What evidence is available for use of the newest mineralocorticoid receptor antagonist, finerenone, in diabetic kidney disease?

Introduction
Chronic kidney disease (CKD) is common in patients with diabetes.¹ Hyperglycemia can result in advanced glycation end products and reactive oxygen species that damage the kidney through proinflammatory and profibrotic changes.² Chronic kidney disease is characterized by reduced glomerular filtration rate (GFR) or urinary albumin excretion for at least 3 months.¹ Approximately 1 in 3 adults with diabetes has CKD; this prevalence has remained stable at roughly 26% from 1988 to 2014.³ Patients with diabetes and CKD are at increased risk of cardiovascular (CV) events such as myocardial infarction (MI), stroke, heart failure (HF), and death.

Overactivation of mineralocorticoid receptors can contribute to progression of CKD.⁴ Guideline-directed medical therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can reduce circulating aldosterone levels in addition to reducing the risk of CV events in patients with diabetes and CKD. However, rebound hyperaldosteronism can occur in some patients through a phenomenon called “aldosterone escape”.⁵ Mineralocorticoid receptor antagonists (MRA), when added to renin-angiotensin system (RAS) blockade, can address aldosterone escape and reduce proteinuria in patients with CKD.⁶ However, MRAs carry a risk of hyperkalemia that has made their use challenging.

In July 2021, the US Food and Drug Administration (FDA) approved the newer-generation nonsteroidal MRA finerenone to reduce the risk of a composite of adverse CV outcomes in adults with CKD associated with type 2 diabetes mellitus (T2DM).⁷ Finerenone is more selective for the mineralocorticoid receptor than spironolactone, has greater affinity for this receptor than eplerenone, and produces only mild effects on serum potassium.^4,8 Because finerenone represents a new option for a prevalent disease with multiple therapeutic options that reduce CV risk, this review discusses the available evidence for finerenone in its FDA-approved indication.

Treatment of Diabetic Kidney Disease
In patients with diabetes and CKD, numerous medical therapies are recommended to reduce the risk of progression and cardiorenal outcomes. These include intensive blood pressure lowering with either an ACE inhibitor or ARB and glycemic control with one of various antihyperglycemic agents.^9-15 In recent years, clinical trials of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) also have demonstrated reduced risk for adverse CV outcomes in patients with T2DM. Some of these agents now carry labeled indications and strong guideline recommendations for their use in patients with T2DM.^10-18

In patients with T2DM and CKD, guideline recommendations from Kidney Disease Improving Global Outcomes (KDIGO) state that first-line treatment should include metformin and an SGLT-2 inhibitor and additional drug therapy as needed for glycemic control with a preference for long-acting GLP-1 RAs.¹⁴ Similar recommendations are provided by the American Association of Clinical Endocrinology.¹⁹ Likewise, the American Diabetes Association (ADA) recommends considering SGLT-2 inhibitors for patients with T2DM and diabetic kidney disease in those with estimated GFR (eGFR) ≥30 mL/min/1.73 m2 and/or urinary albumin >300 mg/g, and a GLP-1 RA to reduce renal outcomes.¹⁰ All of these guideline recognize the potential for these medications to improve cardiorenal outcomes.

Mineralocorticoid receptor antagonists thus far have a more limited role in patients with T2DM. Currently, guidelines from KDIGO and the ADA recommend MRAs be considered in patients with diabetes and resistant hypertension who are not meeting blood pressure targets to improve hypertensive control and albuminuria.¹² Landmark clinical trials demonstrating CV risk reduction with the earlier-generation MRAs spironolactone and eplerenone have been limited to patients with HF.⁵

Current Evidence for Finerenone
In early clinical development, finerenone was studied in shorter-term trials that demonstrated improvements in urinary albumin-to-creatinine ratio (UACR) and N-terminal pro-B-type natriuretic peptide in patients with diabetic nephropathy who were receiving background RAS blockade.^20-22 Finerenone has also shown improvements in biochemical markers in patients with HF.²³

The phase III Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial supported FDA approval of finerenone to reduce the risk of sustained eGFR decline, end stage kidney disease, CV death, non-fatal MI, and hospitalization for HF in adults with CKD associated with T2DM.²⁴ The trial included patients with T2DM and CKD, which was defined using two sets of criteria. The first of these included moderately elevated albuminuria (UACR, 30 to <300), eGFR of 25 to <60 mL/min/1.73 m², and diabetic retinopathy. The second of these included severely elevated albuminuria (UACR, 300 to 5000) and eGFR of 25 to <75 mL/min/1.73 m². Those with non-diabetic renal disease were excluded. Patients were required to have a serum potassium level of 4.8 mmol/L or less.

