Results from the much-anticipated Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial were published recently. This double-blind, placebo-controlled trial evaluated the effects of the “novel” mineralocorticoid receptor antagonist—finerenone—on kidney and cardiovascular outcomes in patients with advanced CKD and type 2 diabetes mellitus. The study tested the hypothesis that finerenone slows the progression of kidney disease and reduces cardiovascular mortality and morbidity (1).
Finerenone (developmental code name BAY 948862) has been described as an effective and selective third-generation nonsteroidal mineralocorticoid receptor antagonist (2). The mechanism of action of finerenone is different than previous “similar” drugs. Although classic mineralocorticoid receptor antagonists bind in the ligand binding domain of the receptor, finerenone causes conformational alterations in the mineralocorticoid receptor through a bulky side chain. The bulky molecule causes the protuberance of the mineralocorticoid receptor helix 12, which has an important role in the activation of the receptor through the binding of key coactivators (2). Although a single oral dose is usually well tolerated, in initial pharmacokinetics studies, exposure to finerenone was higher in patients with moderate and severe kidney function impairment when compared with normal kidney function, with a moderate to high variability among individuals (3).
The medical community reacted with some excitement to the positive results of the trial. The incidence of the primary composite outcome of death from kidney causes or kidney failure, which was considered a persistent reduction of >40% in the eGFR from the baseline, was significantly lower in patients on finerenone than placebo during a median follow-up of 2.6 years (hazard ratio, 0.82; 95% confidence interval, 0.73 to 0.93; P=0.001) (1).
However, certain aspects of this trial warrant further discussion. First, the use of a composite primary outcome requires some caution when interpreting the results (4). Second, after 3 years, the number needed to treat was 29 to prevent one primary outcome event and 42 to avoid one key secondary outcome event (1).
Comparatively, novel drugs have been proposed to patients with CKD and diabetes mellitus in the past years with superior outcomes: dapagliflozin, atrasentan, and canagliflozin. Dapagliflozin showed a 36% lower relative risk (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.79) than placebo for patients with type 2 diabetes for the primary composite outcome—a sustained decrease in the eGFR of ≥50%, kidney failure, or death from kidney or cardiovascular causes (5). The number needed to treat with dapagliflozin to prevent one primary outcome event was 19—lower than with finerenone. In the Study of Diabetic Nephropathy with Atrasentan, the relative risk of the primary outcome was 35% lower in the atrasentan group than in the placebo group (hazard ratio, 0.65; 95% confidence interval, 0.49 to 0.88; P=0.005). The primary outcome was a composite of doubling of serum creatinine level (sustained for ≥30 days) or kidney failure (eGFR<15 ml/min per 1.73 m2 sustained for ≥90 days, maintenance dialysis for ≥90 days, kidney transplantation, or death from kidney failure) (6). The hazard ratio for the comparison of canagliflozin and placebo for the primary outcome (a composite of kidney failure, a doubling of the serum creatinine, or death from kidney or cardiovascular causes) was 0.70—a 30% lower relative risk than placebo (hazard ratio, 0.70; 95% confidence interval, 0.47 to 0.80; P<0.001) (7). Taken together, these recent data suggest that dapagliflozin, atrasentan, and canagliflozin may be better alternatives than finerenone for patients with CKD and diabetes mellitus.
Additionally, FIDELIO-DKD raises another major concern. CKD is a well-recognized risk factor for hyperkalemia, with a prevalence rate ranging from 14% to 20% (8). In line with this concern, the serum potassium levels of patients on finerenone, as well as the incidence of hyperkalemia, were much higher than in patients who were taking placebo in the FIDELIO-DKD trial. Patients in the finerenone group had a higher mean serum potassium level compared with the placebo group. Although the incidences of moderate (>5.5 mEq/L) and severe hyperkalemia (>6.0 mEq/L) were 9.8% and 1.4% in the placebo group, respectively, they were more than two- and three-fold in patients treated with finerenone: 21.7% and 4.5%, respectively. Although no fatal cases were reported, hyperkalemia-related events were twice as likely in patients who used finerenone (18.3%) than in the placebo group (9.0%) (1).
