For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.
And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).
“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana University School of Medicine in Indianapolis, during a press briefing.
After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.
Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.
FIDELIO-DKD assessed 5734 patients with type 2 diabetes and chronic kidney disease from more than 1000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was just over 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline A1c was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
A Suggestion of Less Severe Hyperkalemia
Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.
Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups — in this case 0.2 mmol/L — unlike placebo, said Agarwal.
The overall incidence of hyperkalemia was 16% in the 2827 evaluable patients in the finerenone group and 8% in the 2831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.
The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs 0.9%).
That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Agarwal, citing a previous study he was involved with.
He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.
“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, a cardiologist and professor of medicine at the University of Missouri School of Medicine in Kansas City.
“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Kosiborod told Medscape Medical News.
And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, a nephrologist from the Einstein Medical Center in Philadelphia.
The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m2, she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting-enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).
“Considering this background, it’s a very acceptable adverse-event profile,” Rangaswami told Medscape Medical News.
Renal Drugs That Could Work Together
More than 99% of patients in FIDELIO-DKD were on a RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.
Despite that, both Kosiborod and Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD-type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors — at least those two — as key agents for patients with chronic kidney disease.
Dual treatment with a RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Agarwal.
“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease, to prevent both cardiovascular and kidney complications,” said Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.
“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.
Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.
“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”
FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor; and has received research funding from AstraZeneca and Boehringer Ingelheim. Rangaswami has disclosed no relevant financial relationships.
Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstract FR-OR51. Presented October 23, 2020.