New data from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) presented at the ESC 2018 provides ‘proof-of-concept evidence’ that modulating the interleukin-6 (IL-6) signalling pathway reduces rates of atherosclerotic events and mortality. 
Catakinumab targets interleukin-1β, which stimulates the production of IL-6. Previous studies indicate the clinical significance of IL-6 levels and inflammation. For example, plasma levels of IL-6 were shown to predict vascular risk ‘independent of traditional risk factors’.  However, until the current analysis from CANTOS, there has been no data specifically relating to clinical outcomes of IL-6 reduction.
In this analysis a sub-group of 4833 stable atherosclerotic patients in the CANTOS study has IL-6 levels measured at baseline and at 3-months after randomisation (after treatment with either placebo or one of three doses of canakinumab; 50mg, 150mg, or 300mg). 
At 3 months, canakinumab was shown to reduce IL-6 levels by 24.5%, 35.8% and 42.7% for the 50mg, 150mg and 300mg doses, respectively.
Furthermore, the extent of IL-6 reduction was related to the effectiveness of the initial canakinumab dose. Those who responded well to the initial dose experienced long-term benefits, including a 32% reduction major adverse cardiovascular events, and 48% reduction in all cause mortality with continued long-term treatment, compared to those patients who had a less robust response of canakinumab.
This is consistent with the general observation in CANTOS that ‘the magnitude of CV benefits of canakinumab increased substantially in those who achieved the greatest on-treatment reductions in hsCRP’. 
The results of this analysis provides evidence that IL-6 has a greater link with inflammation and CV events than previously thought.
As study lead Paul Ridker MD says: “This analysis could provide pathophysiological insights with relevance for inflammation biology and for the development of novel agents for CV protection.” 
- Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). European Heart Journal 2018; 0, 1-9.
The involvement of IL-6 signalling in atherothrombosis was determined from prospective cohorts linking IL-6 levels to future vascular events1 and from Mendelian randomization studies. 2
Recently, CANTOS has provided evidence that modulation of the IL-6 signalling pathway in humans with canakinumab is associated with reduced cardiovascular event rates, independent of any lipid modification effects.
Individuals receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events (MACE), HRadj 0.68, 95% CI: 0.56–0.82; P < 0.0001, a 52% reduction in cardiovascular mortality , HRadj 0.48, 95% CI 0.34–0.68; P < 0.0001, and a 48% reduction in all-cause mortality, HRadj 0.52, 95% CI: 0.40–0.68; P < 0.0001.3 The important significance of these results is related to the fact that no prior direct evidence has shown that lowering IL-6 is associated with improved cardiovascular outcomes.
Due to the nature of this study, which was performed as a post-hoc analysis of the CANTOS trial, the current results, although suggestive, should be considered as a hypothesis at this stage. The clinical implications and causality still remain to be investigated.
1- Kaptoge S, Seshasai SR, Gao P, et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35:578–589.
2- Swerdlow DI, Holmes MV, Kuchenbaecker KB, el al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214–1224.
3- Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). European Heart Journal 2018; 0, 1-9.