Do patients with Familial Hypercholesterolemia (FH) not develop cardiovascular disease at increased rates?

Familial Hypercholesterolemia Patients Have Significantly Increased Cardiovascular Disease Risk

Patients with Familial Hypercholesterolemia (FH) consistently develop cardiovascular disease at significantly increased rates compared to the general population, with no studies showing otherwise. 1

Evidence for Increased Cardiovascular Risk in FH

• Patients with LDL-C ≥ 190 mg/dL have a 30-year hazard ratio of up to 5.0 for coronary heart disease and up to 4.1 for total atherosclerotic cardiovascular disease (ASCVD) compared to those with LDL-C < 130 mg/dL 1
• Those with clinical or molecularly-confirmed familial hypercholesterolemia have particularly high risk for premature and recurrent coronary events due to lifelong exposure of the endothelium to elevated LDL-C levels 1
• The European Society of Cardiology explicitly states that FH patients are at high risk of cardiovascular disease, requiring aggressive treatment from an early age 1
• FH is characterized by markedly elevated LDL-cholesterol concentrations from conception, leading to accelerated ASCVD and aortic stenosis, impairing quality of life and causing premature death 1

Genetic Basis and Cardiovascular Risk

• FH is most commonly caused by mutations in the LDL receptor gene (LDLR), resulting in impaired clearance of LDL particles from circulation 2, 3
• Other genetic causes include mutations in:
  • Apolipoprotein B 100 gene (APOB) - affecting approximately 3% of FH patients 1
  • Protein convertase subtilisin/kexin type 9 (PCSK9) gene - causing increased degradation of LDL receptors 1
• Genetic testing can identify mutations in these genes in up to 80-90% of clinically diagnosed patients 1
• Cardiovascular disease is significantly more prevalent in FH patients with null mutations (14.87%) compared to those with defective mutations (10.6%) 4

Clinical Evidence of Increased Risk

• Cardiovascular disease is present in 14% of genetically confirmed FH subjects compared to only 3.2% in non-FH subjects (p<0.001) 4
• Despite treatment with lipid-lowering therapies, most FH patients have persistently elevated LDL-C levels, with mean treated levels of 186.5 mg/dL 4
• Only 3.4% of treated FH patients achieve LDL-C levels under 100 mg/dL with conventional therapies 4
• The European Heart Journal recommends immediate initiation of high-intensity statin therapy for most patients with severe hypercholesterolemia due to their high cardiovascular risk 2

Treatment Challenges and Recommendations

• Guidelines recommend LDL-C targets for FH patients of <100 mg/dL (<2.6 mmol/L) for adults or <70 mg/dL (<1.8 mmol/L) for adults with CHD or diabetes 5
• Most FH patients require combination therapy to achieve target LDL-C levels 5, 6
• Treatment options include:
  • High-intensity statins as first-line therapy 1
  • Ezetimibe as add-on therapy 1
  • PCSK9 inhibitors for additional LDL-C lowering 1
  • Lomitapide and ANGPTL3 inhibitors for homozygous FH 1
  • Lipoprotein apheresis for severe cases 1

Importance of Early Intervention

• Mendelian randomization data support that earlier treatment leads to greater reduction in ASCVD events by lowering lifetime exposure to LDL-cholesterol 1
• The estimated number needed to treat for adolescents with FH to prevent one heart attack is only two 1
• Retrospective cohort studies show that statin therapy reduces the risk for clinical coronary heart disease and coronary heart disease mortality in FH patients 1

In conclusion, the scientific evidence consistently demonstrates that FH patients have significantly elevated cardiovascular risk compared to the general population, with no studies showing otherwise. Early diagnosis and aggressive lipid-lowering therapy are essential to reduce this risk.