[Retracted] A Systematic Review and Meta‐Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

Abstract

Objectives. The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). Methods. A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: “AMG 145”, “evolocumab”, “SAR236553/REGN727”, “alirocumab”, “RG7652”, “LY3015014”, “RN316/bococizumab”, “PCSK9”, and “familial hypercholesterolemia” up to November 2020. Study quality was assessed with the Cochrane Collaboration’s tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. Results. A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD −49.14%, 95% CI: −55.81 to −42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. Conclusion. PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.

Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation

“…These results were obtained independently of smoking or hypertension. However, differently to what reported by Ge and colleagues ( Ge et al, 2021 ), in which PCSK9-i led to a slight rise in HDL-c and to a reduction of triglycerides, in our cohort, treatment did not significantly change HDL-c and triglyceride levels, even though the latter tent to decrease. This discrepancy may be possibly attributable to the relatively small sample size in the current study or to specific intrinsic characteristics of our subjects.…”

“…As concerns the blood lipid profile, the directional changes observed for total cholesterol and LDL-c after treatment with PCSK9-i were in line with previous reports of Ge et al who described similar results from PCSK9-i clinical trials involving FH subjects ( Ge et al, 2021 ). These results were obtained independently of smoking or hypertension.…”

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“…As concerns the blood lipid profile, the directional changes observed for total cholesterol and LDL-c after treatment with Frontiers in Molecular Biosciences frontiersin.org PCSK9-i were in line with previous reports of Ge et al who described similar results from PCSK9-i clinical trials involving FH subjects (Ge et al, 2021). These results were obtained independently of smoking or hypertension.…”

A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis

“…PCSK9 is a hepatically produced, COPII-secreted ( Chen et al, 2013 ) serum protein that promotes LDL receptor degradation and thus serum LDL accumulation ( Horton et al, 2009 ; Sahng et al, 2004). Genetic variants of PCSK9 influence atherosclerotic risk and cardiovascular outcomes ( Burke et al, 2017 ; Cohen et al, 2005 ), loss-of-function PCSK9 Cys mutants protect against cardiovascular disease by inhibiting PCSK9 secretion ( Cohen et al, 2005 ; Mayne et al, 2011 ; Zhao et al, 2006 ), and antibodies targeting serum PCSK9 are used therapeutically to control hypercholesterolemia ( Ge et al, 2021 ). Indeed, increased amounts of SNO-PCSK9 in SCoR2 −/− livers ( Figures 1F and 1G ) were associated with both increases in hepatic (i.e., intracellular, processed) PCSK9 ( Figures 1F – 1I ) and decreases in serum PCSK9 ( Figures 1J and 1K ), with no change in PCSK9 mRNA ( Figure 1I ), consistent with an effect of SNO on PCSK9 secretion.…”

“…As with phosphorylation, S-nitrosylation may be targeted for therapeutic gain. Small-molecule inhibition of SCoR2 has a powerful cholesterol-lowering effect suggesting therapeutic benefit ( Figures 5B , 5C , 5K – 5N ) as seen with anti-PCSK9 antibody therapy ( Ge et al, 2021 ). SNO-regulatory enzymes may thus provide distinct access into human disease.…”