Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects

Area of Science:

• Nephrology
• Endocrinology
• Cardiology

Background:

• Diabetic kidney disease (DKD) is a major complication of type 2 diabetes (T2D), with significant residual risk despite current therapies.
• Existing treatments like ACE inhibitors, ARBs, and SGLT2 inhibitors do not fully mitigate CKD progression and cardiovascular disease (CVD) risk.
• Mineralocorticoid receptor (MR) activation contributes to DKD pathogenesis through inflammatory and fibrotic pathways.

Purpose of the Study:

• To evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in managing diabetic kidney disease (DKD).
• To assess the role of MRAs in reducing albuminuria, CKD progression, and cardiovascular outcomes in T2D patients.
• To compare the risk-benefit profiles of steroidal versus non-steroidal MRAs, particularly regarding hyperkalemia.

Main Methods:

• Review of preclinical studies demonstrating MRA effects on albuminuria and fibrotic pathways.
• Analysis of clinical trial data, including the FIDELIO-DKD trial, comparing MRAs with placebo in T2D patients.
• Examination of adverse event profiles, focusing on hyperkalemia incidence with different MRA classes.

Main Results:

• Preclinical studies consistently show MRAs reduce albuminuria and slow CKD progression.
• Steroidal MRAs effectively reduce albuminuria but are associated with a high risk of hyperkalemia.
• The non-steroidal MRA finerenone demonstrated significant slowing of CKD progression and reduced cardiovascular risk in the FIDELIO-DKD trial, with a lower hyperkalemia risk.

Conclusions:

• Non-steroidal MRAs represent a promising therapeutic strategy for DKD, offering renoprotection and cardiovascular benefits.
• Finerenone, a non-steroidal MRA, has proven efficacy in slowing DKD progression and reducing adverse cardiovascular outcomes.
• Further research is warranted to explore the potential additive benefits of combining MRAs with other renoprotective agents like SGLT2 inhibitors.