Finerenone—A New Frontier in Renin-Angiotensin-Aldosterone System Inhibition in Diabetic Kidney Disease

Abstract

Commentary on Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. Commentary on Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. Glycemic control, blood pressure control, and single-agent renin-angiotensin-aldosterone system (RAAS) blockade were, until recently, the pillars of managing diabetic kidney disease (DKD). Although the introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors has further reduced DKD progression, patients continue to have significant residual risk, underlying the importance of identifying new therapies. In FIDELIO-DKD, Bakris et al1Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (247) Google Scholar demonstrate that the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (once daily 10-20 mg), on top of standard of care, is beneficial in DKD management. FIDELIO-DKD was a phase 3 trial conducted in adults with type 2 diabetes mellitus (T2DM) and DKD. Participants either had an estimated glomerular filtration rate (eGFR) of 25 to <60 mL/min/1.73 m2 with a urinary albumin-creatinine ratio (UACR) of 30 to <300 mg/g with diabetic retinopathy, or an eGFR of 25 to <75 mL/min/1.73 m2 with a UACR of 300 to 5,000 mg/g. In total, 5,674 participants were randomized and followed for a median of 2.6 years. Mean baseline eGFR was 44 mL/min/1.73 m2 with a median UACR of 852 mg/g. This was therefore a cohort of patients with T2DM and moderately advanced chronic kidney disease (CKD), with the majority (87%) having severely increased albuminuria. Although 99.9% of participants in FIDELIO-DKD were taking an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at baseline, only 4.5% were taking an SGLT2 inhibitor at baseline owing to the trial era. The primary outcome was a composite kidney outcome of kidney failure, sustained ≥40% decline in eGFR, or death with kidney disease as the underlying cause. Secondary outcomes included a cardiovascular (CV) composite comprising death from CV causes, nonfatal myocardial infarction, nonfatal stroke or hospitalization for heart failure, and a secondary composite kidney outcome identical to the primary outcome but requiring a 57% decline in eGFR. Compared to placebo, finerenone significantly reduced the incidence of the primary and secondary kidney outcomes by 18% and 24%, respectively. After consideration of a finerenone-associated acute decline in eGFR of 2.5 mL/min/1.73 m2 compared to placebo, the finerenone group declined by 2.66 mL/min/1.73 m2 per year versus a 3.97 mL/min/1.73 m2 per year decline in the placebo group, with a crossing of the eGFR curves occurring at approximately 24 months. From a safety perspective, there were no imbalances in the risks of kidney-related adverse events including acute kidney injury, or rates of breast hyperplasia and gynecomastia. Although the risk of hyperkalemia was increased with finerenone, the risk of hyperkalemia leading to study drug discontinuation was generally low (2.3% with finerenone compared to 0.9% with placebo). FIDELIO-DKD is the first to demonstrate that a strategy using 2 different RAAS inhibitors is beneficial with respect to “hard” kidney and CV outcomes. In previous trials such as ONTARGET,2Mann J.F.E. Schmieder R.E. McQueen M. et al.Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.Lancet. 2008; 372: 547-553Abstract Full Text Full Text PDF PubMed Scopus (1296) Google Scholar VA-NEPHRON-D,3Fried L.F. Emanuele N. Zhang J.H. et al.Combined angiotensin inhibition for the treatment of diabetic nephropathy.N Engl J Med. 2013; 369: 1892-1903Crossref PubMed Scopus (739) Google Scholar and ALTITUDE,4Parving H.H. Brenner B.M. McMurray J.J. et al.Cardiorenal end points in a trial of aliskiren for type 2 diabetes.N Engl J Med. 2012; 367: 2204-2213Crossref PubMed Scopus (936) Google Scholar dual RAAS blockade with non–MRA-based therapies increased risk of serious adverse events without significant benefit. ARTS-DN found that the addition of finerenone to RAAS blockade in patients with diabetes and proteinuric DKD reduced UACR in a dose-dependent manner with relatively low rates of hyperkalemia, leading to study drug discontinuation.5Bakris G.L. Agarwal R. Chan J.C. et al.Effect of finerenone on albuminuria in patients with diabetic nephropathy.JAMA. 2015; 314: 884Crossref PubMed Scopus (332) Google Scholar Results of ARTS-DN served as an impetus to study finerenone in a dedicated kidney outcome trial. A recently updated Cochrane systematic review summarized the literature up to but excluding FIDELIO-DKD and included 44 studies, with the majority evaluating the effects of spironolactone and eplerenone.6Chung E.Y. Ruospo M. Natale P. et al.Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.Cochrane Database Syst Rev. 2020; 10 (CD007004)PubMed Google Scholar The authors concluded that the use of MRAs in addition to standard of care in participants with proteinuric CKD may reduce albuminuria, with uncertain effects on kidney failure, CV events, or death, and with increased risk of hyperkalemia. This emphasizes the clinical equipoise for the use of MRAs in the setting of CKD and the importance of the FIDELIO-DKD trial with a pharmacologically distinct MRA. Finerenone does seem to have a more favorable side-effect profile compared to other MRAs. In ARTS, participants with heart failure and CKD stage 3 were randomized to several doses of finerenone, placebo, or spironolactone.7Pitt B. Kober L. Ponikowski P. et al.Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.Eur Heart J. 2013; 34: 2453-2463Crossref PubMed Scopus (264) Google Scholar Although finerenone increased serum potassium levels compared to placebo, the increase was significantly lower compared to spironolactone at all doses of finerenone. Results of kidney outcome trials with SGLT2 inhibitors provide context to the results of FIDELIO-DKD. The CREDENCE trial,8Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1841) Google Scholar a dedicated DKD trial, serves as the obvious comparison. The mean baseline eGFR in CREDENCE was higher than FIDELIO-DKD at 56.2 mL/min/1.73 m2, albeit with a higher median UACR of 927 mg/g and more rapid rate of eGFR decline of 4.59 mL/min/1.73 m2 per year in the placebo group. The primary outcome of CREDENCE was a 57% decrease in eGFR, kidney failure, or death from kidney disease or CV causes, with a hazard ratio (HR) of 0.70 favoring canagliflozin. The primary kidney composite in FIDELIO-DKD included a lower ≥40% sustained eGFR decline, did not include CV death, and had an HR of 0.82 favoring finerenone. Differences in primary outcomes make it impossible to directly compare the efficacy of these drugs in patients with DKD. Additionally, CREDENCE did not enroll participants taking an MRA at baseline, whereas FIDELIO-DKD did include a small number of participants on an SGLT2 inhibitor. Considering the components of the secondary kidney composite, the impact on reducing the risk of a ≥57% decline in eGFR was similar in the 2 trials (HRs of 0.68 and 0.60, favoring finerenone and canagliflozin, respectively), with similar numbers of events and observation periods in both trials. The kidney failure outcome was also similarly defined in both studies, and reported HRs were 0.87 (95% CI, 0.72-1.05) in FIDELIO-DKD versus 0.68 (95% CI, 0.54-0.86) in CREDENCE. Regarding the chronic eGFR slope after the acute “dip” with treatment initiation, the between-group difference favoring the intervention was +1.31 mL/min/1.73 m2 per year in FIDELIO-DKD versus +2.74 mL/min/1.73 m2 per year in CREDENCE. In the DAPA-CKD trial, which included participants with and without T2DM and a similar rate of eGFR decline in the placebo group as FIDELIO-DKD, the between-group difference in chronic eGFR slope was also higher at +1.92 mL/min/1.73 m2 per year.9Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (671) Google Scholar Furthermore, the crossover of the eGFR curves in CREDENCE and DAPA-CKD occurred at approximately 12 months, compared to 24 months in FIDELIO-DKD. Taken together, based on available data, finerenone may have a smaller benefit on hard kidney outcomes compared to canagliflozin and dapagliflozin, though quantitative effect size comparisons are not possible without direct head-to-head comparison trials. The nephrology community has witnessed yet another trial demonstrating kidney and CV protection in patients with established DKD. In terms of a therapeutic hierarchy, finerenone and SGLT2 inhibitors were both studied in addition to baseline single-agent RAAS inhibition and should therefore be prescribed in this manner. Additionally, there now exists a strong rationale for the combined use of SGLT2 inhibitors and nonsteroidal MRAs such as finerenone in DKD, given potentially complementary mechanisms of action (Fig 1). Though it is unknown if large clinical trials using combination RAS inhibitor–SGLT2 inhibitor–MRA will ever be performed, smaller mechanistic clinical studies with these therapies should be conducted to better understand effects on surrogate markers such as eGFR decline and UACR, as well as the potential for combining these therapies with other DKD treatments such as glucagon-like-peptide 1 (GLP-1) receptor agonists.10Lytvyn Y. Bjornstad P. van Raalte D.H. Heerspink H.L. Cherney D.Z.I. The new biology of diabetic kidney disease-mechanisms and therapeutic implications.Endocr Rev. 2020; 41: 202-231Crossref Scopus (26) Google Scholar Though nephrologists should remain vigilant for hyperkalemia when finerenone is eventually used in practice, it is also important that these concerns do not affect uptake of this important new therapeutic option. Bakris and colleagues observed a clinically modest but significant increase of 0.23 mmol/L in serum potassium levels that remained stable from month 4 onwards. Hyperkalemia, even if modest (eg, <5.5 mmol/L), may lead to premature and unnecessary discontinuation of RAAS blockade therapies. However, there are several approaches to mitigate these risks. In addition to dietary advice and use of diuretics, newer potassium binders such as patiromer and sodium zirconium cyclosilicate safely reduce serum potassium levels, and by a greater extent than the 0.23 mmol/L increase attributed to finerenone in FIDELIO-DKD.11Weir M.R. Bakris G.L. Bushinsky D.A. et al.Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.N Engl J Med. 2015; 372: 211-221Crossref PubMed Scopus (395) Google Scholar,12Packham D.K. Rasmussen H.S. Lavin P.T. et al.Sodium zirconium cyclosilicate in hyperkalemia.N Engl J Med. 2015; 372: 222-231Crossref PubMed Scopus (274) Google Scholar Furthermore, the PEARL-HF study demonstrated that the use of patiromer enabled a larger proportion of heart failure patients to take guideline-directed MRA therapy.13Pitt B. Anker S.D. Bushinsky D.A. et al.Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial.Eur Heart J. 2011; 32: 820-828Crossref PubMed Scopus (288) Google Scholar Hyperkalemia also may serve as another justification for the use of MRAs in combination with an SGLT2 inhibitor. In a post hoc analysis of MRA use in DAPA-HF,14Kristensen S.L. Docherty K.F. Jhund P.S. et al.Dapagliflozin reduces the risk of hyperkalaemia in patients with heart failure and reduced ejection fraction: a secondary analysis DAPA-HF.Eur Heart J. 2020; 41PubMed Google Scholar dapagliflozin significantly reduced the risk of hyperkalemia. Multiple options are thus available to mitigate the risk of hyperkalemia and maximize use of finerenone in combination with either an ACEI or ARB. In conclusion, FIDELIO-DKD provides the first evidence of kidney and CV protection with the nonsteroidal MRA finerenone in patients with DKD. Furthermore, the risk of significant hyperkalemia with finerenone and other novel MRAs such as esaxerenone seems to be low.1Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (247) Google Scholar,15Ito S. Kashihara N. Shikata K. et al.Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial.Clin J Am Soc Nephrol. 2020; 15: 1715-1727Crossref PubMed Scopus (21) Google Scholar While further studies with this class of medication are ongoing (FIGARO-DKD; NCT02545049), practice guidelines may evolve to incorporate the use of finerenone in the management of DKD, in combination with ACEIs/ARBs and SGLT2 inhibitors. However, uptake of therapies for the treatment of DKD has been slow. Only 20%-40% of those eligible to take ACEIs or ARBs for the treatment of CKD are actually taking these medications in some jurisdictions, and the use of SGLT2 inhibitors has been similarly slow.16Tuttle K.R. Brosius 3rd, F.C. Cavender M.A. et al.SGLT2 Inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation.Am J Kidney Dis. 2021; 77: 94-109Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Although the solutions to these issues are complex, nephrologists will play a leading role in educating physicians and patients on the appropriate and timely use of these novel and effective therapies. Vikas S. Sridhar, MD, Hongyan Liu, BMSc, and David Z.I. Cherney, MD, PhD. Dr Sridhar and Mr Hongyan Liu contributed equally to this work. No monetary or nonmonetary support was received for the preparation of this editorial. Dr Sridhar is supported by the Department of Medicine Eliot Phillipson Clinician Scientist Training Program and a Banting and Best Diabetes Centre Postdoctoral Fellowship at the University of Toronto . Dr Cherney has received consulting fees or speaking honorarium or both from Janssen, Bayer , Boehringer Ingelheim–Eli Lilly , AstraZeneca , Merck & Co Inc, Prometic, Maze, Novo Nordisk, and Sanofi; has received operating funds from Janssen, Boehringer Ingelheim–Eli Lilly , Sanofi , AstraZeneca , Novo Nordisk, and Merck & Co Inc; is supported by a Department of Medicine, University of Toronto Merit Award; and receives support from the CIHR , Diabetes Canada , and the Heart and Stroke Richard Lewar Centre of Excellence. Mr Hongyan Liu declares that he has no relevant financial interests. Received January 8, 2021 in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form February 7, 2021. Finerenone: Fiddling With Hyperkalemia?American Journal of Kidney DiseasesVol. 78Issue 5PreviewFinerenone was recently approved by the US Food and Drug Administration for treatment of diabetic kidney disease (DKD). However, the commentary from Sridhar et al1 on the FIDELIO trial2 minimizes hyperkalemia and overstates the superiority of finerenone over other mineralocorticoid receptor antagonists (MRAs). The authors state that few patients discontinued finerenone owing to hyperkalemia (2.3% vs 0.9%). However, the enrollment criteria were crafted to minimize this, requiring a potassium level <4.8 mEq/L during screening and run-in, resulting in almost 60% exclusion. Full-Text PDF