The organoprotective effects of finerenone in patients with cardiorenal metabolic syndrome

Type 2 diabetes mellitus (T2DM) is associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS), leading to increased aldosterone levels in the blood. This can result in the development and progression of chronic kidney disease (CKD) and congestive heart failure (CHF). High aldosterone levels, in turn, contribute to insulin resistance, microcirculatory disorders, mitochondrial dysfunction, oxidative stress, inflammation, dyslipidemia, and fibrosis. Additionally, in T2DM patients, persistent oxidative stress and hyperglycemia can trigger pathological activation of mineralocorticoid receptors, even in the absence of aldosterone or cortisol. This results in a vicious cycle of inflammation and fibrosis in the heart and kidneys.

Therefore, targeting mineralocorticoid receptor (MCR) blockade is crucial for reducing fibrosis and other irreversible changes in CKD and CHF, as it can help break this cycle and reduce inflammation and fibrosis. However, spironolactone is not a highly selective MKR antagonist, which is one of the reasons for its many side effects. Eplerenone, with greater selectivity and lower affinity for the MKR, has a weaker cardioprotective effect due to its lower affinity. Finerenone, a first-in-class nonsteroidal mineralocorticoid receptor antagonist indicated for the treatment of CKD with albuminuria in adult patients with T2DM, provides the most significant anti-inflammatory and antifibrotic effects without the side effects associated with steroidal anti-inflammatory medications.

The aim of this review is to evaluate the clinical trial results on the effects of finerenone on cardiovascular and renal outcomes in patients with T2DM. The review provides an up-to-date overview of the current literature on the impact of finerenone on these outcomes and systematically summarizes and describes additional positive cardioprotective benefits associated with its use.

1. Hatamizadeh P, Fonarow GC, Budoff MJ, et al. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol. 2013;9(2):99-111. doi: https://doi.org/10.1038/nrneph.2012.279

2. Song MK, Davies NM, Roufogalis BD, Huang TH. Management of cardiorenal metabolic syndrome in diabetes mellitus: a phytotherapeutic perspective. J Diabetes Res. 2014;2014:313718. doi: https://doi.org/10.1155/2014/313718

3. Vijay K, Neuen BL, Lerma EV. Heart Failure in Patients with Diabetes and Chronic Kidney Disease: Challenges and Opportunities. Cardiorenal Med. 2022;12(1):1-10. doi: https://doi.org/10.1159/000520909

4. Tousoulis D, Oikonomou E, Siasos G, Stefanadis C. Diabetes Mellitus and Heart Failure. EurCardiol. 2014;9(1):37-42. doi: https://doi.org/10.15420/ecr.2014.9.1.37

5. Birkeland KI, Bodegard J, Eriksson JW, et al. Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study. Diabetes Obes Metab. 2020;22(9):1607-1618. doi: https://doi.org/10.1111/dom.14074

6. Trubitsyna NP, Zaitseva NV, Severinа AS, Shamkhalova MS. Chronic kidney disease in patients with type 2 diabetes: new targets of medicine action. Diabetes mellitus. 2022;25(5):492-498. (In Russ.) doi: https://doi.org/10.14341/DM12944

7. Hollenberg NK, Stevanovic R, Agarwal A, et al. Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney Int. 2004;65(4):1435-1439. doi: https://doi.org/10.1111/j.1523-1755.2004.00524.x

8. Engeli S, Schling P, Gorzelniak K, et al. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol. 2003;35(6):807-825. doi: https://doi.org/10.1016/s1357-2725(02)00311-4

9. Ribeiro-Oliveira A Jr, Nogueira AI, Pereira RM, et al. The renin-angiotensin system and diabetes: an update. Vasc Health Risk Manag. 2008;4(4):787-803 doi: https://doi.org/10.2147/VHRM.S1905

10. Giacchetti G, Sechi LA, Rilli S, Carey RM. The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab. 2005;16(3):120-126. doi: https://doi.org/10.1016/j.tem.2005.02.003

11. Shestakova MV. The role of the tissue renin-angiotensin-aldosterone system in the development of metabolic syndrome, diabetes mellitus and itsvascular complications. Diabetes mellitus. 2010;13(3):14-19. (In Russ.) doi: https://doi.org/10.14341/2072-0351-5481

12. Jia G, Hill MA, Sowers JR. Vascular endothelial mineralocorticoid receptors and epithelial sodium channels in metabolic syndrome and related cardiovascular disease. J Mol Endocrinol. 2023;71(3):e230066. doi: https://doi.org/10.1530/JME-23-0066

13. Jia G, Lockette W, Sowers JR. Mineralocorticoid receptors in the pathogenesis of insulin resistance and related disorders: from basic studies to clinical disease. Am J Physiol Regul Integr Comp Physiol. 2021;320(3):R276-R286. doi: https://doi.org/10.1152/ajpregu.00280.2020

14. Galmiche G, Pizard A, Gueret A, et al. Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness. Hypertension. 2014;63(3):520-526. doi: https://doi.org/10.1161/HYPERTENSIONAHA.113.01967

