title: Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study.
abstract: BACKGROUND
  Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury.
  
  
  METHODS
  Twenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm.
  
  
  RESULTS
  Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR.
  
  
  CONCLUSIONS
  A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01610401.
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Saloua
authors.initials: S
authors.lastname: El Messaoudi
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Schreuder
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Roel D
authors.initials: RD
authors.lastname: Kengen
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Petra H
authors.initials: PH
authors.lastname: van den Broek
authors.affiliation: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands; Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.
authors.forename: Dick H J
authors.initials: DH
authors.lastname: Thijssen
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
mesh_terms: D000328:Adult; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D011446:Prospective Studies; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000517:prevention & control*; D016037:Single-Blind Method
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
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