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Common Cholesteryl Ester Transfer Protein Gene Polymorphisms and the Effect of Atorvastatin Therapy in Type 2 Diabetes

¹ Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
² Julius Center for General Practice and Patient Oriented Research, University Medical Center Utrecht, Utrecht, the Netherlands
³ Department of Biochemistry, Erasmus Medical Center, Rotterdam, the Netherlands

OBJECTIVE—The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes.

RESEARCH DESIGN AND METHODS—We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes.

RESULTS—CETP TaqIB and A-629C polymorphisms were tightly concordant (P < 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 ± 0.2 vs. 1.11 ± 0.2 mmol/l, P < 0.05), higher CETP mass (2.62 ± 0.8 vs. 2.05 ± 0.4 mg/l, P < 0.001), and slightly increased, though not significant, plasma TGs (2.7 ± 1.05 vs. 2.47 ± 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P < 0.001, A10-A80 P < 0.001). CETP mass and activity were strongly correlated (r = 0.854, P < 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P < 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P = 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism.

CONCLUSIONS—In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy.

Abbreviations: A10, atorvastatin 10 mg • A80, atorvastatin 80 mg • apo, apolipoprotein • CAD, coronary artery disease • CE, cholesteryl ester • CETP, CE transfer protein • CHD, coronary heart disease • FFA, free fatty acid • LpA-I, lipoprotein A-I • SREBP-1, sterol regulatory element binding protein-1 • TC, total cholesterol • TG, triglyceride

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