Upstream Targets in Pro-Inflammatory Pathway May Provide Novel Therapy to Reduce Cardiovascular Events

Speaking at the Cardiometabolic Health Congress in Boston on Thursday, Paul Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, MA discussed two new clinical trials aimed at reducing cardiovascular events in patients with diabetes or metabolic syndrome.

Because markers of inflammation are strong and consistent predictors of cardiovascular-related events, Ridker and colleagues are looking at pharmaceuticals that reduce upstream targets of the pro-inflammatory pathway. The magnitude of independent risk associated with inflammation is equal to or greater than the risk associated with elevated blood pressure and elevated cholesterol levels.

There is abundant evidence from controlled animal studies and observational studies in humans that targeted anti-inflammatory therapy can reduce cardiovascular events. Ridker believes that the traditional therapy to reduce C-reactive protein (CRP) levels directly is misguided. Instead, he has built his recent studies around targets upstream of CRP, where the inflammatory pathway begins. As he noted, “Don’t target the marker. Target the disease process.”

The discussion also involved the design and early results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial and the Cardiovascular Inflammation Reduction Trial (CIRT). CANTOS is studying the effects of canakinumab, a high-affinity human monoclonal anti-human interleukin-1β antibody, on the inflammatory pathway. Canakinumab is currently indicated for the treatment of IL-1β-driven inflammatory diseases, such as Cryopyrin-Associated Period Syndrome. The antibody was designed to bind to human IL-1β and functionally neutralize the bioactivity of this pro-inflammatory cytokine.

In a pilot group of patients enrolled in CANTOS, investigators measured a 64.6% reduction in C-reactive protein levels, which persisted up to 3 months following the end of therapy. The primary outcomes to be measured in this trial are the rates of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. A major question that the secondary outcomes will explore is whether therapy with an IL-1 inhibitor will prevent the progression of metabolic syndrome to diabetes in these patients.

The CIRT study is a randomized, double-blind, placebo-controlled trial that aims to reduce interleukin-6 (IL-6) with low-dose methotrexate therapy. Unlike other anti-inflammatory agents used to treat cardiovascular inflammation, low-dose methotrexate therapy has no effect on lipids or hemostasis, yet it remains a powerful way to reduce inflammation.

Patients enrolled in CIRT have stable coronary artery disease, a history of myocardial infarction, and also have type 2 diabetes or metabolic syndrome. The primary endpoints of CIRT are rates of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. To date, study sites have enrolled over 1,000 participants. During the presentation, Ridker was actively recruiting new sites to participate in CIRT and help reach the target of 7,000 enrolled patients.

Previous clinical trials, including the Women’s Health Study that Ridker was involved with, have shown an increased relative risk of future cardiovascular events with elevated levels of IL-6. In animal models, methotrexate has been shown to reduce atherogenesis. Observational human studies on patients with rheumatoid arthritis who were taking methotrexate have repeatedly shown a reduced hazard ratio for measures such as cardiovascular mortality, cardiovascular disease, and total mortality.