Interference with the interleukin-6 pathway associated with lower risk of CV events
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)
Introduction and methods
Interleukin-6 (IL-6) is a central pleiotropic inflammatory cytokine, which can affect multiple cell types through binding to membrane-bound or soluble IL-6 receptors. IL-6 plasma levels have been shown to predict future cardiovascular (CV) events, independent of traditional risk factors. No clinical outcomes studies have related IL-6 reduction to CV event reduction thus far [1,2].
Canakinumab is a human therapeutic monoclonal antibody targeting IL-1β. IL-1 strongly induces IL-6. In the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), canakinumab significantly reduced major adverse CV event (MACE) rates compared to placebo, without substantially affecting lipid levels [11]. The CV benefits of canakinumab were greatest in patients with the greatest C-reactive protein (hsCRP) reductions. It is suggested that canakinumab’s reduction in atherothrombotic events involves inhibition of IL-6.
In this sub-study of CANTOS, the relationship between IL-6 reduction and CV event reduction was evaluated in 4,833 patients. In CANTOS, 3 doses of canakinumab (50 mg, 150 mg, or 300 mg) or placebo were administered subcutaneously once every 3 months. For this sub-analysis, IL-6 measurements were done 3 months after baseline, immediately before the administration of the 2nd dose of study treatment. Patients had levels of hsCRP ≥2mg/L, in the absence of a history of chronic or recurrent infections, previous malignancy other than basal cell skin carcinoma, a suspected or known immunocompromised state, or a history of (or at high risk for) tuberculosis or HIV-related disease. The primary endpoint was a composite of recurrent myocardial infarction, stroke, or CV death (MACE). Secondary CV efficacy endpoints included MACE plus hospitalization for unstable angina requiring urgent coronary revascularization (MACE+), CV mortality and all-cause mortality. The median follow-up was 3.7 years.
Main results
- In the placebo group, baseline IL-6 levels correlated with future CV events. Stratified by baseline IL-6 tertiles, the RRs for MACE were 1.0 (referent), 1.15 (95%CI: 0.86–1.54), and 1.47 (95%CI: 1.11–1.94; P-trend across tertiles=0.007), and for MACE+ they were 1.0 (referent), 1.15 (95%CI: 0.87–1.52), and 1.40 (95%CI: 1.08–1.83; P-trend across tertiles=0.01).
- Compared with placebo, canakinumab reduced IL-6 levels at 3 months by 34.9% (P< 0.001), in a dose-dependent manner (placebo-subtracted median percent reductions in IL-6 at 3 months: 24.5%, 35.8%, and 42.7% for the 50mg, 150mg, and 300 mg doses, respectively).
- The proportions of participants achieving on-treatment IL-6 levels below the trial median (1.65 ng/L) were 39%, 50%, and 60% in the canakinumab 50 mg, 150 mg, and 300mg groups, respectively (P<0.0001).
- Compared with the placebo group, individuals in the canakinumab group who achieved on-treatment IL-6 levels below the median value of 1.65 ng/L at 3 months, had a 36% reduction in MACE (HR: 0.64; 95%CI: 0.54–0.77; P< 0.0001), whereas those who did not achieve below median IL-6 levels, had no significant MACE reduction in MACE (HR: 1.06; 95%CI: 0.90-1.25; P=0.49).
- Similar findings were observed for the MACE+ endpoint, CV mortality, and all-cause mortality, as well as in sensitivity analyses that excluded a small number of non-fatal CV events that occurred before 3 months of follow-up, and after several adjustments.
Conclusion
Modulation of the IL-6 signaling pathway through therapy with the IL-1β antibody canakinumab, associates with reduced CV event rates, independent of lipid lowering. These data provide support for the concept that targeting IL-6, a downstream mediator of IL-1 action, has comparable outcome benefits as targeting the pathways that lead to generation of active IL-1β.
Editorial comment
In their editorial article, Klingenberg and Lüscher [4] state that the CANTOS sub-study published by Ridker et al confirms that circulating IL-6 levels contributes independently to coronary artery disease, without the interplay of cholesterol metabolism. The dose-dependency of the effect of canakinumab on reducing MACE provides further credibility, but the current results should be seen as hypothesis-generating, and causality remains to be proven prospectively. The authors conclude: ‘Clearly, future prospective randomized controlled studies on the efficacy and safety of an interleukin-6 receptor antagonists such as tocilizumab in patients with coronary artery disease would prove the current hypothesis generated within the CANTOS trial. In summary, the study by Ridker et al adds an important piece to the emerging evidence that interference with the interleukin-6 pathway may translate into clinical benefit for patients with coronary artery disease.’
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