New Horizons for Probucol, an Old, Mysterious Drug

Intensive low-density lipoprotein (LDL)-lowering therapies involving statins, intestinal cholesterol transporter inhibitor (ezetimibe), and proprotein convertase subtilisin/kexin type 9 inhibitors are associated with a significantly lower number of atherosclerotic cardiovascular events. However, these events have not been completely prevented to date. Therefore, additional pharmacological interventions may be crucial to mitigate “residual risks” other than serum LDL cholesterol (LDL-C) levels. Probucol was developed as an anti-oxidative compound to prevent the degradation of tire rubber and later applied to reduce serum LDL-C levels in patients with hypercholesterolemia. The effect of probucol on the reduction of serum LDL-C levels was not substantial; however, probucol has been widely used in Japan before the launch of statins, particularly in patients with familial hypercholesterolemia (FH). Japanese researchers have demonstrated that probucol reduces LDL-C levels even in Watanabe heritable hyperlipidemic (WHHL) rabbits and in patients with homozygous and heterozygous FH and LDL receptor (LDL-R) deficiency 3) via an enhanced catabolism of LDL independent of LDL-R and increased cholesterol excretion into the bile. Probucol also reduces skin and tendon xanthomas in patients with FH despite a marked reduction in highdensity lipoprotein (HDL) cholesterol (HDL-C) due to enhanced cholesteryl ester transfer protein activity and hepatic expression of scavenger receptor class B type I. Probucol reportedly attenuated atherosclerosis in WHHL rabbits, and thereafter, many studies have proven its clinical efficacy in preventing atherosclerotic cardiovascular events and coronary restenosis after percutaneous coronary intervention as reviewed. After their launch, statins have become the firstline drug choice for the treatment of patients with high LDL-C levels owing to their strong LDL-C lowering effect. Conversely, a randomized controlled trial—Probucol Quantitative Regression Swedish Trial (PQRST)—revealed that administration of probucol for 3 years in patients with hypercholesterolemia lowered LDL-C levels but did not increase the lumen volume of femoral arteries, as revealed by angiography. Thereafter, probucol has disappeared from the market worldwide, except for Japan, partly due to the failure of PQRST, reduction in serum HDL-C level, and possible prolongation of QT interval. However, probucol has been used by Japanese clinicians, particularly lipidologists. We hypothesized for the first time worldwide that reduction in HDL-C levels by probucol may not be harmful but can rather reflect the acceleration of reverse cholesterol transport (RCT), thereby leading to regression of atherosclerotic plaque and xanthomas . Recent evidences have strongly suggested that probucol not only has potent anti-oxidative properties but also enhances HDL-mediated RCT, leading to regression of atherosclerotic plaque as reviewed. In the Probucol Observational Study Illuminating Therapeutic Impact on Vascular Events (POSITIVE), the long-term effects of probucol on cardiovascular events were evaluated in 410 patients with heterozygous FH. The primary outcome was the time to first cardiovascular event involving hospitalization. Multivariate Cox regression analysis revealed that the hazard ratio of probucol use for secondary prevention was 0.13 [95% confidence interval (CI) 0.05–0.34, P<0.001], suggesting that long-term probucol treatment prevents secondary cardiovascular events in very high-risk