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BACKGROUND: Statin treatment has been reported to improve survival in patients with atherosclerosis, partly by improving vascular endothelial function. Elevation of blood glucose concentrations impairs endothelial function and promotes atherogenesis, but the effect of statins on glucose-induced endothelial dysfunction is unknown. Endothelium-dependent dilation (EDD) measured by gauge-strain plethysmography in the forearm is considered to be a reliable marker of endothelial function in forearm resistance vessels. OBJECTIVE: This study examined the combined effects of metformin and atorvastatin treatment on glucose-induced endothelial dysfunction (as EDD) in patients with newly diagnosed type 2 diabetes mellitus (DM). METHODS: Patients with newly diagnosed DM were recruited and were randomly assigned to receive metformin 850 mg/d or metformin 850 mg/d + atorvastatin 10 mg/d for 6 weeks in a single-blind study. All patients underwent glucose loading (75 g oral glucose after 12 hours of fasting) at baseline and at the end of the treatment period. Blood samples were obtained at baseline before glucose loading and 3 hours after loading to determine serum concentrations of cholesterol, lipoproteins, triglycerides, glucose, and glycosylated hemoglobin. EDD was evaluated at baseline and at 1, 2, and 3 hours after loading. The investigators were blinded to the treatment group assignments, and all analyses were performed in a blinded manner. Adverse events (eg, gastrointestinal disorders, myopathy, liver disorders) were monitored based on reported symptoms or signs (eg, myalgias, muscle cramps), clinical examination, and laboratory parameters (eg, increased liver and muscle enzymes). RESULTS: Thirty-two white patients with newly diagnosed type 2 DM were randomly assigned to receive metformin 850 mg/d (n = 17 [12 men]; mean [SD] age, 53.88 [45] years; body mass index [BMI], 28.7 [4.5] kg/m²) or metformin 850 mg/d + atorvastatin 10 mg/d (n = 15 [6 men]; mean age, 52.53 [37] years; BMI, 28.5 [2.1] kg/m²). At baseline, EDD was reduced 1 and 2 hours after glucose loading in both study groups (P < 0.01). Glucose loading was associated with an elevation of blood glucose concentrations at 1 and 2 hours (P < 0.01 vs resting levels before loading), and concentrations returned to resting levels at 3 hours, in both groups at baseline and after treatment. Metformin alone or in combination with atorvastatin was associated with a significant reduction in resting glucose concentrations after 6 weeks (both, P < 0.05 vs baseline), but only the combination of metformin + atorvastatin partly prevented the glucose-induced elevation of serum glucose at 1 hour after loading and the glucose-induced decrease in EDD (both, P < 0.01 vs baseline). CONCLUSIONS: Glucose loading blunted endothelial function, with a deterioration in EDD, in these patients with newly diagnosed type 2 DM. However, combined treatment with metformin and atorvastatin for 6 weeks partly prevented the glucose-induced impairment of EDD in these patients, with a significant difference compared with monotherapy with metformin.

Original publication

DOI

10.1016/j.clinthera.2010.09.007

Type

Journal article

Journal

Clin Ther

Publication Date

09/2010

Volume

32

Pages

1720 - 1728

Keywords

Atherosclerosis, Atorvastatin Calcium, Blood Flow Velocity, Blood Glucose, Body Mass Index, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Drug Therapy, Combination, Endothelium, Vascular, Female, Glucose, Heptanoic Acids, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypoglycemic Agents, Lipids, Male, Metformin, Middle Aged, Plethysmography, Pyrroles, Single-Blind Method, Treatment Outcome, Vasodilation