What is the role of Proconvertase subtilisin/kexin type 1 (PCSK1) inhibitors, such as finerenone (finerenone), in the management of proteinuria in patients with chronic kidney disease, particularly those with diabetic nephropathy?

PCSK9 Inhibitors Have No Role in Proteinuria Management—You're Likely Confusing Them with Finerenone (a Mineralocorticoid Receptor Antagonist)

Critical Clarification: PCSK9i vs. Finerenone

PCSK9 inhibitors (evolocumab, alirocumab) are lipid-lowering agents for cardiovascular risk reduction and have no established role in proteinuria management. 1 The confusion likely stems from similar acronyms: PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) versus finerenone, which is a nonsteroidal mineralocorticoid receptor antagonist (ns-MRA). 1

While emerging preclinical research suggests PCSK9 may interact with megalin receptors in proximal tubules and theoretically influence proteinuria, this remains experimental with no clinical application. 2

Finerenone: The Actual Evidence-Based Agent for Proteinuria in Diabetic Kidney Disease

Patient Selection Criteria

Initiate finerenone in adults with type 2 diabetes who have persistent albuminuria (UACR ≥30 mg/g) despite maximum tolerated RAS inhibitor therapy, eGFR ≥25 mL/min/1.73 m², and serum potassium ≤4.8 mmol/L. 1, 3, 4

• Do not use finerenone in patients with eGFR <25 mL/min/1.73 m² or end-stage renal disease, as landmark trials excluded this population. 3
• Verify normal potassium (≤4.8 mmol/L) before initiation due to hyperkalemia risk. 3, 4

Treatment Sequencing Algorithm

The KDIGO 2022 guidelines establish a clear hierarchy for diabetic kidney disease management: 1

1. First-line foundation: Maximum tolerated dose of ACE inhibitor or ARB 1, 5
2. Second-line priority: SGLT2 inhibitor (larger effects on kidney and cardiovascular outcomes) 1, 3
3. Third-line consideration: Finerenone for patients with persistent albuminuria despite SGLT2 inhibitor or SGLT2i intolerance 1, 3, 4

Dosing Protocol

• eGFR 25-60 mL/min/1.73 m²: Start 10 mg once daily, uptitrate to 20 mg after 1 month if potassium ≤4.8 mmol/L 3, 4
• eGFR >60 mL/min/1.73 m²: Start 20 mg once daily 3, 4

Clinical Benefits on Proteinuria and Outcomes

Finerenone provides substantial cardiorenal protection beyond proteinuria reduction: 1, 4

• 36% reduction in progression to end-stage kidney disease (HR 0.64,95% CI 0.41-0.995) 4
• 14% reduction in composite cardiovascular outcomes (CV death, nonfatal MI, nonfatal stroke, heart failure hospitalization; HR 0.86,95% CI 0.78-0.95) 1, 4
• 18% reduction in kidney composite outcomes (kidney failure, sustained ≥40% eGFR decrease, or kidney death; HR 0.82,95% CI 0.73-0.93) 1
• Significant proteinuria reduction demonstrated in FIDELIO-DKD and FIGARO-DKD trials 1, 6

Potassium Monitoring Protocol

Check serum potassium at 1 month after initiation, then every 4 months during maintenance therapy. 3

Management thresholds: 3

• Potassium ≤4.8 mmol/L: Continue current dose, monitor every 4 months
• Potassium 4.9-5.5 mmol/L: Continue current dose without adjustment, maintain monitoring
• Potassium >5.5 mmol/L: Immediately hold finerenone, recheck potassium, restart at 10 mg daily when potassium returns to ≤5.0 mmol/L

Safety Profile

• Hyperkalemia occurred in 14% with finerenone versus 6.9% with placebo in pooled trial data 1
• Permanent discontinuation due to hyperkalemia was rare (1.7% vs 0.6% placebo) with no deaths from hyperkalemia over 3 years 1
• SGLT2 inhibitor co-administration reduces hyperkalemia risk 3

Common Pitfalls to Avoid

• Do not confuse PCSK9 inhibitors with finerenone—they are entirely different drug classes with different indications 1, 2
• Do not initiate finerenone before optimizing RAS inhibitor therapy at maximum tolerated dose 3, 4
• Do not permanently discontinue finerenone for a single potassium >5.5 mmol/L episode—temporary interruption with dose reduction upon restart manages most cases 3
• Do not use finerenone as monotherapy—it requires background RAS inhibitor therapy 1, 4