Long-Term Probucol Treatment Prevents Secondary Cardiovascular Events: a Cohort Study of Patients with Heterozygous Familial Hypercholesterolemia in Japan

Abstract

Aim:The POSITIVE study assessed whether long-term treatment with probucol, a potent anti-oxidant and cholesteryl ester transfer protein (CETP) activator, is associated with a lowered risk of cardiovascular events in a very high-risk population: familial hypercholesterolemia (FH).

Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia

“…In addition, we reported previously that the extent of regression of Achilles tendon thickness was closely correlated with the reduction in serum HDL-C in patients with FH during probucol treatment 4,5) . We also reported that small HDL particles from probucoltreated patients are more potent than untreated HDL in removing cholesterol from peripheral tissues 6) , that RCT was enhanced by stabilizing the expression of hepatic SR-BI (scavenger receptor class B, type 1) 7) , and that long-term probucol treatment prevented secondary cardiovascular event in patients with heterozygous FH 8) ; however, previous studies did not investigate whether probucol treatment changes the antioxidative properties of HDL.…”

“…Probucol lowers HDL-C levels which are not associated with the risk of cardiovascular events 8) . The controversial and anti-atherogenic feature of probucol is most likely attributable to changes in HDL properties and their molecular mechanisms.…”

“…Heterozygous FH was defined as having at least two major features, or at least one major and one minor feature. The major features of FH are total cholesterol (TC) of 260 mg/dL and above; tendon xanthoma or tuberous xanthoma; reduced or abnormal receptor activity noted by LDL receptor analysis, and the minor features are palpebral xanthoma; juvenile (＜50 years) corneal arcus; juvenile (＜50 years) ischemic heart disease 8) . Eight healthy normolipidemic volunteers without a history of hypercholesterolemia or CAD were enrolled as control subjects.…”

Characteristics and Vascular Complications of Familial Hypercholesterolemia in Korea

“…Although a study performed in Finland showed that FH increased the risk of stroke 20 times 31) , stroke mortality in FH patients was not higher than that in probucol is not actively prescribed in Korean FH patients. Meanwhile, probucol is more commonly used in Japanese FH patients 46) , with supportive evidence of long-term cardiovascular benefits 49) . In addition, a combination of statins, ezetimibe, and resins showed further lowering of LDL-C levels without serious safety issues in Japan 50,51) .…”

Molecular Mechanisms of HDL-Cholesterol Elevation by Statins and Its Effects on HDL Functions

“…To further assess the clinical efficacy of probucol treatment in clinical settings, the POSITIVE study (Probucol observational study illuminating therapeutic impact on vascular events) was performed, assessing whether longterm probucol treatment was associated with a lowered risk of cardiovascular events in a very high-risk population of patients with FH in Japan 97) . The study cohort included 410 patients with heterozygous FH.…”