Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial.
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.
Balletshofer
B M
BM
Department of Endocrinology and Vascular Medicine, University of Tübingen, Germany. Bernd.Balletshofer@med.uni-tuebingen.de
Goebbel
S
S
Rittig
K
K
Enderle
M
M
Schmölzer
I
I
Wascher
T C
TC
Ferenc Pap
A
A
Westermeier
T
T
Petzinna
D
D
Matthaei
S
S
Häring
H U
HU
D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D011725:Pyridines / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects
D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D014280:Triglycerides; D009569:Nitric Oxide; D005340:Fibrinogen; D002097:C-Reactive Protein; D002784:Cholesterol; C086276:cerivastatin