While recent data shed light on the synergistic contribution of elevated cholesterol and inflammation to atherosclerosis, more study is needed before anti-inflammatory drugs can join statins as standard preventive treatment, according to a European consensus statement.
The European Society of Cardiology (ESC) consensus statement on inflammation in atherosclerosis follows the finding from the CANTOS trial that interleukin (IL)-1beta inhibitor canakinumab (Ilaris) reduced inflammation and, as a result, lowered the incidence of cardiovascular events in patients with elevated high-sensitivity C-reactive protein (CRP) of >2 mg/L who had a previous heart attack, stated José Tuñón, MD, of the University Hospital Fundación Jiménez Díaz in Madrid, and colleagues in the ESC Working Group on Atherosclerosis and Vascular Biology.
In patients with a median LDL cholesterol (LDL-C) level of 82.4 mg/dL, most of whom were taking a statin, canakinumab reduced total and cardiovascular mortality risk by 31% with no further effect on LDL-cholesterol. However, according to a secondary analysis of CANTOS, the benefit was seen only in those whose CRP levels declined to <2 mg/L and not in those with CRP levels of ≥2 mg/L, they noted.
“CANTOS data exclude the possibility that the monoclonal antibody canakinumab reduces cardiovascular risk through lipid-dependent mechanisms linked to IL-1b,” Tuñón’s group wrote in the European Journal of Preventive Cardiology.
“We are on the cusp of a new era in cardiovascular disease prevention. The basis of protection against cardiovascular disease will continue to be a healthy lifestyle…[as well as] lipid-lowering medication and antithrombotic therapies…proven to be useful in the prevention of cardiovascular events. With further evidence, anti-inflammatory drugs could become one more tool in the treatment of atherosclerosis,” Tuñón said in a news release.
The consensus authors noted that another class of LDL-lowering drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) human monoclonal antibodies, significantly reduced LDL-C and the risk of cardiovascular events without a corresponding effect on plasma levels of CRP and other inflammatory markers.
:LDL-lowering drugs are effective regardless of CRP levels, so we need to know if the same is true for anti-inflammatory medications….and to see if they can reduce cardiovascular risk even further in patients who have achieved the LDL cholesterol target (<70 mg/d),” the group noted.
In an accompanying editorial, Viviane Rocha, MD and Raul Santos, MD, both of the University of Sao Paulo Medical School Hospital, commented, “Although questions on the anti-inflammatory properties of non-statin LDL-C-lowering agents [such as the PCSK9 inhibitors] still remain, there is robust evidence [including PROVE-IT findings] showing that reducing both LDL-C and hsCRP is better than reducing only one of these markers….Even in patients with very low levels of LDL-C, hsCRP is still a risk predictor. The previously controversial evidence that a ‘dual target’ for maximized atheroprotection is indeed beneficial is building up.”
Tuñón’s group pointed out that “Anti-inflammatory drugs will not replace lipid-lowering drugs, but look set to become a complementary therapy in patients with atherosclerosis…More clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1b pathway, reduces the cardiovascular risk.”
In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1b blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis,” they wrote.
Tuñón disclosed support from FIS and the Spanish Society of Cardiology, and relevant relationships with Sanoﬁ-Renegeron, Amgen, and Pﬁzer. Co-authors disclosed multiple relevant relationships with industry.
Rocha and Santos disclosed relevant relationships with Amgen, Sanoﬁ, Akcea, Astra Zeneca, Biolab, Esperion, Kowa, Pﬁzer, Merck, and Sanoﬁ/Regeneron.