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Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes

¹ Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark² Division of General Internal Medicine, Department of Internal Medicine, University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands³ Department of Clinical Chemistry, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands⁴ Department of Thrombosis Research, Ribe County Hospital, University of Southern Denmark and Department of Clinical Biochemistry, 6700 Esbjerg, Denmark⁵ Department of Clinical Biochemistry, Frederiksberg Hospital, 2000 Frederiksberg, Denmark⁶ Faculty of Health Sciences, University of Aarhus, 8000 Aarhus, Denmark⁷ Department of Medical Endocrinology, University of Copenhagen, Rigshospitalet, 2000 Copenhagen, Denmark⁸ Department of Endocrinology, University of Lund, S-20502 Malmö, Sweden

(Correspondence should be addressed to S S Lund; Email: sqrl{at}steno.dk)

Objective: In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.

Design and methods: Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index27 kg/m²) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.

Results: Levels of tumour necrosis factor-, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.

Conclusions: In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.