Background: Matrix metalloproteinases (MMPs) are critically involved in the development of unstable plaques. Although arteriosclerotic lesions in patients with diabetes mellitus are more unstable than those of nondiabetic subjects, nothing is known about serum levels of MMPs in these patients or about mechanisms to modulate MMP levels. We investigated MMP levels in diabetic and nondiabetic coronary artery disease (CAD) patients and performed a clinical trial to assess the effect of the PPARgamma-activating, antidiabetic thiazolidinedione rosiglitazone on MMP levels in diabetic CAD patients.
Methods and results: In CAD patients, MMP-2, -8, and -9 serum levels were significantly higher in type 2 diabetic subjects compared with age-, sex-, and body mass index-matched nondiabetics. Thirty-nine diabetic patients with CAD were randomized to receive rosiglitazone 4 mg (twice daily) or placebo for 12 weeks. Rosiglitazone treatment, but not placebo, significantly reduced MMP-9 levels already after 2 weeks by -19.6% (-38.3% to 8.6%, P<0.05), and levels remained suppressed until the end of the study. In addition, rosiglitazone significantly decreased serum amyloid A (SAA) and tumor necrosis factor-alpha levels.
Conclusion: MMP-9 levels are increased in type 2 diabetic patients with CAD, and treatment of these patients with the antidiabetic PPARgamma-activator rosiglitazone significantly reduces MMP-9, tumor necrosis factor-alpha, and SAA serum levels. These data support anti-inflammatory and potential antiatherogenic effects of thiazolidinediones.