Background
In the United States (US), 34.2 million people had diabetes in 2018.¹ Diabetes is the main cause of end-stage renal disease (ESRD), and in 2017, 47% of newly diagnosed ESRD cases were primarily due to diabetes.^1,2 Despite advancements in diabetes treatment, prevalence of diabetic kidney disease (DKD) is increasing. DKD is associated with a high risk of mortality and adverse cardiovascular (CV) and renal outcomes.²

Traditionally, in DKD patients, angiotensin II (Ag-II) has been considered the primary component of the renin-angiotensin-aldosterone system (RAAS) that leads to renal injury, ESRD, CV events, and mortality. Recently, it was found that DKD patients have high aldosterone levels and increased mineralocorticoid receptor (MR) activity, which highlights the importance of aldosterone and Ag-II in DKD progression.^3,4 Poorly selective steroid-based mineralocorticoid receptor antagonists (MRA) reduce albuminuria and blood pressure in CKD patients on RAAS inhibitors;^5-7 they have, however, a higher likelihood of sex hormone-related side effects and hyperkalemia.^8,9 These adverse effects are more prominent in older diabetic patients with CKD that represent a large number of patients with diabetes. To reduce adverse effects in these vulnerable patients and delay CKD progression, non-steroidal MRAs such as finerenone have been developed, but their safety and efficacy in DKD patients has been heretofore unknown.¹⁰

Methods
The FIDELIO-DKD trial was a multicentric, international, phase 3, randomized, double-blind, placebo-controlled clinical trial.¹¹ It evaluated the safety and efficacy of finerenone in slowing CKD progression and reduction of CV events in patients ≥18 years old with type 2 diabetes (T2DM) and advanced CKD. Eligible patients had CKD, were on maximally tolerated dose of RAAS inhibitors, and had serum potassium levels ≤4.8. CKD was defined as either albuminuria ≥30 to ≤300 mg/g with eGFR ≥25 to <60 ml/min/1.73m2 and diabetic retinopathy, or as albuminuria ≥300 to ≤5000 mg/g with eGFR ≥25 to <75 ml/min/1.73m2. After a period during which CV and anti-hyperglycemic medications were optimized and randomized, enrolled patients were assigned to oral finerenone (those with an eGFR ≥60 ml/min received 20 mg, those with eGFR <60 received 10 mg) or placebo. After one month, the dose was increased if serum potassium and eGFR were stable and decreased if they were not.

The primary outcome was renal, assessed in a time-to-event analysis for a composite of death from renal cause, ≥40% reduction in eGFR during 4 weeks, kidney failure, dialysis ≥90 days, or transplantation.¹¹ The secondary outcome was CV outcomes, which included a composite of death from CV causes, myocardial infarction (MI), stroke, or hospitalization for heart failure (HF).¹¹ In secondary analysis authors evaluated the effect of finerenone on primary and secondary cardiorenal outcomes stratified by presence or absence of cardiovascular disease (CVD).¹²

Results
For the study, 13,911 individuals were screened, and 5,674 patients were included in the trial (mean age 66.6 yrs, 30% female) with a median follow-up of 2.6 years. The study population was predominantly white (63.3%), and 2,605 (46%) participants had CVD at baseline. Altogether 46% and 45.8% of participants receiving finerenone and placebo, respectively, had CVD at baseline. Participants with CVD were more likely men, white, had longer diabetes duration, and were more likely receiving platelet aggregation inhibitors, beta-blockers, and statins. Mean finerenone dose and median follow-up were comparable between those with or without CVD.

The incidence of primary composite renal outcome was lower in the finerenone versus placebo arm; 504 (17.8%) in the finerenone group and 600 (21.1%) patients in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73 to 0.93; P=0.001).¹¹ The relative effects of finerenone on the composite renal outcome were statistically similar in patients with and without a history of CVD (p=0.07). However, in patients with CVD, the composite renal outcome occurred in 15.3% of the finerenone treated versus 20.5% of the placebo group (HR, 0.70; 95% CI, 0.58-0.84; P=0.016) for a larger absolute benefit. Likewise, the relative effects of finerenone on eGFR slope or reduction in urine albumin creatinine ratio (UACR) was not modified by CVD history. Although incidence of adverse effects including hyperkalemia was higher in the finerenone versus placebo group, the rate of drug discontinuation and hospitalization due to hyperkalemia was similar in both arms, and these incidences were similar across groups stratified by CVD history. A modest reduction in systolic blood pressure was observed in the finerenone group regardless of CVD. There was no change in weight in the two groups, even when stratified by CVD history.

