Clinical Trial Results. org Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity.

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Clinical Trial Results. org Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity C-Reactive Protein The PIOSTAT Study Markolf Hanefeld, MD, PhD; Nikolaus Marx, MD; Andreas Pfützner, MD, PhD; Werner Baurecht, MSc; Georg Lübben, MD; Efstrathios Karagiannis, MD; Ulf Stier, MD; Thomas Forst, MD Published in JACC January 23, 2007

Clinical Trial Results. org The PIOSTAT Study: Background Markers of inflammation include high sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1. Markers of inflammation include high sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1. Elevations of these markers have been associated with higher rates of future CV events. Elevations of these markers have been associated with higher rates of future CV events. Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Background (cont.) Statins are associated with a reduction in these inflammatory markers. Statins are associated with a reduction in these inflammatory markers. A new class of drugs, the thiazolidinediones (TZDs) (PPAR-γ agonists), have also been shown to have anti-inflammatory properties, reducing CRP, MMP-9, (MCP)-1, and soluble CD40L. A new class of drugs, the thiazolidinediones (TZDs) (PPAR-γ agonists), have also been shown to have anti-inflammatory properties, reducing CRP, MMP-9, (MCP)-1, and soluble CD40L. The TZD Pioglitazone has recently been associated with a reduction in cardiovascular endpoints in patients with type 2 diabetes mellitus. The TZD Pioglitazone has recently been associated with a reduction in cardiovascular endpoints in patients with type 2 diabetes mellitus. Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Background (cont.) However, there is only scarce information on the benefits of treatment with TZDs, alone or in combination with statins, in patients with CVD and increased hs-CRP levels. However, there is only scarce information on the benefits of treatment with TZDs, alone or in combination with statins, in patients with CVD and increased hs-CRP levels. This study aimed to investigate the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non- diabetic subjects with CVD and elevated hs-CRP levels. This study aimed to investigate the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non- diabetic subjects with CVD and elevated hs-CRP levels. Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Study Design 125 patients, ages years, with CVD and/or HTN and hs-CRP level >1.0mg/l and 1.0mg/l and <10 mg/l prior to randomization Prospective. Double-Blind. Randomized. Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks, significant hepatic or renal disease, or CHF 125 patients, ages years, with CVD and/or HTN and hs-CRP level >1.0mg/l and 1.0mg/l and <10 mg/l prior to randomization Prospective. Double-Blind. Randomized. Exclusion Criteria: Diabetes mellitus or chronic inflammatory diseases, statin therapy within 4 weeks, significant hepatic or renal disease, or CHF R PioglitazoneMonotherapy 30 mg n=39 SimvastatinMonotherapy 20 mg n=43 Simvastatin Plus Pioglitazone 30 mg + 20 mg n=43 45 mg 40 mg mg after 2 wks 6 week follow-up  Primary Endpoint: Changes in hs-CRP  Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides, glucose, HbA 1c, Homeostasis Model Assessment (HOMA), Weight, BMI  Primary Endpoint: Changes in hs-CRP  Secondary Endpoint: MMP-9, MCP-1, PAI-1, cholesterol, triglycerides, glucose, HbA 1c, Homeostasis Model Assessment (HOMA), Weight, BMI after 2 wks Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Baseline Characteristics Characteristic Pioglitazone (n=39) Simvastatin(n=43) Pioglitazone + Simvastatin (n=43) Age (yrs), mean  SD 59.5± ± ±8.6 BMI (kg/m 2 ) mean  SD 30.8± ± ±4.1 Men/Women, n 13/2616/2718/25 CVD, n (%) 38 (97.4) 41 (95.3) 43 (100.0) Hypertension, n (%) 36 (92.3) 39 (90.7) RAS inhibition therapy, n (%) 23 (59.0) 21 (48.8) 27 (62.8) Antithrombotic therapy, n (%) 6 (15.4) 10 (23.3) 8 (18.6) Calcium channel blockers, n (%) 7 (17.9) 10 (23.3) 7 (16.3) Metabolic Syndrome, n (%) 19 (48.7) 24 (55.8) 23 (53.5) Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Primary Endpoint There were no significant differences in the baseline