Metformin, but not rosiglitazone, attenuates the increasing plasma levels of a new cardiovascular marker, fibulin-1, in patients with type 2 diabetes Running title: Metformin attenuates fibulin-1 levels

Objective The extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes and circulates in increased concentrations in diabetes. Metformin is an anti-diabetic drug with beneficial CVD effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. Research Design and Methods After a four-week run-in period, 371 eligible patients with type 2 diabetes were randomized to treatment groups in a factorial design including insulin alone (control), +metformin, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. Results Plasma fibulin-1 increased in all groups throughout the two-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed, when the mean change in plasma fibulin-1 was compared between metformin and not-metformin treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA1c levels to comparable levels and in combination even further. Conclusions Metformin attenuate the increase in plasma fibulin-1 concentrations in type 2 diabetes, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy which can be influenced by metformin. Page 2 of 21 Diabetes Care