Ridker’s translational research combines the tools of
epidemiology,
vascular biology, and
randomized clinical trials to determine the root causes of
heart disease,
stroke, and
diabetes. He is responsible for the clinical development of high sensitivity C-reactive protein (
hsCRP), a marker of inflammation, that is used to evaluate the risk of heart attack and stroke, and coined the term “residual inflammatory risk” to describe patients who are at risk due to vascular inflammation rather than
high cholesterol levels. Early in his career, Ridker recognized that elevated cholesterol levels were absent in almost half of all heart attack victims and that the pro-inflammatory response detected by hsCRP and the central signaling cytokine
Interleukin 6 were responsible for a large proportion of “unexplained risk”. Ridker is best known for his work developing inflammatory biomarkers and his clinical trials defining anti-inflammatory treatments for cardiovascular disease. In 1997, Ridker showed that elevated levels of hsCRP and interleukin-6 in healthy individuals were a major risk marker for future heart attack, stroke, diabetes, and cardiovascular death, independent of traditional risk factors. Critical proof of the inflammation hypothesis of atherosclerosis came when Ridker and his international collaborators focused on the
NLRP3 to
Interleukin-1b to Interleukin-6 pathway of innate immunity and its role in coronary disease. Toward this end, in 2010, Ridker obtained parallel funding from the
National Heart Lung and Blood Institute and from the pharmaceutical industry to design and conduct two multi-national cardiovascular inflammation reduction trials known as CANTOS and CIRT. The CANTOS (
Canakinumab Anti-inflammatory Thrombosis Outcomes Study) reported in late 2017 that inflammation inhibition with
Canakinumab, a
monoclonal antibody targeting interleukin-1-beta, can significantly reduce future risks of heart attack, need for expensive coronary revascularization procedures, and cardiovascular deaths among high-risk heart disease patients with residual inflammatory risk.
Canakinumab had no effects on either cholesterol or blood pressure, and thus these data provided the fundamental first proof-of-concept for the inflammation hypothesis of atherosclerosis. In contrast, the federally funded CIRT (Cardiovascular Inflammation Reduction Trial) showed no benefit to low-dose
Methotrexate but also no evidence of lowering Interleukin-1b, Interleukin-6 nor CRP. Thus, the positive CANTOS trial and the informative null CIRT trial defined the need to reduce signaling from the NLRP3 to Interleukin-1 to Interleukin-6 in order to lower vascular event rates. These findings were replicated with low-dose
Colchicine in the 2019 COLCOT and 2020 LoDoCo2 trials. Ongoing work from Ridker’s group is testing whether direct targeting of Interleukin-6 itself can improve cardiovascular outcomes. Ridker’s work has had wide biologic implications beyond atherosclerosis and heart disease. By reducing inflammation in the tumor microenvironment, CANTOS also demonstrated highly significant reductions in lung cancer and lung cancer fatality. These data have generated broad interest within the academic and pharmacologic communities resulting in multiple trials studying Interleukin-1 inhibition with or without adjunctive checkpoint inhibition as a novel therapy for non small cell lung cancers. Work from CANTOS has also demonstrated the potential human benefits of targeted Interleukin-1 therapy on
anemia,
renal failure, and large joint
osteoarthritis. In his work as a clinical trialist, Ridker has designed, conducted, and served as Trial Chair of the Steering Committee of PRINCE, VAL-MARC, PREVENT, LANCET, JUPITER, SPIRE-1, SPIRE-2, CANTOS and CIRT, as well as the ongoing PROMINENT, ACTIV-4B, and ZEUS trials. ==Honors and awards==