PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events - PIONEER
The goal of the trial was to evaluate the effect on inflammatory biomarkers of arteriosclerosis of treatment with pioglitazone compared with glimepiride among patients with type II diabetes.
Patients Enrolled: 192
Mean Follow Up: 6 months
Mean Patient Age: Mean age 63 years
AGe 40-75 years, HbA1c 6.6% to 9.9%, absence of significant hepatic or renal disease, absence of congestive heart failure, no cigarette smoking, and no known carotid artery disease.
Patients at a single center were randomized to pioglitazone (45 mg; n=89) or glimepiride (1 to 6 mg; n=84). At baseline and 26 week follow-up, patients were evaluated for HgA1c, insulin, lipids, C-reactive protein, and other parameters. Patients also underwent ultrasound to assess carotid intima-media thickness.
Baseline HbA1c was 7.5%, and mean body mass index was 32 kg/m2. Intima-media thickness at baseline was 0.95 mm in the pioglitazone group and 0.92 in the glimepiride group. Baseline characteristics were well matched between groups.
HbA1c was reduced by 6 months in both treatment arms from baseline (0.8% for pioglitazone and 0.6% for glimepiride, p<0.001 each; p=NS for between group comparison). However, the reduction in other parameters was greater in the pioglitazone group compared with glimepiride, including glucose (17.8 mg/dl for pioglitazone vs 4.8 mg/dl for glimepiride, p<0.001), insulin (4.7 uU/ml vs 0.4 uU/ml, p<0.001), LDL/HDL ratio (p<0.05). The HDL increase from baseline was larger in the pioglitazone group (8 mg/dl vs 1 mg/dl, p<0.001). Inflammatory markers were also reduced to a greater extent in the pioglitazone group compared with glimepiride, including CRP (-0.10 mg/dl for pioglitazone vs +0.24 mg/dl for glimepiride, p<0.05), MMP-9 (p<0.01), and MCP-1 (p<0.05). The carotid IMT reduction was greater with pioglitazone (-54 µm vs -11 µm, p<0.001). Results were similar in patients who had reductions in HbA1c and those who did not have reductions in HbA1c (i.e., responders and non-responders).
Among patients with type II diabetes, treatment with pioglitazone was associated with greater reductions in inflammatory biomarkers of arteriosclerosis and carotid IMT at 6 months compared with glimepiride despite similar changes in HbA1c. Whether these changes translate into clinical outcomes remains to be determined. However, as the authors note, carotid IMT has been shown to be a strong correlate of cardiovascular risk and stroke. Given the findings of the present study, a larger, 5,000 patient trial to evaluate clinical outcomes among type 2 diabetic patients is underway, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial.
Pfützner A, et al. Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control: Results From the Pioneer Study. J Am Coll Cardiol 2005;45:1925–31.
Keywords: Stroke, Insulin, Follow-Up Studies, Immunosuppressive Agents, Diabetes Mellitus, Type 2, Carotid Artery Diseases, Risk Factors, Smoking, Glucose, Sulfonylurea Compounds, C-Reactive Protein, Body Mass Index, Biological Markers, Heart Failure, Thiazolidinediones
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