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Blocking key protein reduces inflammatory
markers in metabolic syndrome
Findings shed light on mechanism
of condition associated with heart disease, type 2 diabetes
BOSTON - April 24, 2006 - 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.
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.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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