This study will investigate whether etanercept will result in improved inflammatory indices, glucose tolerance and endothelial function in patients with the metabolic syndrome.
Metabolic syndrome is an increasingly prevalent disorder associated with elevated risks of type II DM (diabetes mellitus) and cardiovascular morbidity and mortality. A subclinical inflammatory state is thought to contribute to the pathophysiology of metabolic syndrome, insulin resistance, and coronary artery disease (CAD). Tumor Necrosis Factor (TNF) -alpha is an inflammatory cytokine that is increased in a spectrum of inflammatory diseases as well as in insulin resistance. TNF-alpha antagonists are clinically effective in the inflammation of arthritides, and have recently been shown by our group to decrease inflammatory cardiovascular risk markers in metabolic syndrome. Data suggests that adiponectin, a recently discovered adipocytokine that may protect against the development of insulin resistance and atherosclerosis, may be downregulated by TNF-alpha. In addition, population based studies have shown that those with the highest levels of TNF-alpha have an increased relative risk of cardiovascular morbidity while rheumatoid arthritis patients treated with TNF-alpha blockade appear protected from cardiovascular disease. We will perform a 6-month study in which we will administer etanercept, a TNF-alpha receptor fusion protein, to subjects with metabolic syndrome to investigate its effect on surrogate markers of cardiovascular disease, including inflammatory markers, adiponectin and glucose tolerance and endothelial function. The results of the proposed study will have broad implications regarding the physiological role of TNF-alpha on the inflammatory cascade, cardiovascular indices and endothelial function.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
40
50 mg one syringe sc 2X per week for three months followed by 50 mg one syringe sc 1X per week for three months
50 mg one syringe sc 2x per week for three months followed by 50 mg one syringe sc 1X per week for three months
MGH
Boston, Massachusetts, United States
C-reactive Protein (CRP)
As a measure of C-reactive protein (CRP), which is an inflammatory marker, Log10 of the CRP at 6 months is reported
Time frame: 6 months
Interleukin-6 (IL-6)
6 month value of IL-6 (pg/mL)
Time frame: 6 months
Adiponectin
The ratio of circulating high molecular weight (HMW) adiponectin to total adiponectin ratio (HMW:total Adiponectin) at 6 months is reported.
Time frame: 6 months
Glucose Tolerance
Fasting glucose (mg/dL) at 6mo
Time frame: 6 months
Endothelial Function
Reactive Hyperemia Index (RHI) using peripheral artery tonometry (using Endo-PAT 2000). Peripheral artery tonometry measures blood flow in the tip of the index finger at baseline and in response to vaso-occlusion (inflated blood pressure cuff). The reactive hyperemia index is an index of vasodilation after occlusion compared to baseline. A higher value indicates better vasoreactivity. As this is a relatively new test, there are no thoroughly validated clinically utilized norms.
Time frame: 6 months
White Blood Cell (WBC) Count
Change in WBC during study (WBC at six months minus WBC at baseline)
Time frame: Baseline to 6 months
Cardiac Echo Ejection Fraction (EF)
change in EF (6mo - baseline). Please note that the value given is the absolute change in EF (which has units of percent), not the percent change in the variable.
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Time frame: Baseline to 6 months
Body Composition
6 month visceral adipose tissue (cm\^2) - cross-sectional area of the visceral adipose tissue at the level of the 4th lumbar vertebrae was measured using single-slice abdominal computed tomography (CT) scan
Time frame: 6 months
Tumor Necrosis Factor (TNF) Receptor
Circulating concentrations of Tumor necrosis factor receptor 2 (TNFR2) at 6 months
Time frame: 6 months
Other Adipocytokines
circulating resistin at 6 months
Time frame: 6 months
Lipid Levels
total cholesterol (mg/dL) at 6 months
Time frame: 6 months
Adipocyte Messenger Ribonucleic Acid (mRNA) Levels of Adipocytokines Including Tumor Necrosis Factor (TNF) -Alpha
fold-change in subcutaneous adipose tissue expression of TNF-alpha (mRNA) after 6 months
Time frame: 6 months