title: Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis.
abstract: Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.
authors.affiliation: Department of Vascular Medicine, University Medical Center Utrecht, The Netherlands.
authors.forename: J P H
authors.initials: JP
authors.lastname: van Wijk
authors.forename: R
authors.initials: R
authors.lastname: Buirma
authors.forename: A
authors.initials: A
authors.lastname: van Tol
authors.forename: C J M
authors.initials: CJ
authors.lastname: Halkes
authors.forename: P P Th
authors.initials: PP
authors.lastname: De Jaegere
authors.forename: H W M
authors.initials: HW
authors.lastname: Plokker
authors.forename: Y J M
authors.initials: YJ
authors.lastname: van der Helm
authors.forename: M
authors.initials: M
authors.lastname: Castro Cabezas
mesh_terms: D001053:Apolipoproteins / Q000097:blood; D002352:Carrier Proteins / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D053298:Chylomicron Remnants; D002914:Chylomicrons / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood*
chemical_list: D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D053298:Chylomicron Remnants; D002914:Chylomicrons; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008074:Lipoproteins; D014280:Triglycerides; D019821:Simvastatin