PIOSTAT - PIOSTAT
The goal of the trial was to evaluate pioglitazone, simvastatin, and the combination among nondiabetic patients with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels.
Patients Enrolled: 125
Mean Follow Up: 12 weeks
Mean Patient Age: Mean age 59 years
Increased CV risk, defined as prior MI, angiographic evidence of CVD, unstable angina, atherosclerotic vascular lesions, or electrocardiographic evidence of ischemia, stroke, transient ischemic attack, or peripheral arterial disease and/or hypertension; and activated inflammation, defined as a CRP level >1 mg/L and <10 mg/L
Known or newly detected diabetes mellitus or chronic inflammatory diseases; statin therapy within the last 4 weeks; significant hepatic or renal disease; or congestive heart failure (New York Heart Association functional class I-IV)
Change in hs-CRP from baseline to 12-week follow-up
Patients were randomized in a double-blind manner to 12 weeks of treatment with simvastatin plus placebo (40 mg; n = 43), pioglitazone plus placebo (45 mg; n = 39), or simvastatin plus pioglitazone combination (n = 43). Hs-CRP was measured at baseline and 12-week follow-up.
At baseline, mean hs-CRP was 3.64 mg/L in the pioglitazone group, 3.26 mg/L in the simvastatin group, and 3.49 mg/L in the combination group. Metabolic syndrome (MetS) was present in 53% of patients.
Hs-CRP at 12 weeks was reduced from baseline in all three treatment groups, but to a greater degree with the combination therapy group (from 3.49 mg/L to 2.06 mg/L, p < 0.001) than the pioglitazone and simvastatin monotherapy groups (3.64 mg/L to 2.48 mg/L and 3.26 mg/L to 2.81 mg/L). Results were consistent for the subgroup of patients with MetS at baseline.
Matrix metalloproteinase-9 was reduced from baseline to 12 weeks in the pioglitazone group (from 375.2 to 297.5 ng/ml) and the combination group (from 385.8 to 307.4 ng/ml), but increased in the simvastatin group (from 383.0 to 477.5 ng/ml; all p < 0.05). There was no change in low-density lipoprotein (LDL) cholesterol from baseline to 12 weeks in the pioglitazone group (from 3.50 to 3.56 mmol/L), but LDL was significantly reduced from baseline in the simvastatin group (from 3.60 to 2.32 mmol/L) and the combination group (from 3.68 to 2.40 mmol/L). Glucose was reduced from baseline in the pioglitazone group (from 5.63 to 5.23 mmol/L) and did not significantly change in the simvastatin group (from 5.60 to 5.56 mmol/L) or the combination group (5.70 to 5.50 mmol/L).
Peripheral edema occurred in 11.4% of the pioglitazone group, 22.2% of the combination group, and 7.0% of the simvastatin group. Both pioglitazone and combination therapy were associated with increases in body weight at 12 weeks.
Among nondiabetic patients with CVD and elevated hs-CRP, treatment with the combination of pioglitazone and simvastatin was associated with a greater reduction in hs-CRP at 12 weeks compared with monotherapy.
Pioglitazone, a thiazolidinedione, is an agonist of the peroxisome proliferator-activated receptor (PPAR gamma), which improves insulin sensitivity. Pioglitazone was shown to reduce the composite of death, myocardial infarction (MI), or stroke by 3 years in the PROactive trial in type 2 diabetics, but as with the present study, was associated with an excess of edema. A small, 50-patient study of nondiabetic patients undergoing coronary stent implantation demonstrated a reduction in neointima formation associated with pioglitazone. Data from the present study extend observations of pioglitazone in nondiabetic patients to show a reduction in inflammatory parameters.
Hanefeld M, Marx N, Pfutzner A, et al. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol 2007;49:290-7.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Vascular Medicine, Hypertension
Keywords: Ischemic Attack, Transient, Follow-Up Studies, Diabetes Mellitus, Type 2, Peripheral Arterial Disease, Edema, Insulin Resistance, Glucose, Matrix Metalloproteinase 9, Thiazolidinediones, Hypertension, Neointima, Inflammation, Stroke, Myocardial Infarction, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Peroxisome Proliferator-Activated Receptors, Stents, Metabolic Syndrome X, Lipoproteins, LDL, C-Reactive Protein, PPAR gamma, Hypoglycemic Agents
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