For a patient with severe hypertriglyceridemia or homozygous familial hypercholesterolemia and persistently elevated low‑density lipoprotein cholesterol despite maximally tolerated statin (and ezetimibe), what is the only approved angiopoietin‑like protein 3 inhibitor, its dosing schedule, and recommended monitoring?

Evinacumab: The Only FDA-Approved ANGPTL3 Inhibitor

Evinacumab is currently the only FDA-approved angiopoietin-like protein 3 (ANGPTL3) inhibitor, indicated specifically for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 years and older, administered at 15 mg/kg intravenously every 4 weeks. 1

Mechanism of Action

Evinacumab is a fully human monoclonal antibody that inhibits ANGPTL3, a liver-expressed protein that normally inhibits lipoprotein lipase and endothelial lipase. 1 This mechanism is critical because:

• It reduces LDL-C independently of the LDL receptor, making it effective even in patients with absent or defective LDL receptors (common in HoFH). 1
• Loss-of-function variants in ANGPTL3 are associated with 41% lower risk of coronary artery disease, validating this therapeutic target. 1
• The drug lowers LDL-C, triglycerides, and other lipids through enhanced lipoprotein metabolism. 2, 3

FDA-Approved Indication

Evinacumab is approved exclusively for HoFH as an adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 12 years and older. 1 While efficacy has been demonstrated in heterozygous familial hypercholesterolemia (HeFH) and other forms of hypercholesterolemia, current FDA approval is limited to HoFH only. 1

Dosing Schedule

The approved dose is 15 mg/kg administered by intravenous infusion over approximately 1 hour once monthly (every 4 weeks). 1, 3

Clinical Efficacy

The ELIPSE HoFH trial established evinacumab's efficacy in 65 HoFH patients on stable maximally tolerated lipid-lowering therapy with baseline LDL-C ≥70 mg/dL:

• 47.1% relative reduction in LDL-C at week 24 compared to 1.9% increase with placebo (between-group difference: -49.0 percentage points, P < 0.001). 1
• Absolute LDL-C reduction of 132.1 mg/dL from a baseline mean of 255 mg/dL. 1
• Effective in patients with 2 null variants (-43.4% vs +16.2% placebo) and non-null variants (-49.1% vs -3.8% placebo). 1
• Also reduces triglycerides by approximately 50%. 4, 2

When to Consider Evinacumab

According to the 2022 ACC Expert Consensus Decision Pathway, evinacumab should be considered for: 1

• HoFH patients with inadequate response to statins with or without ezetimibe and PCSK9 inhibitors
• Patients requiring specialized therapies under the care of a lipid specialist 1
• Those with severe hypertriglyceridemia in addition to HoFH 5

The International Atherosclerosis Society recommends evinacumab in patients with markedly elevated LDL-C despite conventional therapy or rapidly progressive atherosclerotic cardiovascular disease, especially when lipoprotein apheresis is unavailable or not feasible. 1

Monitoring Requirements

While specific monitoring protocols are not extensively detailed in the guidelines, based on clinical trial data and standard practice:

• Lipid panel monitoring: Assess LDL-C response at regular intervals (typically every 3-6 months after initiation). 1
• Liver enzyme monitoring: Continuous monitoring is recommended, particularly when used in combination with lomitapide. 6
• Cardiovascular imaging: CT coronary angiography, carotid ultrasonography, and echocardiography should be used to assess ASCVD severity and progression. 1
• No antidrug antibodies developed in clinical trials, but this should be considered if loss of efficacy occurs. 1

Safety Profile

Evinacumab demonstrated favorable tolerability in clinical trials:

• Adverse events were similar between evinacumab and placebo groups. 1
• No patients discontinued treatment due to adverse events. 1
• Common adverse events include nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. 2
• Important caveat: Evinacumab reduces HDL-C by approximately 30%, though the clinical significance remains unclear. 4, 2

Combination Therapy Considerations

Evinacumab can be combined with other lipid-lowering therapies for additive LDL-C reduction in HoFH:

• Combination with lomitapide (MTP inhibitor) has shown remarkable improvement in LDL-C levels, xanthoma resolution, and atherosclerotic plaque regression in long-term follow-up. 6
• Should be used adjunctive to maximally tolerated conventional therapy (statins, ezetimibe, PCSK9 inhibitors). 1
• May be considered with lomitapide in patients with rapidly progressive ASCVD. 1

Treatment Goals for HoFH

When using evinacumab, target the following LDL-C goals based on cardiovascular risk: 1

• <100 mg/dL in absence of ASCVD or other major risk factors
• <70 mg/dL with imaging evidence of ASCVD or additional major risk factors
• <55 mg/dL with previous ASCVD event

Critical Limitations

• No cardiovascular outcomes data exist for evinacumab; effects on cardiovascular morbidity and mortality have not been studied. 1
• Cost and access: Evinacumab is expensive and may be covered under major medical benefits through physician purchase, specialty pharmacy, or specialty distribution. 1
• Administration burden: Requires monthly IV infusions, unlike subcutaneous PCSK9 inhibitors. 1
• HDL-C reduction: The clinical significance of 30% HDL-C reduction requires further clarification. 4

Referral to Lipid Specialist

All HoFH patients, particularly those requiring evinacumab, should be managed under the care of a lipid specialist. 1 The complexity of managing severe hypercholesterolemia with specialized therapies necessitates expert oversight for optimal outcomes and safety monitoring.