If a child is diagnosed with definite Familial Hypercholesterolemia (FH) based on rigorous criteria, initiate treatment as early as 6-8 years of age to significantly improve long-term outcomes and prevent premature cardiovascular disease.
For adults with FH, especially those transitioning from pediatric care, aggressively treat with high-intensity statins, ezetimibe, PCSK9 inhibitors, and potentially inclisiran, striving for the lowest possible LDL cholesterol levels to minimize cardiovascular risk.
To ensure the most accurate diagnosis of Familial Hypercholesterolemia, utilize the Dutch Lipid Clinic Network (DLCN) criteria, which have been externally and internally validated as highly predictive for FH.
Before diagnosing FH, always rule out other medical conditions that can cause elevated LDL cholesterol, such as high triglycerides, type 2 diabetes, untreated thyroid disease, or renal disease.
Look for physical manifestations of FH, including tendon xanthomas (cholesterol deposits on tendons, especially extensor tendons of hands and Achilles), arcus cornealis (a cholesterol ring in the cornea), and xanthelasmata (deposits on eyelids), as these can aid in early diagnosis.
If clinical diagnosis of FH is strong, pursue genetic testing to definitively confirm the presence of a mutation, as this provides an unambiguous diagnosis without overlap, unlike cholesterol levels alone.
For children with heterozygous FH, establish a very healthy lifestyle early on, including extensive anti-smoking education, comprehensive dietary counseling for healthy food choices, and regular physical exercise.
Despite lifestyle interventions, statin therapy should be initiated in children with FH, typically around age six, as lifestyle measures alone are insufficient to cure the condition.
When prescribing statins for children with FH, rosuvastatin can be a preferred option due to its ability to be dosed at a low 2.5 mg, making it a tiny, manageable pill for a child.
While conservative guidelines suggest an LDL cholesterol goal of at least below 130 mg/dL for children with FH, recognize that a healthy endothelium ideally has much lower LDL levels, suggesting potential benefit from more aggressive treatment.
For individuals with homozygous FH, implement a state-of-the-art quadruple therapy consisting of high-dose statins, ezetimibe, evolocumab (or similar PCSK9 inhibitor), and evinacumab (an NGPTL3 monoclonal antibody) to achieve relatively normal LDL levels.
For children with severe homozygous FH, advocate for the use of evinacumab, as it is a ‘golden rescue’ that can significantly reduce LDL levels and often obviate the need for LDL apheresis, though currently approved for adults.
Do not dismiss the causal link between elevated LDL cholesterol and atherosclerotic cardiovascular disease (ASCVD), as evidenced by the severe and often premature outcomes in FH patients with single-gene mutations that solely raise LDL.
Do not rely on high HDL cholesterol as a primary protective factor against ASCVD, as clinical trials with CETP inhibitors that only raised HDL without lowering LDL or ApoB showed no reduction in heart attacks or strokes.
When considering CETP inhibitors, prioritize those that robustly lower LDL cholesterol (e.g., by 50% on top of high-intensity statins) and have a clean safety profile, as LDL lowering is the validated mechanism for cardiovascular benefit.
Recognize the potential of potent CETP inhibitors like obicetrapib to reduce the risk of type 2 diabetes by improving pancreatic beta-cell function and reducing lipotoxicity, an effect observed across multiple CETP inhibitor trials.
Understand that potent CETP inhibition may offer protection against septicemia by maintaining high HDL levels, which can function as a sink for endotoxins and other inflammatory mediators during infection.
If you have elevated Lp(a), consider the potential of obicetrapib to significantly lower Lp(a) levels (e.g., by 56% at a 10mg dose), although clinical outcome data specifically for Lp(a) lowering with this drug are still pending.
For APOE4 carriers, consider strategies that substantially raise ApoA1 levels (such as potent CETP inhibitors), as ApoA1 can traverse the blood-brain barrier and potentially offset the detrimental effects of dysfunctional APOE4 on brain cholesterol metabolism and Alzheimer’s risk.
If you are an APOE4 carrier, proactively take steps to prevent exacerbating risk factors for Alzheimer’s and cardiovascular disease, as early intervention and comprehensive management can significantly improve your long-term outcomes.
If you are an APOE4 carrier, be aware of your increased risk for cardiovascular disease due to higher LDL cholesterol and a pro-inflammatory state, and manage these factors aggressively.
Prioritize non-HDL cholesterol and ApoB as superior prognostic markers and measures of therapeutic efficacy compared to LDL cholesterol calculated by the Friedewald formula, as they more accurately reflect the total burden of atherogenic lipoproteins.