When do you switch to a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor, such as Alirocumab (Alirocumab) or Evolocumab (Evolocumab), from statin and Ezetimibe (Ezetimibe) therapy?

When to Switch to PCSK9 Inhibitors from Statin and Ezetimibe

Add a PCSK9 inhibitor when LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) despite maximally tolerated statin plus ezetimibe therapy in patients with clinical ASCVD who are at very high risk. 1

Stepwise Approach to Lipid-Lowering Therapy

Step 1: Maximize Statin Therapy First

• Initiate high-intensity statin therapy as first-line treatment for all patients with clinical ASCVD 1
• Ensure the patient is on maximally tolerated statin dose before considering additional agents 1
• Verify patient adherence to statin therapy before escalating treatment 2

Step 2: Add Ezetimibe Before PCSK9 Inhibitors

• Add ezetimibe when LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin therapy 1
• Ezetimibe should always be tried before PCSK9 inhibitors due to lower cost, established safety profile, and proven cardiovascular benefit 2, 1
• Ezetimibe provides an additional 15-20% LDL-C reduction when combined with statins 3
• Reassess LDL-C levels after 4-12 weeks of statin plus ezetimibe therapy 2

Step 3: Add PCSK9 Inhibitor - Specific Criteria

Very High-Risk ASCVD Patients:

Add a PCSK9 inhibitor when ALL of the following are met 1:

• Patient is on maximally tolerated statin PLUS ezetimibe
• LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) OR non-HDL-C ≥100 mg/dL (≥2.6 mmol/L)
• Patient meets very high-risk criteria (see below)

Very high-risk is defined as: 1

• History of multiple major ASCVD events (recent ACS within 12 months, history of MI, ischemic stroke, or symptomatic PAD), OR
• One major ASCVD event PLUS multiple high-risk conditions including: age ≥65 years, heterozygous familial hypercholesterolemia, prior coronary revascularization, diabetes, hypertension, CKD (eGFR 15-59 mL/min/1.73 m²), current smoking, persistently elevated LDL-C ≥100 mg/dL despite maximal therapy, or history of heart failure

Special Populations Requiring PCSK9 Inhibitors

Familial Hypercholesterolemia

Heterozygous FH (HeFH):

• Add PCSK9 inhibitor when LDL-C remains ≥100 mg/dL (≥2.6 mmol/L) despite maximally tolerated statin plus ezetimibe in patients aged 30-75 years 2, 1
• Consider at LDL-C ≥140 mg/dL if additional risk factors present (diabetes with target organ damage, Lp(a) >50 mg/dL) 2

Homozygous FH (HoFH):

• PCSK9 inhibitors are indicated for patients with some residual LDL receptor activity (>2%) 2
• Evolocumab reduces LDL-C by approximately 30% in HoFH patients, with efficacy related to residual LDL receptor function 1

Severe Primary Hypercholesterolemia

• Baseline LDL-C ≥190 mg/dL (≥4.9 mmol/L) 1
• LDL-C remains ≥100 mg/dL (≥2.6 mmol/L) on maximally tolerated statin plus ezetimibe 1
• Consider at LDL-C ≥130 mg/dL if baseline was ≥220 mg/dL 1

Statin-Intolerant Patients

• PCSK9 inhibitors can be added to ezetimibe in patients with documented statin intolerance who have clinical ASCVD and LDL-C ≥70 mg/dL 1
• Both evolocumab and alirocumab are well-tolerated in statin-intolerant patients with minimal muscle-related adverse events 1, 4

International Guideline Variations

European Society of Cardiology (2019):

• More aggressive LDL-C target of <55 mg/dL (<1.4 mmol/L) for very high-risk patients 1
• Recommends PCSK9 inhibitor when target not achieved on maximal statin plus ezetimibe (Class I recommendation for secondary prevention) 1

Canadian Cardiovascular Society (2021):

• Add PCSK9 inhibitor when LDL-C remains ≥100 mg/dL (≥2.6 mmol/L) on maximally tolerated statin plus ezetimibe 1

BMJ Guideline (2022):

• Strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk 1

Clinical Efficacy and Monitoring

Expected LDL-C Reduction:

• PCSK9 inhibitors provide 50-65% additional LDL-C reduction when added to statin therapy 1, 3
• Mean LDL-C levels of approximately 35 mg/dL are achievable, with many patients reaching <25 mg/dL 1, 4

Cardiovascular Outcomes:

• Both evolocumab (FOURIER trial) and alirocumab (ODYSSEY OUTCOMES) demonstrated 15% relative risk reduction in major adverse cardiovascular events 1, 4
• Absolute risk reduction of 1.5-1.6% over 2-3 years 1
• Greater absolute benefit in patients with diabetes and ASCVD 2

Monitoring:

• Assess LDL-C levels 4 weeks after initiating PCSK9 inhibitor therapy 2
• Very low LDL-C levels (<25 mg/dL) can be safely achieved without adverse effects on cognition, hemorrhagic stroke, or hormone production 4

Common Pitfalls to Avoid

• Do not skip ezetimibe: Always add ezetimibe before PCSK9 inhibitors unless contraindicated—this is cost-effective and evidence-based 1, 2
• Verify true statin intolerance: Many patients labeled as statin-intolerant can tolerate lower doses or alternate statins 4
• Ensure adherence: Confirm patient adherence to statin and ezetimibe before escalating to expensive PCSK9 inhibitor therapy 2
• Consider cost: PCSK9 inhibitors are expensive; discuss net benefit, safety, and cost with patients before initiating 1
• Check for latex allergy: PCSK9 inhibitor auto-injectors may contain latex 4