High-density lipoprotein and apolipoprotein A-I deficiency induced by combination therapy with probucol and bezafibrate

The effects of the administration of slow-release bezafibrate to hypercholesterolaemic patients who were already receiving long-term probucol treatment (mean 865 days, 500–1000 mg·day^–1) were investigated. Bezafibrate was administered at either 200 mg·day^–1 (13 males, 13 females, mean age 55.2 years) or 400 mg·day^–1 (11 males, 14 females, mean age 57.2 years), and blood was taken at 0, 3, 6 and 12 months after the beginning of combination therapy. Overall, serum total cholesterol (TC), triglyceride (TG), very low density lipoprotein (VLDL)-TC, high-density lipoprotein (HDL)-TG, VLDL-TG, VLDL-phospholipid (PL), lipoprotein (a) [Lp(a)], apolipoprotein (apo) C-III, apo E levels and LCAT activity decreased significantly with this combination therapy, while HDL cholesterol (C), HDL3-C, HDL-PL, apo A-I and apo A-II levels significantly increased, as assessed by analysis of variance (ANOVA). Five patients (one receiving 200 mg·day^–1, four receiving 400 mg·day^–1 bezafibrate) showed drastic reductions in HDL-C (HDL-C levels were reduced by a mean of 46.2%, 59.3% and 61.6% at 3, 6 and 12 months, respectively) after beginning combination therapy. These HDL-C reductions were maintained for the 1 year of combination therapy, but then returned to pre-combination treatment levels 1 month after discontinuation of bezafibrate. Serum probucol concentrations and cholesteryl ester transfer protein (CETP) mass were assayed at 6 months, and the probucol concentration was higher in the HDL-deficient group (56.2 vs 26.5 g/ml). In contrast, CETP mass was significantly lower in HDL-deficient patients than in non-HDL-deficient patients (2.08 vs 2.87 mg·l^–1). When the patients in the non-HDL-deficient group were divided into two groups, receiving low (200 mg·day^–1, n–25) and high (400 mg·day^–1, n–21) doses of bezafibrate, the former group showed a significant increase in probucol-lowered HDL-C and apo A-I, although these levels did not return to pre-probucol treatment levels, while the latter group showed no changes in HDL. These data suggest that the addition of a low dose of bezafibrate to probucol tended to reverse probucol-induced HDL lowering, while 9.8% (5 of 51 patients) of the patients exhibited a severe HDL deficiency. Since it is unclear whether or not such an extreme HDL reduction is harmful, HDL deficiency should be carefully monitored with this combination therapy.Part of this work was presented at the XIth International Symposium on Drugs Affecting Lipid Metabolism (DALM), 15 May 1992, Florence, Italy.