levels of hs-CRP between the three groups.There were no significant differences in the baseline levels of hs-CRP between the three groups. At 12 weeks, pioglitazone and the combination regimen had an additive effect in reducing hs-CRPAt 12 weeks, pioglitazone and the combination regimen had an additive effect in reducing hs-CRP Reduction in hs-CRP Levels at 12 weeks n = 39 p<0.001 Reduction in hs-CRP (mg/l) n = 43 Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Primary Endpoint The combination of pioglitazone plus simvastatin had additive effects on hs-CRP, with a 40% reduction from simvastatin monotherapy (p=0.01).The combination of pioglitazone plus simvastatin had additive effects on hs-CRP, with a 40% reduction from simvastatin monotherapy (p=0.01). A subgroup analysis was performed in patients with and without metabolic syndrome (MetS), and the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without metabolic syndrome.A subgroup analysis was performed in patients with and without metabolic syndrome (MetS), and the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without metabolic syndrome. Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Secondary Endpoint Characteristic Pioglitazone (n=39) Simvastatin(n=43) Pioglitazone + Simvastatin (n=43) MMP-9 (ng/ml) Baseline Baseline 12 weeks 12 weeks ± ± 140.3* ± ± 250.9* ± ± 152.4* MCP-1 (pg/ml) Baseline Baseline 12 weeks 12 weeks ± ± ± ± ± ± PAI-1 (ng/ml) Baseline Baseline 12 weeks 12 weeks 30.5 ± ± 16.9* 35.2 ± ± ± ± 17.4* Total Cholesterol Baseline Baseline 12 weeks 12 weeks 5.60 ± ± ± ± 0.96* 5.67 ± ± 0.95* Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Secondary Endpoint (Cont.) Characteristic Pioglitazone (n=39) Simvastatin(n=43) Pioglitazone + Simvastatin (n=43) LDL-cholesterol (mmol/l) Baseline Baseline 12 weeks 12 weeks 3.50 ± ± ± ± 0.88* 3.68 ± ± 0.91* HDL-cholesterol (mmol/) Baseline Baseline 12 weeks 12 weeks 1.41 ± ± ± ± 0.42* 1.44 ± ± 0.45* Triglycerides (mmol/l) Baseline Baseline 12 weeks 12 weeks 1.50 ± ± ± ± ± ± 0.39* Glucose (mmol/l) Baseline Baseline 12 weeks 12 weeks 5.63 ± ± 0.51* 5.60 ± ± ± ± 0.68 Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Secondary Endpoint (Cont.) Characteristic Pioglitazone (n=39) Simvastatin(n=43) Pioglitazone + Simvastatin (n=43) HbA 1c Baseline Baseline 12 weeks 12 weeks 5.47 ± ± 0.45* 5.43 ± ± ± ± 0.35 HOMA Baseline Baseline 12 weeks 12 weeks 3.27 ± ± 0.97* 3.52 ± ± ± ± 1.15* Body Weight (kg) Baseline Baseline 12 weeks 12 weeks 85.9 ± ± 15.4* 87.4 ± ± ± ± 12.8* BMI Baseline Baseline 12 weeks 12 weeks 30.6 ± ± 5.2* 30.5 ± ± ± ± 4.0* Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Secondary Endpoints (Cont.) Homeostasis Model Assessment (HOMA) decreased in those receiving pioglitazone monotherapy (p=0.003) and pioglitazone plus simvastatin (p<0.001). Homeostasis Model Assessment (HOMA) decreased in those receiving pioglitazone monotherapy (p=0.003) and pioglitazone plus simvastatin (p<0.001). The correlation between changes in HOMA and hs- CRP was significant in the piolgitazone monotherapy group (r=0.43; p=0.006). The correlation between changes in HOMA and hs- CRP was significant in the piolgitazone monotherapy group (r=0.43; p=0.006). The PAI-1 and MMP-9 also significantly decreased in the pioglitazone (monotherapy and combination with simvastatin) groups. The PAI-1 and MMP-9 also significantly decreased in the pioglitazone (monotherapy and combination with simvastatin) groups. Hanefeld et al. JACC Jan 23; 49(3):290-7.

Clinical Trial Results. org The PIOSTAT Study: Summary Pioglitazone and simvastatin exerted anti- inflammatory effects in non-diabetic patients with CVD and elevated hs-CRP. Pioglitazone and simvastatin exerted anti- inflammatory effects in non-diabetic patients with CVD and elevated hs-CRP. Combining the two drugs resulted in an additive effect on low-grade inflammation, without a significant increase in serious adverse events. Combining the two drugs resulted in an additive effect on low-grade inflammation, without a significant increase in serious adverse events. For subgroups, the additive effect was only significant for patients without MetS. For subgroups, the additive effect was only significant for patients without MetS. Hanefeld et al. JACC Jan 23; 49(3):290-7.