15. Lother A, Berger S, Gilsbach R, et al. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension. 2011;57(4):746-754. doi: https://doi.org/10.1161/HYPERTENSIONAHA.110.163287

16. Man JJ, Lu Q, Moss ME, et al. Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis. Arterioscler Thromb Vasc Biol. 2021;41(11):2740-2755. doi: https://doi.org/10.1161/ATVBAHA.121.316929

17. Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res. 2005;96(6):643-650. doi: https://doi.org/10.1161/01.RES.0000159937.05502.d1

18. Caprio M, Newfell BG, la Sala A, et al. Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ Res. 2008;102(11):1359-1367. doi: https://doi.org/10.1161/CIRCRESAHA.108.174235

19. Gant CM, Minovic I, Binnenmars H, et al. Lower Renal Function Is Associated With Derangement of 11-β Hydroxysteroid Dehydrogenase in Type 2 Diabetes. J Endocr Soc. 2018;2(7):609-620. doi: https://doi.org/10.1210/js.2018-00088

20. Hayashi T, Shibata H, Kurihara I, et al. High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C β Signaling. Int Heart J. 2017;58(5):794-802. doi: https://doi.org/10.1536/ihj.16-649

21. Daza-Arnedo R, Rico-Fontalvo J, Aroca-Martínez G, et al. Insulin and the kidneys: a contemporary view on the molecular basis. Front Nephrol. 2023;3:1133352. doi: https://doi.org/10.3389/fneph.2023.1133352

22. Murray IV, Paolini MA. Histology, Kidney and Glomerulus. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023

23. Haruhara K, Kanzaki G, Sasaki T, et al. Associations between nephron number and podometrics in human kidneys. Kidney Int. 2022;102(5):1127-1135. doi: https://doi.org/10.1016/j.kint.2022.07.028

24. Thomas MC, Brownlee M, Susztak K, et al. Diabetic kidney disease. Nat Rev Dis Primers. 2015;1:15018. doi: https://doi.org/10.1038/nrdp.2015.18

25. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49(2):355-364. doi: https://doi.org/10.1161/01.HYP.0000255636.11931.a2

26. Whaley-Connell A, Habibi J, Wei Y, et al. Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat. Am J Physiol Renal Physiol. 2009;296(5):F1013-F1022. doi: https://doi.org/10.1152/ajprenal.90646.2008

27. Jo R, Itoh H, Shibata H. Mineralocorticoid receptor overactivation in diabetes mellitus: role of O-GlcNAc modification. Hypertens Res. 2024;47(8):2126-2132. doi: https://doi.org/10.1038/s41440-024-01734-3

28. Jia G, Lastra G, Bostick BP, et al. The mineralocorticoid receptor in diabetic kidney disease. Am J Physiol Renal Physiol. 2024;327(3):F519-F531. doi: https://doi.org/10.1152/ajprenal.00135.2024

29. Calhoun DA. Aldosterone and cardiovascular disease: smoke and fire. Circulation. 2006;114(24):2572-2574. doi: https://doi.org/10.1161/CIRCULATIONAHA.106.668715

30. Jia G, Habibi J, DeMarco VG, et al. Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females. Hypertension. 2015;66(6):1159-1167. doi: https://doi.org/10.1161/HYPERTENSIONAHA.115.06015

31. Schrier RW. Aldosterone ‘escape’ vs ‘breakthrough’. Nat Rev Nephrol. 2010;6(2):61. doi: https://doi.org/10.1038/nrneph.2009.228

32. Chilton RJ, Silva-Cardoso J. Mineralocorticoid receptor antagonists in cardiovascular translational biology. Cardiovasc Endocrinol Metab. 2023;12(3):e0289. doi: https://doi.org/10.1097/XCE.0000000000000289

33. 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(2):199-211. doi: https://doi.org/10.1053/j.ajkd.2007.10.040

34. van den Meiracker AH, Baggen RG, Pauli S, et al. Spironolactone in type 2 diabetic nephropathy: Effects on proteinuria, blood pressure and renal function. J Hypertens. 2006;24(11):2285-2292. doi: https://doi.org/10.1097/01.hjh.0000249708.44016.5c

35. 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: https://doi.org/10.1002/14651858.CD007004.pub4

36. Pradhan A, Vohra S, Sethi R. Eplerenone: The Multifaceted Drug in Cardiovascular Pharmacology. J Pharm Bioallied Sci. 2020;12(4):381-390. doi: https://doi.org/10.4103/jpbs.JPBS_338_19

37. Chatterjee S, Moeller C, Shah N, et al. Eplerenone is not superior to older and less expensive aldosterone antagonists. Am J Med. 2012;125(8):817-825. doi: https://doi.org/10.1016/j.amjmed.2011.12.018

38. Funder JW. Aldosterone Research: 65 Years, and Counting. Vitam Horm. 2019;109:1-15. doi: https://doi.org/10.1016/bs.vh.2018.09.001

39. Messaoudi S, Azibani F, Delcayre C, Jaisser F. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol. 2012;350(2):266-272. doi: https://doi.org/10.1016/j.mce.2011.06.038

