High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)< 1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42±19 mg/dL and area under the RLP-C curve 415±82 mg · L -1 · h-1, respectively) than did control subjects (7±3 mg/dL and 101±35 mg · L -1 · h-1, respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13±3 mg/dL and 136±53 mg · L -1 · h-1, respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24±10 versus 6.3±5.9 mg · L -1 · h-1, P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.