New signals of a potential additive benefit from the nonsteroidal mineralocorticoid antagonist finerenone (Kerendia) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor in patients with type 2 diabetes and chronic kidney disease (CKD) emerged in a follow-up report from the FIDELITY analysis, which combined data from more than 13,000 patients who received finerenone in either of the two pivotal trials with the agent.
The analysis showed that the 877 patients enrolled in either the FIDELIO DKD or FIGARO DKD trials taking an SGLT2 inhibitor at baseline had a 37% relative reduction in their urinary albumin-to-creatinine ratio (UACR) compared with placebo-treated patients after a median of 3 years on treatment.
Among the remaining 12,149 patients who did not receive an SGLT2 inhibitor, finerenone cut the average UACR by 32% compared with placebo, said Peter Rossing, DMSc, MD, who presented the findings on February 27 at the World Congress of Nephrology 2022 in Kuala Lumpur, Malaysia.
Primary endpoint results for FIDELIO-DKD and FIGARO-DKD also suggest similar additive effects of finerenone plus an SGLT2 inhibitor.
Results of the composite renal endpoint in each study — progression to kidney failure, renal death, or a ≥ 57% decline in estimated glomerular filtration rate (eGFR) from baseline — showed a 58% relative risk reduction in patients who received agents from both drug classes and a 20% relative risk reduction in those who only received finerenone, a between-group difference that was not significant.
For the composite cardiovascular event endpoint — cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for heart failure — the rate fell by 37% compared with placebo in patients who also received an SGLT2 inhibitor, and by 13% compared with placebo in those who received finerenone but no SGLT2 inhibitor, also a difference that was not significant.
“A Lot of Interest in Finerenone” in US
“The benefits of finerenone on cardiovascular and kidney outcomes were consistent, irrespective of SGLT2 inhibitor use at baseline,” concluded Rossing, professor and head of research at the Steno Diabetes Center in Copenhagen, Denmark.
The new findings are a “suggestion that the two classes might be additive [in their effects], but more data are needed,” Rossing said during his presentation.
But he cautioned that in both pivotal trials randomization did not consider SGLT2 inhibitor use. All patients in the two trials were already receiving a renin-angiotensin system (RAS) inhibitor as background treatment, either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB).
The consequence of treatment with finerenone combined with an SGLT2 inhibitor is of growing importance because “an SGLT2 inhibitor is now recommended in most guidelines” for the type of patients enrolled in the two finerenone trials, explained Rossing.
He also noted that the first guideline to recommend routine use of finerenone in indicated patients appeared recently in the annual update to Standards of Medical Care in Diabetes — 2022 published by the American Diabetes Association, as reported by Medscape Medical News.
The 2022 Standards states: “In patients with CKD who are at increased risk for cardiovascular events or CKD progression or are unable to use an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (finerenone) is recommended to reduce CKD progression and cardiovascular events.”
Results from FIDELIO-DKD, reported in The New England Journal of Medicine in 2020, and the main study, FIGARO-DKD, published in the same journal in 2021, led the US Food and Drug Administration to approve finerenone in July 2021 to slow the progression of renal disease in patients with type 2 diabetes and CKD.
“My impression is that in the United States there is a lot of interest in finerenone,” Rossing said during the discussion following his presentation.
Finerenone has also been recently approved in the European Union.
“Consistent“ Benefits Irrespective of SGLT2 Inhibitors
“The cardiovascular and kidney benefits of finerenone were consistent irrespective of SGLT2 inhibitor use. This is definitely interesting and warrants a randomized controlled trial” to examine the relationship in a more rigorous way, commented Tejas Desai, MD, a nephrologist with the US Department of Veterans Affairs, Charlotte, North Carolina.
That study, CONFIDENCE, is on its way, Rossing said during his talk. The randomized phase 2 trial has a planned enrollment of 800 patients with type 2 diabetes and CKD and three treatment groups: finerenone plus placebo, the SGLT2 inhibitor empagliflozin (Jardiance) plus placebo, or finerenone plus empagliflozin. The study will launch later in 2022 has a planned completion date of late 2023.
“SGLT2 inhibitors compared with finerenone is where all of this is headed. We need a large trial that adjudicates the best medication to use with a RAS inhibitor,” said Desai in an interview.
The new analyses from the combined FIDELITY study expand on a previous report presented at the European Society of Cardiology Annual Congress in 2021 and published in the European Heart Journal.
“Impressive“ Effect on Cardiovascular Events
The main findings from FIDELITY presented in those earlier reports, in 13,026 patients, showed there was a significant 14% relative reduction in the composite cardiovascular endpoint with finerenone compared with placebo during a median 3 years of follow-up.
The same report documented, in the total combined cohort, a significant 23% relative reduction in the composite renal endpoint in those taking finerenone compared with placebo.
“Reducing the risk of cardiovascular endpoints by a relative 14% is impressive,” and the time course showed a “relatively quick onset of action,” Desai noted.
He also characterized the enrolled patients, which included many with stage 3 or 4 CKD, as “not the sickest population of patients with CKD,” but rather “relatively healthier patients with CKD.”
Desai also downplayed the importance of the observed reduction in UACR associated with finerenone in FIDELITY.
“UACR is a surrogate marker. Results from many studies have shown improvements in UACR only to not show protection against falls in eGFR rate,” Desai said.
He was also reassured by the low incidence of hyperkalemia that led to discontinuation, which occurred in 1.7% of patients taking finerenone and in 0.6% of those taking placebo.
The types of patients enrolled in FIDELIO-DKD and FIGARO-DKD, who did not have eGFR rates below 25 mL/min/1.73m2, are not particularly susceptible to this adverse effect, he said, noting, “I’m not overly concerned with hyperkalemia in this CKD population,”
“I’m more concerned about [hyperkalemia in] patients with CKD and an eGFR of less than 25 mL/min/1.73m2, but this was less than 1% of the enrolled population,” Desai observed.
FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, which markets finerenone (Kerendia). Rossing has reported being a consultant for Bayer and other drug companies, and receiving research funding from AstraZeneca and Novo Nordisk. Desai has reported no relevant financial relationships.
World Congress of Nephrology 2022. Abstract LBCT-002. Presented February 27, 2022.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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