Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”
Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”
In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.
Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD , a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.
Finerenone looks better for safety
Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.
Dr. Deepak L. Bhatt
For treating patients with T2D and CKD ,finerenone overall “looks like a major advance,” Dr. Bhatt said in an interview.
In addition to the positive efficacy results, several experts also focused on what they saw as superior safety of finerenone in the trial, compared with the historical safety of the steroidal mineralocorticoid receptor antagonists (MRAs) now in use: spironolactone and eplerenone.
“I’m a big believer in spironolactone, but it has issues with side effects, and eplerenone never seemed to catch on,” said Dr. Bhatt, who is also executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.
“A lot of physicians like these MRAs, but acknowledge that side effects have kept these drugs from being used to the extent they should.” The existing MRAs, especially spironolactone, have become a key drug class for treating heart failure with reduced ejection fraction (and, some claim, for also treating heart failure with preserved ejection fraction), as well as treatment-resistant hypertension and primary aldosteronism. By design, FIDELIO-DKD did not enroll patients with heart failure because treatment with an MRA is indicated for those with heart failure with reduced ejection fraction.
The spironolactone adverse effect that generates the greatest concern is hyperkalemia. During his discussion of FIDELIO-DKD as designated discussant, Christoph Wanner, MD , noted a recent study in which the incidence of hyperkalemia severe enough to cause study discontinuation was 23% among patients treated with spironolactone for heart failure, which contrasts with the 2.3% rate in FIDELIO-DKD among finerenone recipients. This hyperkalemia incidence from finerenone also improved on the historical performance of other drugs, like aliskiren (Tekturna), said Dr. Wanner, professor and head of nephrology at the University of Würzburg (Germany).
The FIDELIO-DKD results place finerenone alongside the RAS- and SGLT2-inhibitor drug classes as appropriate treatments for most patients with T2D and CKD. “We have entered a new era of effective treatment for diabetic kidney disease,” Dr. Wanner declared.
“The overall safety profile of finerenone looked better, including hyperkalemia,” said Dr. Bhatt. “Hyperkalemia with spironolactone is not necessarily as bad as the perception. With careful monitoring of spironolactone, the hyperkalemia is manageable. But the perception is that it’s bad, and along with gynecomastia it’s a real killer.”
While some dismiss gynecomastia as a major concern (for men) with spironolactone treatment, “if medical students learn one thing about spironolactone, it’s that it can cause gynecomastia,” adding to the negative image that the approved MRAs carry, Dr. Bhatt said.
“The hyperkalemia was manageable. This is very important because of past problems with potassium when using spironolactone,” Dr. Filippatos said. Finerenone also looks “more cardiorenal protective” than the steroidal MRAs, exerting renal benefits in FIDELIO-DKD never previously described for a steroidal MRA.
Some of the uncertainty about the efficacy of finerenone in patients with a history of cardiovascular disease will lift when results are available in about another year from the FIGARO-DKD pivotal trial of finerenone, which enrolled more than 7,000 patients with T2D and CKD (entry criteria very similar to FIDELIO-CKD). A big difference is that FIGARO-DKD has a composite CVD event metric as its primary endpoint, and includes hospitalization for heart failure as one facet of the composite.
FIDELIO-DKD was sponsored by Bayer. Dr. Filippatos has been a lecturer on behalf of, served as a researcher for, or both for Bayer and also for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Bayer and also from several other companies, and he also is an adviser to several companies. Dr. Wanner has received honoraria from Bayer, and also from AstraZeneca, Boehringer Ingelheim, FMC, Gilead, GlaxoSmithKline, Lilly, and Merck.