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IL-1β inhibitor has no positive effect on arterial structure or function

Choudhury RP, et al, JACC, 2016

Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance


Choudhury RP, Birks JS, Mani V, et al.
J Am Coll Cardiol. 2016;68(16):1769
 

Background

Systemic markers of inflammation, such as c-reactive protein (CRP), are related to CV prognosis. Moreover, treatment strategies that lower CV risk have also been associated with a reduction of systemic inflammatory markers. However, it is not clear whether targeting inflammation reduces CV risk [1,2].
 
Atherosclerosis is well-established as a disease with an important inflammatory component. It has been investigated that interleukin (IL)-1β, a mediator of inflammation, is an important in the pathogenesis of atherosclerosis and its complications, as well as in the pathogenesis of type 2 diabetes mellitus (T2DM). The inhibition of IL-1β may favourably affect vascular disease progression [3,4].
 
In this placebo-controlled, phase II study, the effects of IL-1β inhibition with the human monoclonal antibody canakinumab on arterial (carotid arteries and aorta) structure and function was evaluated using MRI. Moreover, the effects of canakinumab on measures of diabetes control and on inflammation indicators were assessed in patients with atherosclerotic vascular disease and impaired glucose tolerance (IGT) or T2DM (n=189). Patients were 1:1 randomized to either placebo or canakinumab 150 mg monthly, for a duration of 12 months.
 

Main results

 

Conclusion

In patients with T2DM and established CV disease, the IL-1β inhibitor canakinumab reduced markers of inflammation (hs-CRP and IL-6) compared with placebo, modestly increased levels of triglycerides and total cholesterol, and reduced lipoprotein(a) levels. Although the effect on these markers, there was no obvious effect on measures of vascular structure or function of the carotid arteries and the aorta.
 

Editorial Comment [5]

In their editorial article, Zhao XQ et al congratulate the investigators for their study and point out the possible reasons for the disappointing results that include: And they conclude: ‘Identifying individuals with increased residual cardiovascular risk, despite intensive statin therapy, remains an unmet clinical need. Future imaging studies are warranted to evaluate the link between individualized vascular response to therapy, in addition to clinical risk factors and biomarkers, and subsequent vascular events. If verified, this link might improve residual cardiovascular risk prediction and potentially guide further therapy. Notwithstanding these negative results, we eagerly await the results of the ongoing event-based CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial, which is also evaluating targeted IL-1β inhibition with canakinumab.’
 
Find this article online at JACC
 

References

1. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836–43.
2. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–9.
3. Tipping PG, Hancock WW. Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques. Am J Pathol 1993;142:1721–8.
4. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464:1357–61.
5. Zhao XQ, Yuan C, Shah PK. Imaging to Assess the Effect of Anti-Inflammatory Therapy in Aortic and Carotid Atherosclerosis. J Am Coll Cardiol. 2016;68(16):1781