Studies in Cholesterol Metabolism: Relationship to Statin Efficacy, Obesity and Lipoprotein Fractions

Michel R Hoenig (2011). Studies in Cholesterol Metabolism: Relationship to Statin Efficacy, Obesity and Lipoprotein Fractions PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Michel R Hoenig
Thesis Title Studies in Cholesterol Metabolism: Relationship to Statin Efficacy, Obesity and Lipoprotein Fractions
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2011-05
Thesis type PhD Thesis
Supervisor A/Prof Philip Walker
Dr John Bingley
Total pages 99
Total colour pages 4
Total black and white pages 95
Subjects 11 Medical and Health Sciences
Abstract/Summary Background: Low density lipoprotein cholesterol (LDL-C) predicts cardiovascular events and lowering LDL-C by blocking endogenous cholesterol synthesis with statin therapy is a proven intervention for cardiovascular disease. However, the LDL-C response to statin therapy varies greatly between individuals and may be related to differences in cholesterol metabolism, insulin resistance and genetically-determined differences in drug disposition. Objectives: The aims of this work are to prospectively study the relationship between markers of cholesterol metabolism (cholestanol, desmosterol), genetic variation in ABCB1 and LDL-C response to atorvastatin. Cholesterol metabolism is also influenced by obesity and insulin resistance and hence we also sought to describe the relationship between visceral obesity, insulin sensitivity, cholesterol metabolism, lipid fractions and LDL-C response to atorvastatin. Methods: High-risk vascular patients were genotyped for the C3435T polymorphism in ABCB1 and treated with atorvastatin 80mg for 6 weeks. LDL-C response to atorvastatin was related to baseline cholestanol:cholesterol ratio (CCR), desmosterol, ABCB1 genotype and insulin sensitivity using the QUICK Index. A subset of the cohort underwent magnetic resonance imaging (MRI) to quantify visceral fat area (VFA) and to assess the relationship between visceral obesity, cholesterol metabolism and lipid fractions. Results: 154 patients were enrolled. Markers of cholesterol synthesis (desmosterol)correlated positively with LDL-C response to atorvastatin while markers of cholesterol absorption (cholestanol) correlated negatively. Insulin resistance was associated with higher cholesterol synthesis markers and lower absorption markers and an enhanced response to atorvastatin. However, the relationship between insulin resistance and LDL-C response to atorvastatin was completely dependent on variations in cholesterol metabolism. In contrast, the CC genotype at the C3435T polymorphism in ABCB1 is associated with reduced atorvastatin efficacy independently of cholesterol metabolism. Increasing visceral obesity, quantified as the VFA, was positively correlated to cholesterol synthesis markers, very low density lipoprotein cholesterol (VLDL-C) and negatively correlated to LDL-C and cholesterol absorption markers. Conclusions: Markers of cholesterol metabolism and genotype of the C3435T polymorphism in ABCB1 may be used to predict LDL-C response to atorvastatin therapy. This finding is likely to be increasingly relevant as progressively lower LDL-C targets are Page 7 of 99 sought. Insulin resistance is associated with an enhanced response to atorvastatin but this is not independent of the increased cholesterol synthesis and reduced absorption with insulin resistance. LDL-C may not be an appropriate therapeutic target in future guideline statements given that it is negatively correlated with VFA and therefore may not represent true cardiovascular risk in an increasingly obese world with higher VLDL-C levels and increased cholesterol synthesis.
Keyword cholesterol
statin
personalised medicine
Pharmacogenomics
Cardiovascular Risk
obesity
insulin resistance
Additional Notes 30, 64, 86, 91

 
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Created: Sat, 24 Sep 2011, 16:12:13 EST by Dr Michel R Hoenig on behalf of Library - Information Access Service