What is the recommended treatment for patients with elevated Low-Density Lipoprotein (LDL) cholesterol levels using Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors?

PCSK9 Inhibitor Treatment for Elevated LDL Cholesterol

PCSK9 inhibitors (evolocumab or alirocumab) should be added to maximally tolerated statin therapy plus ezetimibe in patients with established atherosclerotic cardiovascular disease (ASCVD) who have LDL-C ≥70 mg/dL, or in patients with familial hypercholesterolemia without ASCVD who have LDL-C ≥180 mg/dL (or ≥140 mg/dL with additional risk factors). 1, 2

Patient Selection Algorithm

For Patients with Established ASCVD

Step 1: Verify Background Therapy

• Ensure patient is on maximally tolerated statin therapy plus ezetimibe, or has documented intolerance to at least three different statins 1
• Confirm adherence to current lipid-lowering regimen before escalating therapy 2

Step 2: Assess LDL-C Threshold

• Initiate PCSK9 inhibitor if LDL-C ≥70 mg/dL despite optimal background therapy 2
• Patients with multiple major ASCVD events (recent acute coronary syndrome, prior MI, ischemic stroke, or symptomatic peripheral arterial disease) are highest priority 2
• Patients with one major ASCVD event plus high-risk conditions (age ≥65, diabetes, hypertension, CKD, current smoking, prior revascularization) also qualify 2

Step 3: Expected Outcomes

• PCSK9 inhibitors reduce LDL-C by approximately 50-60% when added to statin therapy 1, 3, 4
• This translates to reduction in non-fatal cardiovascular events including MI, stroke, and unstable angina requiring hospitalization 1, 5, 6

For Patients with Familial Hypercholesterolemia WITHOUT Clinical ASCVD

Heterozygous FH (HeFH):

• LDL-C ≥180 mg/dL (4.5 mmol/L) despite maximally tolerated statin plus ezetimibe warrants PCSK9 inhibitor 1, 2
• Lower threshold of LDL-C ≥140 mg/dL (3.6 mmol/L) applies when additional risk factors are present 1, 2:
  • Lipoprotein(a) >50 mg/dL 1
  • Diabetes with target organ damage (proteinuria) or major risk factors 1
  • Marked hypertension (≥160/100 mmHg) 1
  • Current smoking 1
  • Premature ASCVD in first-degree relatives (<55 years males, <60 years females) 1
  • Age >40 years without treatment 1

Homozygous FH (HoFH):

• Evolocumab is recommended as adjunctive therapy with or without apheresis 1
• Critical caveat: PCSK9 inhibitors are NOT effective in patients with negative/negative LDLR mutations with <2% LDL receptor activity 1
• Some residual LDL receptor function is required for efficacy 1, 2

Specific Agent Selection

Both FDA-approved PCSK9 inhibitors are effective options 5, 6:

Evolocumab (Repatha):

• Indicated for cardiovascular risk reduction in established CVD 5
• Dosing: 140 mg every 2 weeks or 420 mg monthly subcutaneously 5
• Approved for adults and pediatric patients ≥10 years with HeFH or HoFH 5

Alirocumab (Praluent):

• Indicated for cardiovascular risk reduction in established CVD 6
• Approved for adults with primary hyperlipidemia including HeFH, adults with HoFH, and pediatric patients ≥8 years with HeFH 6

Special Populations

Diabetes Patients:

• Patients with diabetes and ASCVD show greater absolute risk reduction with PCSK9 inhibitor therapy compared to non-diabetics 2
• Particularly beneficial in those with target organ damage or additional major risk factors 2
• Very low LDL-C levels (<25 mg/dL) achieved with PCSK9 inhibitors do not adversely affect glycemic control or increase diabetes risk in short-term studies 1

Pediatric Patients:

• Evolocumab approved for ages ≥10 years with HeFH or HoFH 5
• Alirocumab approved for ages ≥8 years with HeFH 6

Monitoring and Response Assessment

Initial Assessment:

• Measure LDL-C at 4 weeks after initiating PCSK9 inhibitor therapy 1, 2
• This allows early identification of non-responders and dose adjustment if needed 1

Safety Monitoring:

• Very low LDL-C levels (<25 mg/dL) appear safe in trials up to 4 years duration 1
• No increase in adverse events including muscle symptoms, liver enzyme elevation, cognitive dysfunction, or hemorrhagic stroke 1
• Cognitive function specifically evaluated and found safe even at very low LDL-C levels 1

Critical Pitfalls to Avoid

Do not initiate PCSK9 inhibitors without:

• First maximizing statin therapy (or documenting intolerance to multiple statins) 1
• Adding ezetimibe before PCSK9 inhibitor due to lower cost and established safety 2
• Confirming patient adherence to current therapy 2

Do not use PCSK9 inhibitors in:

• Homozygous FH patients with negative/negative LDLR mutations (<2% receptor activity) as they will not respond 1

Long-term uncertainties (though not contraindications) include 1:

• Impact beyond 4 years of treatment
• Effects in chronic kidney disease not requiring dialysis
• Long-term diabetes risk (Mendelian studies suggest possible increased lifetime risk)
• Cost-effectiveness considerations should be incorporated into decision-making 2