Anti-inflammatory therapies for cardiovascular disease

Abstract

Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1β generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.

Keywords: Atherosclerosis; C reactive protein; Canakinumab; Colchicine; Darapladib; Inflammasome; Inflammation; Interleukin-6; Methotrexate; Salsalate.

Figure 1

Inflammatory pathways as potential targets for atherosclerotic therapies. IL-1b, interleukin-1-beta; IL-18, interleukin-18; IL-6, interleukin-6; TNF-α, tumour necrosis factor-alpha; MMP-9, matrix metalloproteinase-9; Lp-PLA2, lipoprotein-associated phospholipase A2; sPLA2, secretory phospholipase A2; ICAM-1, intercellular adhesion molecule type 1; VCAM, vascular cellular adhesion molecule; PAI-1, plasminogen activator inhibitor type-1; SAA, serum amyloid A; CRP, C-reactive protein; hsCRP, high-sensitivity C-reactive protein.; 5-LO, 5-lipoxygenase; FLAP, 5-lipoxygenase-activating protein; SIRT1, sirtuin-1; CCR2/CCR5, chemokine receptor types 2 and 5.

Figure 2

Interleukin-6 and serum amyloid A levels at the site of coronary occlusion and in the peripheral blood.

Figure 3

Plasma level of interleukin-6 and the risk of future vascular events.

Figure 4

Genetic polymorphism in the IL-6 regulatory pathway associate with lifelong lower levels of C-reactive protein and with concordantly lower vascular event rates.^,

Figure 5

Phase III trials of anti-inflammatory agents under evaluation in cardiovascular disease. Trials are grouped by agents that do and do not impact primarily on the central IL-1, TNF-α, IL-6 signalling system.

Figure 6

Phase II data demonstrating dose-dependent effects of canakinumab, a monoclonal antibody targeting IL-1β, on plasma levels of fibrinogen, IL-6, and C-reactive protein.

Figure 7

Effects of aspirin when compared with placebo in the primary prevention of future vascular events, stratified by the baseline level of C-reactive protein.

Figure 8

Primary result of the LoDoCo trial of colchicine in the secondary prevention of vascular events.