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CLINICAL RESEARCH: CLINICAL TRIAL

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^_* and Thomas Forst, MD

^_* GWT, Center for Clinical Studies, Dresden, Germany
University Ulm, Medical Department II, Ulm, Germany
Institute for Clinical Research and Development, Mainz, Germany
Acromion, Frechen, Germany
^|| Takeda Pharma, Aachen, Germany.

Manuscript received April 11, 2006; revised manuscript received August 24, 2006, accepted August 28, 2006.

^_* Reprint requests and correspondence: Dr. Markolf Hanefeld, Forschungshereich Endokrinologie and Stoffwechsel, Zentrum für Klinische Studien, GWT-TUD mbH, Fiedlerstrasse 34, 01307 Dresden, Germany. (Email: hanefeld{at}gwtonline-zks.de).

OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels.

BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)- agonists lower inflammatory markers and reduce CVD in type 2 diabetes.

METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman’s rank test.

RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 ± 2.42 mg/l to 2.48 ± 1.77 mg/l and 3.26 ± 2.02 mg/l to 2.81 ± 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 ± 1.97 mg/l to 2.06 ± 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group.

CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.

Abbreviations and Acronyms   CVD = cardiovascular disease   HOMA = homeostasis model assessment   hs-CRP = high-sensitivity C-reactive protein   MCP = macrophage chemoattractant protein   MetS = metabolic syndrome   MMPs = matrix metalloproteinases   PAI = plasminogen activator inhibitor   PPAR = peroxisome proliferator-activated receptor   TZD = thiazolidinediones

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