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J Am Coll Cardiol. 2005 Jun 21;45(12):1925-31.

Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study.

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IKFE-Institute for Clinical Research and Development, Parcusstrasse 8, D-55116 Mainz, Germany.



This study was performed to assess whether the anti-inflammatory and antiatherogenic effects of pioglitazone suggested by animal experiments are reproducible in man and independent from improvements in metabolic control.


Type 2 diabetes is associated with increased cardiovascular risk.


A total of 192 patients were enrolled into a six-month, prospective, open-label, controlled clinical study. They were randomized to receive either pioglitazone (45 mg) or glimepiride (1 to 6 mg, with the intent to optimize therapy). Biochemical and clinical markers to assess therapeutic effects included HbA1c, fasting glucose, insulin, adiponectin, lipids, high-sensitivity C-reactive protein (hsCRP), intracellular adhesion molecule, vascular cell adhesion molecule, vascular endothelial growth factor, fibrinogen, von Willebrand factor, matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, soluble CD40 ligand, and carotid intima-media thickness (IMT).


The study was completed by 173 patients (66 female, 107 male; age [+/- SD]: 63 +/- 8 years; disease duration: 7.2 +/- 7.2 years; HbA1c: 7.5 +/- 0.9%; pioglitazone arm: 89 patients). A comparable reduction in HbA1c was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for glucose (p < 0.001 vs. glimepiride group at end point), insulin (p < 0.001), low-density lipoprotein/high-density lipoprotein ratio (p < 0.001), hsCRP (p < 0.05), MMP-9 (p < 0.05), MCP-1 (p < 0.05), and carotid IMT (p < 0.001), and an increase was seen in high-density lipoprotein (p < 0.001) and adiponectin (p < 0.001). Spearman ranks analysis revealed only one correlation between the reduction in cardiovascular risk parameters and the improvement in the metabolic parameters (MMP-9 and fasting blood glucose, p < 0.05)


This prospective study gives evidence of an anti-inflammatory and antiatherogenic effect of pioglitazone versus glimepiride. This effect is independent from blood glucose control and may be attributed to peroxisome proliferator-activated receptor gamma activation.

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