News from CANTOS: Modulation of the interleukin-6 signalling pathway reduces cardiovascular events

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Macrovascular Residual Risk Studies

6 November 2018

New insights from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) provide proof of concept evidence that targeting the interleukin-6 (IL-6) pathway with canakinumab reduces cardiovascular events independent of lipid lowering.

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). Eur Heart J 2018; doi:10.1093/eurheartj/ehy310

STUDY SUMMARY

Objective:

To investigate whether the beneficial cardiovascular outcomes observed in CANTOS are also mediated via effects of canakinumab on IL-6 signalling.

Study design:

CANTOS was a randomized, double-blind placebo-controlled trial which evaluated three doses of canakinumab (50 mg, 150 mg, or 300 mg) once every 3 months for the prevention of atherosclerotic events.1 The current report describes a substudy of CANTOS.

Study population:

Data from 4,833 patients in CANTOS with IL-6 levels measured before randomization and 3 months after treatment with placebo or canakinumab were analysed.

Efficacy variable:

· The primary endpoint in CANTOS was a composite of recurrent myocardial infarction, stroke, or cardiovascular death (MACE).

· The key pre-specified secondary cardiovascular efficacy endpoint was the primary endpoint plus hospitalization for unstable angina requiring urgent coronary revascularization.

Additional major endpoints were adjudicated cardiovascular mortality and all-cause mortality.

Methods:

Patients allocated to canakinumab were divided on an a priori basis to 2 groups based on IL-6 measurement at 3 months (<1.65 ng/L or ≥ 1.65 ng/L, the median on-treatment value for those allocated to active therapy after the first dose).

Cox proportional-hazards models stratified by time since index myocardial infarction were used to estimate relative hazards for MACE, cardiovascular mortality, and all-cause mortality in these two groups, compared with those allocated to placebo.

Main results:

In the placebo group, baseline levels of IL-6 were associated with increased risk of future cardiovascular events, by 15% for those in the middle tertile and 47% for those in the top tertile, compared with the lowest tertile.
Compared with placebo, canakinumab reduced IL-6 levels at 3 months by 34.9% overall (p< 0.001). These effects were dose-dependent; median percent reductions were 24.5% in the 50 mg group, 35.8% in the 150 mg group, and 42.7% in the 300 mg group.
Patients who achieved an IL-6 value <1.65 ng/L had significant reductions in primary and key secondary MACE endpoints, as well as cardiovascular and all-cause mortality (Table 1). There was no significant benefit in the canakinumab group with on-treatment IL-6 levels ≥ 1.65 ng/L

Table 1. Adjusted Hazard ratios (95% CI) for MACE and mortality endpoints in patients attaining IL-6 values <1.65 ng/L

Endpoint	Adjusted Hazard ratio*	p-value
Primary MACE	0.68 (0.56–0.82)	<0.0001
Key secondary MACE	0.70 (0.59–0.84)	<0.0001
Cardiovascular mortality	0.48 (0.34–0.68)	<0.0001
All-cause mortality	0.52 (0.40–0.68)	<0.0001

* Adjusted for baseline characteristics including age, gender, smoking status, hypertension, diabetes, and body mass index, and baseline levels of low-density lipoprotein cholesterol and IL-6.

Authors’ conclusion:

CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering.

COMMENT

The CANTOS study was widely regarded as a landmark study providing proof of concept evidence for chronic subclinical inflammation as a modifiable contributor to residual cardiovascular risk, independent of lipid lowering.1 There is, however, also strong circumstantial evidence for a role for IL-6, which is strongly induced by IL-1β, the target of canakinumab,2 as it has been shown to be predictive of future vascular events.3 The results of this CANTOS analysis provide support for this proposal. These findings provide direct evidence that IL-6 contributes to atherothrombosis, expanding on data from Mendelian randomization studies4,5 and prospective cohort studies. Additionally, the results are supportive of the ‘lower is better’ concept for inflammatory risk, at least for canakinumab treatment, as seen in trials for LDL-cholesterol.6 Taken together, these findings provide a rationale for targeting IL-6 to reduce residual cardiovascular risk.

Cardiovascular disease is indisputably multifactorial. While elevated cholesterol is undoubtedly a major risk factor for cardiovascular disease, with LDL cholesterol established as the major lipid for intervention, other factors are also relevant.7 Indeed, the results from both the landmark CANTOS publication1 and this analysis clearly offer new therapeutic possibilities. Together these findings make a case for considering both cholesterol and inflammatory risk as contributors to residual cardiovascular risk, and highlight IL-6 as a potential therapeutic target for intervention.

References

1. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.

2. Loppnow H, Libby P. Proliferating or interleukin-1 activated human vascular smooth muscle cells secrete copious interleukin-6. J Clin Invest 1990;85:731–8.

3. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–72.

4. Sarwar N, Butterworth AS, Freitag DF et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012;379:1205–13.

5. Swerdlow DI, Holmes MV, Kuchenbaecker KB et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214–24.

6. 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.

7. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26. doi: 10.1186/1475-2840-13-26.

Key words

: CANTOS; inflammatory risk; interleukins, cardiovascular risk