (ESC) virtual meeting and online in the New England Journal of Medicine.

The heart failure hospitalization results were right in line with those seen from SGLT2 drugs, noted ESC session study discussant Kevin Damman, MD, PhD, of the University Medical Center Groningen in the Netherlands.

Renal Outcomes

The trial missed significance on the secondary composite of kidney failure, a sustained drop in estimated glomerular filtration rate (eGFR) of at least 40%, or death from renal causes (9.5% with finerenone vs 10.8% with placebo, HR 0.87, 95% CI 0.76-1.01).

But the magnitude was in line with the prior FIDELIO-DKD trial, as were the overall results, although that trial had a more advanced chronic kidney disease (CKD) population, Pitt noted.

And a different composite renal endpoint definition that is often used in trials, with a 57% rather than 40% drop in eGFR from baseline, did turn up significant for the third-generation MRA drug. Notably, progression to end-stage kidney disease was significantly less common with the drug (0.9% vs 1.3%, HR 0.64, 95% CI 0.41-0.995).

Primary renal events were much less common in this less advanced kidney disease population, which likely accounted for the difference between trials, Damman noted. Slowing the downward trajectory of eGFR is probably more important, but those results are yet to be seen, he added.

In the pooled FIDELITY analysis of the two trials, presented at the same ESC session, CV risk rose as eGFR fell and as albumin levels rose. Patients with urine albumin to creatinine ratios (UACR) above 300 mg/g had high risk even at normal eGFR.

FIGARO-DKD had some 60% of patients who qualified for the trial based on elevated albuminuria but preserved kidney function (eGFR ≥60 ml/min/1.73 m2). Overall between the two trials’ 13,026 patients, 40% fell in that category and 8.5% had severe albuminuria but normal eGFR.

Implications for Practice

With the two trials, “I think we can confidently say finerenone is effective in type 2 diabetes and renal disease across the entire spectrum of renal disease,” concluded Pitt at an ESC press conference. “This is really an advance for our patients.”

Just as important, he argued, are the implications for urine analysis.

Many different specialists have their hands on these patients — from primary care to cardiology — but albuminuria often goes unchecked if eGFR is normal, he pointed out.

“It’s essential that you get a urine sample,” Pitt said. “If you have albuminuria, that patient has an increased risk. And now we know we can do something about that. That patients should be started on therapy…Most of us neglect those patients and it’s a tremendous opportunity to intervene early.”

It’s “absolutely” time to screen all diabetes patients for albuminuria, said FIDELITY co-presenter Rajiv Agarwal, MD, of Indiana University in Indianapolis. “This is not about kidney disease anymore,” he said at the session. “You’re going to protect from more cardiovascular events if you identify these patients early and put them on finerenone than just looking at kidney failure.”

For cardiologists, that requires a change in clinical practice, he said. “This is prevention of cardiac failure. In type 2 diabetes, you can identify this risk simply by measuring UACR.”

Adverse Events

Overall, the drug was well tolerated with no overall difference in adverse events. Gynecomastia was identical between groups; nor were there impacts on glucose control. Blood pressure impacts were modest (-2.6 mmHg systolic from baseline vs placebo).

As expected, though, the MRA drug did cause more hyperkalemia (10.8% vs 5.3%), albeit with none leading to death and few resulting in hospitalization (0.6% vs 0.1%) or drug discontinuation (1.2% vs 0.4%).

“I don’t think you could see the same kind of picture with a steroidal MRA,” Pitt noted. However, he added, “I think it’s going to take a lot of education, because there are a lot of misconceptions about the risk and what to do and people get frightened.”

Damman agreed that with the elevated hyperkalemia risk, “there could be a clinical inertia” of reluctance to prescribe. And, he added, finerenone will be an add-on agent, so polypharmacy is a concern.

Combination Potential

Across the two trials, 7.2% of patients received a GLP-1 receptor agonist and 6.7% got an SGLT2 inhibitor. Subgroup analysis showed no significant interaction on the impact of finerenone by use of those drugs at baseline.

“The numbers are relatively small,” he said. “But the point estimates seem to show that those on an SGLT2 antagonist or GLP-1 agonist seem to have a better effect of finerenone. … All of our expectations are, from the preclinical data and from the trends, that people should be on both.”

MRAs generally have not been used as widely as they should be once patients develop significant renal dysfunction, commented Colin Baigent, BM BCh, of the University of Oxford in England, who served as session discussant for FIDELITY. “This is a reassuring result that we could be using it in a wider range of patients with chronic kidney disease [CKD].”

A key question is how to extrapolate use to CKD patients without diabetes, “because this is not a diabetes drug,” noted Agarwal.

The trials excluded patients with symptomatic heart failure with reduced ejection fraction, for which MRA use is a class Ia recommendation in guidelines. So considering the HF hospitalization reduction, “there’s much more to learn,” suggested session panelist Frank Ruschitzka, MD, of the Heart Center at University Hospital Zurich. “We probably have a HFpEF [heart failure with preserved ejection fraction] drug at our hands.”

The FINEARTS-HF trial is underway to look at finerenone in HF with an ejection fraction of 40% or greater.

Disclosures

The trial was funded by Bayer.

Pitt disclosed relationships with AstraZeneca, Bayer, Bayer Healthcare, Boehringer Ingelheim, Brainstorm Medical, Cereno Scientific, G3 Pharmaceuticals, KBP Biosciences, Lexicon Pharmaceuticals, PhaseBio, Proton Intel, Sanofi and Genzyme, Sarfez, scPharmaceuticals, SQ Innovation, Tricida, and Vifor Pharma. He holds patents related to eplerenone and histone-acetylation-modulating agents.

Damman disclosed no relevant relationships with industry.

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