FIDELIO-DKD: Finerenone Cuts CV Events in Diabetic Kidney Disease

In patients with chronic kidney disease (CKD) and type 2 diabetes, finerenone, an investigational mineralocorticoid receptor antagonist (MRA), both protects the kidney and provides a significant reduction in cardiovascular events, an analysis of the FIDELIO-DKD trial shows.

The key secondary CV endpoint—a composite of CV death, MI, stroke, or hospitalization for heart failure—was reduced by a relative 14% with finerenone versus placebo (P = 0.85), with consistent benefits in patients with and without a prior history of cardiovascular disease. The improved outcomes also were consistent in subgroup analyses defined by type of prior CVD, including MI and/or ischemic stroke, CAD, and PAD.

Gerasimos Filippatos, MD (Attikon University Hospital, Athens, Greece), reported the results today during the virtual American Heart Association 2020 Scientific Sessions.

Generally, adverse events were similar with finerenone and placebo, but the rate of hyperkalemia was doubled in the active treatment group (18.3% vs 9.0%). Hyperkalemia associated with clinical consequences, including permanent treatment discontinuation and hospitalization, was infrequent, and there were no cases leading to death.

The increases in potassium were manageable, Filippatos said. “Overall, we found finerenone to be an effective investigational treatment option for cardiovascular protection in patients with chronic kidney disease and type 2 diabetes.”

FIDELIO-DKD

Patients with CKD and type 2 diabetes are at an especially high risk for CV events, Filippatos noted, adding that overactivation of the mineralocorticoid receptor in these types of patients can lead to injury of the heart, kidney, and blood vessels.

Finerenone (Bayer AG) is a nonsteroidal, selective MRA shown to have potent anti-inflammatory and anti-fibrotic effects in the cardiovascular system in animal models, and FIDELIO-DKD—conducted at 913 sites in 48 countries, was designed to assess its impact in patients with both CKD and type 2 diabetes. After a run-in period during which CV and diabetes medications were optimized, investigators randomized 5,734 patients to finerenone 10 or 20 mg once daily (depending on renal function) or placebo. Median follow-up was 2.6 years.

As seen in the main results, published last month in the New England Journal of Medicine, finerenone reduced the risk of the primary composite outcome consisting of various renal endpoints, including kidney failure, a sustained decrease in estimated glomerular filtration rate from baseline of 40% or greater, and renal death (HR 0.82; 95% CI 0.73-0.93).

The analysis presented by Filippatos at AHA 2020, also published online in Circulation, delved deeper into the CV outcomes. Of note, 7.7% of patients had heart failure and 45.9% had a history of CVD, including CAD, ischemic stroke, or PAD, at baseline.

The rate of the composite CV outcome was 13.0% in the finerenone group and 14.8% in the placebo group (HR 0.86; 95% CI 0.75-0.99). When assessed individually, three of the endpoint’s four components, with the exception of stroke, indicated an advantage for finerenone:

·       CV death (HR 0.86; 95% CI 0.68-1.08)

·       Hospitalization for heart failure (HR 0.86; 95% CI 0.68-1.08)

·       Nonfatal MI (HR 0.80; 95% CI 0.58-1.09)

·       Nonfatal stroke (HR 1.03; 95% CI 0.76-1.38)

There was no difference in the treatment effect in terms of the composite CV outcome based on whether patients had a prior history of CVD (HR 0.85; 95% CI 0.71-1.02) or did not (HR 0.86; 95% CI 0.68-1.08).

Likewise, the safety profile did not differ based on the presence or absence of CVD, Filippatos reported.

New Era of Treatment for Diabetic Kidney Disease

Discussant Christoph Wanner, MD (University Hospital of Würzburg, Germany), said the results of the trial are robust, noting that the increase in hyperkalemia with finerenone is manageable.

“Until today, adequate [renin-angiotensin-aldosterone system] blockade was limited because of rising potassium levels and we . . . learned to enroll and not to exclude the most vulnerable patients, those with impaired kidney function and high cardiovascular risk, into large clinical outcome trials. And we see good safety,” he said.

In recent years, newer treatments for diabetic kidney disease like the sodium-glucose co-transporter 2 (SGLT2) inhibitors and this novel MRA “are shifting the focus away from glucose management towards organ protection,” he said. “So finerenone is both a cardiovascular and kidney protective medication in individuals with type 2 diabetes, and is an option where SGLT2 inhibitors are not preferred, or [can be] used in combination. We [have] entered a new era of effective treatments for diabetic kidney disease.”

He noted that results from the FIGARO-DKD trial of finerenone, which has a primary CV composite endpoint, are due to be reported next year.

Commenting during a press briefing, Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston), who was not involved in the study, noted that another MRA, spironolactone, has also been shown to increase hyperkalemia. “It seems . . . that this drug has a better safety profile and the efficacy also seems to be quite good,” he said, adding that  pending further analyses digging into the potassium levels in the trial, “I think [finerenone] seems very promising for a full range of patients with chronic kidney disease.”

Sripal Bangalore, MD (NYU Langone Health, New York, NY), told TCTMD that anything that can reduce the very high event rates seen in patients with CKD and diabetes “is definitely clinically relevant and meaningful.”

The hyperkalemia issue can be handled as long as it’s recognized, he said. “The key is to make sure that these patients are closely followed, at least initially, before you uptitrate the medication, and make sure that the potassium levels are closely monitored.”

From a cardiology perspective, Bangalore pointed out, MRAs are generally not used outside of heart failure because of the lack of data. “Now we have some data in a non-heart failure, diabetic CKD cohort [showing] that potentially we may have benefit. So I think this does open up the use [of finerenone] in clinical practice and potentially—in terms of future directions—use of MRAs for non-heart failure indications,” he said.