Effect of Monoclonal Antibodies to PCSK9 on high-sensitivity C-reactive protein levels: A Meta-Analysis of 16 Randomized Controlled Treatment Arms

Sahebkar A, Di Giosia P, Stamerra CA, et al.
Br J Clin Pharmacol. 2016; published online ahead of print

Background

A possible pleiotropic effect of PCSK9 inhibitors in terms of anti-inflammatory actions, besides lowering LDL cholesterol and other lipid parameters, has not been systematically assessed, although there is evidence suggesting that PCSK9 may affect metabolic pathways beyond cholesterol metabolism. For example data indicate that PCSK9:

• is connected to vascular inflammation and apoptosis [1]
• is secreted by human smooth muscle cells and is functionally active and capable of reducing LDL receptor expression in macrophages, suggesting a possible role in foam cell formation and atherogenesis [2]
• might promote atherosclerosis by stimulating inflammation, endothelial dysfunction, and hypertension [3]
• down-regulates gene expression of stress response and inflammation in liver cells independent of its effects on cholesterol uptake [4]

Moreover:

• an in vivo study showed that infection and inflammation stimulate PCSK9 expression [5]
• small interfering RNA (siRNA)-mediated knockdown of PCSK9 in human macrophages reduced inhibitor of nuclear factor kappa B alpha (IkB-a) degradation and nuclear factor kappa beta (Nf-kB) nuclear translocation, thereby reducing the expression of pro-inflammatory genes [6]

This meta-analysis of randomised controlled trials, assessed the overall effect of PCSK9 inhibition on systemic inflammation, by investigating the impact of PCSK9 inhibitors on plasma hs-CRP concentrations. hs-CRP is the most widely used method for quantifying inflammation in CVD [7-9].

Main results

• Random-effects meta-analysis did not show any significant effect of PCSK9 inhibitors on hs-CRP levels: weighed mean difference (WMD): 0.002 mg/L; CI 95%: -0.017 to 0.021; P = 0.807; I₂ = 50.98%
• The results were consistent across different PCSK9 inhibitors, and were not influenced by the dosing frequency or by the presence or not of familial hypercholesterolemia (FH):
• evolocumab WMD: 0.002 mg/L; CI 95%: -0.02 to 0.02; P = 0.855; I2 = 50.98%
• alirocumab WMD: 0.15 mg/L; CI 95%: -0.11 to 0.40, P = 0.259; I₂ = 0%
• biweekly WMD: 0.13 mg/L; CI 95%: -0.20 to 0.46; P = 0.433; I₂ = 55.19%
• monthly WMD: 0.003 mg/L; CI 95%: -0.01 to 0.01; P = 0.59; I₂ = 0%
• FH WMD: 0.03 mg/L; CI 95%: -0.04 to 0.11; P = 0.396; I₂ = 57.30%
• non-FH WMD: 0.0 mg/L; CI 95%: -0.01 to 0.01; P = 0.979; I₂ = 0%

• A slight increase in plasma hs-CRP was observed in the subgroup of trials with < 6 PCSK9 inhibitor injections:
• ≥ 6 injections WMD: -0.01 mg/L; CI 95%: -0.02 to 0.01; P = 0.531; I₂ = 45.07%
• < 6 injections WMD: 0.06 mg/L; CI 95%: 0.01 to 0.11; P = 0.011; I₂ = 0%

• No association could be found between changes in hs-CRP levels and changes in plasma LDL-C concentrations (P = 0.697) and cumulative dosage of the drug (P = 0.980)

Conclusion

The administration of PCSK9 inhibitors for the duration of 12 weeks had no impact on hs-CRP concentrations in the meta-analysis of available randomised clinical trials.

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