The incidence of the composite CV outcome, comprising time to first event of CV death (HR, 0.86 [95% CI, 0.68-1.08]), non-fatal MI (HR, 0.80 [95% CI, 0.58-1.09]), non-fatal stroke (HR, 1.03 [95% CI, 0.76-1.38]), or hospitalization for HF (HR, 0.86 [95% CI, 0.68-1.08]) was lower in the finerenone group than in the placebo group, namely 367 patients (13%) versus 420 patients (14.8%), yielding an HR of 0.86 (95% CI, 0.75-0.99; P =0.034). Incidence of CV death, MI, and hospitalization for HF was lower in the finerenone group, while the incidence of stroke was similar in both groups. Likewise, the effect of finerenone on the incidence of composite CV outcomes was not modified by CVD history (p=0.85) or HF (p=0.33).

Conclusion
Finerenone is safe and efficacious in patients with CKD and T2DM. It protects the kidney and reduces CV events, regardless of prior CVD. The data suggest it may benefit in both primary and secondary prevention of CV events in high-risk T2DM patients with advanced CKD. Although finerenone is associated with higher incidence of hyperkalemia, the hospitalization rate due to hyperkalemia or drug discontinuation was the same in finerenone and placebo arms.

Commentary/Perspective
Patients with T2DM and CKD are at high risk of adverse CV events. The FIDELIO-DKD trial evaluated safety and outcome of finerenone in vulnerable patients with advanced CKD due to T2DM and a history of CVD.¹¹ The trial revealed reduction in the progression rates of CKD, and a lower incidence of CVD events, and the observed benefits were clinically significant and obtained on a RAAS inhibitor therapy background. This new therapy, which is beneficial in a non-HF and advanced diabetic CKD cohort, seems very promising as it tackles both renal and CV outcomes, which could potentially help millions with DKD without evident HF.

When evaluating individual CV endpoints, three of the four components, except for stroke, indicated an advantage for finerenone. It is known that reducing blood pressure may provide additional benefit in improving stroke outcomes;¹³ given minimal impact of finerenone on blood pressure, this could reflect an effect of finerenone on non-fatal stroke. FIDELIO-DKD also showed a greater absolute benefit of finerenone on composite kidney outcome in patients with CVD.

The underlying mechanism of the observed benefit is unknown, although one hypothesis includes primary hyperaldosteronism in CVD patients or MR overactivation have highly negative impact in patients with damaged vasculature as this pathophysiology could be blunted by finerenone. It may be this agent class has previously unrecognized effects on vascular tissue, for example via inflammatory pathways, and future studies may further elucidate the mechanism.

A remaining question is whether this cardiorenal benefit of finerenone is limited to this drug alone or applies also to other cardiometabolic drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and GLP1 receptor agonist (GLP-1RA). Authors should be commended because they included patients taking SGLT2i (4.6%) and GLP-1RA (5.1%) while patients taking MRAs were excluded from other kidney-specific trials including the CREDENCE trial.¹⁴ These results will have important implications for diabetic patients with advanced CKD and concomitant CVD and require the addition of cardiometabolic therapies such as SGLT2i and GLP-1RA. As clinical trials are conducted in a standardized environment, results can be difficult to replicate in the real world, particularly in key subgroups with multiple concomitant therapies. It will be interesting to see whether similar outcomes can be obtained in clinical practice.

This study had several limitations. The history of CVD was determined by review of medical records, thereby patients with subclinical CVD have likely been classified as no CVD – this may have important implications for patients seen in preventive cardiology practices. Most vulnerable patients, including those with poorly controlled diabetes, severe hypertension, or HF were excluded, which could have given further insight in the impact of finerenone. Likewise, patients with CKD not due to T2DM and non-albuminuric CKD were excluded, and only 4.7% participants were Black, which limits generalizability of the findings. The authors could have taken steps to enroll more minority patients. To learn more about safety and efficacy of finerenone in other high-risk patients, future studies should take steps to enroll patients with non-albuminuric CKD, advanced CKD (eGFR <25 ml/min/1.73m2), HF, poorly controlled T2DM, or hypertension.

