Familial Hypercholesterolemia: Challenges for a High-Risk Population: JACC Focus Seminar 1/3

J Am Coll Cardiol. 2023 Apr 25;81(16):1621-1632. doi: 10.1016/j.jacc.2023.02.038.


The availability of statins, ezetimibe, and PCSK9 inhibitors has significantly improved the prognosis of familial hypercholesterolemia (FH). However, a great number of individuals with FH do not achieve guideline-recommended low-density lipoprotein (LDL) cholesterol levels despite maximal lipid-lowering therapy. Novel therapies that lower LDL independent of LDL receptor activity can help mitigate atherosclerotic cardiovascular disease risk in most homozygous FH and many heterozygous FH patients. However, access to novel therapies remains limited for heterozygous FH patients with persistent elevation of LDL cholesterol despite treatment with multiple classes of cholesterol-lowering therapies. Conduction of cardiovascular outcomes clinical trials in patients with FH can be challenging because of difficulty in recruitment and long periods of follow-up. In the future, the use of validated surrogate measures of atherosclerosis may allow for clinical trials with fewer study participants and shorter duration, thereby expediting access to novel treatments for patients with FH.

Keywords: LDL cholesterol; clinical trials; familial hypercholesterolemia; lipid-lowering therapies.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents* / therapeutic use
  • Atherosclerosis* / drug therapy
  • Cholesterol
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hyperlipoproteinemia Type II* / drug therapy
  • Hyperlipoproteinemia Type II* / genetics
  • Proprotein Convertase 9


  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol