Patients with diabetes continue to die of coronary artery disease (CAD) at rates 2 to 4 times higher than patients without diabetes, despite advances in treatment of cardiovascular disease. The role of glycemic control therapies, independent of their glucose-lowering effects, on cardiovascular disease is a recurring question. We examined the association of glycemic control therapies with extent of CAD as measured by coronary angiogram obtained at baseline in 1,803 subjects in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial who had type 2 diabetes mellitus, documented moderate to severe CAD, and no previous cardiac revascularization procedures. The association between glycemic control therapy use recorded at baseline and percent coronary artery stenosis and myocardial jeopardy index was analyzed by multiple regression models. Insulin use at study entry was associated with 23% fewer highly stenotic lesions (> or =70%) (p <0.001) and a significantly lower myocardial jeopardy index compared with subjects not on insulin, despite a worse cardiac risk factor profile, more unstable angina, and increased inflammatory markers in insulin users. Subjects taking thiazolidinediones (TZDs) for > or =6 months had 17% fewer highly stenotic lesions (p = 0.02) and significantly lower C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1 levels compared with those not taking TZDs. In conclusion, this cross-sectional study of patients with type 2 diabetes mellitus and CAD showed that treatment with insulin or TZDs was associated with fewer highly stenotic lesions, independent of disease duration, glycemic control, and other risk factors.