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United States Department of Agriculture

Agricultural Research Service

Research Project: DIET AND BIOMARKERS OF CARDIOVASCULAR HEALTH Title: Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial

Authors
item Matthan, Nirupa -
item Resteghini, Nancy -
item Robertson, Michele -
item Ford, Ian -
item Shepherd, James -
item Packard, Chris -
item Buckley, Brendan -
item Jukema, J Wouter -
item Lichtenstein, Alice -
item Schaefer, Ernst -

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 3, 2009
Publication Date: July 3, 2009
Citation: Matthan, N., Resteghini, N., Robertson, M., Ford, I., Shepherd, J., Packard, C., Buckley, B.M., Jukema, J., Lichtenstein, A.H., Schaefer, E. 2009. Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: Insights from the PROSPER trial. Journal of Lipid Research. 51:202-209.

Interpretive Summary: Cholesterol homeostasis, defined as the balance between cholesterol absorbed and synthesized, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Drugs such as statins work by targeting a key enzyme that is involved in cholesterol synthesis in the body. While this drug has been shown to be efficacious in lowering CHD events and mortality, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy markers of cholesterol synthesis and fractional cholesterol absorption were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with and without a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers and increased concentrations of the cholesterol absorption markers were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.

Technical Abstract: Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (-12% and -11%) and lathosterol (-50% and -56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.

Last Modified: 10/24/2014