Endocrinol Metab.  2021 Apr;36(2):279-295. 10.3803/EnM.2021.964.

Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia

• Tomlinson B
• Patil NG
• Fok M
• Lam CWK

• KMID: 2515455
• DOI: http://doi.org/10.3803/EnM.2021.964

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.

Keyword

Alirocumab; Evolocumab; Hydroxymethylglutaryl-CoA reductase inhibitors; Hyperlipoproteinemia type II; PCSK9 protein; human; RNA; small interfering

Figure

• 

  Fig. 1 Action of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies and inclisiran. LDL, low-density lipoprotein; mAbs, monoclonal antibodies.

• 

  Fig. 2 Low-density lipoprotein cholesterol (LDL-C) change from baseline to week 12 by underlying genetic abnormality in the Trial Assessing Long-Term Use of PCSK9 Inhibition in Subjects with Genetic LDL Disorders (TAUSSIG) study with evolocumab added to conventional drug therapy in patients with homozygous familial hypercholesterolemia. Mean change in LDL-C is shown in parentheses after each genetic abnormality category. Adapted from Raal et al., with permission from Elsevier [63]. LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; GoF, gain-of-function; ARH, autosomal recessive hypercholesterolemia. aApheresis patient; bPatient missed apheresis before the week 12 blood draw due to a snowstorm; cWeek 12 immediately after vacation, dietary indiscretion suspected.

• 

  Fig. 3 Levels of calculated low-density lipoprotein cholesterol (LDL-C) over time (intention-to-treat analysis) in ODYSSEY FH I and FH II in patients with heterozygous familial hypercholesterolemia (FH) treated with alirocumab (ALI) or placebo (PBO). Adapted from Kastelein et al., with permission from Oxford University Press [72]. LLT, lipid-lowering therapy; LS, least squares; SE, standard error.

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