Study of TNF-Antagonism in 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). 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, but have not been examined in the metabolic syndrome population. Moreover, 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. We propose a study in which we administer etanercept, a TNF-alpha receptor fusion protein, to subjects with metabolic syndrome to examine its effect on inflammatory markers,CRP, adiponectin and insulin resistance. This would be the first study to investigate the anti-inflammatory properties and insulin sensitizing potential of TNF-alpha blockade on the growing population with metabolic syndrome.

Inclusion criteria

Inclusion criteria

based on a modified WHO definition of metabolic syndrome

• Hyperinsulinemia in the upper quartile of the non-diabetic population defined as >= 10 mU/mL (Framingham Data, oral communication,James Meigs, MD) or fasting glucose 110-126 mg/dL

Plus two of the following:

• Abdominal obesity defined by waist hip ratio > 0.90 for men and > 0.85 for women or BMI > 30 kg/m2
• Dyslipidemia including serum triglycerides ³ 150 mg/dl or serum HDL < 0.9 mmol/L for men (35 mg/dL) and < 1.0 mmol/L (39mg/dL) for women
• Hypertension defined as blood pressure >= 140/90 or on medication

Exclusion criteria

• Positive PPD (³ 5mm induration) on screening
• Current Infection
• Therapy with glucocorticoid or immunosuppressant at time of recruitment or within past 3 months
• Reception of live vaccine within 1 week of recruitment
• History of blood dyscrasia including any kind of anemia, thrombocytopenia, pancytopenia. Women with a reversible cause of anemia that has resolved will be eligible.
• History of malignancy (except patients with surgically cured basal cell or squamous cell skin cancers who will be eligible)
• History of organ transplantation
• History of CNS demyelinating disorder or any first degree relative with multiple sclerosis
• History of CHF classes I-IV
• Current use of insulin, any oral anti-hyperglycemic agents, pentoxyfylline, beta-agonists
• Current use of fibrate or niacin
• Initiation of statin therapy within prior 6 weeks or expecting a change in statin dose over the upcoming 3 months
• Hemoglobin < 11 g/dl
• Positive pregnancy test
• Women of child-bearing potential not currently using non-hormonal birth control methods including barrier methods (IUD, condoms, diaphragms) or abstinence
• Patients with known autoimmune or inflammatory conditions (excluding patients with stable, treated hypothyroidism)