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

• Published in: Atherosclerosis Vol. 178; no. 1; pp. 147 - 155
• Main Authors: van Wijk, J.P.H., Buirma, R., van Tol, A., Halkes, C.J.M., De Jaegere, P.P.Th, Plokker, H.W.M., van der Helm, Y.J.M., Castro Cabezas, M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 2005; Elsevier
• Subjects: Apolipoproteins - blood; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Carrier Proteins - blood; Cholesterol Ester Transfer Proteins; Chylomicron Remnants; Chylomicrons; Chylomicrons - blood; Coronary Artery Disease - blood; Coronary heart disease; Dose-Response Relationship, Drug; Fasting - blood; Female; Glycoproteins - blood; Heart; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipids - blood; Lipoproteins - blood; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Postprandial lipemia; Postprandial Period; Secondary prevention; Simvastatin - administration & dosage; Simvastatin - pharmacology; Statins; Triglycerides - blood; Vasodilator agents. Cerebral vasodilators; Secondary prevention; Postprandial lipemia; Chylomicrons; Statins; Premature; Vitamin; Cardiovascular disease; Lipids; Hyperlipoproteinemia; Lipoprotein; Vascular disease; Prevention; Chylomicron; Lipemia; Cholesterol HDL; Atherosclerosis; Hyperlipemia; Dyslipemia; High dose; Human; Fasting; Enzyme; Postprandial; Simvastatin; Oral administration; Enzyme inhibitor; Metabolic diseases; Cholesterol LDL; Statin derivative; Triglyceride; Coronary heart disease; Loading test; Chemotherapy; Hypercholesterolemia; Treatment; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Antilipemic agent
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2004.08.009

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/m 2; 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.