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


BACKGROUND
Type 2 diabetes is associated with increased cardiovascular risk.


METHODS
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).


RESULTS
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)


CONCLUSIONS
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.
Pfützner
Andreas
A
IKFE-Institute for Clinical Research and Development, Parcusstrasse 8, D-55116 Mainz, Germany. AndreasP@ikfe.de
Marx
Nikolaus
N
Lübben
Georg
G
Langenfeld
Matthias
M
Walcher
Daniel
D
Konrad
Thomas
T
Forst
Thomas
T
D000209:Acute-Phase Proteins / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D001161:Arteriosclerosis / Q000209:etiology*; D015415:Biomarkers / Q000097:blood; D001779:Blood Coagulation Factors / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000000981:diagnostic imaging* / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D011446:Prospective Studies; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D017539:Tunica Intima / Q000000981:diagnostic imaging / Q000187:drug effects; D017540:Tunica Media / Q000000981:diagnostic imaging / Q000187:drug effects; D014463:Ultrasonography
D000209:Acute-Phase Proteins; D015415:Biomarkers; D001779:Blood Coagulation Factors; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C057619:glimepiride; D000077205:Pioglitazone