Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study

• Published in: PloS one 2014-04, Vol.9 (4), p.e96062
• Main Authors: El Messaoudi, Saloua, Schreuder, Tim H, Kengen, Roel D, Rongen, Gerard A, van den Broek, Petra H, Thijssen, Dick H J, Riksen, Niels P
• Format: Article
• Language: English
• Subjects: Adenosine; Adult; Animal models; Antidiabetics; Atherosclerosis; Biology and Life Sciences; Brachial Artery - drug effects; Brachial Artery - physiopathology; Caffeine; Cardiovascular disease; Cardiovascular diseases; Coronary vessels; Diabetes; Diabetes mellitus; Drug therapy; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Female; Forearm; Forearm - blood supply; Health aspects; Heart attacks; Humans; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; In vivo methods and tests; Injury prevention; Internal medicine; Ischemia; Kinases; Male; Medical research; Medicine and Health Sciences; Metformin; Metformin - pharmacokinetics; Metformin - pharmacology; Metformin - therapeutic use; Middle Aged; Mortality; Myocardial infarction; Patients; Perfusion (Physiology); Pharmacology; Physiology; Prospective Studies; Randomization; Regional Blood Flow; Reperfusion; Reperfusion Injury - prevention & control; Research and Analysis Methods; Risk factors; Rodents; Short term; Single-Blind Method; Studies; Toxicology; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096062

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. 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. 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