During a run-in phase, the dosage of background RAS blockers was increased to maximum tolerated labeled dosages.²⁴ Patients were then randomized to placebo or oral finerenone, which was titrated to 20 mg once daily in patients with stable eGFR, and was withheld if serum potassium concentrations exceed 5.5 mmol/L, and restarted when concentrations returned to 5.0 mmol/L or below.

The primary composite outcome of FIDELIO-DKD included kidney failure (initiation of long-term dialysis, kidney transplantation, or an eGFR <15 mL/min/1.73 m²), a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes.²⁴ After a median follow-up of 2.6 years, the primary outcome was significantly improved with finerenone versus placebo (Table 1). Among the component endpoints, only sustained decrease in eGFR was significant. However, this may be attributable to its higher incidence than other component endpoints. In contrast, death from renal causes occurred in only 2 patients in each group, and a HR was not calculated. Stratified analyses of the primary composite endpoint indicated generally consistent effects in prespecified groups with high and low values of serum potassium, eGFR, glycated hemoglobin, and systolic blood pressure (SBP). However, no benefit was seen with finerenone in patients with baseline body mass index (BMI) ≥30 kg/m² (n=2995) or with no history of CV disease (n=3069).

Finerenone also significantly improved the key secondary endpoint of death from CV causes, nonfatal MI, nonfatal stroke, and hospitalization for HF (Table 1). None of the components of this endpoint were individually significant, although the incidences for all except for nonfatal stroke again were lower with finerenone.

Adverse events of any severity occurred with similar frequency in finerenone and placebo groups (87.3% and 87.5%, respectively) as did serious adverse events (31.9% and 34.3%).²⁴ Hyperkalemia-related adverse events were more frequent with finerenone (18.3% vs 9.0%), as was discontinuation due to hyperkalemia (2.3% vs 0.9%). Patients treated with finerenone experienced an increase in serum potassium of approximately 0.2 mmol/L throughout the trial.

Analysis and Implications of FIDELIO-DKD
The FIDELIO-DKD trial benefitted from its randomized and blinded design (including a blinded adjudication committee), which overall places the study at low risk of bias.²⁴ The trial included a large number of patients from multiple countries and adherence was high (>92% in both groups). That finerenone demonstrated a significant benefit in patients already treated with maximum tolerated doses of ACE inhibitors and ARBs (both in >98% of patients) indicates an important additional beneficial effect. The HR point estimate of 0.82 indicates a clinically relevant reduction in the primary composite endpoint, although this does not quite reach the 20% relative risk reduction the study was powered to detect. The roughly 0.2 mmol/L increase in serum potassium is lower than that observed with spironolactone and eplerenone in the RALES and EPHESUS trials (both 0.3 mmol/L), lending credence to the clinical benefit of the unique mechanism of finerenone.^24-26

Some limitations of FIDELIO-DKD leave residual questions. For example, generalizability may be limited because of a predominance of elderly White males (mean age, 65.6 years; 70.2% male; 63.3% White); diabetic kidney disease is more common in women and non-White individuals.^24,27,28 Patients also had well controlled diabetes and hypertension (mean glycated hemoglobin, 7.7%; mean SBP, 138.0 mmHg).²⁴ Additionally, most patients had advanced CKD (mean eGFR, 44.3 mL/min/m²), most with severely elevated albuminuria (87.5% had UACR ≥300). While this represents an understudied population of patients with high albuminuria, it limits generalizability to patients with earlier-stage CKD.²⁹ The effects of finerenone in patients with less advanced CKD will be elucidated in the FIGARO-DKD trial, which compared with FIDELIO-DKD, has reported less severe baseline measures for UACR (51.2% of patients with values ≥300) and eGFR (mean, 67.8 mL/min/1.73 m²).^24,30 Lastly, unlike the RALES and EPHESUS trials, FIDELIO-DKD excluded patients with HF with reduced ejection fraction, making comparisons to other MRA trials challenging. ^24-26

Additionally, very few patients in FIDELIO-DKD received concomitant novel therapies indicated to reduce adverse CV outcomes.²⁴ For example, at baseline, SGLT-2 inhibitors and GLP-1 RAs were used in only approximately 150 and 400 patients, respectively. Not surprisingly, subgroup analyses for the primary composite endpoint were nonsignificant in patients who received these agents. Surprisingly, however, HR point estimates indicated greater risk for the primary composite endpoint with finerenone in patients receiving SGLT-2 inhibitors or GLP-1 RAs (HRs, 1.38 and 1.17, respectively). Further research is needed to clarify this potential harm.

