The Ascent of Mineralocorticoid Receptor Antagonists in Diabetic Nephropathy

Author(s): Luxitaa Goenka, Raghavan Padmanaban, Melvin George*

Journal Name: Current Clinical Pharmacology
Continued as Current Reviews in Clinical and Experimental Pharmacology

Volume 14 , Issue 2 , 2019

Graphical Abstract:


Diabetic nephropathy is defined as a decline in the renal function and an increase in the amount of albuminuria (>300 mg/day). The interruption of the renin-angiotensin-aldosterone system (RAAS) by well-established therapies such as angiotensin-converting enzyme inhibitor, angiotensin receptor blockers, calcium channel blockers or diuretics has been beneficial in reducing the progression of renal diseases; however, there is an increase in the levels of aldosterone due to the aldosterone escape phenomenon. Newer and novel approaches to counteract this aldosterone breakthrough while accentuating the anti-hypertensive and anti-proteinuric effects of these agents would be ideal and mineralocorticoid receptor antagonists fit in this slot perfectly. This review attempted to evaluate the safety and efficacy of and mineralocorticoid receptor antagonists for diabetic nephropathy. Presently mineralocorticoid receptor antagonists such as spironolactone, eplerenone and finerenone are being investigated as both monotherapies and as additional therapies. Clinical studies have shown that these drugs have been effective in the reduction of blood pressure, urinaryalbumin- excretion and estimated glomerular filtration rate. The commonly observed adverse effects are hyperkalemia, gynaecomastia and vaginal bleeding, that are bothersome with spironolactone seems to be avoidable if these patients are switched to non-steroidal and mineralocorticoid receptor antagonists such as finerenone and eplerenone. Most of the studies have only evaluated the shortterm effects of mineralocorticoid receptor antagonists on diabetic nephropathy. Hard outcomes such as cardiovascular events, creatinine doubling, progression to end-stage renal disease, mortality and the need for temporary or permanent dialysis need to be studied with these molecules.

Keywords: Diabetic nephropathy, eplerenone, finerenone, spironolactone, mineralocorticoid receptor antagonists, aldosterone.

