No anti-inflammatory effects of PCSK9 inhibitors administered for 12 weeks

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

Literature - Sahebkar A, et al. Br J Clin Pharmacol. 2016

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


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]
  • 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)


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.

Find this article online


1. Kühnast S, van der Hoorn JW, Pieterman EJ, et al. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res. 2014 Oct;55:2103-12
2. Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220:381-6
3. Giugliano RP, Sabatine MS. Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65:2638-51
4. Lan H, Pang L, Smith MM, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J Cell Physiol. 2010;224:273-81
5. Feingold KR, Moser AH, Shigenaga JK, et al. Inflammation stimulates the expression of PCSK9. Biochem Biophys Res Commun. 2008 Sep 19;374:341-4
6 . Almontashiri NA, Vilmundarson RO, Ghasemzadeh N, et al. Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies. PLoS One. 2014 Sep 2;9:e106294
7. Ridker PM, Cannon CP, Morrow D, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-8
8. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100:230-5
9. Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med.;359:2195-207

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free