Action of atorvastatin in combined hyperlipidemia - Preferential reductionof cholesteryl ester transfer from HDL to VLDL1 particles

Combined hyperlipidemia (CHL) is characterized by a concomitant elevation o f plasma levels of triglyceride-rich, very low density lipoproteins (VLDLs) and cholesterol-rich, low density lipoproteins (LDLs). The predominance of small, dense LDLs contributes significantly to the premature development o f coronary artery disease in patients with this atherogenic dyslipoproteine mia. In the present study, we evaluated the impact of atorvastatin, a newly developed inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) redu ctase, on the cholesteryl eater transfer protein (CETP)-mediated remodeling of apolipoprotein (apo) B-containing lipoprotein subspecies, and more spec ifically, the particle subpopulations of VLDL and LDL in CHL. In parallel, we evaluated the atorvastatin-induced modulation of the quantitative and qu alitative features of atherogenic apo B-containing and cardioprotective apo AI-containing lipoprotein subspecies. Atorvastatin therapy (10 mg/d for a 6-week period) in patients with a lipid phenotype typical of CHL (n=18) ind uced reductions of 31% (P<0.0001) and 36% (P<0.0001) in plasma total choles terol and LDL cholesterol, respectively. In addition, atorvastatin signific antly reduced VLDL cholesterol, triglycerides, and apo B levels by 43% (P<0 .0001), 27% (P=0.0006),and 31% (P<0.0001), respectively. The plasma concent rations of triglyceride-rich lipoproteins (VLDL1, Sf 60 to 400; VLDL2, Sf 2 0 to 60; and intermediate density lipoproteins, Sf 12 to 20) and of LDL, as determined by chemical analysis, were markedly diminished after drug thera py (-30% and -28%, respectively; P<0.0007). Atorvastatin significantly redu ced circulating levels of all major LDL subspecies, ie, light (-28%, P<0.00 08), intermediate (-27%, P<0.0008), and dense (-32%, P(0.0008) LDL; moreove r, in terms of absolute lipoprotein mass, the reduction in dense LDL levels (mean -62 mg/dL) was preponderant. In addition, the reduction in plasma de nse LDL concentration after therapy was significantly correlated with a red uction in plasma VLDL1 levels (r=0.429, P=0.0218), Atorvastatin induced a s ignificant reduction (-7%, P=0.0039) in total CETP-dependent CET activity, which accurately reflects a reduction in plasma CETP mass concentration. To tal CETP-mediated CET from high density lipoproteins to apo B-containing li poproteins was significantly reduced (-26%, P<0.0001) with drug therapy. Fu rthermore, CETP activity was significantly correlated with the atorvastatin -induced reduction in plasma VLDL1 levels (r=0.456, P=0.0138). Indeed, ator vastatin significantly and preferentially decreased CET from HDL to the VLD L1 subfraction (-37%, P=0.0064), thereby reducing both the levels (-37%, P= 0.0001) and the CE content (-20%, P<0.005) of VLDL1. We interpret our data to indicate that 2 independent but complementary mechanisms may be operativ e in the atorvastatin-induced reduction of atherogenic LDL levels in CHL: f irst, a significant degree of normalization of both the circulating levels and the quality of their key precursors, ie, VLDL1, and second, enhanced ca tabolism of the major LDL particle subclasses tie, light, intermediate, and dense LDL) due to upregulation of hepatic LDL receptors.