Blocking key protein reduces inflammatory markers in metabolic syndrome

Findings shed light on mechanism of condition associated with heart disease, type 2 diabetes

Researchers from Massachusetts General Hospital (MGH) have shown, for the first time, that blocking the action of a critical protein can improve multiple inflammatory pathways in patients with the metabolic syndrome a cluster of symptoms associated with increased risk of cardiovascular disease and type 2 diabetes. If supported in future studies, the findings may suggest new strategies for improving the cardiovascular risk in patients with the metabolic syndrome. This preliminary report appears in the April 24 Archives of Internal Medicine.

"This proof of principle sheds light on the physiology of inflammation and its relation to cardiac risk in obese patients," says Steven Grinspoon, MD, of the MGH Program in Nutritional Metabolism and Neuroendocrine Unit, the report's senior author. "And it's the first study of the medication etanercept, currently prescribed to treat arthritis and psoriasis, used in patients with the metabolic syndrome."

Metabolic syndrome is a group of symptoms that includes abdominal obesity, high triglycerides and LDL ("bad") cholesterol along with low HDL ("good") cholesterol, insulin resistance or glucose intolerance, and abnormal levels of several inflammatory proteins. The occurrence of the syndrome is increasing, and it is estimated to affect more than 50 million Americans currently. Also called insulin resistance syndrome, metabolic syndrome increases the risk of heart attack, stroke and other cardiovascular disorders, as well as type 2 diabetes. While there are many questions about the mechanism behind metabolic syndrome, current evidence suggests that inflammatory proteins released by abdominal fat may be an underlying cause of the increased cardiovascular risk.

One of the key inflammatory proteins released by fat cells is tumor necrosis factor (TNF), which is known to increase insulin resistance and the production of other inflammatory markers. Etanercept, marketed under the brand name Enbrel, treats several inflammatory disorders by blocking the action of TNF. The current study was designed to see whether using the drug might also reduce the inflammatory effects of metabolic syndrome, as measured by levels of C-reactive protein (CRP), which also has been associated with increased risk of cardiovascular disease.

The researchers enrolled 56 patients ages 37 to 54 who met standard criteria for metabolic syndrome but did not have diabetes, cardiovascular disease or any other inflammatory disorder. Half of them received weekly injections of etanercept and half received a placebo during the four-week study period. On each weekly visit, participants also had a physical examination and blood tests for levels of glucose, insulin and various markers including CRP.

At the end of the study period the CRP levels of participants who received etanercept were 34 percent lower than those of participants receiving the placebo. Levels of Interleukin-6 and fibrinogen, other inflammatory factors associated with increased cardiovascular risk, were also reduced in those who received the active medication; but levels of adiponectin a factor that reflects reduced inflammation had increased, also suggesting lower risk. No significant side effects were reported.

"It has been speculated that blocking TNF could reduce systemic inflammation in abdominally obese people, and we are very excited that giving this drug had such a dramatic effect on these major markers," Grinspoon says. "We were surprised that it didn't also affect insulin resistance, but that could be because the study was only four weeks long. We're planning longer term studies to get a more complete picture of how this strategy might someday be used to reduce the risks associated with metabolic syndrome." Grinspoon is an associate professor of Medicine at Harvard Medical School.

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The study was supported by grants from Amgen Inc., which markets etanercept under the brand name Enbrel, and the National Institutes of Health. Amgen did not participate in the design, analysis or reporting of the study. Grinspoon's co-authors are first author Elizabeth Bernstein, MD, Jacqueline Berry, Sunnie Kim and Bridget Canavan all of the MGH Program in Nutritional Metabolism and Neuroendocrine Unit.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.


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