Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia

Abstract

Patients with familial hypercholesterolemia (FH) are at high or very high risk for cardiovascular disease. Those with heterozygous FH (HeFH) often do not reach low-density lipoprotein cholesterol (LDL-C) targets with statin and ezetimibe therapy, and those with homozygous FH (HoFH) usually require additional lipid-modifying therapies. Drugs that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9) offer a novel approach to reduce LDL-C. The monoclonal antibodies, alirocumab and evolocumab, given by subcutaneous injection every 2 or 4 weeks produce reductions in LDL-C of 50% to 60% in patients with HeFH, allowing many of them to achieve their LDL-C goals. Patients with HoFH show a reduced and more variable LDL-C response, which appears to depend on residual LDL receptor activity, and those with receptor-negative mutations may show no response. Inclisiran is a long-acting small interfering RNA therapeutic agent that inhibits the synthesis of PCSK9. Subcutaneous doses of 300 mg can reduce LDL-C by more than 50% for at least 6 months and the responses in HeFH and HoFH patients are similar to those achieved with monoclonal antibodies. These PCSK9 inhibitors are generally well tolerated and they provide a new opportunity for effective treatment for the majority of patients with FH.

Homozygous Familial Hypercholesterolemia

“…Genetic testing, and PCSK9 and angiopoietin-like 3 inhibitors, have emerged as promising diagnostic tools and therapies, respectively. 3 , 4 HoFH, an autosomal codominant disorder, involves defective LDL receptor structure or function because of loss-of-function variants in LDLR, APOB, or LDLRAP genes or gain-of-function variants in PCSK9. Two pathogenic variants in LDLR were identified in our patient.…”

Lomitapide en hipercolesterolemia familiar heterocigota: reporte de caso

“…Se ha considerado que la respuesta a estos medicamentos depende de la función residual del LDLR. Los pacientes con HFHo generalmente responden menos que aquellos con HFHe y, en general, a cualquier tratamiento que involucre el LDLR como las estatinas, donde esta respuesta es aún menor en pacientes con formas recesivas homocigotas de la enfermedad, dada la no respuesta al tener dos alelos comprometidos (23). Consideramos que la falta de respuesta e incluso el aumento del cLDL en nuestra paciente se relaciona a haploinsuficiencia del LDLR, al tener un comportamiento clínico similar a la HFHo.…”

The biological relevance of PCSK9: when less is better…

“…Investigation of the anticholesterol therapeutic potential of PCSK9 inhibition has led to the development of injectable PCSK9neutralizing monoclonal antibodies, namely evolocumab or alirocumab, which have proved to be particularly effective (Stein et al 2012;Sullivan et al 2012). They are now approved drugs for the treatment of FH and refractory hypercholesterolemia (Ma et al 2021;Tomlinson et al 2021). Surely, this achievement is one of the most glowing examples of "bench to bedside" translational research in recent medical history.…”