title: Impact of 6 weeks of treatment with low-dose metformin and atorvastatin on glucose-induced changes of endothelial function in adults with newly diagnosed type 2 diabetes mellitus: A single-blind study.
abstract: 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.
authors.affiliation: 1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece. drtousoulis@hotmail.com
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Katerina
authors.initials: K
authors.lastname: Koniari
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Antigoni
authors.initials: A
authors.lastname: Miliou
authors.forename: Marina
authors.initials: M
authors.lastname: Noutsou
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papageorgiou
authors.forename: Kyriakoula
authors.initials: K
authors.lastname: Marinou
authors.forename: Elli
authors.initials: E
authors.lastname: Stefanadi
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
mesh_terms: D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control; D000069059:Atorvastatin; D001783:Blood Flow Velocity / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D010991:Plethysmography; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D016037:Single-Blind Method; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008055:Lipids; D011758:Pyrroles; D008687:Metformin; D000069059:Atorvastatin; D005947:Glucose