Paul Ridker

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. CANTOS also demonstrated that the magnitude of inflammation reduction, as measured by on-treatment levels of Interleukin-6, drives the cardiovascular benefit with 36% decreases in cardiovascular death and all-cause mortality among robust Canakinumab responders. 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 the inexpensive generic oral agent 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 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. Between 1998 and 2005, Ridker showed that individuals with elevated hsCRP but low levels of cholesterol were at substantial risk and that statin drugs used to lower cholesterol also lowered hsCRP and thus had important anti-inflammatory properties. This work, largely funded by the National Institutes of Health, eventually led to the design and conduct of the multi-national JUPITER primary prevention trial which in 2008 demonstrated that individuals with elevated hsCRP levels could reduce by half their risk of future heart attack or stroke by taking statin therapy, even if cholesterol levels were already low. The JUPITER trial data changed cardiovascular prevention guidelines worldwide.

Paul M. Ridker (born 1959) is a cardiovascular epidemiologist and biomedical researcher. He is currently the Eugene Braunwald Professor of Medicine at Harvard University and Brigham and Women's Hospital, where he directs the Center for Cardiovascular Disease Prevention. Ridker also holds an appointment as Professor in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health.

Ridker was born in St. Louis, Missouri in 1959. He attended Brown University for his undergraduate studies, graduating with a Bachelor of Science in 1981. He attended Harvard Medical School, where he received his MD in 1986; Ridker completed his residency at Brigham and Women’s Hospital and West Roxbury VA Medical Center in Boston, Massachusetts. In 1992, Ridker earned a Master of Public Health degree at the Harvard T.H. Chan School of Public Health.