Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes

OBJECTIVE - Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF. RESEARCH DESIGN AND METHODS - We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA_1c >8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose <120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy. RESULTS - After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA_1c. The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6 ± 1 to 4 ± 1 ng/l; P < 0.01). Troglitazone therapy was associated with increases in LDL size (26.21 ± 0.22 to 26.56 ± 0.25 nm; P = 0.04) and HDL cholesterol (33 ± 3 to 36 ± 3 mg/dl; P = 0.05) and decreases in triglycerides (197 ± 19 to 155 ± 23 mg/dl; P = 0.07) and C-reactive protein by 60% (8 ± 3 to 3 ± 1 ng/l, P < 0.01). CONCLUSIONS - For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.