Effect of Simvastatin on markers of triglyceride‐rich lipoproteins in familial hypercholesterolaemia

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Abstract
Background We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B‐48 and remnant‐like particle‐cholesterol (RLP‐C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG‐CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB‐48 and RLP‐C in FH patients after long‐ and short‐term simvastatin therapy and after a wash‐out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant‐like emulsion labeled with cholesteryl 13C‐oleate.Methods Fifteen FH patients were studied after > 6 months 40 mg day−1 simvastatin treatment (long‐term), a wash‐out period (4 weeks), and 4 weeks of simvastatin treatment (short‐term). Apolipoprotein B‐48 was determined by SDS‐PAGE and Western blotting/enhanced chemiluminescence and RLP‐C by an immunoseparation assay. The FCR of the chylomicron remnant‐like emulsion was determined from the appearance of 13CO2 in the breath and by multicompartmental mathematical modelling.Results Both long‐ and short‐term treatment with simvastatin were associated with decreases in the plasma concentration of apoB‐48 (P < 0·05) and RLP‐C (P < 0·001), but there was no significant change in the FCR of the emulsion.Conclusions We suggest that long‐ and short‐term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride‐rich remnants in heterozygous FH, as measured by fasting apoB‐48 and RLP‐C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up‐regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the 13CO2 breath test.

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