In order to further address these concerns, first we must revisit a seminal study published 20 years ago in the same prestigious journal: the Randomized Aldactone Evaluation Study, widely known by its acronym RALES. In summary, this trial showed that “blocking of mineralocorticoids receptors with spironolactone, in addition to standard therapy, significantly diminishes morbidity and mortality risk in patients with severe heart failure” (9). The incidence of serious hyperkalemia was minimal and had no statistical significance: 14 patients of 841 (2%, P=0.42) in the spironolactone group versus ten patients of 822 (1%) in the placebo group. Although 62 patients (8%) in the spironolactone group discontinued treatment due to adverse events, against 40 patients (5%) in the placebo group, this was probably due to a higher incidence of breast pain or gynecomastia among men using spironolactone (P<0.001) (9). Conversely, in the FIDELIO-DKD trial, there were many more patients who discontinued the drug due to hyperkalemia in the finerenone group (64 of 2827, 2.3%) compared with the group of patients receiving placebo (25 of 2831, 0.9%) (1).
As expected, rate of prescriptions of spironolactone increased following publication of RALES; however, in parallel, there was also a substantial “unexpected” rise in the number of hospital admissions and deaths associated with iatrogenic hyperkalemia (Figure 1) (10).
;)
Figure 1.: Hospital admission and in-hospital death rates associated with hyperkalemia in patients hospitalized with heart failure who were also treated with ACE inhibitors following publication of the Randomized Aldactone Evaluation Study (RALES) study. The bars indicate in a 4-month period, the rate of hospital admission due to hyperkalemia per 1000 patients (A) and the in-hospital death rate associated with hyperkalemia per 1000 patients (B). Starting at the second interval of the year 1999, the line shows the projected rates of hospital admissions due to hyperkalemia (A) and in-hospital death rates associated with hyperkalemia (B) derived from interventional ARIMA models, with I bars representing the 95% confidence intervals. ACE, angiotensin-converting enzyme; ARIMA, autoregressive integrated moving average. Adapted from ref.
10, with permission.
Beyond its formal landmark results and academic conclusion, RALES taught the medical community, in a harsh manner, a quite intuitive “between the lines” lesson: that results obtained in controlled environments (randomized controlled trials) should be translated to the “real world” with caution (11).
Finally, we are concerned that the positive outcomes of FIDELIO-DKD may lead to wider (and indiscriminate) prescription of finerenone, which could potentially increase drug-induced hyperkalemia cases in the population of patients with CKD. Our previous experience with RALES cautions us about what also might come following publication of impactful results from controlled trials. Whether we actually learned this lesson or whether a substantial part of the RALES legacy has already been forgotten will only be discovered in the years to come (11). Until more robust evidence is available, we must still be careful when deciding to prescribe finerenone to patients with advanced CKD.
Disclosures
J.A. Moura-Neto reports serving as Vice President Northeast of the Brazilian Society of Nephrology and serving as Associate Editor of Blood Purification and Section Editor of the Brazilian Journal of Nephrology. C. Ronco reports consultancy agreements with Asahi, Astute, Baxter, Biomerieux, Cytosorbents, GE, Jafron, Medtronic, OCD, and Toray; receiving honoraria from Astute, Baxter, B. Braun, Estor, Fresenius, GE, Jafron, Medtronic, and Toray; contributions to Nephrology and Cardiorenal Medicine; and serving as Editor-in-Chief of Blood Purification and Associate Editor of Nephrology Dialysis and Transplantation.
Funding
None.
Acknowledgments
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s). The authors are grateful to the New England Journal of Medicine and the Massachusetts Medical Society for permission to adapt Figure 1.
References
1. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators: Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 383: 2219–2229, 2020
2. Haller H, Bertram A, Stahl K, Menne J: Finerenone: A new mineralocorticoid receptor antagonist without hyperkalemia: An opportunity in patients with CKD? Curr Hypertens Rep 18: 41, 2016
3. Heinig R, Kimmeskamp-Kirschbaum N, Halabi A, Lentini S: Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment. Clin Pharmacol Drug Dev 5: 488–501, 2016
4. Cordoba G, Schwartz L, Woloshin S, Bae H, Gøtzsche PC: Definition, reporting, and interpretation of composite outcomes in clinical trials: Systematic review. BMJ 341: c3920, 2010
5. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators: Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383: 1436–1446, 2020
6. Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D; SONAR Committees and Investigators: Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomised, placebo-controlled trial [published erratum appears in
Lancet 393: 1936, 2019]. Lancet 393: 1937–1947, 2019
7. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 2295–2306, 2019
8. Di Lullo L, Ronco C, Granata A, Paoletti E, Barbera V, Cozzolino M, Ravera M, Fusaro M, Bellasi A: Chronic hyperkalemia in cardiorenal patients: Risk factors, diagnosis, and new treatment options. Cardiorenal Med 9: 8–21, 2019
9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J; Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341: 709–717, 1999
10. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA: Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 351: 543–551, 2004
11. Moura-Neto JA, Ronco C: Finerenone and chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 384: e42, 2021
