Despite the prognosis of patients with familial hypercholesterolemia (FH) being significantly improved by the availability of statins, ezetimibe and PSCK9 inhibitors, many individuals with FH do not achieve guideline-recommended LDL-C levels, according to a focus seminar published April 17 in JACC.

Daein Choi, MD, et al., look at major challenges and obstacles in treating FH patients, as well as how to optimize the conduct of cardiovascular outcomes trials in this population to improve access to novel therapies..

They discuss the importance of being able to identify patients with FH who are at very high risk and how using genotyping to assess patients with hypercholesterolemia could help. For example, one study has shown that 6.7% participants had LDL-C ≥190 mg/dL, of whom 1.7% were found to have a monogenic mutation in LDLR, APOB or PCSK9. When compared with patients with LDL-C <130 mg/dL, patients with LDL-C ≥190 mg/dL without a monogenic mutation were found to have a six-fold increased risk for coronary artery disease (CAD), but those with an FH mutation were found to have a 22-fold increased risk for CAD.

Regardless of the advances in novel therapies to treat FH with PSCSK9 inhibition, a significant number of patients with FH, especially homozygous FH patients with null/null mutations in LDLR, do not achieve guideline-recommended LDL-C levels. For patients with heterozygous and homozygous FH, statins have been first-line treatment of elevated LDL-C-for prevention of clinical ASCVD. LDLR-independent lipid-lowering treatments are available for patients with homozygous FH, and others are under development, but efforts are needed to extend eligibility for and expedite access to novel therapies.

Additionally, clinical trials in patients with FH have primarily focused on LDL-C reduction, thus demonstrating the benefits of novel therapies on cardiovascular outcomes is increasingly difficult. With the development of surrogate endpoints validating cardiovascular outcomes, trials may be able to overcome challenges by having shorter duration periods and needing fewer participants.

The authors note that, although statins and PCSK9 inhibitors are effective LDL-C-lowering therapies in most patients with heterozygous and homozygous FH patients, most patients do not meet the guideline-recommended LDL-C goals illustrating "an unmet need for additional LDL-C–lowering therapies, and future studies identifying high-risk FH patients will allow proper use of novel therapies."

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: PCSK9 protein, human, Proprotein Convertase 9, Hypercholesterolemia, Ezetimibe, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Artery Disease, Loss of Function Mutation, Genotype, Hyperlipoproteinemia Type II, Apolipoproteins B, Lipids

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