Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial

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.

Fig. 1.

Plasma lipid and lipoprotein profile (mmol/L) in cases and controls at baseline (A), on treatment (B), and difference (on treatment-baseline) (C). The values for total, LDL-, and HDL- cholesterol are untransformed mean (bar is sd). The triglyceride values are geometric means (bar is SD) calculated from the log-transformed values (except for absolute difference). The absolute change values are untransformed mean (bar is SD) (absolute difference of the raw values).

Fig. 2.

Change in plasma cholesterol homeostasis marker profile (on treatment-baseline) in all subjects. Values are untransformed mean (bar is SEM) of the ratios of the cholesterol homeostasis markers-cholesterol.

Fig. 3.

Tertiles of change (on treatment-baseline) in cholesterol synthesis, as reflected by plasma lathosterol concentrations (as a ratio to cholesterol) and percent change in plasma LDL-cholesterol lowering (A and B), triglyceride lowering (C and D), and HDL-cholesterol raising (E and F) in cases and controls, respectively. Bar is 95% confidence interval.

Fig. 4.

Tertiles of change (on treatment-baseline) in cholesterol absorption, as reflected by plasma campesterol concentrations (as a ratio to cholesterol) and percent change in plasma LDL-cholesterol lowering (A and B), triglyceride lowering (C and D), and HDL-cholesterol raising (E and F) in cases and controls, respectively. Bar is 95% confidence interval.