Cardiologists often see high-risk patients with T2DM and CKD in their clinical practice and they are usually concerned about CKD progression and recurrence of CV events despite blood pressure and glycemic control. Arrhythmias are another major concern that lead to symptoms, hospitalizations, and increased cost. Secondary analysis of FIDELIO-DKD trial shows that finerenone also reduces risk of new-onset atrial fibrillation or atrial flutter (AF/Fl); also, there was significant reduction of cardiorenal events irrespective of underlying AF/Fl.¹⁵ High prevalence of AF/Fl in T2DM and CKD patients invokes the need for more upstream intervention for the primary prevention and better treatment of AF/Fl and its underlying cardiometabolic etiologies.

Top line data from ongoing CV outcome trial of finerenone (i.e., FIGARO-DKD)¹⁶ which included patients with moderate CKD as well as T2DM patients on SGLT2i/GLP1RA, were recently announced. This revealed net cardioprotective effects of finerenone on a composite outcome of CV mortality plus non-fatal CV events. We await the full reporting of the FIAGRO-DKD results as it will give more information about finerenone in milder DKD and in the context of combination therapy. Pooled analysis of data from both trials will likely give robust evidence for finerenone use for both primary and secondary CVD prevention, with a large impact on cardiorenal outcomes. Finerenone is currently under review by the US Food and Drug Administration (FDA).

In recent years, newer treatments for T2DM and DKD are shifting focus away from glucocentric views towards organ protection, and finerenone is the latest addition. In our opinion, once approved, finerenone will likely play a major role in future DKD management especially in reduction of CKD progression and future CV events.

References

1. National Diabetes Statistics Report (CDC website). 2020. Available at: https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed 05/30/2021.
2. 2018 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States (United States Renal Data System website). 2018. Available at: https://www.usrds.org/annual-data-report/previous-adrs/. Accessed 05/30/2021.
3. Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 2001;37:677-88.
4. Messaoudi S, Azibani F, Delcayre C, Jaisser F. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol 2012;350:266-72.
5. Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev 2014;4:CD007004.
6. Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 2001;345:925-26.
7. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006;1:940-51.
8. Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 2008;51:199-211.
9. Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol 2014;34:333-39.
10. Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol 2012;350:310-17.
11. 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;383:2219-29.
12. Filippatos G, Anker SD, Agarwal R, et al. Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation 2021;143:540-52.
13. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016;387:957-67.
14. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
15. Filippatos G, Bakris GL, Pitt B, et al. Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes. J Am Coll Cardiol 2021;78:142-52.
16. Bayer's finerenone meets primary endpoint in Phase III FIGARO-DKD cardiovascular outcomes study in patients with chronic kidney disease and type 2 diabetes (Bayer Global website). 2021. Available at: https://media.bayer.com/baynews/baynews.nsf/id/F6AC5A8D4B0647AAC12586D100282B80?open&ref=irrefndcd. Accessed 06/08/21.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Nonstatins, Novel Agents, Statins, Acute Heart Failure

Keywords: Metabolic Syndrome, Mineralocorticoid Receptor Antagonists, Renin-Angiotensin System, Antihypertensive Agents, Aldosterone, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Angiotensin II, Platelet Aggregation Inhibitors, Creatinine, Receptors, Mineralocorticoid, Diabetic Nephropathies, Albuminuria, Blood Pressure, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Hyperkalemia, Diabetic Retinopathy, Double-Blind Method, Secondary Prevention, Confidence Intervals, Maximum Tolerated Dose, Follow-Up Studies, Atrial Fibrillation, Renal Dialysis, Kidney, Renal Insufficiency, Chronic, Kidney Failure, Chronic, Renal Insufficiency, Heart Failure, Potassium, Hospitalization, Pharmaceutical Preparations, Myocardial Infarction, Stroke, Hypoglycemic Agents, Albumins

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