Guidelines for management of diabetes and CKD have not yet been updated with recommendations on use of finerenone. With a movement toward early initiation of SGLT-2 inhibitors and/or GLP-1 RAs for CV risk reduction in T2DM, it remains to be seen whether findings from FIDELIO-DKD will be observed in practice. The trial was performed between 2015 and 2018, prior to widespread recommendations for early use of these agents.^10-15,24 Because finerenone does not affect plasma glucose, it may be reserved for use after SGLT-2 inhibitors and GLP-1 RAs, which can additionally offer glycemic control. However, there is currently some concern for addition of finerenone to these agents given the inability to rule out a harmful effect based on findings from FIDELIO-DKD.

Conclusion
The nonsteroidal MRA finerenone demonstrated improvements in composite kidney outcomes compared with placebo in patients with T2DM and CKD who received background RAS blockade in a well-designed phase III trial. Concerns about external validity are rooted in low representation of non-White patients and those with lower levels of albuminuria. Still unclear are the effects of finerenone when used in addition to SGLT-2 inhibitors and GLP-1 RAs, which are becoming standard early therapies in T2DM because of their CV risk reduction. Current guideline recommendations on use of MRAs in T2DM are limited to patients with resistant hypertension, and future revisions may remain narrow in scope given the patient population recruited in FIDELIO-DKD.

References

1. Kidney Disease Improving Global Outcomes (KDIGO). Chapter 1: Definition and classification of CKD. Kidney Int Suppl (2011). 2013;3(1):19-62. doi:10.1038/kisup.2012.64
2. Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol. 2011;1(3):1175-1232. doi:10.1002/cphy.c100049
3. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA. 2016;316(6):602-610. doi:10.1001/jama.2016.10924
4. Allison SJ. Finerenone in chronic kidney disease. Nat Rev Nephrol. 2021;17(1):13. doi:10.1038/s41581-020-00371-6
5. Lytvyn Y, Godoy LC, Scholtes RA, van Raalte DH, Cherney DZ. Mineralocorticoid antagonism and diabetic kidney disease. Curr Diab Rep. 2019;19(1):4. doi:10.1007/s11892-019-1123-8
6. Chung EY, 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(10):CD007004. doi:10.1002/14651858.CD007004.pub4
7. Kerendia. Package insert. Bayer HealthCare; 2021.
8. Dojki FK, Bakris G. Nonsteroidal mineralocorticoid antagonists in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017;26(5):368-374. doi:10.1097/mnh.0000000000000340
9. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427
10. American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S151-S167. doi:10.2337/dc21-S011
11. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S111-S124. doi:10.2337/dc21-S009
12. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S125-S150. doi:10.2337/dc21-S010
13. Das SR, Everett BM, Birtcher KK, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(9):1117-1145. doi:10.1016/j.jacc.2020.05.037
14. Kidney Disease Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115. doi:10.1016/j.kint.2020.06.019
15. Rangaswami J, Bhalla V, de Boer IH, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020;142(17):e265-e286. doi:10.1161/CIR.0000000000000920
16. Farxiga. Package insert. AstraZeneca Pharmaceuticals LP; 2021.
17. Jardiance. Package insert. Boehringer Ingelheim Pharmaceuticals Inc; 2021.
18. Invokana. Package insert. Janssen Pharmaceuticals Inc; 2020.
19. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocr Pract. 2020;26(1):107-139. doi:10.4158/CS-2019-0472
20. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894. doi:10.1001/jama.2015.10081
21. Katayama S, Yamada D, Nakayama M, et al. A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy. J Diabetes Complications. 2017;31(4):758-765. doi:10.1016/j.jdiacomp.2016.11.021
22. Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105-2114. doi:10.1093/eurheartj/ehw132
23. Pei H, Wang W, Zhao D, Wang L, Su GH, Zhao Z. The use of a novel non-steroidal mineralocorticoid receptor antagonist finerenone for the treatment of chronic heart failure: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(16):e0254. doi:10.1097/md.0000000000010254
24. 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. doi:10.1056/NEJMoa2025845
25. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-717. doi:10.1056/nejm199909023411001
26. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. doi:10.1056/NEJMoa030207
27. Narres M, Claessen H, Droste S, et al. The incidence of end-stage renal disease in the diabetic (compared to the non-diabetic) population: A systematic review. PLoS One. 2016;11(1):e0147329. doi:10.1371/journal.pone.0147329
28. United States Renal Data System. 2020 Annual Data Report. United States Renal Data System. Published 2020. Accessed August 23, 2021. https://adr.usrds.org/2020
29. Agarwal R, Anker SD, Bakris G, et al. Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone. Nephrol Dial Transplant. 2020. doi:10.1093/ndt/gfaa294
30. Ruilope LM, Agarwal R, Anker SD, et al. Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial. Am J Nephrol. 2019;50(5):345-356. doi:10.1159/000503712

Prepared by:
Ryan Rodriguez, PharmD, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2021

The information presented is current as August 23, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.