Renal and Cardiovascular Protection Alternatives When Finerenone Is Not Used
Nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) provide cardiorenal benefit with finerenone; when finerenone is avoided due to hyperkalemia risk, renal and cardiovascular protection should be prioritized with sodium–glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs). [1] Steroidal MRAs (spironolactone, eplerenone) and other ns-MRAs such as esaxerenone are additional options, but outcome evidence for kidney and cardiovascular protection is limited for most of these agents and hyperkalemia risk remains a key limitation. [1]
Medication Selection Algorithm
Alternative agents for cardiorenal protection in kidney disease with type 2 diabetes should follow this framework. [1]
- SGLT2 inhibitors (for example, empagliflozin, dapagliflozin) are recommended for chronic kidney disease with type 2 diabetes to prevent CKD progression and cardiovascular events. [1]
- GLP-1 RAs (for example, liraglutide, semaglutide, dulaglutide) are prioritized when SGLT2 inhibitors cannot be used or are not tolerated, with cardiovascular benefit shown across randomized trials and kidney benefit primarily reflected by reductions in albuminuria. [1]
- Steroidal MRAs (spironolactone, eplerenone) reduce albuminuria, but clinical outcome trials for kidney failure or cardiovascular events in diabetes and CKD are not available. [1]
- Other ns-MRAs (esaxerenone) reduce albuminuria, but only finerenone has demonstrated proven clinical cardiovascular and kidney benefits with rigorously evaluated outcome data. [1]
Key Evidence Supporting These Recommendations
SGLT2 inhibitor therapy is recommended as first-line pharmacotherapy to reduce CKD progression and cardiovascular events in type 2 diabetes with chronic kidney disease. [1] GLP-1 RA therapy has demonstrated moderate-quality evidence for reduction in major adverse cardiovascular events (MACE) in type 2 diabetes with chronic kidney disease, with kidney benefit primarily supported by reductions in severely increased albuminuria rather than harder kidney endpoints. [1] Steroidal MRAs have demonstrated reduction in albuminuria, but data showing reduction in clinical outcomes are not available in diabetes and CKD. [1] Only finerenone has been rigorously evaluated with respect to clinical cardiovascular and kidney outcomes among ns-MRAs. [1]
Monotherapy Versus Combination Therapy
SGLT2 inhibitors represent a foundational therapy for renal and cardiovascular protection in this population. [1] A nonsteroidal MRA can be added to a renin–angiotensin system inhibitor (RAS inhibitor) and an SGLT2 inhibitor in eligible patients, but this recommendation is specifically about using an ns-MRA when finerenone is tolerated. [1] For patients in whom finerenone is not used due to hyperkalemia risk, the clinically relevant alternative strategy is to use SGLT2 inhibitors and add a GLP-1 RA when additional cardiovascular or renal risk reduction is needed or when SGLT2 inhibitors are not tolerated. [1] Steroidal and nonsteroidal MRAs should not be combined due to hyperkalemia risk. [1]
Hyperkalemia-Risk-Directed Clinical Nuances
ns-MRAs increase serum potassium concentration and risk of hyperkalemia, which is the main constraint for selecting therapy when hyperkalemia risk is high. [1] In clinical development for ns-MRAs, eligibility was restricted to patients with normal serum potassium after maximizing RAS blockade, and standardized potassium monitoring protocols were used to keep hyperkalemia rates acceptable. [1] SGLT2 inhibitors may reduce the risk of hyperkalemia when used concomitantly with an RAS inhibitor and an ns-MRA, supporting the prioritization of SGLT2 inhibitor–based regimens when hyperkalemia risk is a concern. [1] When finerenone is avoided due to hyperkalemia risk, shifting to SGLT2 inhibitors with or without GLP-1 RAs avoids the incremental potassium-elevating effect of MRAs. [1]
Initiation Thresholds and Safety Monitoring Priorities
For ns-MRAs, initiation should be limited to patients with consistently normal serum potassium with regular serum potassium monitoring after initiation. [1] When hyperkalemia risk precludes ns-MRA use, potassium monitoring priorities should shift to RAS inhibitor safety, since RAS blockade also requires serum creatinine and potassium monitoring after initiation or dose change. [1]
Common Pitfalls to Avoid
Steroidal MRAs should not be used as a substitute for finerenone when the goal is combined renal and cardiovascular outcome benefit, because clinical outcome data in diabetes and CKD are not available. [1] Steroidal and nonsteroidal MRAs should not be combined because of increased hyperkalemia risk. [1]
Therapeutic Goals of Therapy
Renal and cardiovascular therapeutic goals in type 2 diabetes with chronic kidney disease include prevention of CKD progression and reduction of cardiovascular events. [1] GLP-1 RA kidney effects are supported mainly by reductions in albuminuria, while SGLT2 inhibitors and ns-MRAs target broader cardiorenal risk reduction as supported by trial evidence. [1]