Efficiency and Safety of Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody on Hypercholesterolemia: A Meta‐Analysis of 20 Randomized Controlled Trials

Abstract

BackgroundProprotein convertase subtilisin/kexin9 (PCSK9) monoclonal antibody significantly reduces low-density lipoprotein cholesterol level in patients with hypercholesterolemia. The goal of this study was to review recently reported randomized controlled trials to investigate the therapeutic effects and safety of PCSK9 inhibitors.Methods and ResultsThe clinical randomized controlled trials published from inception to March 19, 2015 were identified from The Cochrane Library databases, PUBMED, and EBASE. Randomized controlled trials of at least 8 weeks duration using PCSK9 inhibitors in treating patients with hypercholesterolemia were included. Mean difference (MD) with a 95% CI was used to calculate the continuous data, the standardized mean difference with a 95% CI was used when the unit was not unified, and risk ratio with a 95% CI was used for dichotomous data. After screening, 20 trials fulfilled the inclusion criteria. PCSK9 inhibitors significantly decreased the levels of low-density lipoprotein cholesterol (MD=−65.29 mg/dL, 95% CI: −72.08 to −58.49), total cholesterol (MD=−60.04 mg/dL, 95% CI: −69.95 to −50.13), triglycerides (MD=−12.21 mg/dL, 95% CI: −16.21 to −8.22) and apolipoprotein-B (MD=−41.01 mg/dL, 95% CI: −46.07 to −35.94), lipoprotein(a) (standardized mean difference=−0.94, 95% CI: −1.12 to −0.77) and increased the levels of high-density lipoprotein cholesterol (MD=3.40 mg/dL, 95% CI: 3.12 to 3.68) and apolipoprotein-A1 (MD=6.75 mg/dL, 95% CI: 4.64 to 8.86). There was no significant difference in the incidence of treatment-emergent adverse events (risk ratio=1.01, 95% CI: 0.98 to 1.04), serious treatment-emergent adverse events (risk ratio=1.01, 95% CI: 0.88 to 1.17), and the discontinuation of treatment between the 2 groups (risk ratio=1.07, 95% CI: 0.86 to 1.34).ConclusionsThe meta-analysis indicated that PCSK9 inhibitors had a strong effect in lowering low-density lipoprotein cholesterol and other lipid levels with satisfactory safety and tolerability in patients with hypercholesterolemia.

Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

“…The end result of activity of PCSK9 is, therefore, a reduction in the number of LDL receptors on the cell surface. Inhibitors of PCSK9 increase cell surface LDL receptor expression and reduce LDL cholesterol levels by more than 60% ( 6 ).…”

Disadvantages of Current LDL-cholesterol Lowering and the Role of PCSK9 Inhibitors.

“…Reactions at the subcutaneous site of drug injection were present in 2% of the study participants on alirocumab and 4% of those on evolocumab 92 . The incidence of treatment termination due to side effects did not differ significantly between PCSK9 inhibitors (alirocumab and evolocumab) and comparison drugs (2-10%) 93 .…”

“…Reakcije na ubodnom mjestu supkutane primjene lijeka pojavile su se u 2 % ispitanika na alirokumabu i 4 % na evolokumabu 92 . Učestalost prekida liječenja zbog nuspojava nije se znatno razlikovala između inhibitora PCSK9 (alirokumaba i evolokumaba) i komparatora (2 -10 %) 93 .…”

Therapeutic Potential and Critical Analysis of the PCSK9 Monoclonal Antibodies Evolocumab and Alirocumab

“…There were significant LDL reductions with PCSK9 monoclonal antibodies in patients with FH (−79.0 mg/dL; 95% CI = −99.5 to −58.6 mg/dL) and non-FH (−65.3 mg/dL; 95% CI = −72.1 to −58.6 mg/dL) and in trials of 12 weeks or less (−70.9 mg/dL; 95% CI = −77.3 to −64.5 mg/dL) and trials of more than 12 weeks (−55.0 mg/dL; 95% CI = −70.7 to −31.3 mg/dL). 32 Whereas there are several trials evaluating the impact of PCSK9 monoclonal antibodies in heterozygous FH, 32 the TESLA Part B trial evaluated the impact of PCSK9 monoclonal antibodies specifically in patients with homozygous genetically induced hypercholesterolemia (either autosomal dominant or recessive disorders), and the results deserve special mention. 33 TESLA-B was a randomized, double-blind, placebo-controlled, phase 3 trial undertaken at 17 sites in 10 countries, including the United States.…”