Effects of Etanercept in Patients With the Metabolic Syndrome

Program in Nutritional Metabolism and the Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston.

Correspondence: Steven K. Grinspoon, MD, MGH Program in Nutritional Metabolism, 55 Fruit St, LON 207, Boston, MA 02114 (gro.srentrap@noopsnirgs)

Abstract

Background

Adipose-derived cytokines, including tumor necrosis factor α, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor α with etanercept in patients with the metabolic syndrome.

Methods

Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined.

Results

Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (−2.4 ± 0.4 vs 0.5 ± 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 ± 0.4 vs −0.3 ± 0.3 µg/mL; P=.03). Fibrinogen levels decreased (−68 ± 16 vs −2 ± 31 mg/dL [−2.0 ± 0.47 vs −0.06 ± 0.91 µmol/L]; P=.04) and interleukin 6 levels tended to decrease (−1.2 ± 0.8 vs 0.5 ± 0.5 ng/L; P=.07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (−1 ± 1 vs 2 ± 1 mg/dL [−0.03 ± 0.03 vs 0.05 ± 0.03 mmol/L]; P=.06) compared with the placebo group.

Conclusions

Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor α inhibition on cardiovascular disease in patients with the metabolic syndrome.

Abstract

The prevalence of the metabolic syndrome ranges from 20% to 34% in 40- to 59-year-old men and women in the United States, and this rate is increasing.¹ Evidence suggests a link among obesity, the metabolic syndrome, and coronary heart disease.²–4 The metabolic syndrome is thought to be a state of chronic inflammation, characterized by elevated levels of inflammatory cytokines, including tumor necrosis factor α (TNF-α).⁵ These cytokines are secreted by adipocytes⁶,7 and trigger an inflammatory cascade, resulting in increased C-reactive protein (CRP)⁸ level and a reduced adiponectin level.⁹ Inflammation may contribute to increased coronary artery disease risk in patients with the metabolic syndrome.⁵,10

Secretion of TNF-α by omental adipocytes is one potential mechanism that links excess fat and cardiovascular disease. Prior studies¹¹ have demonstrated a significant relationship between TNF-α and recurrent myocardial infarction rates. Studies¹² have shown that TNF-α can induce secretion of interleukin 6 (IL-6), which then acts as a potent stimulant of hepatic production of CRP. Recent in vitro data have suggested that TNF-α may decrease adiponectin secretion.¹³ A treatment strategy to inhibit the activity of TNF-α may improve inflammatory risk indexes in patients with abdominal obesity and the metabolic syndrome.

Etanercept is a dimeric recombinant form of the extracellular domain of the human p75 TNF-α receptor 2 fused to the Fc fragment of human immunoglobulin G1 (IgG1) used to treat inflammatory arthritis. Etanercept acts as a TNF-α antagonist by interfering in the binding of TNF-α to its cellular receptors and thus blocks the inflammatory response. We conducted a randomized, placebo-controlled study to assess the effects of etanercept administration on CRP as a primary end point in patients with the metabolic syndrome.

Footnotes

Author Contributions: Dr Grinspoon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

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