Tang SCW, Chan GCW, Lai KN. Recent advances in managing and understanding diabetic nephropathy. Faculty Rev 2016.
Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017; 12(12): 2032-45.
[] [PMID: 28522654]
Ahmad J. Management of diabetic nephropathy: Recent progress and future perspective. Diabetes Metab Syndr 2015; 9(4): 343-58.
[] [PMID: 25845297]
Xue R, Gui D, Zheng L, Zhai R, Wang F, Wang N. Mechanistic Insight and Management of Diabetic Nephropathy: Recent Progress and Future Perspective. J Diabetes Res 2017.20171839809
[] [PMID: 28386567]
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): 709-17.
[] [PMID: 10471456]
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
[] [PMID: 21073363]
Eschalier R, McMurray JJV, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 2013; 62(17): 1585-93.
[] [PMID: 23810881]
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351(6): 543-51.
[] [PMID: 15295047]
Sato A. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy. Hypertens Res 2015; 38(6): 367-74.
[] [PMID: 25762415]
Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004; 47(11): 1936-9.
[] [PMID: 15551047]
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996; 98(4): 1063-8.
[] [PMID: 8770880]
Hostetter TH, Rosenberg ME, Ibrahim HN, Juknevicius I. Aldosterone in progressive renal disease. Semin Nephrol 2001; 21(6): 573-9.
[] [PMID: 11709805]
Fujisawa G, Okada K, Muto S, et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004; 66(4): 1493-502.
[ 2004.00913.x] [PMID: 15458443]
Han S-Y, Kim C-H, Kim H-S, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 2006; 17(5): 1362-72.
[] [PMID: 16571782]
Pessôa BS, Peixoto EBMI, Papadimitriou A, Lopes de Faria JM, Lopes de Faria JB. Spironolactone improves nephropathy by enhancing glucose-6-phosphate dehydrogenase activity and reducing oxidative stress in diabetic hypertensive rat. J Renin Angiotensin Aldosterone Syst 2012; 13(1): 56-66.
[] [PMID: 21987533]
Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M. Long-term effects of addition of mineral-ocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: A randomized clinical trial. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 2013. 28: 2823-33.
Kato S, Maruyama S, Makino H, et al. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. Clin Exp Nephrol 2015; 19(6): 1098-106.
[] [PMID: 25795029]
Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009; 20(12): 2641-50.
[] [PMID: 19926893]
Makhlough A, Kashi Z, Akha O, Zaboli E, Yazdanicharati J. Effect of spironolactone on diabetic nephropathy compared to the combination of spironolactone and losartan. Nephrourol Mon 2014; 6(1)e12148
[] [PMID: 24719811]
Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving H-H. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: A randomized, double-masked, cross-over study. Diabetes Care 2005; 28(9): 2106-12.
[] [PMID: 16123474]
Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol 2014; 64(1): 69-78.
[] [PMID: 24621652]
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): 758-65.
[] [PMID: 28025025]
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): 2105-14.
[ 1093/eurheartj/ehw132] [PMID: 27130705]
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): 884-94.
[ 10.1001/jama.2015.10081] [PMID: 26325557]
Liu LCY, Schutte E, Gansevoort RT, van der Meer P, Voors AA. Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease Expert Opin Investig Drugs 2015; 24(8): 1123-35. [ 10.1517/13543784.2015.1059819] [PMID: 26095025]
[26] and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD). NCT02540993 [updated 2019 Oct 15]. Available from:
Craft J. Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure. Proc Bayl Univ Med Cent 2004; 17(2): 217-20. [ 10.1080/08998280.2004.11927973] [PMID: 16200104]
GLEEVEC (imatinib mesylate) tablets for oral use [updated 2001]. Available from:
Sun L-J, Sun Y-N, Shan J-P, Jiang G-R. Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy. J Diabetes Investig 2017; 8(4): 609-18.
[ 10.1111/jdi.12629] [PMID: 28107779]
Currie G, Taylor AHM, Fujita T, et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol 2016; 17(1): 127.
[] [PMID: 27609359]
Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med 1977; 87(4): 398-403.
[] [PMID: 907238]
Mosenkis A, Townsend RR. Gynecomastia and antihypertensive therapy. J Clin Hypertens (Greenwich) 2004; 6(8): 469-70.
[] [PMID: 15308889]
Damman K, Tang WHW, Felker GM, et al. Current evidence on treatment of patients with chronic systolic heart failure and renal insufficiency: practical considerations from published data. J Am Coll Cardiol 2014; 63(9): 853-71.
[ 2013.11.031] [PMID: 24334210]
Putcha N, Allon M. Management of hyperkalemia in dialysis patients. Semin Dial 2007; 20(5): 431-9.
[] [PMID: 17897250]
Pitt B, Bushinsky DA, Kitzman DW, et al. Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease. ESC Heart Fail 2018; 5(3): 257-66.
[ 1002/ehf2.12265] [PMID: 29369537]
Momeni A, Behradmanesh MS, Kheiri S, Karami Horestani M. Evaluation of spironolactone plus hydrochlorothiazide in reducing proteinuria in type 2 diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 2015; 16(1): 113-8.
[] [PMID: 23486907]
Nielsen SE, Schjoedt KJ, Rossing K, et al. Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease. J Renin Angiotensin Aldosterone Syst 2013; 14(2): 161-6.
[] [PMID: 23108194]
Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003; 41(1): 64-8.
[ 95080.E9] [PMID: 12511531]
Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006; 70(3): 536-42.
[] [PMID: 16775595]
Ustundag A, Tugrul A, Ustundag S, Sut N, Demirkan B. The effects of spironolactone on nephron function in patients with diabetic nephropathy. Ren Fail 2008; 30(10): 982-91.
[] [PMID: 19016150]
Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. J Investig Med 2008; 56(4): 714-9.
[] [PMID: 18382267]
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): 1645-52.
[] [PMID: 17142138]
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): 2285-92.
[] [PMID: 17053552]
[45] Spironolactone in Diabetic Nephropathy [home page on Internet]. C2018 [updated 2006 Apr 25; cited 2018 Apr 01]. Available from. (Accessed on April 1 2018).
[46] Spironolactone for Reducing Proteinuria in Diabetic Nephropathy. [home page on Internet]. C2018 [up-dated 2008 Oct 17; cited 2018 Apr 01]. Available from: https: //clinicaltrialsgov/ct2/show/NCT00498537 (Accessed on April 1 2018).
[47] Aldosterone in Diabetic Nephropathy (ALDODN). C2018 [updated 2009 Mar 27; cited 2018 Apr 01]. Available from: (Accessed on April 1 2018).
[48] Efficacy and Safety of Finerenone in Sub-jects With Type 2 Diabetes Mellitus and Diabetic Kidney Dis-ease (FIDELIO-DKD) C2018 [updated 2018 Apr 03; cited 2018 Apr 09]. Available from: (Accessed on April 9 2018).

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [78 - 83]
Pages: 6
DOI: 10.2174/1574884713666181116100946

Article Metrics

PDF: 78