Prof Juan Carlos Kaski, St George's, University of London, UK

Familial hypercholesterolemia (FH), characterized by markedly increased low-density lipoprotein (LDL) cholesterol concentrations, is a hereditary disorder of LDL-cholesterol metabolism. The condition is common as it affects 1 in 250 persons (1–3). The risk of developing coronary artery disease (CAD) is markedly increased in individuals affected by FH and CAD appears -on average- 10 years earlier in life compared with persons not affected by FH (3,4). It is known that statins lower LDL cholesterol levels in patients with heterozygous FH (5). It is not established, however, whether this LDL cholesterol reduction improves clinical outcomes to a similar extent (i.e. 22%) to that observed in the general population receiving statin treatment (6).  The advent of new classes of LDL cholesterol-lowering therapy (i.e. PCSK9) portrayed as potentially effective agents for management of FH patients who do not reach treatment targets despite statin therapy, has made it imperative to know to what extent statins beneficially affect clinical out come in FH patients and what is the residual risk that needs to be addressed specifically.

A very recent retrospective study published in JACC (7) has estimated the relative risk reduction for CAD and mortality by statins in 2,447 patients (of whom 888 were excluded on the basis of age <18 years or previous CAD) heterozygous FH patients. The authors included “all adult heterozygous FH patients, identified by the Dutch screening program for FH between 1994 and 2013, who were free of CAD at baseline”. Hospital, pharmacy, and mortality records between 1995 and 2015 were assessed in these patients. Study primary endpoint was the composite of myocardial infarction, coronary revascularization, and death from any cause.

Patients on statins (n = 1,041) were largely receiving treatment with simvastatin 40 mg (23%) or atorvastatin 40 mg (23%).  Patients receiving statin treatment “experienced 89 CAD events and 17 deaths during 11,674 person-years of follow-up versus statin never-users (n = 518), who had 89 CAD events and 17 deaths during 4,892 person-years (combined rates 8.8 vs. 5.3 per 1,000 person-years, respectively; p < 0.001)”. The hazard ratio of statin use for CAD and all-cause mortality was 0.56 (95% confidence interval: 0.33 to 0.96).

These findings are important as statins appear to be useful for the prevention of CAD events in a large proportion of FH subjects; therefore, the authors claim that “it is important to quantify the residual CAD risk in statin-treated patients. The relative risk reduction by statins is key information in this estimation”. The study (7) thus showed that in patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%.


  1. Sjouke  B., Kusters  D.M., Kindt  I., et al; Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Hear J. 2014;36:560-565.
  2. Hovingh  G.K., Davidson  M.H., Kastelein  J.J.P., O’Connor  A.M.; Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013;34:962-971
  3. Benn  M., Watts  G.F., Tybjærg-Hansen  A., Nordestgaard  B.G.; Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J. 2016;37:1384-1394
  4. Huijgen  R., Kindt  I., Defesche  J.C., Kastelein  J.J.P.; Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. Eur Heart J. 2012;33:2325-2330.
  5. Smilde  T.J., van Wissen  S., Wollersheim  H., et al; Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001;357:577-581.
  6. Baigent  C., Keech  A., Kearney  P.M., et al; Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278
  7. Besseling J, Hovingh GK, Huijgen R, Kastelein JJP, Hutten BA. Statins in Familial Hypercholesterolemia – Consequences for Coronary Artery Disease and All-Cause Mortality. J Am Coll Cardiol. 2016;68(3):252-260. doi:10.1016/j.jacc.2016.04.054