Role of PCSK9 Inhibitors in High Risk Patients with Dyslipidemia: Focus on Familial Hypercholesterolemia

Abstract

Background: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is characterized by substantially increased Low-Density Lipoprotein Cholesterol (LDL-C) levels. Patients with FH have a significantly higher risk for Cardiovascular (CV) events, and the timely reduction of LDL-C is of paramount importance to ameliorate the risk for CV disease. Among the available lipid-lowering therapies, the novel Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have emerged as a very promising class of drugs for the management of such patients. Objective: The purpose of this review is to present available data on the efficacy and safety of the two available PCSK9 inhibitors in patients with FH, and importantly to discuss potential differences between the two drugs. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the impact of evolocumab or alirocumab on lipid and CV parameters in patients with FH. Results: Several studies have assessed the lipid-lowering profile of PCSK9 inhibitors in patients with FH. Both evolocumab and alirocumab were found to significantly reduce LDL-C by more than 50-60% in FH patients. Furthermore, data also support a lower rate of lipid apheresis in FH patients receiving a PCSK9 inhibitor. In terms of CV outcomes, both drugs were found to possess CV-ameliorating effects of the same extent in patients with CV disease. However, alirocumab reduced all-cause mortality, as well, a finding not observed with evolocumab. Several differences in the study population characteristics might explain this and other mild differences observed in the CV trials of these drugs. Conclusion: Available evidence suggests similar potency of alirocumab and evolocumab in reducing lipids and CV events.

O tratamento da hipercolesterolemia familiar com os inibidores de PCSK9: uma revisão integrativa

“…Com relação às características regionais de cada artigo, temos 2 artigos publicados no Reino Unido (Latimer, 2016) sendo um deles em associação com os Estados Unidos da América (Schmidt, 2017), 1 na França (Chapman, 2015), e outro na Grécia (Papademetriou, 2018) ambos também em associação com os EUA, 1 no Japão (Ogura, 2018), 1 no Brasil (Ferrari, 2019), 1 na Itália (Pasta, 2020) e 1 no Canada (Seidah, 2017).…”

“…Quanto a resposta a terapia de inibição, o ensaio de redução de LDL-C com inibição de PCSK9 no transtorno de hipercolesterolemia familiar heterozigótica, foi observada uma redução substancial no LDL-C (43% para 350 mg vs. 55% para 420 mg) (Latimer, 2016), enquanto em associação com estatina e ezetimiba resultou em reduções médias corrigidas por placebo no LDL-C de 60-65%, com mais de 60% dos pacientes atingindo a meta de LDL-C (Chapman, 2015). (Papademetriou, 2018). Os inibidores de PCSK9 mostraram reduzir tambem a Lp (a) em 25-30% em função do nível de linha de base, níveis elevados de Lp (a) constituem um fator causal para DCV acelerada, bem como infarto do miocárdio, estenose da válvula aórtica e acidente vascular cerebral isquêmico (Chapman, 2015).…”

Elevated Lipoprotein(a) Level Influences Familial Hypercholesterolemia Diagnosis

“…In general, statins do not significantly alter Lp(a) values (0 to + 7%) [ 16 ], while several studies describe a small decrease in Lp(a) by statins (−5%) [ 17 , 18 ]. Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 lead to a decrease in the LDL-C by 50–60% and are the only drugs used in clinical practice that diminish Lp(a) level by 30% [ 5 , 19 ]. The most effective currently available treatment for hyperLp(a) is lipoprotein apheresis [ 20 ].…”

PCSK9 Variants in Familial Hypercholesterolemia: A Comprehensive Synopsis

“…Considering that the risk of cardiovascular events in FH patients is significantly increased, timely reduction of LDL-C is essential to reduce the risk of CVD. However, traditional drugs may have difficulty in achieving the goal of decreased blood lipid in FH patients, thus, PCSK9 inhibitors with strong lipid-lowering effects have gradually become a new class of drugs for the treatment of FH ( Fala, 2016 ; Papademetriou et al, 2018 ). In a meta-study, it was found that when evolucomab is given as a 420 mg monthly dose, LDL-C could be reduced by 54.71%, indicating that evolocumab might be a potential drug for FH patients ( Eslami et al, 2017 ).…”