Abstract 3609: Markers of Cholesterol Absorption and Synthesis in Individuals Without and With CHD Events During Treatment With Pravastatin: Insights from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Trial
Cholesterol homeostasis is maintained by a balance between absorption and synthesis, which influences circulating cholesterol levels and subsequent CHD development. Statin therapy which targets the rate limiting enzyme in the cholesterol biosynthetic pathway, is efficacious in lowering plasma LDL-C levels, CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address this difference in outcome plasma markers of cholesterol absorption (campesterol, sitosterol) and synthesis (desmosterol, lathosterol) were measured using gas chromatography in a subset of PROSPER study participants. Analyses were carried out in 223 subjects who had an event (cases) and 257 age, gender and location-matched subjects who did not have an event (controls) while on pravastatin (40 mg/day), pre- and post-treatment. Subjects were 70 – 82 years, with vascular disease or a CHD risk factor: smoking, hypertension, diabetes, or elevated total cholesterol (4.0 –9.0 mmol/L). Relative to pre-treatment values, pravastatin decreased plasma LDL-C (−33 ± 1 vs −33 ± 1%; P=0.67) and triglyceride (−59 ± 13 vs −37 ± 15%; P=0.28) levels and increased HDL-C levels (11 ± 1 vs. 10 ± 1%; P=0.72) to a similar extent in cases and controls. Likewise, the percent change in levels of cholesterol absorption markers (34 ± 3 vs 35 ± 2%; P=0.77 for campesterol; 29 ± 2 vs 30 ± 2%; P=0.78 for sitosterol) and synthesis markers (−27 ± 2 vs −24 ± 2%; P=0.23 for desmosterol; −38 ± 2 vs −40 ± 2%; P=0.33 for lathosterol) were similar between cases and controls (values are untransformed means ± SE). In all subjects, percent change in plasma LDL-C levels was positively associated with cholesterol synthesis markers (r=0.27, p<0.001 for desmosterol; r=0.32, p<0.0001 for lathosterol) and negatively associated with cholesterol absorption markers (r=−0.11, p=0.02 for campesterol; r=−0.11, p=0.02 for sitosterol). These data demonstrate that the decrease in cholesterol synthesis in response to pravastatin treatment is accompanied by a modest compensatory increase in cholesterol absorption. Alterations in cholesterol homeostasis markers are significantly linked to LDL-C lowering response, but not to endpoints in this high-risk elderly population.