PIOSTAT - PIOSTAT

Description:

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.

Study Design

Study Design:

Patients Enrolled: 125
Mean Follow Up: 12 weeks
Mean Patient Age: Mean age 59 years
Female: 62

Patient Populations:

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

Exclusions:

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)

Primary Endpoints:

Change in hs-CRP from baseline to 12-week follow-up

Drug/Procedures Used:

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.

Principal Findings:

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.

Interpretation:

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.

References:

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, Atherosclerotic Disease (CAD/PAD), 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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