Targeting IL-6 in patients at high cardiovascular risk

The understanding that atherosclerosis is a chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anti-cytokine therapies targeting interleukin signalling pathways could serve as adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. 1 Ridker PM Anticytokine agents: Targeting interleukin signaling pathways for the treatment of atherothrombosis. Circ Res. 2019; 124: 437-450 Crossref PubMed Scopus (90) Google Scholar The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) showed that targeting interleukin (IL)-1β reduced cardiovascular event rates without lowering lipids or blood pressure. 2 Ridker PM Everett BM Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377: 1119-1131 Crossref PubMed Scopus (3575) Google Scholar The magnitude of this effect was directly associated with the reduction in IL-6 and the downstream clinical biomarker high-sensitivity C-reactive protein (CRP). CANTOS included a subgroup of 1875 patients with chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 mL/min per 1·73 m2). In this subgroup at high cardiovascular risk, canakinumab significantly reduced major atherosclerotic cardiovascular events, particularly among those who had the greatest reduction in IL-6 and high-sensitivity CRP. 1 Ridker PM Anticytokine agents: Targeting interleukin signaling pathways for the treatment of atherothrombosis. Circ Res. 2019; 124: 437-450 Crossref PubMed Scopus (90) Google Scholar , 2 Ridker PM Everett BM Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377: 1119-1131 Crossref PubMed Scopus (3575) Google Scholar Therefore, there is considerable interest in addressing the effect of IL-6 inhibition on markers of inflammation and thrombosis in patients at high cardiovascular risk, such as patients with chronic kidney disease. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trialZiltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. Full-Text PDF