For a decade the most concrete test of the idea that antioxidants protect the heart was a single molecule: AGI-1067, later called succinobucol, developed by AtheroGenics Inc. of Alpharetta, Georgia. The company was founded in 1993 by researchers from Emory University, went public in 2000 and by 2005 was valued at more than a billion dollars on the strength of one drug candidate.
The idea
AGI-1067 was a chemical relative of probucol, an older cholesterol drug with strong antioxidant activity that had been abandoned because it lowered HDL and lengthened the heart’s QT interval. The new molecule kept the antioxidant and anti-inflammatory effect and was meant to slow atherosclerosis by blocking the oxidation of LDL and the adhesion of inflammatory cells to the artery wall. Early trials measured plaque with intravascular ultrasound and looked encouraging.
The ARISE trial
ARISE enrolled about 6,100 patients who had recently had a heart attack or unstable angina and followed them for two years. In March 2007 the company announced that the drug had missed its primary endpoint: it did not reduce the combined rate of cardiovascular death, heart attack, stroke, hospitalisation and revascularisation. Secondary analyses suggested fewer heart attacks and strokes and a lower rate of new diabetes, and the company tried to reposition the drug for diabetes prevention. Its partner AstraZeneca walked away, the share price collapsed, and AtheroGenics filed for bankruptcy in 2008 and was liquidated in 2009.
What it taught
ARISE was one of several large trials in the 2000s, including the vitamin E and beta-carotene studies, that failed to show that antioxidant supplements or drugs prevent cardiovascular events. The consensus that emerged: oxidative stress is part of the disease process, but swallowing an antioxidant does not reliably change it, and the antioxidant vegetables and fruit that do correlate with lower risk work through many pathways at once. The inflammation hypothesis, by contrast, was later confirmed by the CANTOS trial of canakinumab in 2017 and by low-dose colchicine trials.
Today
Succinobucol is not marketed anywhere. Prevention of heart attacks and strokes rests on blood pressure control, statins and other LDL-lowering drugs, diabetes management, anti-platelet therapy where indicated, and the unglamorous trio of not smoking, moving and eating mostly plants.
This site is an independent reference on antioxidants and heart health and is not connected to the former company.
