Effectiveness of nonsteroidal mineralocorticoid receptor antagonists in patients with diabetic kidney disease

ABSTRACT

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.

Plain Language Summary

This review discusses a group of drugs called mineralocorticoid receptor antagonists (MRAs for short). Some people with diabetes develop kidney and heart problems because their body is producing too much steroid hormone. This causes a protein called the mineralocorticoid receptor inside kidney and heart cells to be overactive, causing excessive inflammation and damage. Over time these excesses can lead to loss of organ function. MRAs can block this effect on the mineralocorticoid receptor and so reduce associated kidney and heart problems. Older types of MRAs called steroidal MRAs have been used clinically for many years. They have side effects such as high blood potassium levels. Nonsteroidal MRAs are a newer type of MRA. Finerenone is the first nonsteroidal MRA approved by the United States’ Food and Drug Administration for reducing kidney and heart damage in people with diabetic kidney disease. Two clinical studies involving more than 13,000 people with Diabetic Kidney Disease have completed. People in these studies who took finerenone had slower worsening of kidney disease and less heart and blood vessel damage compared with people who did not take finerenone (took placebo). Finerenone also has a lower risk of causing side effects compared with steroidal MRAs. Another type of nonsteroidal MRA is esaxerenone, which is currently only available in Japan. Other types of nonsteroidal MRAs are going through clinical trials so are not available for use yet. See Supplementary Figure 1 for an infographic version of this summary.

KEYWORDS:

• Chronic kidney disease
• diabetic kidney disease
• type 2 diabetes
• finerenone
• spironolactone
• esaxerenone
• mineralocorticoid receptor antagonist

Acknowledgments

Medical writing assistance was provided by Andreja Varjačić, PhD, of Envision Pharma Group, and was funded by Bayer Corporation. Envision Pharma Group’s services complied with international guidelines for Good Publication Practice (GPP3).

Disclosure of financial/other conflicts of interest

Edgar Lerma: Employment with Associates in Nephrology; consultancy agreements with Bayer and Vifor; ownership interest in Fresenius Joint Venture; receiving honoraria from Elsevier Publishing, McGraw-Hill Publishing, National Kidney Foundation, UpToDate, and Wolters Kluwer Publishing; serving as a scientific advisor or member of Journal of Clinical Lipidology, International Urology and Nephrology Journal, Journal of Vascular Access, Prescribers Letter, Renal and Urology News, ASN Kidney News, Reviews in Endocrinology and Metabolic Disorders, American Journal of Kidney Diseases Blog, American Heart Association Kidney and Cardiovascular Disease Leadership Group, and SCILL Committee; and speakers bureau for AstraZeneca, Bayer, Otsuka, and Vifor.

George Bakris: Consultant-Merck, Bayer, Vascular Dynamics, KBP Biosciences, Ionis, Alnylam, Astra Zeneca, Quantum Genomics, Horizon, Novo Nordisk. Research support-Steering committee of trials-Bayer, Vascular Dynamics, Quantum Genomics, Alnylam, Novo Nordisk.

William B. White: Cardiovascular safety consultant for Astra-Zeneca, Alnylam, Bristol-Myers Squibb, Cerevel, Horizon, JAZZ, Lipocine, Marius, Millenium (Takeda), Red Hill Pharma, Shanton Pharma, and UCB.

The authors have no other relevant conflicts of interest to disclose. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data sharing statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00325481.2022.2060598

Additional information

Funding

No funding was received for the production of the manuscript.