Effects of Etanercept in Patients With the Metabolic Syndrome

Abstract

Background: Adipose-derived cytokines, including tumor necrosis factor ␣, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor ␣ 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; PϽ.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 ␣ inhibition on cardiovascular disease in patients with the metabolic syndrome.

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

“…As a reported cause of insulin resistance (42) and diabetes complications (43), several small clinical trials have targeted TNF in diabetes (44)(45)(46)(47). The vast majority of these investigations primarily focused on blood glucose control and insulin sensitivity as clinical end points (44)(45)(46); a few of these trials indirectly assessed vasodilator responses via forearm perfusion (46,47).…”

“…The vast majority of these investigations primarily focused on blood glucose control and insulin sensitivity as clinical end points (44)(45)(46); a few of these trials indirectly assessed vasodilator responses via forearm perfusion (46,47). Although anti-TNF therapy successfully lowers inflammatory markers (e.g., C-reactive protein), it largely fails to improve any other defined clinical end point.…”

Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications

“…However, to date, TNF-a antagonism has not demonstrated any clear benefit in type 2 diabetes in man (83)(84)(85)(86)(87). Careful analysis of these clinical studies suggests that all have serious limitations, as they were underpowered and of short duration (13).…”

Adipose Tissue Inflammation and Insulin Resistance

“…TNF-mRNA expression is increased in the adipose depots and correlates with insulin resistant in obese patients (Maury et al, 2009;Kern et al, 2001). However, the treatment of patients with etanercept (a TNFinhibitor drug), for a four-week period, in order to neutralize the elevated TNF-levels, increased circulating resistin and adiponectin levels, reduced muscle fat content, but did not promote improvements in insulin sensitivity (Lo et al, 2007;Bernstein et al, 2006). TNF-possesses stimulatory effects on lipolysis by promoting a rise in cAMP levels and by stimulating the activity of hormone sensitive lipase along with perilipin downregulation via mitogen-activated protein kinase (MAPK) activation (Souza et al, 2003) .…”