What are the best treatments for a patient with Homozygous Familial Hypercholesterolemia (HoFH) due to Low-Density Lipoprotein (LDL) receptor deficiency?

From the Guidelines

For patients with homozygous familial hypercholesterolemia (HoFH) due to absent LDL receptors, the most effective treatment approach is a combination of PCSK9 inhibitors (evolocumab 420mg subcutaneously monthly or alirocumab 150mg every two weeks), lomitapide (starting at 5mg daily orally, gradually increasing to 10-60mg as tolerated), and evinacumab (15mg/kg IV every 4 weeks), used in conjunction with high-intensity statins (rosuvastatin 20-40mg or atorvastatin 40-80mg daily) and ezetimibe (10mg daily), as well as LDL apheresis every 1-2 weeks as an adjunctive therapy. This aggressive approach is necessary due to the extremely high LDL levels (typically >500 mg/dL) and early cardiovascular disease associated with HoFH, which results from the complete lack of functional LDL receptors 1.

Key Components of Treatment:

• PCSK9 inhibitors (evolocumab or alirocumab) to prevent LDL receptor degradation, offering a modest benefit even with minimal receptor function 1.
• Lomitapide to reduce lipoprotein production by inhibiting microsomal triglyceride transfer protein 1.
• Evinacumab to inhibit ANGPTL3 and enhance LDL clearance through non-LDL receptor pathways, with a demonstrated 47.1% relative reduction in LDL-C in patients with HoFH 1.
• High-intensity statins (rosuvastatin or atorvastatin) and ezetimibe, despite their limited efficacy in HoFH patients, as part of a comprehensive lipid-lowering strategy 1.
• LDL apheresis every 1-2 weeks as an adjunctive therapy to maximally lower LDL-C levels, especially in patients with severe HoFH 1.

Monitoring and Considerations:

Regular monitoring of liver function, vitamin levels, and cardiovascular status is crucial when using these therapies, given their potential side effects and the complexity of HoFH management 1. The choice of treatment should be individualized, considering the patient's specific genetic profile, lipid levels, and cardiovascular risk, as well as potential drug interactions and the patient's ability to adhere to the treatment regimen 1.

Given the complexity and severity of HoFH, referral to a lipid specialist is often necessary to ensure optimal management and to consider the use of newer therapies like evinacumab, which has shown significant promise in reducing LDL-C levels in these patients 1.

From the FDA Drug Label

As an adjunct to other LDL-C-lowering therapies in adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C The recommended dosage of PRALUENT is 150 mg once every 2 weeks administered subcutaneously As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH)

The best treatments for a patient with Homozygous Familial Hypercholesterolemia (HoFH) due to Low-Density Lipoprotein (LDL) receptor deficiency include:

• Alirocumab (SQ): 150 mg once every 2 weeks administered subcutaneously 2
• Atorvastatin (PO): as an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults with HoFH 3 Key considerations:
• These treatments should be used as an adjunct to other LDL-C-lowering therapies
• The dosage and administration of these treatments should be followed as recommended in the drug labels 2 3

From the Research

Treatment Options for Homozygous Familial Hypercholesterolemia (HoFH)

• The primary goal of treatment for HoFH is to reduce low-density lipoprotein cholesterol (LDL-C) levels to prevent atherosclerotic cardiovascular disease (ASCVD) 4.
• Conventional lipid-lowering therapy (LLT) is often ineffective in patients with HoFH due to absent or defective LDL-receptor activity, making alternative treatments necessary 4.
• PCSK9 inhibitors have been shown to achieve profound reductions in LDL-C (54%-74%) when added to statins, making them a viable option for patients with HoFH 5.
• Ezetimibe, which reduces LDL-C by 15%-20% when combined with statin, can also be used in combination with PCSK9 inhibitors to further lower LDL-C levels 5, 6.
• Bempedoic acid, which reduces hepatic cholesterol synthesis, is another evidence-based therapy that can be used in combination with PCSK9 inhibitors and ezetimibe to lower LDL-C levels and reduce the risk of major adverse cardiovascular events (MACE) 6.
• LDL apheresis is a treatment option for patients with HoFH, which can reduce LDL-C levels by removing LDL from the blood, and has been shown to be effective in reducing lipoprotein(a) levels as well 7.

Emerging Therapies

• Anti-PCSK9 antibodies, such as evolocumab and alirocumab, have been shown to significantly reduce serum LDL cholesterol levels and decrease cardiovascular event incidence in patients with familial hypercholesterolemia 8.
• Antisense oligonucleotide agents and small interfering RNA (siRNA) for PCSK9 are being developed as alternative strategies against PCSK9 8.

Considerations

• The choice of treatment for HoFH should be individualized based on the patient's specific needs and circumstances, taking into account the potential benefits and risks of each treatment option 5, 6, 4, 7, 8.