IL-6 receptor antagonism modifies PCSK9 levels in NSTEMI patients with hypercholesterolemia
Serum PCSK9 is modified by interleukin-6 receptor antagonism in patients with hypercholesterolaemia following non-ST-elevation myocardial infarction
Literature - Ueland T, Kleveland O, Michelsen AE et al. - Open Heart 2018;5:e000765Introduction and methods
Inhibition of the enzyme proprotein convertase subtilisin-kexin type 9 (PCSK9) leads to significant reductions of low density lipoprotein cholesterol (LDL-c) levels and decreased incidence of CVD in high-risk patients with hyperlipidemia [1-3]. Although several studies link PCSK9 to inflammation independent of lipids, it is unclear whether PCSK9 levels are altered by inflammatory pathways. This study investigated the effects of the humanized anti-IL-6 receptor (IL-6R) antibody, tocilizumab, on serum PCSK9 levels in non-ST elevation myocardial infarction (NSTEMI) patients.
In the context of a randomized, double-blind, placebo-controlled study [4], in which 117 NSTEMI patients, aged 18-80 years, were randomized to receive either an intravenous infusion of tocilizumab 280 mg or matching placebo prior to coronary angiography, the following analyses were performed:
- serum PCSK9 levels in NSTEMI patients in both treatment arms
- the temporal course of PCSK9 levels during hospitalization
- associations of PCSK9 levels with markers of inflammation
- the effect of inhibition of IL-6 signaling with tocilizumab on PCSK9 levels
Main results
- PCSK9 levels were increased during the acute phase of NSTEMI in both treatment groups, and reached their highest levels towards the end of the second day. PCSK9 levels remained elevated compared with healthy controls throughout the treatment period.
- There was no significant modifying effect of percutaneous coronary intervention on the temporal course of PCSK9 levels.
- There was a positive correlation between PCSK9 level and leucocyte count (r=0.27; P=0.004), neutrophil counts (r=0.22; P=0.018) and presence of hypercholesterolemia (r=0.18; P=0.048), but not with inflammatory markers or lipid levels.
- Leucocyte and neutrophil counts decreased during tocilizumab treatment, and the adjusted associations between AUC for PCSK9 and leucocytes and hypercholesterolemia were r=0.20 (P=0.036) and r=0.21 (P=0.031), respectively, which remained after adjustment for statin use
- No effect of tocilizumab on PCSK9 levels was seen in patients without hypercholesterolemia. A significant treatment effect (P=0.025) was detected in patients with hypercholesterolemia, with patients treated with tocilizumab showing a blunted increase in PCSK9 levels.
Conclusion
In patients with an established diagnosis of hypercholesterolemia, tocilizumab blunted the NSTEMI-associated increase in PCSK9 levels and this was correlated with a decrease in neutrophil numbers. Serum PCSK9 levels were not modified by anti-inflammatory treatment and not associated with change in inflammatory markers suggesting a limited influence of inflammation on PCSK9.
References
1. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563–75.
2. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–99.
3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713–22.
4. Kleveland O, Kunszt G, Bratlie M, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016;37:2406–13.
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