Effectiveness of nonsteroidal mineralocorticoid receptor antagonists in patients with diabetic kidney disease
Open accessAbstract
Nonsteroidal mineralocorticoid receptor antagonists (MRAs) are a new class of drugs developed to address the medical need for effective and safer treatment to protect the kidney and the heart in patients with diabetic kidney disease (DKD). There are several drugs within this class at varying stages of clinical development. Finerenone is the first nonsteroidal MRA approved in the US for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). In clinical studies, finerenone slowed CKD progression without inducing marked antihypertensive effects. Esaxerenone is a nonsteroidal MRA with proven blood pressure-lowering efficacy that is currently licensed in Japan for treating hypertension. There are also three other nonsteroidal MRAs in mid-to-late stages of clinical development. Here we overview evidence addressing pharmacological and clinical differences between the nonsteroidal MRAs and the steroidal MRAs spironolactone and eplerenone. First, we describe a framework that highlights the role of aldosterone-mediated pathological overactivation of the mineralocorticoid receptor and inflammation as important drivers of CKD progression. Second, we discuss the benefits and adverse events profile of steroidal MRAs, the latter of which are often a limiting factor to their use in routine clinical practice. Finally, we show that nonsteroidal MRAs differ from steroidal MRAs based on pharmacology and clinical effects, giving the potential to expand the therapeutic options for patients with DKD. In the recently completed DKD outcome program comprising two randomized clinical trials - FIDELIO-DKD and FIGARO-DKD - and the FIDELITY analysis of both trials evaluating more than 13,000 patients, the nonsteroidal MRA finerenone demonstrated beneficial effects on the kidney and the heart across a broad spectrum of patients with CKD and T2D. The long-term efficacy of finerenone on cardiac and renal morbidity and mortality endpoints, along with the anti-hypertensive efficacy of esaxerenone, widens the scope of available therapies for patients with DKD.
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The kidney and heart responded favorably to the nonsteroidal MRA finerenone in a variety of individuals with CKD and T2DM.
“The kidney and heart responded favorably to the nonsteroidal MRA finerenone in a variety of individuals with CKD and T2DM.”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [80]
The available text for sections 6 and 7 lists headings about kidney and heart effects but provides no findings. Searches for finerenone’s kidney and cardiovascular outcomes returned only the contents and links, so this copy does not establish whether the claimed benefits occurred across a variety of patients with CKD and T2DM. (LLM, conf=0.75)
Experimental — accuracy not yet measuredMineralocorticoid receptor antagonists are a novel class of drugs developed for safer, more efficient treatment of diabetic kidney disease while safeguarding the heart and kidneys.
“MRA are a novel class of drugs that were developed in response to the medical community’s need for a safer, more efficient way to treat patients with diabetic kidney disease (DKD) while simultaneously safeguarding their hearts and kidneys.”
From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [80]
Our copy provides section headings on nonsteroidal MRAs in DKD and their clinical effects on the kidney (section 6) and heart (section 7), but no substantive passages establishing the claim. Searches for their development, novelty, comparative safety, and heart-and-kidney protection returned only headings and metadata. (LLM, conf=0.70)
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Cites
Brenner, B. M., Cooper, M. E., de Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H.-H., Remuzzi, G., Snapinn, S. M., Zhang, Z., & Shahinfar, S. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011161 · Cited by 7,493 · see citing works
Dapagliflozin in Patients with Chronic Kidney Disease
Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., Chertow, G. M., Greene, T., Hou, F.-F., Mann, J. F. E., McMurray, J. J. V., Lindberg, M., Rossing, P., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2024816 · Cited by 5,618 · see citing works
Eplerenone in patients with systolic heart failure and mild symptoms
Zannad, F., McMurray, J. J. V., Krum, H., van Veldhuisen, D. J., Swedberg, K., Shi, H., Vincent, J., Pocock, S. J., & Pitt, B. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1009492 · Cited by 3,111 · cited 1× · see citing works
“evaluated in ARTS-HF (39 mg/day) [67] was proven clinically effective in reducing mortality and morbidity in patients with mild HFrEF in the EMPHASIS-HF trial [31].”
MethodEffect of finerenone on chronic kidney disease outcomes in type 2 diabetes
Bakris, G. L., Agarwal, R., Anker, S. D., Pitt, B., Ruilope, L. M., Rossing, P., Kolkhof, P., Nowack, C., Schloemer, P., Joseph, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2025845 · Cited by 2,935 · see citing works
Self-citationCardiovascular events with finerenone in kidney disease and type 2 diabetes
Pitt, B., Filippatos, G., Agarwal, R., Anker, S. D., Bakris, G. L., Rossing, P., Joseph, A., Kolkhof, P., Nowack, C., Schloemer, P., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2110956 · Cited by 1,814 · see citing works
Self-citationCardiorenal end points in a trial of aliskiren for type 2 diabetes
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“outcome (time to first onset of kidney failure, sustained decrease in eGFR of ≥57% from baseline over ≥4 weeks, or renal death) by 23% vs placebo [71].”
BackgroundMethodInfluentialSelf-citationFinerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes
Filippatos, G., Anker, S. D., Agarwal, R., Pitt, B., Ruilope, L. M., Rossing, P., Kolkhof, P., Schloemer, P., Tornus, I., Joseph, A., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051898 · Cited by 294 · cited 1× · see citing works
“nonfatal stroke, or hospitalization for HF) [10,74].”
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Tegegne, B. A., Adugna, A., Yenet, A., Yihunie Belay, W., Yibeltal, Y., Dagne, A., Hibstu Teffera, Z., Amare, G. A., Abebaw, D., Tewabe, H., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1440456 · Cited by 61 · see citing works
- Authors
- Lerma, E., White, W. B., & Bakris, G.
- Affiliations
- University of Illinois Chicago (US)
- University of Connecticut (US)
- American Heart Association (US)
- Corresponding author
- Lerma, Edgar
- Venue
- Postgraduate Medicine
- Publisher
- Informa UK Limited
- Published
- 2022-04-20
- Volume
- 135
- Issue
- 3
- Pages
- 224-233
- ISSN
- 0032-5481 (ISSN-L)
- 1941-9260
- OpenAlex
- W4224280530
- Cited by
- 39
- References
- 12
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 4
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Postgraduate Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- funding
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- non-steroidal mineralocorticoid receptor antagonists, diabetic nephropathy, finerenone, esaxerenone, spironolactone, eplerenone, chronic kidney disease, type 2 diabetes, aldosterone, inflammation, chronic kidney disease progression, hypertension, cardiac morbidity, renal morbidity, FIDELIO-DKD, FIGARO-DKD, adverse events
- MeSH terms
- Mineralocorticoid Receptor Antagonists, Antihypertensive Agents, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Humans, Pyrroles, Sulfones, Renal Insufficiency, Chronic
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