What are the treatment options for patients requiring significant Low-Density Lipoprotein (LDL) cholesterol reduction, particularly those at high risk of cardiovascular events, using Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors?

PCSK9 Inhibitors for LDL Cholesterol Reduction

PCSK9 inhibitors (alirocumab and evolocumab) should be added to maximally tolerated statin therapy (with or without ezetimibe) in very high-risk patients with established atherosclerotic cardiovascular disease (ASCVD) who have LDL-C ≥70 mg/dL (≥1.8 mmol/L), as these agents reduce LDL-C by 50-65% and significantly decrease major cardiovascular events. 1, 2

FDA-Approved Indications

Both alirocumab (PRALUENT) and evolocumab (REPATHA) are FDA-approved for:

• Reducing risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease 3, 4, 3
• Adjunct to diet and other LDL-C-lowering therapies in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 3, 4, 3
• Adjunct therapy in homozygous familial hypercholesterolemia (HoFH) 3, 4, 3

Treatment Algorithm for PCSK9 Inhibitor Initiation

Step 1: Optimize Statin Therapy First

• High-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) is mandatory first-line treatment for patients with ASCVD 1
• Assess LDL-C response after 4-6 weeks 2

Step 2: Add Ezetimibe as Second-Line

• If LDL-C remains ≥70 mg/dL on maximally tolerated statin, add ezetimibe 10 mg daily 1, 2
• Ezetimibe provides an additional 15-20% LDL-C reduction 1
• Reassess LDL-C after 4 weeks 2

Step 3: Consider PCSK9 Inhibitor as Third-Line

Add PCSK9 inhibitor if LDL-C remains ≥70 mg/dL (≥1.8 mmol/L) despite maximally tolerated statin plus ezetimibe in patients with: 1, 2

• Established ASCVD (prior MI, stroke, peripheral arterial disease, ACS)
• Very high-risk features (recurrent events, multivessel disease, diabetes with target organ damage)
• Familial hypercholesterolemia not at goal

Dosing Regimens

Alirocumab (PRALUENT)

• Starting dose: 75 mg subcutaneously every 2 weeks OR 300 mg every 4 weeks 3
• If inadequate response: increase to 150 mg every 2 weeks 3
• For 300 mg dose, administer two 150 mg injections consecutively at different sites 3

Evolocumab (REPATHA)

• Standard dose: 140 mg subcutaneously every 2 weeks OR 420 mg every 4 weeks 1, 4
• Both dosing schedules provide comparable LDL-lowering efficacy 1

Expected LDL-C Reduction

PCSK9 inhibitors reduce LDL-C by 50-65% when added to statin therapy, achieving mean LDL-C levels of approximately 35 mg/dL (0.9 mmol/L) 1, 2

• Many patients achieve LDL-C <25 mg/dL with combination therapy 1
• Efficacy is consistent across patient subgroups, including heterozygous FH 1
• In homozygous FH, evolocumab reduces LDL-C by approximately 30%, with efficacy dependent on residual LDL receptor activity 1

Cardiovascular Outcomes Evidence

The FOURIER trial demonstrated that evolocumab added to statin therapy reduced major cardiovascular events by 15-20% over a median 2.2 years in 27,564 patients with established ASCVD 1, 2

• Evolocumab reduced LDL-C from median 92 mg/dL to 30 mg/dL (59% reduction) 1
• Number needed to treat for 2 years to prevent one major cardiovascular event: 89 1
• The ODYSSEY Outcomes trial showed alirocumab reduced adverse cardiovascular events by 15% with a 57% LDL-C reduction 2

Safety Profile and Monitoring

Common Adverse Effects

• Injection site reactions are the most common side effect but are relatively infrequent and mild 1, 2
• Myalgia occurs slightly more frequently with alirocumab versus placebo 1
• Both agents are well-tolerated in statin-intolerant patients, with muscle-related adverse events comparable to ezetimibe 1

Safety of Very Low LDL-C Levels

No excess adverse events have emerged in patients achieving LDL-C <25 mg/dL over 78 weeks of treatment 1, 2

• Small, non-significant increases in neurocognitive events reported for both agents 1, 2
• Small, non-significant increase in ophthalmologic events with alirocumab 1

Monitoring Schedule

• Assess LDL-C response as early as 4 weeks after initiation 2, 3
• For patients on 300 mg alirocumab every 4 weeks, measure LDL-C just prior to next scheduled dose, as levels can vary between doses 3

Special Populations

Familial Hypercholesterolemia

For HeFH patients with LDL-C >180 mg/dL (>4.5 mmol/L) despite maximally tolerated statin plus ezetimibe, PCSK9 inhibitors are strongly recommended 1

• Lower threshold of >140 mg/dL applies if additional risk factors present (diabetes with target organ damage, Lp(a) >50 mg/dL, premature ASCVD in first-degree relatives, marked hypertension) 1
• PCSK9 inhibitors allow substantial proportions of FH patients to achieve LDL-C <70 mg/dL for the first time 1

Homozygous FH

• Evolocumab is recommended as additional therapy, with or without apheresis 1
• Not recommended in patients with negative/negative LDLR mutations (LDL receptor activity <2%) 1

Statin-Intolerant Patients

PCSK9 inhibitors are well-accepted alternatives in patients unable to tolerate at least three different statins 1

Additional Lipid Benefits

Beyond LDL-C reduction, PCSK9 inhibitors reduce lipoprotein(a) by up to 25% 1, 2

• HDL-C increases by 4.5-12% 1
• These pleiotropic effects may contribute to cardiovascular risk reduction 1

Critical Pitfalls to Avoid

• Do not initiate PCSK9 inhibitors without first maximizing statin therapy and adding ezetimibe - this stepwise approach is essential per guidelines 1, 2
• Do not use PCSK9 inhibitors as monotherapy in statin-tolerant patients - they are adjunctive agents 1, 2
• Do not expect benefit in homozygous FH patients with complete absence of LDL receptor activity - some residual receptor function is required 1
• Do not discontinue therapy prematurely - cardiovascular benefits accrue over time, with preliminary evidence showing event reduction over 1-1.5 years 1, 2