Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms

Ferri, Claudio; Ferretti, Gianna; Pedone, Claudio; Sahebkar, Amirhossein; Bacchetti, Tiziana; Giorgini, Paolo; Grassi, Davide; Stamerra, Cosimo Andrea; Di Giosia, Paolo

doi:10.1111/bcp.12905

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Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms : PCSK9 inhibitors and hs-CRP levels

Author(s): Amirhossein Sahebkar , Paolo Di Giosia , Cosimo Andrea Stamerra , Davide Grassi , Claudio Pedone , Gianna Ferretti , Tiziana Bacchetti , Claudio Ferri , Paolo Giorgini

Publication date Created: June 2016

Publication date (Print): June 03 2016

Journal: British Journal of Clinical Pharmacology

Publisher: Wiley-Blackwell

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Abstract

<div class="section"> <a class="named-anchor" id="bcp12905-sec-0001">  </a> <h5 class="section-title" id="d630380e342">Aims</h5> <p id="d630380e344">Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an emerging class of low‐density lipoprotein cholesterol (LDL‐C)‐lowering agents. In spite of their known effects on lipids, the impact of these drugs on systemic inflammation is less known. We aimed to investigate the effect of PCSK9 inhibitors on high‐sensitivity C‐reactive protein (hs‐CRP) levels through a meta‐analysis of randomized controlled trials (RCTs). </p> </div><div class="section"> <a class="named-anchor" id="bcp12905-sec-0002">  </a> <h5 class="section-title" id="d630380e347">Methods</h5> <p id="d630380e349">A systematic literature search of Medline, SCOPUS and Google Scholar was conducted up to December 2015 to identify RCTs assessing changes in hs‐CRP concentrations during treatment with PCSK9 inhibitors. Quantitative data synthesis was performed using a random‐effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. </p> </div><div class="section"> <a class="named-anchor" id="bcp12905-sec-0003">  </a> <h5 class="section-title" id="d630380e352">Results</h5> <p id="d630380e354">Sixteen treatment arms, with a total of 2546 participants, were included. Random‐effects meta‐analysis did not show any significant effect of PCSK9 inhibitors on hs‐CRP levels (WMD: 0.002 mg l <sup>–1</sup>, CI: –0.017, 0.021; <i>P</i> = 0.807; <i>I</i> <sup>2</sup> = 37.26%). This effect size was robust, not sensitive to any single study, and not affected by the type of PCSK9 inhibitor (evolocumab: WMD: 0.002 mg l <sup>–1</sup>, CI: –0.02, 0.02; <i>P</i> = 0.855; alirocumab WMD: 0.15 mg l <sup>–1</sup>, CI: –0.11, 0.40; <i>P</i> = 0.259; <i>I</i> <sup>2</sup> = 0%), or dosing frequency (biweekly: WMD: 0.13 mg l <sup>–1</sup>, CI: –0.20, 0.46; <i>P</i> = 0.433; <i>I</i> <sup>2</sup> = 55.19%; monthly: WMD: 0.003 mg l <sup>–1</sup>, CI: –0.01, 0.01; <i>P</i> = 0.59; <i>I</i> <sup>2</sup> = 0%). Random‐effects meta‐regression did not suggest any association of changes in hs‐CRP levels with changes in plasma LDL‐C concentrations ( <i>P</i> = 0.697) or cumulative dosage of the drug ( <i>P</i> = 0.980). </p> </div><div class="section"> <a class="named-anchor" id="bcp12905-sec-0004">  </a> <h5 class="section-title" id="d630380e420">Conclusions</h5> <p id="d630380e422">This meta‐analysis of RCTs did not suggest an effect of PCSK9 inhibitors on hs‐CRP concentrations. </p> </div>

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Most cited references 16

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Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.

Gerald F M Watts, Michael Rocco, David Sullivan … (2014)

This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.

Evan A Stein, Dan Gipe, Jean Bergeron … (2012)

Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated. Copyright © 2012 Elsevier Ltd. All rights reserved.