What to do for a patient with tendon xanthomas and Family History (FH) of hyperlipidemia who is on cholesterol-lowering medication but experiencing worsening xanthomas?

From the Guidelines

For a patient with worsening tendon xanthomas despite cholesterol-lowering medication, I recommend intensifying lipid-lowering therapy by adding ezetimibe 10 mg daily to the current statin regimen, as this has been shown to reduce ASCVD risk by 2 percentage points 1. If the patient is already on combination therapy, consider adding a PCSK9 inhibitor such as evolocumab (140 mg subcutaneously every 2 weeks) or alirocumab (75-150 mg subcutaneously every 2 weeks), as these have been found to reduce LDL-C levels by ≥50% and are well-tolerated in patients with familial hypercholesterolemia 1. The presence of tendon xanthomas with a family history suggests familial hypercholesterolemia (FH), a genetic disorder causing severely elevated LDL cholesterol levels. FH often requires multiple medications to achieve adequate LDL reduction. Target LDL levels should be <70 mg/dL or even <55 mg/dL for very high-risk patients, as recommended by the 2018 American Heart Association/American College of Cardiology/Multisociety Cholesterol Guideline 1. Worsening xanthomas indicate inadequate lipid control, so more aggressive therapy is needed. Additionally, ensure the patient is adherent to the current medication regimen and following a low-saturated fat diet. Consider genetic testing to confirm FH diagnosis and cascade screening for family members. Referral to a lipid specialist may be beneficial for optimizing therapy in this challenging case. Some key points to consider in the management of this patient include:

• The use of combination therapy with statins and ezetimibe has been shown to be effective in reducing ASCVD risk 1
• PCSK9 inhibitors are a reasonable addition to maximally tolerated statin and ezetimibe therapy in patients with severe primary hypercholesterolemia and LDL-C ≥ 100 mg/dL 1
• The management of severe primary hypercholesterolemia requires a comprehensive approach, including lifestyle modifications and pharmacotherapy 1

From the FDA Drug Label

The provided drug labels do not directly address the management of worsening tendon xanthomas in a patient with familial hypercholesterolemia (FH) who is already on cholesterol-lowering medication.

The FDA drug label does not answer the question.

From the Research

Tendon Xanthomas in Familial Hypercholesterolemia

• Tendon xanthomas are a common feature of familial hypercholesterolemia (FH) and are associated with an increased risk of cardiovascular disease 2
• The presence of tendon xanthomas in patients with FH has been shown to be associated with a two to four times higher risk for cardiovascular disease 2

Treatment of Tendon Xanthomas

• Intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies has been shown to reduce tendon xanthoma size in patients with heterozygous familial hypercholesterolemia (HeFH) 3
• The addition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and tendon xanthoma size after 3 years of treatment 3
• Personalized lipid-lowering therapy, including maximized statin therapy, ezetimibe, PCSK9 inhibitors, and lipoprotein apheresis, can lead to impressive regression of cutaneous xanthomas in patients with HeFH 4

Differential Diagnosis

• Tendon xanthomas are not always associated with familial hypercholesterolemia, and other conditions such as cerebrotendinous xanthomatosis (CTX) and sitosterolemia should be considered in the differential diagnosis 5
• CTX is a rare, recessive disorder caused by mutations in the CYP27A1 gene, and treatment consists of bile acid supplementation in combination with a statin 5

Lipid-Lowering Therapy

• Statins, ezetimibe, and bile acid sequestrants can be used individually or in combination to lower LDL cholesterol levels 6
• The addition of a bile acid sequestrant or ezetimibe to a statin can produce additional LDL cholesterol reduction, allowing many patients to reach LDL cholesterol targets 6