What is the target low-density lipoprotein (LDL) level in a patient with probable familial hypercholesterolemia (FH)?

From the Guidelines

For patients with probable familial hypercholesterolemia (FH), the target low-density lipoprotein (LDL) level should be less than 55 mg/dL, as recommended by the 2019 ESC/EAS Cholesterol Guidelines for very high-risk patients 1. This aggressive target is recommended because FH patients have significantly elevated cardiovascular risk due to lifelong exposure to high LDL cholesterol levels.

Key Considerations

• The 2019 ESC/EAS guideline defines very high-risk patients as those with documented atherosclerotic cardiovascular disease (ASCVD), with diabetes, at least three major risk factors, or early onset of type 1 diabetes, with advanced chronic kidney disease not on hemodialysis, or with familial hypercholesterolemia plus a major risk factor 1.
• Treatment typically involves high-intensity statin therapy as first-line treatment, often at maximum tolerated doses.
• For many FH patients, combination therapy is necessary, adding ezetimibe and possibly PCSK9 inhibitors like evolocumab or alirocumab when statins and ezetimibe fail to achieve target levels.

Rationale for Aggressive Targets

• The pathophysiology of FH involves genetic defects in LDL receptor function, apolipoprotein B, or PCSK9 protein, leading to severely impaired LDL clearance from the bloodstream.
• Early and intensive lipid-lowering therapy is crucial to reduce the cumulative burden of LDL exposure and decrease the risk of premature cardiovascular events that are characteristic of this condition.

Clinical Implications

• The American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol Guidelines also support a more aggressive approach to LDL-C lowering in very high-risk ASCVD patients, recommending achieving at least a 50% reduction in LDL-C and a 70 mg/dL LDL-C threshold to consider further LDL-C lowering with ezetimibe, and if needed by a PCSK9 inhibitor 1.
• However, the most recent and highest quality evidence from the 2019 ESC/EAS Cholesterol Guidelines supports a target LDL level of less than 55 mg/dL for very high-risk patients, including those with FH 1.

From the Research

Target Low-Density Lipoprotein (LDL) Level in Familial Hypercholesterolemia (FH)

The target LDL level in patients with probable familial hypercholesterolemia (FH) can be summarized as follows:

• For adults with FH, the recommended LDL-C target is <100 mg/dL (<2.6 mmol/L) 2
• For adults with FH and existing cardiovascular disease or diabetes, the recommended LDL-C target is <70 mg/dL (<1.8 mmol/L) 2
• For children with FH, the recommended LDL-C target is <135 mg/dL (<3.5 mmol/L) 2 Key considerations for achieving these targets include:
• Early identification and aggressive treatment of FH to minimize the risk of premature coronary heart disease (CHD) 3
• Use of high-intensity statins as the mainstay of treatment, with combination therapy often necessary in FH patients 4
• Addition of other therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors as needed to achieve target LDL-C levels 3, 5, 2, 4
• Consideration of lipoprotein apheresis for patients with homozygous FH or severe heterozygous FH who do not respond to pharmacotherapy 4