Anti-Inflammatory Therapy in Coronary Artery Disease: Where Do We Stand?

Abstract

Inflammation plays an important role in all stages of atherosclerosis - from endothelial dysfunction, to formation of fatty streaks and atherosclerotic plaque, and its progression to serious complications, such as atherosclerotic plaque rupture. Although dyslipidemia is a key driver of atherosclerosis, pathogenesis of atherosclerosis is now considered interplay between cholesterol and inflammation, with the significant role of the immune system and immune cells. Despite modern therapeutic approaches in primary and secondary cardiovascular prevention, cardiovascular diseases remain the leading cause of mortality worldwide. In order to reduce residual cardiovascular risk, despite the guidelines-guided optimal medical therapy, novel therapeutic strategies are needed for prevention and management of coronary artery disease. One of the innovative and promising approaches in atherosclerotic cardiovascular disease might be inflammation-targeted therapy. Numerous experimental and clinical studies are seeking into metabolic pathways underlying atherosclerosis, in order to find the most suitable pathway and inflammatory marker/s that should be the target for anti-inflammatory therapy. Many anti-inflammatory drugs have been tested, from the well-known broad range anti-inflammatory agents, such as colchicine, allopurinol and methotrexate, to targeted monoclonal antibodies specifically inhibiting a molecule included in inflammatory pathway, such as canakinumab and tocilizumab. To date, there are no approved anti-inflammatory agents specifically indicated for silencing inflammation in patients with coronary artery disease. The most promising results came from the studies which tested colchicine, and studies where the inflammatory-target was NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1 beta (IL-1 $\beta$ )/interleukin-6 (IL-6)/C-reactive protein (CRP) pathway. A growing body of evidence, along with the ongoing clinical studies, suggest that the anti-inflammatory therapy might become an additional strategy in treating atherosclerotic cardiovascular disease. Herein we present an overview of the role of inflammation in atherosclerosis, the most important inflammatory markers chosen as targets of anti-inflammatory therapy, along with the critical review of the major clinical trials which tested non-targeted and targeted anti-inflammatory drugs in patients with atherosclerotic cardiovascular disease.

Keywords: CRP; IL-1β; IL-6; anti-inflammatory therapy; canakinumab; colchicine; coronary artery disease; inflammation; tocilizumab.

Fig. 1.

NLRP3 inflammasome/IL-1$\beta$/IL-6/CRP inflammation pathway with the key experimental anti-inflammatory drugs tested in clinical trials. NLRP3 inflammasome (left), an intracellular multiprotein complex of macrophages, transforms pro-IL-1$\beta$ into its active form IL-1$\beta$. Colchicine primarily inhibits microtubules, which are important part of NLRP3 inflammasome, and was tested in LoDoCo, LoDoCo2, COLCOT, and LoDoCo-MI trials. IL-1$\beta$ (center-left part of the figure) is an proinflammatory cytokine that promotes plaque instability and rupture, and stimulates production of IL-6. This pro-inflammatory molecule can be inhibited by canakinumab, monoclonal antibody, that was tested in CANTOS trial. IL-6 (center-left part of the figure) is another proinflammatory cytokine important for initiation and progression of atherosclerosis. This cytokine can be inhibited in two ways: by tocilizumab (monoclonal antibody which competitively binds to IL-6 receptors, tested in ASSAIL-MI trial), and by ziltivekimab (monoclonal antibody that directly targets IL-6 ligand, tested in RESCUE and ZEUS trials). CRP (right), final product of this pathway. NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; IL-1$\beta$, interleukin-1 beta; IL-6, interleukin-6; CRP, C-reactive protein; LoDoCo, Low Dose Colchicine for CVD Prevention; COLCOT, Colchicine Cardiovascular Outcomes Trial; LoDoCo-MI, Low Dose Colchicine after Myocardial Infarction; ASSAIL-MI, ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction; RESCUE, Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition; ZEUS, Ziltivekimab Cardiovascular Outcomes Study.