40. Chung EYM, Strippoli GFM. Aldosterone Antagonists in Addition to Renin Angiotensin System Antagonists for Preventing the Progression of CKD: Editorial Summary of a Cochrane Review. Am J Kidney Dis. 2021;77(5):810-812. doi: https://doi.org/10.1053/j.ajkd.2020.11.019

41. Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. Chem Med Chem. 2012;7(8):1385-1403. doi: https://doi.org/10.1002/cmdc.201200081

42. Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharmacol. 2022;179(13):3220-3234. doi: https://doi.org/10.1111/bph.15747

43. Chaudhuri A, Ghanim H, Arora P. Improving the residual risk of renal and cardiovascular outcomes in diabetic kidney disease: A review of pathophysiology, mechanisms, and evidence from recent trials. Diabetes Obes Metab. 2022;24(3):365-376. doi: https://doi.org/10.1111/dom.14601

44. Bakris GL, Ruilope LM, Anker SD, et al. A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes. Kidney Int. 2023;103(1):196-206. doi: https://doi.org/10.1016/j.kint.2022.08.040

45. Agarwal R, Tu W, Farjat AE, et al. Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes: A Mediation Analysis. Ann Intern Med. 2023;176(12):1606-1616. doi: https://doi.org/10.7326/M23-1023

46. Korol S, Mottet F, Perreault S, Baker WL, White M, de Denus S. A systematic review and meta-analysis of the impact of mineralocorticoid receptor antagonists on glucose homeostasis. Medicine (Baltimore). 2017;96(48):e8719. doi: https://doi.org/10.1097/MD.0000000000008719

47. Zhao JV, Xu L, Lin SL, Schooling CM. Spironolactone and glucose metabolism, a systematic review and meta-analysis of randomized controlled trials. J Am Soc Hypertens. 2016;10(8):671-682. doi: https://doi.org/10.1016/j.jash.2016.05.013

48. Matsumoto S, Takebayashi K, Aso Y. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism. 2006;55(12):1645-1652. doi: https://doi.org/10.1016/j.metabol.2006.07.025

49. 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: https://doi.org/10.1056/NEJMoa2025845

50. 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(6):540-552. doi: https://doi.org/10.1161/CIRCULATIONAHA.120.051898

51. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021;385(24):2252-2263. doi: https://doi.org/10.1056/NEJMoa2110956

52. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. doi: 10.1093/eurheartj/ehab777. [Corrected and republished from: Eur Heart J. 2022;43(20):1989. doi: https://doi.org/10.1093/eurheartj/ehab886

53. 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: https://doi.org/10.1001/jama.2015.10081

54. Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. N Engl J Med. doi: https://doi.org/10.1056/NEJMoa2410659

55. McGill JB, Agarwal R, Anker SD, et al. Effects of finerenone in people with chronic kidney disease and type 2 diabetes are independent of HbA1c at baseline, HbA1c variability, diabetes duration and insulin use at baseline. Diabetes Obes Metab. 2023;25(6):1512-1522. doi: https://doi.org/10.1111/dom.14999

56. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA) J Hypertens. 2023;41(12):1874-2071. doi:10.1097/HJH.0000000000003480. Corrected and republished from: J Hypertens. 2024;42(1):194. doi: https://doi.org/10.1097/HJH.0000000000003621

57. Chazova IE, Chikhladze NM, Blinova NV, et al. Clinical guidelines of the Russian Medical Society on arterial Hypertension (RSH) and the Eurasian association of Cardiologists (EaC) for the diagnosis and treatment of arterial hypertension (2024). Systemic Hypertension. 2024;21(4):5-110. (In Russ.). doi: https://doi.org/10.38109/2075-082X-2024-4-5-109

58. 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(2):142-152. doi: https://doi.org/10.1016/j.jacc.2021.04.079

59. Filippatos G, Anker SD, Agarwal R, et al. Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial. Circulation. 2022;145(6):437-447. doi: https://doi.org/10.1161/CIRCULATIONAHA.121.057983

60. Filippatos G, Anker SD, Pitt B, et al. Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes. JACC Heart Fail. 2022;10(11):860-870. doi: https://doi.org/10.1016/j.jchf.2022.07.013

61. McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195. Corrected and republished from: Eur Heart J. 2024;45(1):53. doi: https://doi.org/10.1093/eurheartj/ehad613

62. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S179-S218. doi: https://doi.org/10.2337/dc24-S010

63. Shestakova MV, Dobronravov VA, Ametov AS, et al. Prospects of finerenone use in Russian population of patients with chronic kidney disease and type 2 diabetes. Resolution of multidisciplinary. Advisory board. Diabetes mellitus. 2023;26(5):492-499. (In Russ.) doi: https://doi.org/10.14341/DM13020

64. Algoritmy spetsializirovannoi meditsinskoi pomoshchi bol’nym sakharnym diabetom. 12th edition. Ed by I.I. Dedov, M.V. Shestakova, O.Y. Sukhareva. — Moscow: 2025. (In Russ.) doi: https://doi.org/10.14341/algdc2025