Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux.
Type IIB hyperlipidemia is associated with premature vascular disease, an atherogenic lipoprotein phenotype characterised by elevated levels of triglyceride-rich VLDL and small dense LDL, together with subnormal levels of HDL. The dose-dependent and independent effects of a potent HMGCoA reductase inhibitor, Atorvastatin, at daily doses of 10 and 40 mg, were evaluated on triglyceride-rich lipoprotein subclasses (VLDL-1, VLDL-2 and IDL), on the major LDL subclasses (light LDL, LDL-1+LDL-2, D: 1.019-1.029 g/ml; intermediate LDL, LDL-3, D: 1.029-1.039 g/ml and small dense LDL, LDL-4+LDL+5, D: 1.039-1.063 g/ml), on CETP-mediated cholesteryl ester transfer from HDL to apoB-containing lipoproteins, on phospholipid transfer protein activity and on plasma-mediated cellular cholesterol efflux in patients (n=10) displaying type IIB hyperlipidemia. Plasma concentrations of triglyceride-rich lipoprotein subclasses (TRL: VLDL-1, Sf 60-400; VLDL-2, Sf 20-60 and IDL, Sf 12-20) and of LDL (D: 1.019-1.063 g/ml) were markedly diminished after 6 weeks of statin treatment at 10 mg per day (-31 and -36%, respectively; P<0.002) and by 42 and 51%, respectively at the 40 mg per day dose. Increasing doses of atorvastatin progressively normalised both the quantitative and qualitative features of the LDL subclass profile, in which dense LDL predominated at baseline. Indeed, dense LDL levels were reduced by up to 57% at the 40-mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles typical of normolipidemic subjects. In addition, marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (P<0.02) in CETP-mediated CE transfer from HDL. Finally, a significant dose-dependent statin-mediated elevation (+15% at 10 mg; P=0.0003 and +35% at 40 mg; P<0.0001 compared to baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Moreover, atorvastatin (40 mg per day) significantly increased plasma apoAI levels (+24%; P<0.05), thereby suggesting that this statin enhances production of apoAI and with it, formation of nascent pre-beta HDL particles. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing the dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in type IIB dyslipidemia, thereby diminishing the atherosclerotic burden in subjects characterised by high cardiovascular risk.
Guerin
Maryse
M
Institut National de la Santé et de la Recherche Médicale (INSERM Unité 551), Hôpital de la Pitié, Pavillon Benjamin Delessert, 83 Boulevard de l'Hôpital, 75651 Paris, Cedex 13, France. mguerin@infobiogen.fr
Egger
Pascal
P
Soudant
Céline
C
Le Goff
Wilfried
W
van Tol
Arie
A
Dupuis
Reynald
R
Chapman
M John
MJ
D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000032:analysis; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control; D000069059:Atorvastatin; D002352:Carrier Proteins / Q000097:blood; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D006023:Glycoproteins; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000378:metabolism; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D049294:Phospholipid Transfer Proteins; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin