Elevated baseline triglyceride levels modulate effects of HMGCoA reductase inhibitors on plasma lipoproteins.

BACKGROUND: The response in levels of very-low-density (VLDL) and low-density (LDL) lipoproteins varies substantially among hyperlipidemic patients during treatment with HMGCoA reductase inhibitors. Apolipoprotein E genotype and gender are known to contribute to the regulation of steady state levels of plasma lipoproteins. This study explores the effect of these and other potential determinants of the response of VLDL and LDL to treatment with reductase inhibitors. METHODS: Using mixed linear statistical models, the response of lipoprotein lipid values was studied in 142 hyperlipidemic individuals who were treated with reductase inhibitors. Patients received one or more of the following drugs individually for a total of 623 treatment observations: lovastatin, pravastatin, simvastatin, or atorvastatin. For evaluation of the effects of treatment in the aggregate, actual doses were expressed as equivalent doses of atorvastatin, using factors based on random assignment comparisons in 16 reported studies. The analysis factors considered were apolipoprotein E genotype, baseline average triglycerides >170 mg/dL (vs less), and gender. RESULTS: Presence of an apo epsilon4 allele was associated with a trend toward greater reduction of triglyceride levels and a diminished ability of the reductase inhibitors to reduce LDL cholesterol levels. Gender had only minimal effect on the response of either LDL cholesterol or triglycerides. However, the effect of elevated baseline triglycerides on the response of both triglycerides and LDL cholesterol was striking and was exerted in opposite directions. The triglyceride-lowering effect of reductase inhibitors was greater in patients with initial triglyceride levels above 170 mg/dL (P=0.0001). The effect was even greater in patients with initial triglyceride levels over 250 mg/dL (P=0.015). Conversely, for LDL cholesterol levels, elevated baseline triglycerides were associated with a significantly decreased response to the drugs (P=0.0015). CONCLUSIONS: These findings indicate that baseline triglyceride levels are an important predictor of response of plasma lipoproteins to HMGCoA reductase inhibitors, perhaps reflecting fundamental differences in mechanism underlying the hyperlipidemic phenotype.

Mild autoxidation of low density lipoproteins.

The autoxidation of low density lipoproteins was investigated in a closed system, with limited amount of oxygen. The concentrations of several components were monitored: oxygen, aldehydic oxidation products and alpha-tocopherol. The concentration of lipid radicals generated in the processes of lipid peroxidation was monitored by the EPR spin trapping method. It was observed that the consumption of oxygen starts quickly after the onset of incubation at physiological temperature. After prolonged incubation, several types of trapped radicals were formed. At the same time, no consumption of alpha-tocopherol and no formation of aldehydic products of oxidation took place, indicating that the oxidation process is rather mild. The dynamics of oxidation processes were simulated by a mathematical model in which the oxidation is initiated by the degradation products of the pre-existing lipid peroxides. The best agreement between the theoretical predictions and experimental results was obtained with the rate constants which are several orders of magnitude smaller than the corresponding rate constants in "neat' lipids. The possible reasons for the behaviour observed are discussed.