Intense Cholesterol Lowering Therapy with a HMG-CoA Reductase Inhibitor does not Improve Nitric Oxide Dependent Endothelial Function in Type-2-Diabetes

Abstract

Disturbances in nitric oxide (NO) metabolism resulting in endothelial dysfunction play a central role in the pathogenesis of atherosclerosis in hypercholesterolemia and in individuals with type 2 diabetes. It is unclear whether lipid lowering therapy with HMG-CoA-reductase inhibitors might improve endothelial function in subjects with type 2 diabetes as it is demonstrated in non-diabetic subjects with hypercholesterolemia. We examined the influence of 0.2 mg and 0.8 mg cerivastatin on endothelial function in a multicenter, randomised, double-blind, and three-arm placebo-controlled clinical trial. Endothelial function was assessed by nitric oxide-dependent flow mediated vasodilatation (FMD) of the brachial artery. A total of 103 patients with type 2 diabetes were enrolled in the study. Bayer Company undertook a voluntary action to withdraw cerivastatin from market, therefore the study was terminated earlier. At this point 77 patients were randomised, of which 58 completed the study (mean age 60 ± 8 years, HbA1c 7.4 ± 0.9 %). At baseline mean FMD was disturbed in all three therapy arms (5.18 ± 2.31 % in the placebo group, 3.88 ± 1.68 in the 0.2-mg cerivastation group, and 4.86 ± 2.25 in the 0.8-mg cerivastatin group). Despite a significant reduction in cholesterol and LDL-cholesterol-levels after 12 weeks of treatment (decrease in LDL-cholesterol - 26.8 ± 13.9 % in the 0.2-mg group and - 40.3 ± 16.0 % in the 0.8-mg group, p = 0.0001, ANCOVA) there was no difference in flow mediated vasodilatation (p = 0.52 and p = 0.56 vs. placebo, respectively, ANCOVA). HbA1c, CRP, and HDL-cholesterol did not change during the study. Furthermore no difference in safety profile between cerivastatin and placebo was found. Despite a significant improvement in lipid profile under statin therapy, no improvement of endothelial dysfunction in terms of nitric oxide bioavailability could be detected.

Endothelium - nitric oxide - brachial artery - atherosclerosis - diabetes - endothelial dysfunction - flow-mediated vasodilation - statin - ultrasound - vascular - vasodilation - placebo controlled - randomized clinical study - double-blind

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