What are the treatment options for patients with elevated cardiovascular risk, specifically regarding PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) inhibitors?

PCSK9 Inhibitors for Cardiovascular Risk Reduction

PCSK9 inhibitors should be added to therapy in patients with established atherosclerotic cardiovascular disease (ASCVD) who have LDL-C levels ≥70 mg/dL despite maximally tolerated statin plus ezetimibe therapy, as they significantly reduce cardiovascular events and mortality. 1

Overview of PCSK9 Inhibitors

PCSK9 inhibitors are monoclonal antibodies that lower LDL-C by increasing LDL receptor activity, promoting clearance of LDL-C from the bloodstream. Currently available PCSK9 inhibitors include:

• Alirocumab (Praluent): FDA-approved to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease 2
• Evolocumab (Repatha): FDA-approved to reduce the risk of major adverse cardiovascular events (CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease 3

Stepwise Approach to Lipid-Lowering Therapy

1. First-line therapy: High-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) 1
2. Second-line therapy: Add ezetimibe if LDL-C remains elevated despite maximally tolerated statin 1
3. Third-line therapy: Add PCSK9 inhibitor if LDL-C remains elevated despite maximally tolerated statin plus ezetimibe 1

Indications for PCSK9 Inhibitors

Very High-Risk Patients with ASCVD

• Add PCSK9 inhibitor if LDL-C ≥70 mg/dL despite maximally tolerated statin plus ezetimibe 1
• Examples of very high-risk patients: multiple major ASCVD events or one major ASCVD event with multiple high-risk conditions 1

Familial Hypercholesterolemia (FH)

• Heterozygous FH (HeFH): Consider PCSK9 inhibitor if LDL-C remains ≥100 mg/dL despite maximally tolerated statin plus ezetimibe 1, 4
• Homozygous FH (HoFH): PCSK9 inhibitors are indicated as adjunct to other LDL-C-lowering therapies 2, 3
• Pediatric HeFH: Alirocumab is approved for patients aged 8 years and older; evolocumab for patients aged 10 years and older 4, 2, 3

Statin Intolerance

• PCSK9 inhibitors may be considered in patients unable to tolerate appropriate doses of at least three statins 1

Efficacy of PCSK9 Inhibitors

• Reduce LDL-C by 50-60% from baseline when added to statin therapy 1, 5
• FOURIER trial: Evolocumab reduced LDL-C by 59% (from median 92 to 30 mg/dL) and reduced major cardiovascular events by 15% 1
• ODYSSEY OUTCOMES trial: Alirocumab reduced LDL-C by 57% and reduced major adverse cardiovascular events by 15% 4, 5
• Modest increases in HDL-C (4.5-12%) 6

Dosing and Administration

Alirocumab

• Starting dose: 75 mg subcutaneously every 2 weeks or 300 mg every 4 weeks
• Dose adjustment: May increase to 150 mg every 2 weeks if LDL-C response is inadequate 2

Evolocumab

• Standard dosing: 140 mg subcutaneously every 2 weeks or 420 mg monthly 3
• For patients receiving therapy every 4 weeks, measure LDL-C just prior to the next scheduled dose 1

Safety and Tolerability

• Generally well-tolerated with minimal side effects 7, 5
• Most common adverse effect: injection site reactions (<5% of patients) 1, 8
• No significant increase in muscle-related adverse events compared to statin monotherapy 4
• No evidence of increased risk of hemorrhagic stroke 1
• No significant impact on glycemic control, though Mendelian randomization studies suggest potential long-term risk for diabetes 1

Clinical Pearls and Pitfalls

• Undertreatment: Don't delay adding PCSK9 inhibitors when appropriate; focus on achieving ≥50% reduction in LDL-C from baseline 4
• Monitoring: Measure LDL-C 4-12 weeks after initiating therapy or changing doses 4
• Cost considerations: Despite proven efficacy, high cost may limit widespread use; prioritize for highest-risk patients 1, 9
• LDL-C variability: Some patients may show variability in LDL-C response between doses 1
• Combination therapy: Always optimize statin and ezetimibe therapy before adding PCSK9 inhibitors 1

Special Populations

• Elderly: No dose adjustment required based on age
• Renal impairment: No dose adjustment required
• Hepatic impairment: Use with caution; limited data available
• Pregnancy: Limited data; use only if benefit outweighs risk

PCSK9 inhibitors represent a significant advance in lipid-lowering therapy for high-risk patients who cannot achieve adequate LDL-C reduction with statins and ezetimibe alone. Their proven efficacy in reducing cardiovascular events makes them an important tool in the management of patients with elevated cardiovascular risk.