Defining Severe Familial Hypercholesterolemia and the Implications for Clinical Management

Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated autosomal dominant disease characterized by elevations in LDL-cholesterol (LDL-C) since birth and associated with early myocardial infarction (MI) onset.1 Recent data from the 1999-2012 National Health and Nutrition Examination Survey (NHANES) show that FH affects one in 250 adults in the US and European data suggest that up to 8% of the cases of MI could be attributed to FH.2,3

The more severe form classically known as homozygous FH affects up to one in 300,000 people.4 Classically those with a homozygous FH phenotype are at the highest risk of early coronary heart disease (CHD) and mortality, usually before the third decade of life.5 However, with advances in molecular diagnosis it is now known that there is overlap between the phenotypes of heterozygous and homozygous FH.4,6

Recent studies have shown that cholesterol levels in FH are not only determined by the large monogenic defects in the LDL receptor, apolipoprotein B, or PCSK9 genes, but can also be influenced by the small effects of polygenes.7 Another important fact is that the response to LDL-C lowering treatments is heterogeneous and many patients persist with severely elevated LDL-C concentrations despite maximally tolerated use of a potent statin and ezetimibe.

Despite the elevated lifetime cardiovascular disease risk in FH, this risk is heterogeneous.4 Not only severely elevated LDL-C levels (usually >310 mg/dL or 8 mmol/L) but their association with other risk factors like older age (mainly >40 years without previous treatment onset), male gender, smoking, diabetes, low HDL-C, elevated lipoprotein(a) concentrations (>50 mg/dL or 75 nmol/L), and family history of early CHD indicate a higher risk. In addition, previous clinical cardiovascular disease manifestation and possibly an elevated burden of subclinical coronary atherosclerosis might indicate a higher risk FH patient.8

Despite their very high costs, lomitapide, mipomersen and lipoprotein apheresis became standard of care for those individuals with a homozygous FH phenotype where they are approved.5 The latter can also be performed in refractory heterozygotes. The development of PCSK9 inhibitors opens the possibility of a new era on the treatment of refractory FH patients. These drugs are very effective in heterozygotes, independently of the causing FH mutation with reductions of around 50% in LDL-C concentrations on top of regular lipid lowering treatment.9,10

Indeed, treatment with evolocumab and alirocumab may allow FH patients to attain LDL-C values <70 mg/dl (1.8 mmol/L) in more than 60% of cases. This is substantially higher in comparison with statin and ezetimibe treatment where less than 5% of patients treated in the Spanish SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) cohort were able to achieve such levels.11 PCSK9 inhibitors also reduce LDL-C levels, not as much as in heterozygotes but on average 20%, in most homozygotes and are also an alternative for those patients.12 Indeed, evolocumab is approved for homozygous FH patients' treatment.

However, despite their efficacy and good tolerability, PCSK9 inhibitors are expensive medications and therefore for better cost-effectiveness these drugs should be prescribed for the highest risk FH patients. Indeed, individuals with severe FH might benefit in particular from early and more aggressive cholesterol-lowering treatment with PCSK9 inhibitors. Therefore, the International Atherosclerosis Society (IAS) panel has decided to use the best available evidence from both FH and the general population studies in order to use clinical, laboratory, and coronary imaging (by cardiac computed tomography) parameters to characterize the severe FH phenotype.4 These criteria can be seen in the table below. The Panel believes this will help in identifying the highest risk FH patients and optimize resources for their treatment.

Table 1: Proposed Criteria for Definition of Severe FH and LDL-C Treatment Goals According to the IAS Severe Familial Hypercholesterolemia Panel4

A - At presentation (untreated LDL-C)

Severe FH diagnosed if LDL cholesterol >400 mg/dL (10 mmol/L); or LDL cholesterol >310 mg/dL (8.0 mmol/L) and one high-risk feature;*
or LDL cholesterol >190 mg/dL (5 mmol/L) and two high-risk features**

*High-risk features are: age >40 years without treatment; smoking; male sex; lipoprotein(a) >50 mg/dL (75 nmol/L); HDL-C <40 mg/dL (1 mmol/L); hypertension; diabetes mellitus; family history of early cardiovascular disease in first-degree relatives (age <55 years in men and <60 years in women); chronic kidney disease (i.e., estimated glomerular filtration rate <60 mL/min per 1.73m2; and BMI >30 kg/m2.

Realistic treatment goal is to reduce LDL-C by ≥50%; the ideal goal is to achieve LDL cholesterol <100 mg/dL (2.5 mmol/L)

B - Presence of advanced subclinical atherosclerosis

Advanced subclinical atherosclerosis diagnosed with a coronary artery calcium score >100 Agatston units, or >75th percentile for age and sex;†

†Calcium scores calculated using criteria from the Multi-Ethnic Study of Atherosclerosis (

or CT angiography with obstructions >50% or presence of non-obstructive plaques in more than one vessel

Realistic treatment goal is to reduce LDL-C by ≥50%; the ideal goal is to achieve LDL-C <70 mg/dL (1.8 mmol/L)

C - Presence of clinical atherosclerotic cardiovascular disease

Clinical atherosclerotic cardiovascular disease defined as previous MI, angina, coronary revascularization, non-embolic ischemic stroke, or transitory ischemic attack, and intermittent claudication

Realistic treatment goal is to reduce LDL-C by ≥50%; the ideal goal is to achieve LDL-C <70 mg/dL (<1.8 mmol/L)


  1. Gidding SS, Ann Champagne M, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.
  2. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016;133:1067-72.
  3. Nanchen D, Gencer B, Muller O, et al. Prognosis of patients with familial hypercholesterolemia after acute coronary syndromes. Circulation 2016. [Epub ahead of print]
  4. Santos RD, Gidding SS, Hegele RA, et al. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol 2016. [Epub ahead of print]
  5. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
  6. Santos RD. Homozygous familial hypercholesterolemia: phenotype rules! Atherosclerosis 2016;248:252-4.
  7. Futema M, Shah S, Cooper JA, et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem 2015;61:231-8.
  8. Sijbrands EJ, Nieman K, Budoff MJ, Consortium FC. Cardiac computed tomography imaging in familial hypercholesterolaemia: implications for therapy and clinical trials. Curr Opin Lipidol 2015;26:586-92.
  9. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.
  10. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.
  11. Perez de- Isla L, Alonso R, Watts GF, et al. Attainment of LDL cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol 2016;67:1278-85.
  12. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.

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